Page 1
Beta-lactam antibiotics
Penicillins are obtained from the fermentation of majorly P. chrysogenum & minor P. notatum.The first penicillin’s
were the naturally occurring benzylpenicillin (Penicillin G) and phenoxymethylpenicillin (Penicillin V). Its main
drawbacks are poor absorption in the gastrointestinal tract (which means it must be given by injection) and
its susceptibility to bacterial β-lactamases. All β-lactam antibiotics interfere with the synthesis of the bacterial cell
wall peptidoglycan via entering through porins channel. After attachment to penicillin-binding proteins that have
transpeptidase and carboxypeptidase activities, thus preventing formation of the cross-linking i.e. the peptide
chains attached to the backbone of the peptidoglycan. The final bactericidal event is the inactivation of an inhibitor
of autolytic enzymes i.e. autolysins in the cell wall, leading to lysis of the bacterium.
All penicillins have thiazolidine ring (A) is attached to a β-lactam ring (B) that carries a secondary amino group
(RNH–) and have three chiral centers. Substituents can be attached to the amino group. Structural integrity of the 6aminopenicillanic acid nucleus is essential for the biologic activity of these compounds. Hydrolysis of the β -lactam
ring by bacterial β -lactamases yields penicilloic acid, which lacks antibacterial activity.
1
Page 1 of 252
Page 2
The outer membrane, a lipid bilayer present in gram-negative but not gram-positive organisms. Penicillins are
penetrated by porins, proteins that form channels providing hydrophilic access to the cytoplasmic membrane. The
peptidoglycan layer is unique to bacteria and is much thicker in gram-positive organisms than in gram-negative
ones. Together, the outer membrane and the peptidoglycan layer constitute the cell wall. Penicillin-binding proteins
(PBPs) are membrane proteins that cross-ling peptidoglycan. β -Lactamases, if present, reside in the periplasmic
space or on the outer surface of the cytoplasmic membrane, where they may destroy β -lactam antibiotics that
penetrate the outer membrane.
2
Page 2 of 252
Page 3
Mechanism of action
The cell walls of bacteria are essential for their normal growth and development. Peptidoglycan is a heteropolymeric
component of the cell wall that provides rigid mechanical stability by virtue of its highly cross-linked latticework
structure. The peptidoglycan is composed of glycan chains, which are linear strands of two alternating amino sugars
(N-acetylglucosamine and N-acetylmuramic acid or backbone of peptidoglycan) that are cross-linked by peptide
chains. Gram + ve bacteria are more sensitive to penicillins than gram –ve bacteria as 80-90% peptidoglycan is
present in cell wall of the gram + ve bacteria while gram – ve bacteria only contains 10-20%of peptidoglycan. So
penicillins inhibit the peptidoglycan synthesis and now the cell deficient with cell wall will burst. The biosynthesis
of the peptidoglycan involves about 30 bacterial enzymes and may be considered in three stages.
1.
The first stage, precursor formation i.e. formation of Park peptide, takes place in the cytoplasm. First,
N-acetylmuramic acid, attached to uridine diphosphate (UDP) and a pentapeptides which is then transferred
to the C55 lipid carrier in the membrane, with the release of uridine monophosphate. The last reaction in
the synthesis of this compound is the addition of a dipeptide, D-alanyl-D-alanine give Park peptide
i.e.UDP- acetylmuramyI-L-Ala-D-GIn-L-Lys-D-Ala-D-Ala. Synthesis of the dipeptide involves prior
racemization of L-alanine and condensation catalyzed by D-alanyl-D-alanine synthetase. D-Cycloserine is
a structural analog of D-alanine and acts as a competitive inhibitor of both the racemase and the
synthetase & inhibits the incorporation of D-alanine into peptidoglycan.
2.
Second stage is, Formation of building block- UDP-acetylmuramyl-pentapeptide and UDPacetylglucosamine are linked (with the release of the uridine nucleotides) resulting in formation of a
disaccharide pentapeptide complex attached to the carrier. This complex is the basic building block
of the peptidoglycan. In Staphylococcus aureus, the five glycine residues are attached to the peptide chain
at this stage.
3.
The third and final stage involves completion of the cross-link. This is accomplished by a transpeptidation
reaction that occurs outside the cell membrane. The terminal glycine residue of the pentaglycine bridge is
linked to the fourth residue of the pentapeptide (D-alanine), releasing the fifth residue (also D-alanine).
There are additional, related targets for the actions of penicillins and cephalosporins; these are collectively
termed penicillin-binding proteins (PBPs).
™ Cycloserine
is structural analog of D-alanine and inhibits the incorporation of D-alanine into
peptidoglycan the initial tripeptide side-chain on N-acetylmuramic acid by competitive inhibition by
inhibiting alanine racemase, which converts L-alanine to D-alanine, and D-alanyl-D alanine ligase.
™ Vancomycin inhibits the release of the building block unit from the carrier (formation of a disaccharide
pentapeptide complex attached to the carrier.), thus preventing its addition to the growing end of the
peptidoglycan. Vancomycin inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus
of nascent peptidoglycan pentapeptide. This inhibits the transglycosylase, preventing further elongation
of peptidoglycan and cross-linking. The peptidoglycan is thus weakened, and the cell becomes susceptible
3
Page 3 of 252
Page 4
to lysis. The cell membrane is also damaged, which contributes to the antibacterial effect.
™ Bacitracin interferes with the regeneration of the C55 lipid carrier by blocking its dephosphorylation.
Bacitracin is highly nephrotoxic when administered systemically and is only used topically.
™ Penicillins, cephalosporins and other β-lactams inhibit the final transpeptidation by forming covalent
bonds with penicillin-binding proteins that have transpeptidase and carboxypeptidase activities, thus
preventing formation of the cross-links.
™ Fosfomycin is a analog of phosphoenolpyruvate, it is structurally unrelated to any other antimicrobial
agent. It inhibits the cytoplasmic enzyme enolpyruvate transferase by covalently binding to the cysteine
residue of the active site and blocking the addition of phosphoenolpyruvate to UDP-Nacetylglucosamine.
This reaction is the first step in the formation of UDP-N-acetylmuramic acid, the precursor Nacetylmuramic acid, which is found only in bacterial cell walls. The drug is transported into the bacterial
cell by glycerophosphate or glucose 6-phosphate transport systems.
Resistance
Natural resistance to the penicillins occurs in organisms that either lack a peptidoglycan cell wall (for example,
Mycoplasma) or that has cell walls that are impermeable to the drugs. Acquired resistance to the penicillins by
plasmid transfer by bacterial conjugation.
1.
β-Iactamase enzymes hydrolyzes the cyclic amide bond of the β-Iactam ring, which results in loss of
bactericidal activity. These are more produced in gram + ve bacteria while gram – ve bacteria produce it in
less amount. These
lactamases act on penicillins, cephalosporins, monobactams etc. β-Lactamases are
either constitutive or, more commonly, are acquired by the transfer of plasmids. Some of the β-Iactam
antibiotics are poor substrates for β-Lactamases and resist cleavage; thus they retain their activity against βIactamase-producing organisms. Mainly two species S. aureus and S. epidermis produce large
lactamases and additionally have high molecular weight PBP with low activity for
lactam.
Methicillin resistant S. aureus and S. epidermis infections are treated by vancomycin, Rifampicin
and linezolid.
2.
Decreased permeability to drug: Decreased penetration of the antibiotic through the outer cell membrane
i.e. via porins prevents the drug from reaching the target penicillin-binding proteins (PBPs).
3.
Altered penicillin binding proteins: Modified PBPs have a lower affinity for β-Iactam antibiotics,
requiring clinically unattainable concentrations of the drug to effect binding and inhibition of bacterial
growth. This mechanism may explain methicillin-resistant staphylococci.
Classification
A. Acid resistant penicillin : Penicillin V
B. Penicillinase or β-lactamase resistant (Antistaphylococcal) : Methicillin, Oxacillin, Cloxacillin
C. Extended spectrum
4
Page 4 of 252
Page 5
•
Aminopenicillins (also active against H. influenzae, Pneumonococci): Ampicillin, Amoxicillin
•
Carboxypenicillin (Pseudomonas and proteus or Antipseudomonal): Carbenicillin, Ticarcillin
•
Ureidopenicillin (Pseudomonas and Klebsiella): Piperacillin, Mezlocillin
D. β-lactamase inhibitors: Clavulanic acid and Sulbactam
E. other β-lactam antibiotics :
•
Carbapenem : Imipenem
•
Monobactams : Aztreonam
ADME of penicillins
Absorption of penicillin G and all the penicillinase-resistant penicillins is decreased by food in the stomach since
gastric emptying time is reduced and the drugs are destroyed in the acidic environment. Metabolism of these drugs
by the host is usually insignificant, but some metabolism of penicillin G has been shown to occur in patients with
impaired renal function. The primary route of excretion is through the organic acid (tubular) secretory system
of the kidney as well as by glomerular filtration. Probenecid inhibits the secretion of penicillins and hence
enhances the half of penicillins. Nafcillin is primarily eliminated through the biliary route.
Adverse effects of penicillins
1.
Hypersensitivity: Reactions allergy to penicillins includes urticarial rash, fever, bronchospasm, vasculitis,
serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, and anaphylaxis.
Hypersensitivity
reactions may appear in the absence of a previous known exposure to the drug. This may be caused by
unrecognized prior exposure to penicillin in the environment (e.g., in foods of animal origin or from the
fungus-producing penicillin). It must be stressed that fatal episodes of anaphylaxis have followed the
ingestion of very small doses of this antibiotic or skin testing with minute quantities of the drug. Penicillins
and their breakdown products act as haptens after covalent reaction with proteins. The most
abundant breakdown product is the penicilloyl moiety [major determinant moiety (MDM)], which is
formed when the b-lactam ring is opened. A large percentage of IgE-mediated reactions are to the MDM
but at least 25% of reactions are to other breakdown products, and the severities of the reactions to the
various components are comparable. Antipenicillin antibodies are detectable in virtually all patients who
have received the drug and in many who have never knowingly been exposed to it. When allopurinol and
ampicillin are administered concurrently, the incidence of rash also increases. To prevent
anaphylaxis shock from penicillins Noradrenaline is given.
2.
Nephritis: All penicillins, but particularly methicillin can cause Bright’s diseases; have the potential to
cause acute interstitial nephritis.
3.
Platelet dysfunction: This involves decreased agglutination, is observed with the antipseudomonal
penicillins (Carbenicillin and ticarcillin). It is generally a concern when treating patients predisposed to
hemorrhage or those receiving anticoagulants.
5
Page 5 of 252
Page 6
4.
Neurotoxicity: The penicillins are irritating to neuronal tissue and can provoke seizures if injected
intrathecally or if very high blood levels are reached. Epileptic patients are especially at risk.
Clinical uses of the penicillins
1.
bacterial meningitis (e.g. caused by Neisseria meningitidis, Streptococcus
pneumoniae): benzylpenicillin, high doses intravenously
2.
bone and joint infections (e.g. with Staphylococcus aureus): flucloxacillin
3.
skin and soft tissue infections (e.g. with Strep. pyogenes or Staph. aureus):
benzylpenicillin, flucloxacillin; animal bites: co-amoxiclav
4.
bronchitis (mixed infections common): amoxicillin
5.
urinary tract infections (e.g. with Escherichia coli): amoxicillin
6.
gonorrhea: amoxicillin (plus probenecid )
7.
syphilis: procaine benzylpenicillin
8.
Serious infections with Pseudomonas aeruginosa: ticarcillin, piperacillin.
CARBAPENEMS
A carbapenem is the β -lactam antibiotic of choice for treatment of enterobacter infections because it is resistant to
destruction by the β –lactamase produced by these organisms. Imipenem, an example of a carbapenem, acts in the
same way as the other β-lactams. It has a very broad spectrum of antimicrobial activity, being active against many
aerobic and anaerobic Gram-positive and Gram-negative organisms. Imipenem was originally resistant to all βlactamases, but some organisms now have chromosomal genes that code for imipenem-hydrolysing β-lactamases. It
is sometimes given together with cilastatin, which inhibits its inactivation by renal enzymes. Meropenem is
similar but is not metabolised by the kidney.
MONOBACTAMS
Penicillin-allergic patients tolerate aztreonam without reaction. The main monobactam is aztreonam , a simple
monocyclic β-lactam and resistant to most β-lactamases. It is given parenterally and has a plasma half-life of 2
hours. Aztreonam has an unusual spectrum of activity and is effective only against Gram-negative aerobic rods
such as pseudomonas, Neisseria meningitidis and Haemophilus influenzae. It has no action against Gram-positive
organisms or anaerobes.
Unwanted effects are, in general, similar to those of other β-lactam antibiotics, but this agent does not necessarily
cross-react immunologically with penicillin and its products, and so does not usually cause allergic reactions in
penicillin-sensitive individuals.
6
Page 6 of 252
Page 7
β-LACTAMASE INHIBITORS
Clavulanic acid and Sulbactam extends the spectrum of penicillin due to destruction of penicillins by β -lactamase
and that the inhibitor is active against the β lactamase producing microorganism. These substances resemble β lactam molecules but they have very weak antibacterial action. They are potent inhibitors of many but not all
bacterial β -lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. β -Lactamase
inhibitors are most active against class A β -lactamases (plasmid-encoded transposable element [TEM] -lactamases
in particular), such as those produce by staphylococci, H influenzae, N gonorrhoeae, salmonella, shigella, E coli,
and K pneumoniae. They are not good inhibitors of class C β -lactamases, which typically are chromosomally
encoded and inducible produced enterobacter, serratia, and pseudomonas. β -Lactamase inhibitors are available only
in fixed combinations with specific penicillins. Ampicillin-sulbactam & Amoxicillin – Clavulanic acid is active
against β -lactamase-producing S aureus and H influenzae b
CEPHALOSPORINS
•
Cephalosporins that contain a methylthiotetrazole group (e.g. cefatriaxone, cefamandole,
cefoperazone, cefmetazole) frequently cause hypoprothrombinemia and bleeding disorders.
Administration of vitamin K can prevent this.
•
Drugs with the methylthiotetrazole ring (cefoperazone) can also cause severe disulfiram reactions;
consequently, alcohol and alcohol-containing medications must be avoided.
7
Page 7 of 252
Page 8
BETA-LACTAM ANTIBIOTICS AT A GLANCE
™ All penicillins have thiazolidine ring (A) is attached to a β-lactam ring (B)
™ Penicillins, cephalosporins and other β-lactams inhibit the final transpeptidation by forming covalent bonds with
penicillin-binding proteins that have transpeptidase and carboxypeptidase activities, thus preventing formation of
the cross-links.
™ Methicillin resistant S. aureus and S. epidermis infections which produces high amount of lactamases are treated by
vancomycin, Rifampicin and linezolid.
™ Penicillins and their breakdown products act as haptens after covalent reaction with proteins. The most abundant
breakdown product is the penicilloyl moiety which is responsible for their hypersensitivity.
™ Carbenicillin and ticarcillin can cause platelets dysfunction.
™ Methicillin can cause Bright’s diseases; have the potential to cause acute interstitial nephritis.
™ Penicillin-allergic patients tolerate monobactam aztreonam without hypersensitivity reaction. Other alternative is
erythromycin or macrolides antibiotics.
™ Clavulanic acid and Sulbactam are beta-lactamase inhibitors which prolong the half life of penicillins.
™ Probenecid inhibits the tubular secretion of penicillins and hence increases half life.
™ D-Cycloserine is a structural analog of D-alanine and acts as a competitive inhibitor of both the racemase and the
synthetase & inhibits the incorporation of D-alanine into peptidoglycan
™ Vancomycin inhibits the release of the building block unit from the carrier i.e. UDP-acetylmuramyl-pentapeptide and
UDP-acetylglucosamine are linked (with the release of the uridine nucleotides) resulting in formation of a disaccharide
pentapeptide complex attached to the carrier.
8
Page 9
SULFONA
AMIDES (FO
OLATE ANT
TAGONIST)
Sulfonamiddes are derived
d from the dyee Prontosil whhich is inactivee prodrug convverted in vivo into
i
sulfanilam
mide in
body and several
s
other azo
a dyes contaaining a sulfonnamide group. Folate or follic acid (pterooylglutamic accid) is
required foor DNA syntheesis in both baccteria and in huumans. Folic accid is biosyntheesized from Ptteridine, PABA
A and
glutamic acid.
a
Mammaliian cells (and some
s
bacteria) lack the enzym
mes required foor folate syntheesis from PAB
BA and
depend on exogenous so
ources of folatee; therefore, thhey are not sussceptible to sullfonamides. Huumans have sppecific
t
it intto cells. By coontrast, most species
s
of bacteria, as well as the
uptake meechanisms havee evolved to transport
asexual forrms of malariaal protozoa, laack the necessary transport mechanisms
m
annd cannot makke use of prefformed
folate but must
m synthesizze their own de novo i.e. from
m its precursorss. This is a prim
me example off a difference thhat has
proved to be extremely
y useful for chemotherapy e.g. methotrexxate. Sulfonam
mides contain the sulfanilam
mide
s
analo
ogue of p-aminobenzoic acidd (PABA). More specificallly, sulfonamid
des are compeetitive
moiety-a structural
inhibitors of dihydroptteroate synthttase which is responsible for
f the incorp
poration of PA
ABA into Pteridine
t form dihyd
dropteroic aciid, which then conjugate with
w
glutamicc acid to givee dihydrofolicc acid.
residues to
Sensitive microorganism
m
ms are for sulfoonamides are who
w must synthhesize their ow
wn folic acid; bacteria
b
that caan use
preformed folate are not affected. Sulfo
fonamides are bacteriostaticc not bactericcidal (i.e. they suppress divission of
b do not kill them), and arre therefore onnly really effecctive in the prresence of adequate host deffenses.
the cells but
Presence of pus or prroducts of tissue breakdow
wn, because these
t
contain thymidine and
a
purines, which
w
u
directly
y, bypassing th
he requiremen
nt for folic aciid and diminisshing the actioon of sulfonam
mides.
bacteria utilize
Similarly some local anaesthetics, which
w
are PA
ABA esters lik
ke procaine, can
c antagonizze the antibaccterial
effect of th
hese agents.
t
ic acid by Dih
hydrofolate red
ductase. The tetrahydrofoli
t
ic acid
Dihydrofoolic acid is then reduced to tetrahydrofoli
is used ass one carbon transfer. Thiss conversion have differentiaal sensitivity inn humans and bacteria towaards its
9
Page 10
antagonist i.e. trimethoprim is antagonist of dihydrofolate reductase and inhibits preferentially bacteria enzyme
then human. In some malarial protozoa, this enzyme is somewhat less sensitive than the bacterial enzyme to
trimethoprim but more sensitive to pyrimethamine and proguanil, which are used as antimalarial agents. The
human enzyme, by comparison, is very sensitive to the effect of the folate analogue methotrexate, which is used in
cancer chemotherapy. Methotrexate is inactive in bacteria because, being very similar in structure to folate, it
requires active uptake by cells. Trimethoprim and pyrimethamine enter the cells by diffusion.
Thus pyrimethamine and a sulfonamide (sulfadoxine) are used to treat falciparum malaria. An antibacterial
formulation that contains both a sulfonamide and trimethoprim is co-trimoxazole widely used; this combination
has become progressively less effective because of the development of sulfonamide resistance.
Resistance
Sulfonamide resistance may occur as a result of mutations that
1.
Cause overproduction of PABA
2.
Cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides, or
3.
Impair permeability to the sulfonamide. Dihydropteroate synthase with low sulfonamide affinity is often
encoded on a plasmid that is transmissible and can disseminate rapidly and widely. Sulfonamide-resistant
dihydropteroate synthase mutants also can emerge under selective pressure.
Classification of sulfonamides
Class
Sulfonamide
Duration
Absorbed and excreted rapidly or short acting
Sulfadiazine, sulfaisoxazole,
4-6 hr
Intermediate acting
Sulfamethoxazole
10 hr
Poorly absorbed active in bowel lumen
Sulfasalazine
-
Topically used
Mefenide, sulphacetamide, silver sulfadiazine
-
Long acting sulfonamides
Sulfadoxine
100 hr
Adverse effects
1.
Crystalluria was relatively high with the older, less soluble sulfonamides; the incidence of this problem is
very low with more soluble agents such as sulfisoxazole. Crystalluria has occurred in dehydrated patients
with the acquired immune deficiency syndrome (AIDS) who were receiving sulfadiazine for Toxoplasma
encephalitis. Fluid intake should be sufficient to ensure a daily urine volume of at least 1200 ml (in adults).
Alkalinization (with bicarbonate) of the urine may be desirable if urine volume or pH is unusually low
because the solubility of sulfisoxazole increases greatly with slight elevations of pH.
10
Page 11
2.
Acute Hemolytic Anemia hemolysis is related to an erythrocytic deficiency of glucose-6-phosphate
dehydrogenase activity.
3.
Stevens-Johnson syndrome or Hypersensitivity Reactions
4.
Kernicterus administration of sulfonamides to newborn infants, especially if premature, may lead to the
displacement of bilirubin from plasma albumin. In newborn infants, free bilirubin can become deposited in
the basal ganglia and subthalamic nuclei of the brain, causing an encephalopathy called kernicterus. The
drugs should not be given to pregnant women as they can cross the placenta.
Sulfisoxazole is a rapidly absorbed and excreted sulfonamide with excellent antibacterial activity. Since its high
solubility eliminates much of the renal toxicity inherent in the use of older sulfonamides, it has essentially
replaced the less-soluble agents like sulfadiazine and hence produces less crystalluria and also hematuria.
Sulfaisoxazole acetyl is tasteless and hence preferred for children’s.
Sulfamethoxazole can cause crystalluria because of the high percentage of the acetylated, relatively insoluble form
of the drug in the urine. It also is marketed in fixed-dose combinations with trimethoprim due to similar half life as
co-trimoxazole. This combination is mostly used for urinary tract infections.
Sulfadiazine has maximum prone to cause crystalluria. But it attains therapeutic concentration in brain. So it can be
employed for meningitis.
Sulfasalazine is broken down by intestinal bacteria to sulfapyridine, an active sulfonamide that is absorbed and
eventually excreted in the urine, and 5-aminosalicylate, which reaches high levels in the feces. 5-Aminosalicylate is
the effective agent in inflammatory bowel disease, whereas sulfapyridine is responsible for most of the toxicity.
Toxic reactions include Heinz-body anemia, acute hemolysis in patients with glucose-6-phosphate dehydrogenase
deficiency, and agranulocytosis. Sulfasalazine can cause a reversible infertility in males owing to changes in sperm
number and morphology. There is no evidence that the compound alters the intestinal microflora of patients with
ulcerative colitis.
Sulphacetamide mainly used for ophthalmic infections, mainly Chlamydia trachoma. Other drugs can be used is
tetracycline for ocular blindness.
Silver sulfadiazine is used topically to reduce microbial colonization and the incidence of infections of wounds
from burns. It should not be used to treat an established deep infection. Silver is released slowly from the
preparation in concentrations that are selectively toxic to the microorganisms. Silver sulfadiazine is considered
by most authorities to be one of the agents of choice for the prevention of burn infection.
Mefenide is a pseudo sulfonamide (α‐amino‐p‐toluene‐sulfonamide) in which SO2NH2 grp is not directly
linked to the anilino grp and mainly used for prevention of burn infection and it is even active in pus cell. The drug
and its metabolite have weak carbonic anhydrase activity.
11
Page 12
Sulfadoxine is longest acting i.e. 7-9 days and combined with pyrimethamine for the prophylaxis and treatment of
malaria caused by mefloquine -resistant strains of Plasmodium falciparum. Because of severe and sometimes fatal
reactions, including the Stevens-Johnson syndrome, the drug should be used for prophylaxis only where the risk of
resistant malaria is high.
ADME
All sulfonamides are bound in varying degree to plasma proteins, particularly to albumin. The extent to which this
occurs is determined by the hydrophobicity of a particular drug and its pKa; at physiological pH, drugs with a high
pKa exhibit a low degree of protein binding, and vice versa. The sulfonamides undergo metabolic alterations in vivo,
especially in the liver. The major metabolic derivative is the N4-acetylated sulfonamide. Acetylation, which occurs
to a different extent with each agent, is disadvantageous because the resulting products have no antibacterial activity
and yet retain the toxic potential of the parent substance. Sulfonamides are eliminated from the body partly as the
unchanged drug and partly as metabolic products. The largest fraction is excreted in the urine, and the half-life of
sulfonamides in the body thus depends on renal function. In acid urine, the older sulfonamides are insoluble and
may precipitate, forming crystalline deposits that can cause urinary obstruction.
Drug Interactions
1.
Sulfonamides can potentiate the effects of oral anticoagulants, the sulfonylurea hypoglycemic agents,
and the hydantoin anticonvulsants drug by mechanisms that appear to involve primarily inhibition of
metabolism and, possibly, displacement from albumin. Dosage adjustment may be necessary when a
sulfonamide is given concurrently.
2.
Procaine, a local anesthetic should not be given with sulfonamides as procaine itself release PABA.
Co-trimoxazole (Trimethoprim + Sulfamethoxazole)
Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial dihydrofolic acid reductase, which
converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA.
Trimethoprim is about 50,000 times less efficient in inhibition of mammalian dihydrofolic acid reductase.
Pyrimethamine, another benzylpyrimidine, selectively inhibits dihydrofolic acid reductase of protozoa compared
with that of mammalian cells. As noted above, trimethoprim or pyrimethamine in combination with a sulfonamide
blocks sequential steps in folate synthesis, resulting in marked enhancement (synergism) of the activity of both
drugs. The combination often is bactericidal, compared with the bacteriostatic activity of a sulfonamide alone.
Trimethoprim is usually given orally, alone or in combination with sulfamethoxazole, which has a similar half-life
i.e. about 10 hr. Trimethoprim-sulfamethoxazole can also be given intravenously. Because trimethoprim is more
lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug. Therefore,
when 1 part of trimethoprim is given with 5 parts of sulfamethoxazole (the ratio in the formulation), the peak
plasma concentrations are in the ratio of 1:20, which is optimal for the combined effects of these drugs in
12
Page 13
vitro. Trimethoprim concentrates in prostatic fluid and in vaginal fluid, which are more acidic than plasma.
Therefore, it has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial.
The adverse effect of co-trimoxazole includes bone marrow depression, more risk to cause thrombocytopenia with
concurrent administration with diuretics.
Trisulpha
Clinical uses of sulfonamides
•
Combined with trimethoprim (co-trimoxazole) for Pneumocystis carinii.
•
Combined with pyrimethamine for drug-resistant malaria and for toxoplasmosis.
•
In inflammatory bowel disease: Sulfasalazine (sulfapyridine- 5-aminosalicylate)
•
For infected burns (silver sulfadiazine and Mefenide
•
For some sexually transmitted infections (e.g. trachoma, chlamydia, chancroid).
•
For ocular infection (sulphacetamide)
•
For acute urinary tract infection (now seldom used).
given topically).
SULFONAMIDES AT A GLANCE
™ Sulfonamides are PABA analogue. They are competitive inhibitors of dihydropteroate synthtase which is
responsible for the incorporation of PABA into Pteridine residues to form dihydropteroic acid, which then conjugate
with glutamic acid to give dihydrofolic acid.
™ Trimethoprim is antagonist of dihydrofolate reductase which reduces dihydrofolic acid to tetrahydrofolic which is
involved in the DNA synthesis.
™ Crystalluria, kernicterus, Steven-Jonson syndrome & acute hemolytic anemia are common adverse effect of
sulfonamides.
™ Sulphaisoxazol high solubility eliminates much of the renal toxicity inherent in the use of older sulfonamides.
™ Mefenide is a pseudo sulfonamide (α‐amino‐p‐toluene‐sulfonamide) & have weak carbonic anhydrase activity.
™ Sulfasalazine is broken down by intestinal bacteria to sulfapyridine, an active sulfonamide that is absorbed and
eventually excreted in the urine, and 5-aminosalicylate, which reaches high levels in the feces. 5-Aminosalicylate is
the effective agent in inflammatory bowel disease, whereas sulfapyridine is responsible for most of the toxicity.
™ Co-trimoxazole (Trimethoprim + Sulfamethoxazole) are combined together because of almost their same half life
i.e. 10 hr
™ Pyrimethamine + sulfadoxine combination is used as an antimalarial.
13
Page 14
14
Page 15
Quinolones (DNA gyrase or the topoisomerase IV enzyme
inhibitors)
The quinolones are a family of synthetic broad-spectrum antibiotics. The fluoroquinolones include the broadspectrum agents ciprofloxacin, levofloxacin , ofloxacin , norfloxacin and moxifloxacin, as well as a narrowspectrum drug used in urinary tract infections-nalidixic acid.
They prevent bacterial DNA from unwinding and duplicating. Since bacteria and humans unwind DNA with
different enzymes, most of those enzymes (topoisomerases) in humans are not affected. The parent of the quinolone
(aka fluoroquinolone) class is nalidixic acid. The majority of quinolones in clinical use belong to the subset of
fluoroquinolones, which have a fluorine atom attached to the central ring system, typically at the 6-position or C-7
position.
Ciprofloxacin is the most commonly used fluoroquinolone and will be described as the type agent. It is a broadspectrum antibiotic effective against both Gram-positive and Gram-negative organisms. It has excellent activity
against the Enterobacteriaceae (the enteric Gram-negative bacilli), including many organisms resistant to
penicillins, cephalosporins and aminoglycosides, and it is also effective against H.influenzae, penicillinaseproducing N.gonorrhoeae, Campylobacter sp. and pseudomonas.
Mechanism of action
Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA
replication and transcription. DNA gyrase contains two subunit A (2) & B (2). A subunit carries out nicking of DNA
while B subunit introduce – ve supercoils and then B subunit reseals the strands. All FQs bind to A subunit with
high affinity and interferes with its strand cutting and resealing function. Quinolones can enter cells easily via porins
and therefore are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma
pneumoniae. For many gram-negative bacteria DNA gyrase is the target, whereas topoisomerase IV is the target for
many gram-positive bacteria. It is believed that eukaryotic cells do not contain DNA gyrase or topoisomerase IV.
Adverse effects
Some of the serious adverse effects which occur more commonly with fluoroquinolones than with other antibiotic
drug classes include CNS and tendon or articular toxicity and sometimes associated with an QTc interval
prolongation and cardiac arrhythmias.
Ciprofloxacin through inhibition of P450 enzymes can lead to
theophylline toxicity in asthmatics treated with the fluoroquinolones
•
Moxifloxacin carries a higher risk of QTc prolongation
•
Gatofloxacin has been most frequently linked to disturbed blood sugar levels and
•
Sparfloxacin was associated with phototoxicity and QTc prolongation,
15
Page 16
Clinical uses of the fluoroquinolones
•
First line drug to treat urinary tract infections (norfloxacin , ofloxacin ).
•
Eradication of Salmonella typhi in carriers
•
Pseudomonas aeruginosa respiratory infections in patients with cystic fibrosis.
•
Chronic Gram-negative bacillary osteomyelitis or bone joint and soft tissue
infections.
•
Gonorrhoea (norfloxacin , ofloxacin ).
•
Anthrax
•
ENT (ofloxacin)
•
Ofloxacin is also given in Tuberculosis
•
Lomefloxacin have 100 % bioavailability
16
Page 17
PROTEIN SYNTHESIS INHIBITIORS (TETRACYCLINES,
CHLORAMPHENICOL, MACROLIDES, AMINOGLYCOSIDES, CLINDAMYCIN)
Protein synthesis
17
Page 18
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
Step-1 Polysome formation (individual 30S-50S subunits combine to form 70S ribosome arranged on mRNA)
¾
IF-1 Prevents premature binding of tRNAs to A site
¾
IF-2 Facilitates binding of fMet-tRNAfMet to 30S ribosomal subunit
¾
IF-3 Binds to 30S subunit; prevents premature association of 50S subunit; enhances specificity of P site for
fMet-tRNAfMet
Step 2-The charged tRNA unit carrying amino acid binds to the acceptor site A on the 70S ribosome.
Bacterial ribosomes have three sites that bind aminoacyl-tRNAs, the aminoacyl (A) site, the peptidyl (P) site, and the exit (E)
site. Both the 30S and the 50S subunits contribute to the characteristics of the A and P sites, whereas the E site is largely confined
to the 50S subunit. The initiating AUG is positioned at the P site, the only site to which fMettRNAfMet can bind. The fMettRNAfMet is the only aminoacyl-tRNA that binds first to the P site; during the subsequent elongation stage, all other
incoming aminoacyl-tRNAs (including the Met-tRNAMet that binds to interior AUG codons) bind first to the A site and
only subsequently to the P and E sites. The E site is the site from which the “uncharged” tRNAs leave during elongation.
Step-3 The peptidyl tRNA at the donor site (P site), with amino acids then binds the growing to new amino acid at A
site and this process is called as transpeptidation.
Step- 4 The uncharged tRNA left at the donor site (P-site) is released via E-site and the new amino acid chain with
its tRNA shifts to the peptidyl site called as translocation.
1.
Aminoglycosides binds to the 30S ribosomal subunit and interferes with initiation of protein synthesis by
fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA. They can cause
i. Premature termination of translation with detachment of the ribosomal complex and
incompletely synthesized protein.
ii. Aminoglycosides binding to the 30S subunit also causes misreading of mRNA.
iii. Incorporation of incorrect amino acids resulting in the production of abnormal or
nonfunctional proteins.
2.
Linezolid inhibits protein synthesis by binding to the P site of the 50S ribosomal subunit and preventing
formation of the larger ribosomal-fMet-tRNA complex that initiates protein synthesis.
3.
Free tetracyclines are crystalline amphoteric substances of low solubility. They are available as
hydrochlorides, which are more soluble. Such solutions are acid and, with the exception of
chlortetracycline, fairly stable. Tetracycline’s chelate divalent metal ions, which can interfere with
their absorption and activity. Chlortetracycline, the prototype of this class.
4.
Tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of
aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex. This prevents the addition of
amino acid to growing chain.
5.
Macrolides antibiotics (Erythromycin, clarithromycin, azithromycin, Roxithromycin) are bacteriostatic
agents that inhibit protein synthesis by binding reversibly to the 50S ribosomal subunits of sensitive
organisms. Erythromycin appears to inhibit the translocation step wherein the nascent peptide chain
18
Page 19
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
temporarily residing at the A site of the transferase reaction fails to move to the P, or donor, site.
Alternatively, macrolides may bind and cause a conformational change that terminates protein synthesis by
indirectly interfering with transpeptidation and translocation.
6.
Chloramphenicol readily penetrates bacterial cells, probably by facilitated diffusion. Chloramphenicol
acts primarily by binding reversibly to the 50S ribosomal subunit (near the binding site for the macrolide
antibiotics and clindamycin, which chloramphenicol inhibits competitively). Although binding of tRNA at
the codon recognition site on the 30S ribosomal subunit is undisturbed, the drug apparently prevents the
binding of the amino acid-containing end of the aminoacyl tRNA to the acceptor site on the 50S ribosomal
subunit. The interaction between peptidyltransferase and its amino acid substrate cannot occur, and
peptide bond formation is inhibited.
19
Page 20
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
TETRACYCLINES
Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. They are active
against many gram-positive and gram-negative bacteria, including anaerobes, rickettsiae (Rocky Mountain spotted
fever), chlamydiae (Lymphogranuloma Venereum, brucellosis), spirochetes (Lyme diseases), mycoplasmas
(Mycoplasma pneumonia), Treponema pallidum (syphilis), Vibrio cholerae, against some protozoa, e.g.
amebas.
Mechanism of action
Messenger RNA (mRNA) attaches to the 30S subunit of bacterial ribosomal RNA. The P (peptidyl) site of the 50S
ribosomal RNA subunit contains the nascent polypeptide chain; normally, the aminoacyl tRNA charged with the
next amino acid (aa) to be added to the chain moves into the A (acceptor) site, with complementary base pairing
between the anticodon sequence of tRNA and the codon sequence of mRNA. Tetracyclines bind reversibly to the
30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the
mRNA-ribosome complex. This prevents the addition of amino acid to growing chain. These drugs enter gramnegative bacteria by passive diffusion through the hydrophilic channels formed by the porin proteins of the outer cell
membrane and by active transport via an energy-dependent system that pumps all tetracyclines across the
cytoplasmic membrane.
Resistance to the Tetracyclines
Resistance is primarily plasmid-mediated and often is inducible. The majority of penicillinase-producing
staphylococci are now also insensitive to tetracyclines. The three main resistance mechanisms are:
1.
Decreased accumulation of tetracycline as a result of either decreased antibiotic influx or acquisition of an
energy-dependent efflux pathway;
2.
Production of a ribosomal protection protein that displaces tetracycline from its target, a "protection" that
also may occur by mutation; and
3.
Enzymatic inactivation of tetracyclines.
The glycylcyclines are synthetic analogues of the tetracyclines i.e. minocycline, tigecycline. The glycylcyclines
exhibit antibacterial activities typical of earlier tetracyclines, and also display activity against tetracycline-resistant
organisms containing genes responsible for efflux mechanisms or ribosomal protection. The glycyclcyclines also
appear to be active against other resistant pathogens including methicillin-resistant S. aureus and S. epidermidis,
penicillin-resistant S. pneumoniae, and vancomycin-resistant enterococci.
Absorption, Distribution, and Excretion
20
Page 21
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
All tetracyclines are adequately but incompletely absorbed after oral ingestion. However, taking these drugs concomitantly with dairy foods in the diet decreases absorption because of the formation of nonabsorbable chelates of
the tetracyclines with calcium ions. Nonabsorbable chelates are also formed with other divalent and trivalent cations
(for example, those found in magnesium and aluminum antacids, and in iron preparations). Doxycycline (95%) and
minocycline (100%) have max. oral absortion.
They accumulate in reticuloendothelial cells of the kidney, liver, spleen, and bone marrow, and in bone, dentine,
and enamel of unerupted teeth. With the exception of Doxycycline (liver), the primary route of elimination
for most tetracyclines is the kidney. Doxycycline is one of the safest of the tetracyclines for use in patients with
renal impairment. Its half-life may be significantly shortened by concurrent therapy with barbiturates, phenytoin,
rifampin, or other inducers of hepatic microsomal enzymes. Minocycline persists in the body long after its
administration is stopped, possibly due to retention in fatty tissues. Minocycline enters the brain in the absence of
inflammation, and also appears in tears and saliva. All tetracyclines cross the placental barrier and concentrate
in fetal bones and dentition.
Adverse effects of Tetracyclines
1.
Photosensitivity Demeclocycline, Doxycycline
2.
Gastric discomfort: Epigastric distress commonly results from irritation of the gastric mucosa and is often
responsible for non-compliance in patients treated with these drugs.
3.
Children receiving long- or short-term therapy with a tetracycline may develop permanent brown
discoloration of the teeth. The deposition of the drug in the teeth and bones probably is due to its
chelating property and the formation of a tetracycline-calcium orthophosphate complex. Treatment of
pregnant patients with tetracyclines may produce discoloration of the teeth in their children.
4.
Tetracyclines are deposited in the skeleton during gestation and throughout childhood and may depress
bone growth in premature infants.
5.
Minocycline may cause vestibular toxicity as it concentrates in the endolymph of the ear and affects
function.
6.
Diabetes insipidus as Demeclocycline antagonize the ADH action and reduces urine concentration ability
of the kidney.
7.
Like all antimicrobial agents, the tetracyclines administered orally or parenterally may lead to the
development of superinfections caused by strains of bacteria or fungi resistant to these agents.
Vaginal, oral, and even systemic infections are observed. The incidence of these infections appears to be
much higher with the tetracyclines than with the penicillins.
8.
Liver damage (Doxycycline) but oxytetracycline & tetracycline is safe.
9.
Kidney damage causing fancony syndrome like condition which is due to proximal tubular damage caused
by degraded products like epitetracycline, anhydrotetracycline and epianhydrotetracycline. Exposure
to acidic pH, moisture and heat favors such degredation.
21
Page 22
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
TETRACYCLINES AT A GLANCE
™ Tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of
aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex.
™ Children receiving long- or short-term therapy with a tetracycline may develop permanent brown
discoloration of the teeth.
™ Doxycycline (95%) and minocycline (100%) have max. oral absorption.
™ Minocycline may cause vestibular toxicity.
™ Demeclocycline antagonize the ADH action and reduces urine concentration ability of the kidney.
™ Photosensitivity Demeclocycline, Doxycycline
22
Page 23
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
MACROLIDES
(Erythromycin, clarithromycin, azithromycin, Roxithromycin)
Macrolide antibiotics contain a many-membered lactone ring (14-membered rings for erythromycin and
clarithromycin and a 15-membered ring for azithromycin) to which are attached one or more deoxy sugars.
Clarithromycin differs from erythromycin only by methylation of the hydroxyl group at the 6 position, and
azithromycin differs by the addition of a methyl-substituted nitrogen atom into the lactone ring. These structural
modifications improve acid stability and tissue penetration and broaden the spectrum of activity.
Erythromycin usually is bacteriostatic, but may be bactericidal in high concentrations against very susceptible
organisms. The antibiotic is most active in vitro against aerobic gram-positive cocci and bacilli. So these are also
called as alternative to penicillin’s or can be given to patients having hypersensitivity reaction towards
penicillins.
Clarithromycin is slightly more potent than erythromycin against sensitive strains of streptococci and staphylococci.
Clarithromycin has good activity against Mycobacterium, H. pylori Chlamydia, and Mycoplasma pneumonia.
So it is also given in tuberculosis, leprosy, peptic ulcer.
Azithromycin and clarithromycin have enhanced activity against M. avium-intracellulare or mycobacterium
avium complex (MAC) as well as against some protozoa (e.g., Toxoplasma gondii and Plasmodium spp.)
Azithromycin is slightly less active than erythromycin and clarithromycin against staphylococci and streptococci.
Azithromycin is highly active against chlamydia. Azithromycin differs from erythromycin and clarithromycin
mainly in pharmacokinetic properties as having maximum half life. A 500-mg dose of azithromycin produces
relatively low serum concentrations of approximately 0.4 µg/mL. However, azithromycin penetrates into most
tissues (except cerebrospinal fluid) and phagocytic cells extremely well, with tissue concentrations exceeding
serum concentrations by 10- to 100-fold. The drug is slowly released from tissues (tissue half-life of 2–4 days) to
produce an elimination half-life approaching 3 days.
ADME
Erythromycin base is inactivated by gastric acid; the drug is administered as enteric-coated tablets. Esters of
erythromycin base (e.g., stearate, estolate, and ethylsuccinate) have improved acid stability, and their
absorption is less altered by food. The lauryl salt of the propionyl ester of erythromycin (erythromycin
estolate) is the best-absorbed oral preparation. Azithromycin administered orally is absorbed rapidly and
distributes widely throughout the body, except to the brain and CSF. Roxithromycin is acid stable. Clarithromycin
give active metabolite 14-hydroxyclarithromycin.
Mechanism of action
23
Page 24
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
Macrolide antibiotics are bacteriostatic agents that inhibit protein synthesis by binding reversibly to the 50S
ribosomal subunits of sensitive organisms. Erythromycin appears to inhibit the translocation step wherein the
nascent peptide chain temporarily residing at the A site of the transferase reaction fails to move to the P, or donor,
site. Alternatively, macrolides may bind and cause a conformational change that terminates protein synthesis by
indirectly interfering with transpeptidation and translocation.
Resistance
Resistance to erythromycin is usually plasmid-encoded. Three mechanisms have been identified:
1.
Ribosomal protection by inducible or constitutive production of methylase enzymes, mediated by
expression of ermA, ermB, and ermC, which modify the ribosomal target and decrease drug binding;
2.
Production (by Enterobacteriaceae) of esterases that hydrolyze macrolides.
3.
Reduced permeability of the cell membrane or active efflux.
Adverse Reactions
1. Gastrointestinal intolerance, which is due to a direct stimulation of gut motility, is the most common reason
for discontinuing erythromycin and substituting another antibiotic.
2. Erythromycins, particularly the estolate, can produce acute cholestatic hepatitis (fever, jaundice,
impaired liver function) and hypersensitivity reaction.
Drug Interactions
Erythromycin metabolites can inhibit cytochrome P450 enzymes and thus increase the serum concentrations of
numerous drugs, including theophylline, terfenadine, cisapride, oral anticoagulants, cyclosporine, and
methylprednisolone. Erythromycin increases serum concentrations of oral digoxin by increasing its bioavailability.
This interaction is minimum with azithromycin.
MACROLIDES AT A GLANCE
™ Erythromycin appears to inhibit the translocation step.
™ Called as alternative to penicillin’s or can be given to patients having hypersensitivity reaction
towards penicillins.
™ Azithromycin and clarithromycin have enhanced activity against M. avium-intracellulare or
mycobacterium avium complex (MAC) and also used in tuberculosis and leprosy.
24
Page 25
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
AMINOGLYCOSIDES
The aminoglycoside group includes gentamicin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin, and
neomycin. These drugs are used primarily to treat infections caused by aerobic gram-negative bacteria;
streptomycin is an important agent for the treatment of tuberculosis. In contrast to the inhibitors of microbial
protein synthesis (tetracyclines, chloramphenicol), which are bacteriostatic, the aminoglycosides are bactericidal
inhibitors of protein synthesis. These agents are polycations containing two or more amino sugars joined in
glycosidic linkage to a hexose nucleus, which usually is in a central position. This hexose, or aminocyclitol, is either
streptidine (found in streptomycin) or 2-deoxystreptamine (found in all other available aminoglycosides). All
members of the group share the same spectrum of toxicity, most notably nephrotoxicity and ototoxicity,
which can involve the auditory and vestibular functions of the eighth cranial nerve.
Mechanism of action
The primary intracellular site of action of the aminoglycosides is the 30S ribosomal subunit, which consists of 21
proteins and a single 16S molecule of RNA. At least three of these ribosomal proteins and perhaps the 16S
ribosomal RNA as well, contribute to the streptomycin-binding site. Aminoglycoside binds to the 30S ribosomal
subunit and interferes with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon
(AUG) of mRNA. They can cause
I.
Premature termination of translation with detachment of the ribosomal complex and incompletely
synthesized protein.
II.
III.
Aminoglycoside binding to the 30S subunit also causes misreading of mRNA.
Incorporation of incorrect amino acids resulting in the production of abnormal or nonfunctional proteins.
Resistance
The genes encoding aminoglycoside-modifying enzymes are acquired primarily by conjugation and transfer of
resistance plasmids. These enzymes phosphorylate, adenylate, or acetylate specific hydroxyl or amino groups.
Amikacin is not suitable substrate for these inactivating enzymes; thus strains that are resistant to multiple other
drugs tend to be susceptible to amikacin. The metabolites of the aminoglycosides may compete with the unaltered
drug for transport across the inner membrane, but they are incapable of binding effectively to ribosomes and
interfering with protein synthesis.
ADME
The aminoglycosides are polycations and therefore highly polar. They are not absorbed from the
gastrointestinal tract and are usually given intramuscularly or intravenously. Less than 1% of a dose is
absorbed after either oral or rectal administration. The drugs are not inactivated in the intestine and are
eliminated quantitatively in the feces. Long-term oral or rectal administration of aminoglycosides may result in
25
Page 26
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
accumulation to toxic concentrations in patients with renal impairment. So these are mostly given by intravenous
or intramuscular route. Because of their polar nature, the aminoglycosides do not penetrate into most cells, the
central nervous system (CNS), and the eye. Administration of aminoglycosides to women late in pregnancy may
result in accumulation of drug in fetal plasma and amniotic fluid. Streptomycin and tobramycin can cause hearing
loss in children born to women who receive the drug during pregnancy. The aminoglycosides are excreted almost
entirely by glomerular filtration.
Adverse effects
1.
Ototoxicity involves progressive damage to, and eventually destruction of, the sensory cells in the cochlea
and vestibular organ of the ear. Streptomycin and gentamicin are more likely to interfere with vestibular
function, whereas neomycin and amikacin mostly affect hearing. Netilmicin is less ototoxic than other
aminoglycosides and is preferred when prolonged use is necessary.
™ Ototoxicity is potentiated by the concomitant use of other ototoxic drugs (e.g. loop diuretics like
furosemide, ethacrynic acid) or other nephrotoxic antimicrobial agents (e.g. vancomycin or
amphotericin) can potentiate nephrotoxicity and should be avoided if possible.)
2.
Nephrotoxicity Neomycin, tobramycin, and gentamicin are the most nephrotoxic.
3.
In very high doses, aminoglycosides can produce a curare-like effect with neuromuscular blockade that
results in respiratory paralysis. It results from inhibition of the Ca2+ uptake necessary for the exocytotic
release of acetylcholine. This paralysis is usually reversible by calcium gluconate (given promptly) or
neostigmine.
AMINOGLYCOSIDE AT A GLANCE
™ The aminoglycosides are polycations and therefore highly polar. They are not absorbed from the
gastrointestinal tract and are usually given intramuscularly or intravenously.
™ All members of the group share the same spectrum of toxicity, nephrotoxicity and ototoxicity, which
can involve the auditory and vestibular functions of the eighth cranial nerve.
™ Aminoglycoside binding to the 30S subunit also causes misreading of mRNA.
™ Netilmicin is less ototoxic than other aminoglycosides and is preferred when prolonged use is
necessary.
™ Amikacin is a not a substrate for inactivating enzymes which phosphorylate, adenylate, or acetylate
specific hydroxyl or amino groups.
26
Page 27
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
Antimycobacterial drugs
The main mycobacterial infections in humans are tuberculosis and leprosy-typically chronic infections caused by
Mycobacterium tuberculosis and M. leprae, respectively. A particular problem with both these organisms is that
they can survive inside macrophages after phagocytosis, unless these cells are 'activated' by cytokines produced by
T-helper 1 lymphocytes. The lipid-rich mycobacterial cell wall is impermeable to many agents.
Drugs used to treat tuberculosis
First line of drugs: Isoniazid, Rifampicin, Ethambutol, Streptomycin and Pyrazinamide
Second line of drugs: Cycloserine, ofloxacin, ciprofloxacin, Clarithromicin
To decrease the probability of the emergence of resistant organisms, compound drug therapy is a frequent strategy.
This commonly involves:
•
an initial phase of treatment (about 2 months) with a combination of isoniazid , rifampicin and
pyrazinamide (plus ethambutol if the organism is suspected to be resistant)
•
a second, continuation phase (about 4 months) of therapy with isoniazid and rifampicin; longer-term
treatment is needed for patients with meningitis, bone/joint involvement or drug-resistant infection.
Isoniazid
Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls.
Isoniazid is a prodrug that is activated by the mycobacterial catalase-peroxidase. The activated form of isoniazid
forms a covalent complex with an acyl carrier protein which blocks mycolic acid synthesis and kills the cell.
Isoniazid is bacteriostatic for "resting" bacilli, but is bactericidal for rapidly dividing microorganisms. Isoniazid also
inhibits mycobacterial catalase-peroxidase (the isoniazid-activating enzyme), which may increase the likelihood
of damage to the mycobacteria from reactive oxygen species and H2O2. Exposure to isoniazid leads to a loss of acidfastness and a decrease in the quantity of methanol-extractable lipids in the microorganisms.
The most common mechanism of isoniazid resistance is mutations in catalase-peroxidase (katg) that decrease its
activity, preventing conversion of the prodrug isoniazid to its active metabolite. Another mechanism of resistance is
related to a mutation in the mycobacterial inhA and KasA genes involved in mycolic acid biosynthesis.
Metabolism, which involves largely N-4 acetylation, depends on genetic factors that determine whether a person
is a slow or rapid acetylator of the drug, with slow inactivators enjoying a better therapeutic response. The half-life
in slow inactivators is 3 hours and in rapid inactivators, 1 hour.
27
Page 28
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
A variety of other adverse reactions have been reported, including fever, hepatotoxicity, peripheral neuritis,
hematological changes, Adverse effects involving the central or peripheral nervous systems are largely
consequences of a deficiency of pyridoxine Pyridoxal-hydrazone formation occurs mainly in slow acetylators.
Isoniazid may cause haemolytic anaemia in individuals with glucose 6-phosphate dehydrogenase deficiency, and
it decreases the metabolism of the antiepileptic agents phenytoin , ethosuximide and carbamazepine , resulting in
an increase in the plasma concentration and toxicity of these drugs.
Rifampicin (Streptomyces mediterranei)
Rifampin inhibits DNA-dependent RNA polymerase of mycobacteria and other microorganisms by forming a
stable drug-enzyme complex, leading to suppression of initiation of chain formation (but not chain elongation) in
RNA synthesis. More specifically, the β subunit of this complex enzyme is the site of action of the drug, although
rifampin binds only to the holoenzyme. Nuclear RNA polymerases from a variety of eukaryotic cells do not bind
rifampin, and RNA synthesis is correspondingly unaffected in eukaryotic cells. High concentrations of rifamycin
antibiotics can inhibit RNA synthesis in mammalian mitochondria, viral DNA-dependent RNA polymerases, and
reverse transcriptases. Rifampin is bactericidal for both intracellular and extracellular microorganisms.
Rifampin is distributed throughout the body and is present in effective concentrations in many organs and body
fluids, including the CSF. This is perhaps best exemplified by the fact that the drug may impart an orange-red
color to the urine, feces, saliva, sputum, tears, and sweat; patients should be so warned.
Rifampicin causes induction of hepatic metabolizing enzymes CYP1A2, 2C9, 2C19, and 3A4, its administration
results in a decreased half-life for a number of compounds, including HIV protease and non-nucleoside reverse
transcriptase inhibitors, digitoxin, digoxin, quinidine, disopyramide, mexiletine, tocainide, ketoconazole,
propranolol, metoprolol, clofibrate, verapamil, methadone, cyclosporine, corticosteroids, oral anticoagulants,
theophylline, barbiturates, oral contraceptives, halothane, fluconazole, and the sulfonylureas.
Ethambutol
Ethambutol has no effect on organisms other than mycobacteria. It is taken up by the bacteria and exerts a
bacteriostatic effect after a period of 24 hours, although the mechanism by which this occurs is unknown. The main
adverse effect is optic neuritis results in visual disturbances manifesting initially as red-green colour blindness
progressing to a decreased visual acuity. Color vision should be monitored during prolonged treatment.
Pyrazinamide
Pyrazinamide is inactive at neutral pH but tuberculostatic at acid pH. It is effective against the intracellular
organisms in macrophages because, after phagocytosis, the organisms are contained in phagolysosomes where the
pH is low. Resistance develops rather readily, but cross-resistance with isoniazid does not occur. The drug is well
absorbed after oral administration and is widely distributed, penetrating well into the meninges. It is excreted
28
Page 29
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
through the kidney, mainly by glomerular filtration. Unwanted effects include gout, which is associated with high
concentrations of plasma urates.
Cycloserine
Cycloserine is a broad-spectrum antibiotic that inhibits the growth of many bacteria, including coliforms and
mycobacteria. It is water-soluble and destroyed at acid pH. It acts by competitively inhibiting bacterial cell wall
synthesis. It does this by preventing the formation of D-alanine and the D-Ala-D-Ala dipeptide that is added to
the initial tripeptide side-chain on N-acetylmuramic acid, i.e. it prevents completion of the major building block
of peptidoglycan. Cycloserine inhibits Recemase enzymes which convert L-amino acids to D-amino acids.
Ethionamide
Ethionamide is also an inactive prodrug that is activated by a mycobacterial redux system. EtaA, an NADPHspecific, FAD-containing monooxygenase, converts ethionamide to a sulfoxide, and then to 2-ethyl-4aminopyridine. Ethionamide inhibits mycobacterial growth by inhibiting the activity of the inhA gene product, the
enoyl-ACP reductase of fatty acid synthase II. This is the same enzyme that activated isoniazid inhibits. Although
the exact mechanisms of inhibition may differ, the results are the same: inhibition of mycolic acid biosynthesis and
consequent impairment of cell-wall synthesis. A wide variety of disturbances may occur, ranging from headache and
irritability to depression, convulsions and psychotic states.
Para aminosalicylic acid (PAS)
Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against M tuberculosis. It is
structurally similar to p-aminobenzoic aid (PABA) and to the sulfonamides
29
Page 30
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ANTIFUNGAL DRUGS
Classification
1.
Antibiotics
a.
Polyenes : Amphotericin B, Nystatin, Hamycin, Natamycin
b.
Heterocyclic benzofuran : Griseofulvin
2.
Antimetabolite : Flucytosine
3.
Azoles
a.
Imidazoles (Topical) : Clotrimazole, Econazole, Miconazole
(Systemic): Ketoconazole
b. Triazoles (Systemic) : Fluconazole, Itraconazole
4.
Allylamine : Terbinafine
5.
Other topical agents : Tolfenamate, Benzoic acid, Quinodochlor, Ciclopirox, Undecylenic acid
Amphotericin B
Amphotericin B is an amphoteric polyene (7 double bonds) macrolide (macrolide = containing a large lactone ring
of 12 or more atoms). It is nearly insoluble in water and given by I.V. Amphotericin B is selective in its fungicidal
effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes. Ergosterol,
a cell membrane sterol, is found in the cell membrane of fungi, whereas the predominant sterol of bacteria
and human cells is cholesterol. Amphotericin B binds to ergosterol and alters the permeability of the cell by
forming amphotericin B-associated pores in the cell membrane. As suggested by its chemistry, amphotericin B
combines avidly with lipids (ergosterol) along the double bond-rich side of its structure and associates with water
molecules along the hydroxyl-rich side. This amphipathic characteristic facilitates pore formation by multiple
amphotericin molecules, with the lipophilic portions around the outside of the pore and the hydrophilic regions
lining the inside. The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell
death. Some binding to human membrane sterols does occur, probably accounting for the drug's prominent toxicity.
Adverse effect includes Nephrotoxic, avoid other drugs such as aminoglycosides, Vancomycin, cyclosporine.
Slowly bone marrow depression and anemia.
5-Flucytosine has supra-additive action with AMB in case fungi sensitive to both. AMB increases the
penetration of 5-FC by forming pore.
30
Page 31
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
5-Flucytosine
All susceptible fungi are capable of deaminating flucytosine to 5-fluorouracil, a potent antimetabolite that is used
in cancer chemotherapy. Fluorouracil is metabolized first to 5-fluorouracil-ribose monophosphate (5-FUMP)
by the enzyme uracil phosphoribosyl transferase (UPRTase, also called uridine monophosphate pyrophosphorylase).
As in mammalian cells, 5-FUMP then is either incorporated into RNA (via synthesis of 5-fluorouridine
triphosphate) or metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (5-FdUMP), a potent inhibitor of
thymidylate synthetase. DNA synthesis is impaired as the ultimate result of this latter reaction. The selective action
of flucytosine is due to the lack or low levels of cytosine deaminase in mammalian cells, which prevents metabolism
to fluorouracil.
Flucytosine causes reversible neutropenia, thrombocytopenia, and occasional bone marrow depression. Caution
must be exercised in patients undergoing radiation or chemotherapy with drugs that depress bone marrow. Hepatic
dysfunction with elevation of serum transaminases and alkaline phosphatase may occur.
Azoles
The major effect of imidazoles and triazoles on fungi inhibits the fungal cytochrome P450 3A enzyme, lanosine
14α-demethylase, which is responsible for converting lanosterol to ergosterol, the main sterol in the fungal
cell membrane. The resulting depletion of ergosterol alters the fluidity of the membrane, and this interferes with the
action of membrane-associated enzymes. The depletion of membrane ergosterol reduces the binding sites for
amphotericin.
Ketoconazole is only administered orally. It dissolves in the acidic gastric contents and is absorbed through
the gastric mucosa. Food, antacids, cimetidine, and rifampin impair absorption. Coca-Cola being acidic has been
shown to improve absorption of ketoconazole. The drug is highly bound to plasma proteins. Ketoconazole cause
inhibits of the cytochrome P-450 system enzymes in the liver and raises the blood levels of warfarin, diazepam,
31
Page 32
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
sulfonylureas, and cyclosporine. it inhibits gonadal (Testosterone) and adrenal steroids synthesis. Hence
replaced by Itraconazole.
Itraconazole
•
Food, antacids, cimetidine and proton pump inhibitors impair absorption.
•
Rifampin, Phenobarbitone, Phenytoin, Carbmazapine induce the metabolism of Itraconazole.
•
Itraconazole inhibits metabolism in the similar way as that of ketoconazole like terfenadine, astemizole,
warfarin,sulfonylureas.
•
It donot have antiadrenogenic activity as that of testosterone.
Fluconazole lacks endocrinal side effect caused by ketoconazole. No food alteration. Have excellent
penetratibility to CSF and ocular fluids. It is used as a prophylactic to prevent fungal infection in bone marrow
transplant.
Griseofulvin
It causes a fungistatic action given orally. It interacts with fungal microtubules and interfering with mitosis.
Other drugs which cause mitotic arrest are vinca and colchicines. It is taken up selectively by newly formed skin and
concentrated in the keratin tissues like nails and hairs. It potently induces cytochrome P450 enzymes and causes
several clinically important drug interactions like warfarin. It can cause in tolerance with alcohol.
Terbinafine
It is a fungicidal noncompetitive inhibitor of squalene epoxidase and prevents the ergosterol synthesis. It is
first line drug for dermatophytes and onychomycosis.
Whitfield ointments contain benzoic acid 5% and salicylic acid 3%.
Quinodochlor is antifungal, antibacterial, amoebicide.
Ciclopirox is broad spectrum antifungal.
Undecylenic acid is used in combination of zinc salt.
Tolnaftate is effective in the treatment of most cutaneous mycoses.
32
Page 33
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ANTICANCER DRUGS
A cancer cell has generally four features uncontrolled proliferation, dedifferentiation and loss of function.
Invasiveness (intrusion on and destruction of adjacent tissues), metastasis (spread to other locations in the body via
lymph or blood). Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells.
These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or
infectious agents. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA
replication, or are inherited. A cancer can arise due to inactivation of tumor suppressive genes or activation of
oncogenes.
Cancers are classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the
origin of the tumor.
•
Carcinoma: Malignant tumors derived from epithelial cells. This group represents the most common
cancers, including the common forms of breast, prostate, lung and colon cancer.
•
Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells.
•
Lymphoma and leukemia: Malignancies derived from hematopoietic (blood-forming) cells
•
Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary;
in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the
tailbone; in horses most often found at the poll (base of the skull).
•
Blastic tumor or blastoma: A tumor (usually malignant) which resembles an immature or embryonic
tissue. Many of these tumors are most common in children.
Classification of anticancer drugs
A. Drugs acting directly on cells
1. Alkylating agents
a.
Nitrogen mustards : Mechlorethamine, Cyclophosphamide, Chlorambucil, Melphalan,
Ifosfamide
2.
b.
Ethylenimine : Thio-TEPA
c.
Alkyl sulfonate : Busulfan
d.
Nitrosoureas : Carmustine, Lomustine
e.
Triazine : Dacarbazine
Antimetabolite
a.
Folate antagonist : Methotrexate
b.
Purine antagonist : 6-Mercaptopurine, 6-Thioguanine, Azathioprine, Pentostatin
c.
Pyrimidine antagonist : 5-Fluorouracil, Cytarabine (Ara C or cytosine arabinoside)
33
Page 34
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
3.
Vinca alkaloids : Vinncristine (oncoovin), Vinblastine
4.
Taxanes : Paclitaxel,, Docetaxel
5.
Epipod
dophyllotoxin : Etoposide
6.
Campo
othecin : Topootecan, Irinoteccan
7.
Antibiotics : Actinnomycin D, Doxorubicin,, Daunorubicin, Bleomyccin, Mitomycin C,
mycin
Mithram
8.
Miscelllaneous : Hyddroxyurea, Proccarbazine, L-assparaginase, Ciisplatin, Carbooplatin
B. Drugs
D
altering hormon
nal milieu
1. Glucocorticcoids : Prednisoolone and otheers
2. Estrogens : Fosfestrol, Ethhinylestradiol
3. Antiestrogeen : Tamoxifenn
4 Antiandrogen : Flutamidee
4.
5. 5-α reductase inhibitor : Finastride
F
6 GnRH analogues : Nafereelin, Goserelinn
6.
34
Page 35
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
35
Page 36
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Most commonly, chemotherapy acts by killing cells that divide rapidly, one of the main properties of cancer cells.
This means that it also harms cells that divide rapidly under normal circumstances: cells in the bone marrow,
digestive tract and hair follicles; this results in the most common side effects of chemotherapy—
myelosuppression (decreased production of blood cells), mucositis (inflammation of the lining of the digestive
tract) and alopecia (hair loss).
Cell cycle specific drugs
G1
:
Vinblastine
S
:
Methotrexate, Cytarabine, 6-MP, 6-TG, Doxorubicin, Daunorubicin
G2
:
Etoposide, Topotecan, Bleomycin, Daunorubicin
M
:
Vincristine, Vinblastine, Paclitaxel
36
Page 37
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Alkylating agents
The chemootherapeutic allkylating agentts have in com
mmon the propeerty of becominng strong electtrophiles throuugh the
formation of carbonium
m ion intermeediates or relaated transitionn complexes. The alkylatingg agents exertt their
cytotoxic effects
e
via tran
nsfer of their alkyl
a
groups too various celluular constituentts. Alkylationss of DNA withhin the
nucleus prrobably represeent the major innteractions thatt lead to cell deeath. Howeverr, these drugs react chemically with
sulfhydryl, amino, hydro
oxyl, carboxyl, and phosphaate groups of other
o
cellular nucleophiles
n
ass well. The geeneral
m of action off these drugs involves intraamolecular cyclization to foorm an ethylen
neimonium ioon that
mechanism
may directtly or through formation
f
of a carbonium ionn transfer an allkyl group to a cellular consttituent. In addittion to
alkylation,, a secondary mechanism thhat occurs witth nitrosoureass involves carbbamoylation of
o lysine residuues of
proteins thhrough formatio
on of isocyanaates.
The major site of alkyllation within DNA
D
is the N77 position of guanine,
g
howeever, other basses are also alkkylated
d
includiing N1 and N33 of adenine, N3
N of cytosine,, and O6 of guuanine, as welll as phosphate atoms
to lesser degrees,
and proteinns associated with
w DNA. Noormally, guaniine residues inn DNA exist prredominantly as
a the keto tauutomer
and readilyy make Watson
n-Crick base pairs by hydroggen bonding wiith cytosine ressidues. Howevver, when the N 7 of
guanine iss alkylated (to
o become a qu
uaternary am
mmonium nitroogen), the guaanine residue is more acidiic and
the enol taautomer is fav
vored. The moodified guanin
ne can mispairr with thyminee residues durring DNA syntthesis,
leading to the substitutio
on of an adeninne-thymine baase pair for a guanine-cytosin
g
ne base pair. Second,
S
alkylattion of
t opening of the imidazole ring or depurinnation by excission of
the N7 labilizes the imidazole ring, makking possible the
o on both strannds of DNA thhrough cross-linking.
guanine reesidues. These interactions caan occur on a single strand or
The latterr effect leads to DNA stran
nd breakage through
t
scissioon of the sugaar-phosphate backbone of DNA.
Cross-link
king of DNA appears to bee of major im
mportance to the cytotoxic action of alk
kylating agentts, and
replicatingg cells are mostt susceptible too these drugs. Thus, althouggh alkylating agents
a
are not cell cycle-sp
pecific,
cells are most
m susceptiblee to alkylation in late G1 and S phases of the cell cycle andd express blockk in G2.
37
Page 38
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
hlorethamin
ne was develooped as a vesiccant (nitrogen mustard)
m
durinng World War I. Its ability to cause
a. Mech
lymphocyttopenia led to its
i use in lymphhatic cancers. Because
B
it cann bind and react at two separaate sites, it is caalled a
"bifunctionnal agent." Meechlorethamin
ne is also a poowerful vesicaant (blisteringg agent), and is
i administeredd only
IV, becausse it can cause severe
s
tissue damage
d
if extraavasation occurrs.
b. Cyclo
ophospham
mide & Ifosp
phamide Booth Cyclophospphamide and Iffosfamide are first
f biotransfoormed
to 4-hydroxylated intermediates by the cytochroome P-450 syystem. The hyydroxylated inttermediates unndergo
breakdownn to form the active compouunds, phosphorramide mustarrd and acroleinn. Reaction off the phosphorramide
mustard with
w
DNA is considered
c
to be the cytotoxxic step. The most promineent toxicities of
o both drugs (after
38
Page 39
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
alopecia, nausea, vomiting, and diarrhea) are bone marrow depression, especially leukocytosis, and hemorrhagic
cystitis, which can lead to fibrosis of the bladder. The latter toxicity has been attributed to acrolein in the urine in
the case of cyclophosphamide and toxic metabolites of ifosfamide. Adequate hydration as well as intravenous
injection of MESNA (sodium 2-mercaptoethane sulfonate), which inactivates the toxic compounds, minimizes
this problem. Other toxicities include effects on the germ cells resulting in amenorrhea, testicular atrophy, and
sterility. A fairly high incidence of neurotoxicity has been reported in patients on high-dose ifosfamide,
probably due to the metabolite, chloroacetaldehyde. Secondary malignancies may appear years after therapy.
c. Lomustine and Carmustine are lipid-soluble and cross the blood-brain barrier, they may be used
against tumours of the brain and meninges. However, most nitrosoureas have a severe cumulative depressive effect
on the bone marrow that starts 3-6 weeks after initiation of treatment.
d. Busulfan can cause pulmonary fibrosis and hyperuricemia
e. Dacarbazine is a prodrug and inhibits RNA and protein synthesis. But it can cause myelotoxicity and severe
nausea and vomiting.
Methotrexate is folate antagonist and one of the most widely used antimetabolites in cancer chemotherapy.
Folates are essential for the synthesis of purine nucleotides and thymidylate, which in turn are essential for DNA
synthesis and cell division. The main action of the folate antagonists is to interfere with thymidylate synthesis. In
structure, folates consist of three elements: a pteridine ring, p-aminobenzoic acid and glutamic acid . Folates are
actively taken up into cells, where they are converted to polyglutamates. In order to act as coenzymes, folates must
be reduced to tetrahydrofolate (FH4). This two-step reaction is catalysed by dihydrofolate reductase, which
converts the substrate first to dihydrofolate (FH2), then to FH4. FH4 functions as an essential cofactor
carrying the methyl groups necessary for the transformation of 2´-deoxyuridylate (DUMP) to the 2´deoxythymidylate (DTMP) required for the synthesis of DNA and purines. During the formation of DTMP from
DUMP, FH4 is converted back to FH2, enabling the cycle to repeat. Methotrexate has a higher affinity than FH2 for
dihydrofolate reductase and thus inhibits the enzyme, depleting intracellular FH4. The binding of methotrexate to
dihydrofolate reductase involves an additional bond not present when FH2 binds. The reaction most sensitive to
FH4 depletion is DTMP formation.
39
Page 40
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Methotrexate is also metabolized to poly-glutamate derivatives. This property is important, because the
polyglutamates, which also inhibit dihydrofolate reductase, remain within the cell even in the absence of
extracellular drug.
MTX has an unusually strong affinity for dihydrofolate reductase, and effectively inhibits the enzyme. Its inhibition
can only be reversed by a thousand-fold excess of the natural substrate, dihydrofolate or by administration of
leucovorin (folinic acid), which bypasses the blocked enzyme and replenishes the folate pool. Leucovorin, or
folinic acid, is the N5-formyl group-carrying form of FH4. Leucovorin is taken up more readily by normal cells
than by tumor cells. Doses of leucovorin must be kept minimal to avoid interference with the antitumor
action of the methotrexate.
6-mercaptopurine (6-MP) is the thiol analog of hypoxanthine. It and thioguanine (6-TG) were the first
purine analogs to prove beneficial for treating neoplastic disease. Azathioprine, an immunosuppressant, exerts its
effects after conversion to 6-MP. Both 6-TG and 6-MP are excellent substrates for hypoxanthine guanine
phosphoribosyl transferase (HGPRT) and are converted in a single step to the ribonucleotides 6thioguanosine-5`-monophosphate (6-thioGMP) and 6-thioinosine-5`-monophosphate (T-IMP), respectively.
Because T-IMP is a poor substrate for guanylyl kinase, the enzyme that converts guanosine monophosphate (GMP)
40
Page 41
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
to guanosine diphosphate (GDP), T-IMP accumulates intracellularly. Small amounts of 6-MP, however, also can be
incorporated into cellular DNA in the form of thioguanine deoxyribonucleotide. T-IMP inhibits the first step in the
de novo synthesis of the purine base.
6-MP undergoes metabolism in the liver to the 6-methylmercaptopurine (S-CH3) derivative or to thiouric
acid. The latter reaction is catalyzed by xanthine oxidase. Because allopurinol a xanthine oxidase inhibitor, is
frequently administered to cancer patients receiving chemotherapy to reduce hyperuricemia, it is important to
decrease the dose of 6-MP in these individuals to avoid accumulation of the drug and exacerbation of toxicities. Side
effects include nausea, vomiting, and diarrhea. Bone marrow depression is the chief toxicity. Hepatotoxicity has also
been reported.
6-TG (6-Thioguanine) must first be converted to the nucleotide form, which then inhibits the biosynthesis of the
purine ring and the phosphorylation of GMP to GDP. 6-TG can also be incorporated into RNA and DNA. Crossresistance occurs between 6-MP and 6-TG. Unlike 6-MP, allopurinol does not potentiate 6-TG action because very
little of the drug is metabolized to thiouric acid. Otherwise, toxicities are the same as those for 6-MP.
Pentostatin
has a different mechanism of action. It inhibits adenosine
deaminase, the enzyme that
transforms adenosine to inosine. This action interferes with critical pathways in purine metabolism and can have
significant effects on cell proliferation.
41
Page 42
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
5-Flurouracil is pyrimidine antagonist must be converted to the corresponding deoxynucleotide (5-FdUMP)
which competes with deoxyuridine monophosphate (dUMP) for thymidylate synthetase. 5-FdUMP acts as a
pseudosubstrate and is entrapped with the enzyme and its N5, N10-methylene Tetrahydrofolic acid coenzyme in a
ternary complex that cannot proceed to products. DNA synthesis decreases due to lack of thymidine, leading to
imbalanced cell growth and cell death. Leucovorin is given with 5-FU because the reduced folate coenzyme is
required in the thymidylate synthetase reaction. Lack of sufficient coenzyme reduces the effectiveness of the
antipyrimidine. 5-FU is also incorporated into RNA and low levels have been detected in DNA.
42
Page 43
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Cytarabine is an analogue of the naturally occurring nucleoside 2´-deoxycytidine. The drug enters the target cell
and undergoes the same phosphorylation reactions as the endogenous nucleoside to give cytosine arabinoside
trisphosphate, which inhibits DNA polymerase. The main unwanted effects are on the bone marrow and the
gastrointestinal tract. It also causes nausea and vomiting.
Vinca alkaloids are vincristine, vinblastine and vindesine. Vinorelbine is a semisynthetic vinca alkaloid with
similar properties that is mainly used in breast cancer. The drugs bind to tubulin and inhibit its polymerisation
into microtubules, preventing spindle formation in dividing cells and causing arrest at metaphase. Vincristine
can cause neuropathy. While Vinblastine is a more potent myelosuppressant.
Paclitaxel binds reversibly to tubulin, but unlike the vinca alkaloids, it promotes polymerization and
stabilization of the polymer rather than disassembly. The target for Paclitaxel is alpha and beta tubulins. They
polymerize to give microtubules. For this process microtubule associated protein (MAP) and GTP is required. Taxol
brings polymerization in absence of MAP & GTP. Due to enhanced microtubules cause detrimental effects on
dividing cells which leads to blockage of cell cycle, thereby cause the death of the cell. Because of serious
43
Page 44
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
hypersensitivity reactions (dyspnea, urticaria, and hypotension), the patient to be treated with paclitaxel is
currently premedicated with dexamethasone and diphenhydramine as well as with an H2 blocker. Bone
marrow suppression and cumulative neurotoxicity also found.
Etoposide inhibits Topoisomerase II. Binding of the drugs to the enzyme-DNA complex results in the
persistence of the transient cleavable form of the complex and thus renders it susceptible to irreversible doublestrand breaks. Unwanted effects include nausea and vomiting, myelosuppression and hair loss.
The campothecins irinotecan and topotecan, isolated from the stem of the tree Camptotheca
acuminata, bind to and inhibit topoisomerase I, high levels of which occur throughout the cell cycle. Diarrhoea
and reversible bone marrow depression occur but, in general, these alkaloids have fewer unwanted effects than
most other anticancer agents.
CYTOTOXIC ANTIBIOTICS
1. Doxorubicin and Daunorubicin has several cytotoxic actions. It binds to DNA and inhibits both
DNA and RNA synthesis, but its main cytotoxic action appears to be inhibition of topoisomerase II (a
DNA gyrase). Doxorubicin can cause cardiomyopathy. Cytochrome P-450 reductase (present in cell
nuclear membranes) catalyzes reduction of the anthracyclines to semiquinone free radicals. These in turn
reduce molecular 02, producing superoxide ions and hydrogen peroxide that mediate single strand scission
of DNA. Tissues with ample superoxide dismutase (SOD) or glutathione peroxidase activity are protected.
Tumors and the heart are generally low in SOD. In addition, cardiac tissue lacks catalyase and thus
cannot dispose of hydrogen peroxide. This may explain the cardiotoxicity of anthracyclines.
2. Dactinomycin or Actinomycin D is mainly used for treating pediatric cancers. It intercalates in
the minor groove of DNA between adjacent guanosine-cytosine pairs, interfering with the movement
of RNA polymerase along the gene and thus preventing transcription. There is also evidence that it has
a similar action to that of the anthracyclines on topoisomerase II. It produces no cardiotoxicity. The major
dose-limiting toxicity is bone marrow depression, and the drug is immunosuppressive.
3. Bleomycins are a group of metal-chelating glycopeptide antibiotics that degrade preformed DNA,
causing chain fragmentation and release of free bases. This action is thought to involve chelation of
ferrous iron and interaction with oxygen, resulting in the oxidation of the iron and generation of
superoxide and/or hydroxyl radicals. Bleomycin is most effective in the G2 phase of the cell cycle and
mitosis, but it is also active against non-dividing cells (i.e. cells in the G0 phase). It is often used to treat
germline cancer. Generally
a DNA-bleomycin-Fe(ll) complex appears to undergo oxidation to
bleomycin-Fe(lll); the liberated electrons react with oxygen to form superoxide or hydroxide radicals,
which in turn attack the phosphodiester bonds of the DNA, resulting in strand breakage and chromosomal
aberrations In contrast to most anticancer drugs, bleomycin causes little myelosuppression: its most
serious toxic effect is pulmonary fibrosis.
44
Page 45
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
4. Mitomycin functions as a bifunctional alkylating agent, binding preferentially at O6 of the guanine
nucleus. It cross-links DNA and may also degrade DNA through the generation of free radicals. It causes
marked delayed myelosuppression and can also cause kidney damage and fibrosis of lung tissue
5. Plicamycin or Mithramycin also exerts its cytotoxicity through restriction of DNA-directed RNA
synthesis. Resistance is due to P-glycoprotein efflux. Plicamycin has a relative toxic specificity for
osteoclasts preventing their resorption, and lowers plasma calcium concentration in hypercalcemic
patients--especially those with bone tumors. Toxicities include hemorrhage as well as effects on the bone
marrow, liver, and kidneys.
Miscellaneous anticancer drugs
Procarbazine has weak MAO inhibitor, have disulfiram like action. Oxidative metabolism of this drug by
microsomal enzymes generates azoprocarbazine and H2O2, which may be responsible for DNA strand
scission. Bone marrow depression is the major toxicity. Nausea, vomiting, and diarrhea are common. The drug is
also neurotoxic, causing symptoms ranging from drowsiness to hallucinations to paresthesias. Because it inhibits
monoamine oxidase, patients should be warned against ingesting foods that contain tyramine (for example, aged
cheeses, beer, and wine). Procarbazine is both mutagenic and teratogenic.
Hydroxycarbamide or hydroxyurea is a urea analogue that inhibits ribonucleotide reductase, thus
interfering with the conversion of ribonucleotides to deoxyribonucleotides. It is mainly used to treat leukaemia
but has the familiar spectrum of unwanted effects, bone marrow depression being significant.
L-Asparaginase catalyzes the deamination of asparagine to aspartic acid and ammonia. The form of the
enzyme used chemotherapeutically is derived from bacteria. Some neoplastic cells require an external source of
45
Page 46
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
asparagine, because of their limited capacity to make sufficient L-asparagine to support growth and function. LAsparaginase hydrolyzes blood asparagine and thus deprives the tumor cells of this nutrient required for
protein synthesis. L-Asparaginase is used to treat childhood acute lymphocytic leukemia in combination with
vincristine. It has different and unique adverse effect of liver abnormalities, a decrease in clotting factors, and, as
well as pancreatitis, seizures, and coma due to ammonia toxicity.
Platinum compounds
Cisplatin is a water-soluble planar coordination complex containing a central platinum atom surrounded by two
chlorine atoms and two ammonia groups. Its action is analogous to that of the alkylating agents. When it enters the
cell, Cl- dissociates, leaving a reactive complex that reacts with water and then interacts with DNA. It causes
intrastrand cross-linking, probably between N7 and O6 of adjacent guanine molecules, which results in local
denaturation of DNA.
Cisplatin has revolutionized the treatment of solid tumours of the testes and ovary. Therapeutically, it is given by
slow intravenous injection or infusion. It is seriously nephrotoxic and most emetic anticancer drug. The 5-HT3
receptor antagonists (ondansetron) are very effective in preventing vomiting and have transformed cisplatinbased chemotherapy. Tinnitus and hearing loss in the high-frequency range may occur, as may peripheral
neuropathies, hyperuricaemia and anaphylactic reactions.
Carboplatin is a derivative of cisplatin . Because it causes less nephrotoxicity, neurotoxicity, ototoxicity, nausea
and vomiting than cisplatin (although it is more myelotoxic).
Resistance to anticancer drugs
Multidrug resistance is often associated with increased expression of a normal gene (the MDR1 gene) for a cell
surface glycoprotein (P-glycoprotein) involved in drug efflux. This transport molecule requires ATP to expel
variety of foreign molecules (not limited to antitumor drugs) from the cell. It is expressed constitutively in normal
tissues such as the epithelial cells of the kidney, large intestine, and adrenal gland as well as in a variety of tumors.
Multidrug resistance can be reversed experimentally by calcium channel blockers, such as verapamil, and a variety
of other drugs, which inhibit the transporter. Other mechanisms of multiple drug resistance involve over expression
of the multidrug resistance protein 1 (MRP1), a member of the ATP binding cassette transmembrane transporter
super family that now consists of nine members (MRP1-MRP9). MRP1, the most extensively studied, increases
resistance to natural product drugs such as anthracyclines.
Testicular carcinoma
:
Bleomycin, Carboplatin, Melphalan, Chlorambucil
Ovarian cancer
:
Melphalan, Chlorambucil, cyclophosphamide
46
Page 47
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Breast cancer
:
Tamoxifen, Methotrexate, estrogens
Hood kin’s cancer
:
MOPP (Mtx, Doxorubicin, 6-MP, Prednisolone)
Burkitt’s lymphoma
:
Cyclophosphamide
Prostate carcinoma
:
Finastride, estrogens
Ewings sarcoma
:
Doxorubicin, Vincristine, Actinomycin D
Some toxicity of anticancer drugs can be overcome by co-administration of drugs
1.
Cisplatin : ondansetron (to minimize nausea and vomiting)
2.
Methotrexate : Folinic acid ( to replenishes the folate pool for normal cells)
3.
6-Mercaptopurine : Allopurinol (to minimize the hyperuricemia)
4.
Cyclophosphamide : Mensa (to minimize nephrotoxicity caused by acrolein)
5.
Paclitaxel : Dexamethasone (to minimize hypersensitivity reactions)
47
Page 48
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ANTIVIRAL DRUGS
Viruses are small (usually in the range 20-30 nm) infective agents that are incapable of reproduction outside their
host cells. The free-living (e.g. outside its host) virus particle is termed a virion, and consists of segments of nucleic
acid (either RNA or DNA) enclosed in a protein coat comprised of symmetrical repeating structural units and called
a capsid . The viral coat, together with the nucleic acid core, is termed the nucleocapsid. Some viruses have, in
addition, a further external lipoprotein envelope, which may be decorated with antigenic viral glycoproteins or
phospholipids acquired from its host when the nucleocapsid buds through the membranes of the infected cell.
Certain viruses also contain enzymes that initiate their replication in the host cell.
Viral life cycles share a general pattern:
1.
Attachment to a host cell via envelope or glycoproteins to receptors on host. These 'receptors' are normal
membrane constituents-receptors for cytokines, neurotransmitters or hormones, ion channels, integral
membrane glycoproteins. Following attachment, the receptor-virus complex enters the cell (often by
receptor-mediated endocytosis), during which time the virus coat may be removed by host cell enzymes
(often lysosomal in nature). Some bypass this route.
2.
Release of viral genes and possibly enzymes into the host cell.
3.
Replication of viral components using host-cell machinery.
4.
Assembly of viral components into complete viral particles.
5.
Release of viral particles to infect new host cells.
Replication in DNA viruses
Viral DNA enters the host cell nucleus, where transcription into mRNA occurs catalysed by the host cell RNA
polymerase. Translation of the mRNA into virus-specific proteins then takes place. Some of these proteins are
enzymes that then synthesise more viral DNA, as well as proteins comprising the viral coat and envelope. After
assembly of coat proteins around the viral DNA, complete virions are released by budding or after host cell lysis.
Replication in RNA viruses
Enzymes within the virion synthesise its mRNA from the viral RNA template, or sometimes the viral RNA serves as
its own mRNA. This is translated by the host cell into various enzymes, including RNA polymerase (which directs
the synthesis of more viral RNA), and also into structural proteins of the virion. With these viruses, the host cell
nucleus is usually not involved in viral replication, although some RNA viruses (e.g. orthomyxoviruses) replicate
exclusively within the host nuclear compartment.
48
Page 49
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Replicatioon in retroviru
uses
The virionn in retrovirusses1 contains a reverse trannscriptase enzyyme (virus RN
NA-dependent DNA polymeerase),
which makkes a DNA cop
py of the viral RNA. This DN
NA copy is inteegrated into thhe genome of thhe host cell, annd it is
then termeed a provirus. The provirus DNA
D
is transccribed into bothh new viral geenome RNA ass well as mRN
NA for
translation in the host intto viral proteinns, and the com
mpleted virusess are released by
b budding. Many
M
retroviruses can
replicate without
w
killing the
t host cell.
Host-viruss interaction
The first defence
d
is the simple barrier function of inttact skin, whicch most virusess are unable to penetrate. How
wever,
broken skkin (e.g. at sitess of wounds orr insect bites) and
a mucous membranes aree more vulneraable to viral attack.
a
Should thhe virus gain entry
e
to the boody, then the host
h
can deployy both the innnate and subseqquently the addaptive
immune response.
r
The infected
i
cell prresents, on its surface,
s
viral peptides
p
compleexed with majoor histocompattibility
complex (MHC)
(
class I molecules. Thhis complex is recognized by T lymphocytees, which then kill the infecteed cell.
This mayy be accomplisshed by the reelease of lytic proteins (suchh as perforins, granzymes) or by triggerinng the
apoptotic pathway in th
he infected celll by activation of its Fas receeptor. Apoptossis may also bee triggered indirectly
through thhe release of a cytokine suchh as tumour neccrosis factor (T
TNF)-α. If the virus
v
escapes immune
i
detection by
cytotoxic lymphocytes by
b modifying the
t expression of the peptide-MHC compleex, it may still fall victim to natural
n
killer (NK
K) cells. But some
s
viruses allso have a deviice for evadingg NK cells as well.
w
49
Page 50
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Classification
A. Anti-influenza virus : Amantidine, Rimantidine (Prevent uncoating step), Neuraminidase inhibitors and
inhibitors of viral coat disassembly
B. Antiherpes virus : Idoxuridine, Acyclovir, Ganciclovir, Penciclovir, Foscarnet, Vidarabine, Trifluuridine
(All mainly inhibit DNA polymerase)
C. Anti-reverse transcriptase inhibitor or RNA dependent DNA polymerase inhibitor :
a.
Nucleoside derivatives : Zidovudine, Stavudine, Lamivudine, Zalcitabine, Didanosine
b.
Non nucleoside derivatives : Nevirapine, Efavirenz, Delavirdine
D. Protease inhibitors : Ritonavir, Indinavir, Nelfinavir, Saquinavir
E. Nonselective antiviral : Lamivudine, Ribavirin, interferon
F. Inhibitors of HIV fusion with host cells: enfurvitide
50
Page 51
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
51
Page 52
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
A. Neuraminid
N
dase inhibittors and inhibitors of viral coat disassemb
bly
Viral neuuraminidase is one
o of three trransmembrane proteins codedd by the influeenza genome. Infection withh these
RNA viruuses begins wiith the attachm
ment of the viraal haemaglutinnin to neuramiinic (sialic) accid residues on
o host
cells. Thee viral particlle then enterss the cell by an
a endocytic process. The endosome is acidified following
influx off H+ through another viral protein, the M2 ion chann
nel. This facillitates the disaassembly of thee viral
structure, allowing the RNA
R
to enter the
t host nucleuus, thus initiatiing a round of viral replicatioon. Newly repllicated
virions esscape from th
he host cell byy budding from
m the cell meembrane. Virall neuraminidasse promotes thhis by
severing the
t bonds linkiing the particlee coat and host sialic acid.
The neuraaminidase inhiibitors zanamivvir and oseltaamivir are acttive against booth influenza A and B viruses. The
drug is inn the expectatiion that it mayy offer some defence
d
againsst 'bird flu', shoould this mutaate into an orgganism
capable of infecting hum
mans.
Amantidine quite an olld drug used as antiparkinsonnian drug. andd seldom recom
mmended todaay, effectively blocks
b
the M2 ioon channels, thu
us inhibiting viral
v
disassembly. It is active against influennza A virus (ann RNA virus) but
b has
no action against influen
nza B virus. Thhe closely relatted rimantadin
ne is similar inn its effects.
B. Antih
herpes viru
us drugs
Acyclov
vir is acyc
clic guano
osine deriv
vative. In viitro activity against
a
Epsteinn-Barr virus (E
EBV),
cytomegaalovirus (CMV
V), and human herpesvirus-6
h
(
(HHV-6)
is preesent but compparatively weakker
52
Page 53
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Mechanism of action
Acyclovir inhibits viral DNA synthesis. Its selectivity of action depends on interaction with two distinct viral
proteins: HSV thymidine kinase and DNA polymerase. It is converted first to the monophosphate derivative by
the virus-specified thymidine kinase and then to the di- and triphosphate compounds by host cell enzymes.
Because it requires the viral kinase for initial phosphorylation, acyclovir is selectively activated, and the
active metabolite accumulates, only in infected cells. Cellular uptake and initial phosphorylation are facilitated
by HSV thymidine kinase. The affinity of acyclovir for HSV thymidine kinase is about 200 times greater than for
the mammalian enzyme. Cellular enzymes convert the monophosphate to acyclovir triphosphate, which is present
in forty- to one hundredfold higher concentrations in HSV-infected than in uninfected cells and competes for
endogenous deoxyguanosine triphosphate (dGTP). The immunosuppressive agent mycophenolate mofetil
potentiates the antiherpes activity of acyclovir and related agents by depleting intracellular dGTP pools. Acyclovir
triphosphate competitively inhibits viral DNA polymerases and, to a much smaller extent, cellular DNA
polymerases. Acyclovir triphosphate also is incorporated into viral DNA, where it acts as a chain terminator
because of the lack of a 3`-hydroxyl group. By a mechanism termed suicide inactivation, the terminated DNA
template containing acyclovir binds the viral DNA polymerase and leads to its irreversible inactivation.
Adverse effect: it is teratogenic and cause testicular toxicity; Intravenous infusion may be associated with
reversible renal dysfunction (due to crystalline nephropathy) or neurologic toxicity (eg, tremors, delirium,
seizures).
Valacyclovir
is the L-valyl ester of acyclovir. It is rapidly converted to acyclovir after oral administration via intestinal and
hepatic first-pass metabolism, resulting in serum levels that are three to five times greater than those achieved with
oral acyclovir and approximate those achieved with intravenous acyclovir administration. Valacyclovir has also
been shown to be effective in preventing cytomegalovirus disease after organ transplantation
Ganciclovir
This acyclic analogue of guanosine is the drug of choice for cytomegalovirus infection. This is a frequent
opportunistic infection in immunocompromised or AIDS patients and has been a formidable obstacle to successful
transplantation of organs and bone marrow (which necessitates immunosuppressive therapy). Ganciclovir has
serious unwanted actions, including bone marrow depression and potential carcinogenicity, and is consequently
used only for life- or sight-threatening cytomegalovirus infections in patients who are immunocompromised.
Foscarnet
is a synthetic non-nucleoside analogue of pyrophosphate that inhibits viral DNA polymerase by binding
directly to the pyrophosphate-binding site. It can cause serious nephrotoxicity. Given by intravenous infusion, it is
a second-line drug in cytomegalovirus eye infection in immunocompromised patients.
53
Page 54
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Famiciclovir is prodrug of penciclovir.
C. Nucleoside Reverse transcriptase inhibitors
The HIV-encoded, RNA-dependent DNA polymerase, also called reverse transcriptase, converts viral RNA into
proviral DNA that is then incorporated into a host cell chromosome. Available inhibitors of this enzyme are either
nucleoside/nucleotide analogs or nonnucleoside inhibitors. Nucleoside and nucleotide analogs must enter cells and
undergo phosphorylation to generate synthetic substrates for the enzyme. The fully phosphorylated analogs block
replication of the viral genome both by competitively inhibiting incorporation of native nucleotides and by
terminating elongation of nascent proviral DNA because they lack a 3-hydroxyl group as DNA polymerase can
only form phophodiester bond if 3`-OH free is available.
The selective toxicity of these drugs depends on their ability to inhibit the HIV reverse transcriptase without
inhibiting host cell DNA polymerases. Although the intracellular triphosphates for all these drugs have low affinity
for human DNA polymerase-α and -β, some are capable of inhibiting human DNA polymerase-γ, which is the
mitochondrial enzyme. As a result, the important toxicities common to this class of drugs result in part from the
inhibition of mitochondrial DNA synthesis. These toxicities include anemia, granulocytopenia, myopathy,
peripheral neuropathy, and pancreatitis.
Zidovudine
Zidovudine (AZT) have azide grp at 3` position, is a synthetic thymidine analog with potent activity. Intracellular
zidovudine is phosphorylated by thymidine kinase to zidovudine 5¢-monophosphate, which is then phosphorylated
by thymidylate kinase to the diphosphate and by nucleoside diphosphate kinase to zidovudine 5¢-triphosphate.
Zidovudine 5¢-triphosphate terminates the elongation of proviral DNA because it is incorporated by reverse
transcriptase into nascent DNA but lacks a 3¢-hydroxyl group. The monophosphate competitively inhibits cellular
thymidylate kinase, and this may reduce the amount of intracellular thymidine triphosphate.
AZT is toxic to bone marrow. For example, severe anemia and leukopenia occur in patients receiving high doses.
Headaches are also common. Seizures have been reported in patients with advanced AIDS. AZT's toxicity is
potentiated if glucuronidation is decreased by co-administration of drugs like probenecid, acetaminophen or
paracetamol, Iorazepam, indomethacin, and cimetidine. These drugs are themselves glucuronidated and thus can
interfere with the glucuronidation of AZT.
Didanosine
Lacks –OH grp at 3` position. Didanosine is administered as either chewable, buffered tablets or in a buffered
solution. Absorption is good if taken in the fasting state; food causes decreased absorption. The buffering of
stomach contents may interfere in the absorption of other drugs that require an acidic milieu for absorption,
such as ketoconazole. Pancreatitis, which may be fatal, is a major toxicity of didanosine treatment, and requires
monitoring of serum amylase. The dose-limiting toxicity of didanosine is peripheral neuropathy.
54
Page 55
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Zalcita
abine
analog off deoxycytidin
ne, as mono thherapy in patiennts who cannoot tolerate AZT
T. Peripherall neuropathy is the
major tooxicity and is probably a consequence of the inhibiition of the mammalian
m
m
mitochondrial
DNA
polymeraase γ. Pancreattitis resulting inn death has occcurred, especiaally if didanosinne is given witth pentamidine.
Stavudine
is an analog of thymidin
ne in which a double bond joins the 2' an
nd 3' carbon of
o the sugar. In
I addition it innhibits
cellular enzymes
e
such as β and γ, DNA
D
polymerrases thus reduucing mitochoondrial DNA synthesis.
s
Stavvudine
penetratess the blood braain barrier. Thee major and moost common cliinical toxicity is
i peripheral neuropathy.
n
Lamivu
udine is 2'-deo
oxy-3'-thiacyttidine analoguee. However, itt does not affeect mitochond
drial DNA syn
nthesis
or bone marrow
m
precu
ursor cells. Addministration with
w trimethoprrim/sulfamethooxazole increasses the area undder the
curve (AU
UC) of lamivud
dine.
Nonnuc
cleoside re
everse trans
scriptase inhibitors : Nevirapine,
N
Effavirenz, Delavvirdine
They direectly inhibit HIV reverse transcriptase withoout need for in
ntracellular phosphorylatioon.
55
Page 56
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
D. Prote
ease (Aspa
artate prote
einase) inh
hibitors: Ritoonavir, Indinavvir, Nelfinavir, Saquinavir
Retroviruuses typically have
h
three gennes: gag, pol, and
a env. The transcript
t
that contains gag and
a pol is trannslated
into a long “polyprotein
n,” a single large polypeptid
de that is cleavved into six prroteins with distinct
d
functioons.
•
T proteins deerived from thee gag gene makke up the interior core of the viral particle.
The
•
T pol gene encodes the prrotease that clleaves the longg polypeptide, an integrase that
The
t
inserts thee viral
D
DNA
into the host
h chromosom
mes, and reverrse transcriptasse.
•
T env gene encodes
The
e
the prooteins of the virral envelope
In HIV and many oth
her viral infections, the mRNA
m
transcriibed from thee provirus is translated intoo two
biochemiccally inert poly
lyproteins. A virus-specific
v
p
protease
then converts
c
the polyproteins
p
innto various struuctural
and functional proteins by cleavage att the appropriatte positions. Because this prootease does nott occur in the host,
h
it
is a usefful target for chemotherapeuutic interventiion. HIV-specific protease inhibitors bindd to the site where
cleavage occurs, and theeir use, in com
mbination with reverse transcrriptase inhibitoors, has transfoormed the theraapy of
AIDS.
Interferrons are a faamily of induccible proteins synthesised
s
byy mammalian cells and now
w generally prooduced
56
Page 57
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
commercially using recombinant DNA technology. There are at least three types, α, β, and γ, constituting a family
of hormones involved in cell growth and regulation and the modulation of immune reactions. IFN-γ, termed
immune interferon, is produced mainly by T lymphocytes as part of an immunological response to both viral
and non-viral antigens, the latter including bacteria and their products, rickettsiae, protozoa, fungal
polysaccharides. IFN-α and IFN-β are produced by B and T lymphocytes, macrophages and fibroblasts in
response to the presence of viruses and cytokines. The IFNs bind to specific ganglioside receptors on host cell
membranes. They induce, in host cell ribosomes, the production of enzymes 2`, 5`oligoadenylate synthtase
and phosphodiesterase that inhibit the translation of viral mRNA into viral proteins, thus halting viral
replication. They have a broad spectrum of action and inhibit the replication of most viruses in vitro
.
57
Page 58
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ANTIMALARIAL DRUGS
Four species of plasmodia infect humans: Plasmodium vivax, Plasmodium falciparum, Plasmodium ovale and
Plasmodium malariae. The insect vector is the female Anopheles mosquito, which breeds in stagnant water, and the
disease it spreads is one of the major killers on our planet. Plasmodium falciparum is the most dangerous species,
causing an acute, rapidly fulminating disease characterized by persistent high fever, orthostatic hypotension and
massive erythrocytosis (swollen and reddish condition of the limbs). Plasmodium falciparum infection can lead to
capillary obstruction and death if treatment is not instituted promptly. Plasmodium vivax causes a milder form
of the disease. P. malariae is common to many tropical regions but Plasmodium ovale is rarely encountered.
Resistance acquired by the mosquito to insecticides, and by the parasite to drugs, has led to new therapeutic
challenges, particularly in the treatment of P. falciparum.
Classification
1.
4-aminoquinolines : Chloroquine , Amodiaquine
2.
8-aminoquinoline : Primaquine, Bulaquine
3.
Quinoline-methanol : Mefloquine
4.
Phenanthrene-methanol : Halofantrine
5.
Hydroxynepthquinone derivative : Atovaquone
6.
Acridine : Mepacrine, Quinacrine
7.
Biguanides : Progquanil (Chloroguanide)
8.
Diaminopyrimidines : Pyrimethamine
9.
Sulfonamides : Sulfadoxine, Sulfamethopyrazine, Dapsone
10. Cinchona alkaloids : Quinine
11. Sesquiterpine : Artimisnin, Artemether
12. Tetracyclines : Doxycycline
Some antimalarial agents, particularly chloroquine and hydroxychloroquine, are also used in the treatment of
rheumatoid arthritis and lupus associated arthritis.
Two types of antimalarial drugs are to be distinguished:
•
The kind one takes as prevention (called prophylactic drugs). This first one is taken as prevention and
requires continuous administration to reduce the risk of infection.
•
The second type, called therapy drugs are taken once the person is already infected.
Drugs used to treat the acute attack
Blood schizonticidal agents are used to treat the acute attack-they are also known as drugs that produce a
'suppressive' or 'clinical' cure. They act on the erythrocytic forms of the plasmodium. In infections with P.
falciparum or P. malariae, which have no exoerythrocytic stage, these drugs effect a cure; with P. vivax or P. ovale,
58
Page 59
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
the drugs suppress
s
the acctual attack, butt exoerythrocyytic forms can re-emerge
r
laterr to cause relappses.
This groupp of drugs inclludes quinolinee-methanols (ee.g. quinine annd mefloquinee), various 4-am
minoquinolinees (e.g.
chloroquin
ne ), the phen
nanthrene haloofantrine, andd agents that innterfere eitherr with the syntthesis of folatee (e.g.
sulfones) or with its action
a
(e.g. pyyrimethaminee
and progu
uanil), as welll as the hydrroxynaphthoquuinone
compound atovaquone. Compounds derived
d
from qinghaosu, for example
e
artem
mether have alsso proved effecctive.
Drugs thaat effect a radical cure
Tissue schizonticidal ageents effect a 'raadical' (in the sense of strikinng at the root of the infection) cure by actiing on
the parasittes in the liverr. Only the 8-aaminoquinolinees (e.g. primaq
quine and tafe
fenoquine) havve this action. These
drugs also destroy gamettocytes and thuus reduce the sppread of infectiion.
59
Page 60
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Chloroquine
1.
Damage mediated by accumulated heme: Chloroquine enters the red blood cells and interferes with a
unique enzyme polymerase that is essential to the survival of the parasites in the red blood cells. The
parasites digest the host cell's hemoglobin to get essential amino acids and iron. However, this process also
releases large amounts of soluble heme that is toxic to the parasites. To protect itself, the parasite
ordinarily polymerizes the heme to hemozoin (a pigment) that is sequestered in the parasite's food
vacuole. Chloroquine inhibits the polymerase and thus soluble heme kills the organism by inhibiting
proteinases in the food vacuole. Chloroquine also binds to ferriprotoporphyrin IX, which is formed from
the breakdown of hemoglobin in infected erythrocytes. The resulting complex damages the membranes and
leads to lysis of both the parasite and the red blood cell.
2.
Decreased DNA synthesis: The drug can also decrease DNA synthesis in the parasite by disrupting the
tertiary structure of the nucleic acid by forming chloroquine-DNA complex.
3.
Alkalinization of food vacuole: Chloroquine is taken up into the parasite's food vacuole by an active
transport system. Inside the acidic vacuole the drug, which is very basic, combines with a proton and is
trapped, resulting in alkalinization of this organelle. This causes an inability of the parasite to carry out
hemoglobin digestion.
The drug concentrates in erythrocytes, liver, spleen, kidney, lung, and melanin containing tissues as well as
leukocytes. Thus it has a very large volume of distribution.
•
Chloroquine is active against Entamoeba Histolytica, Giardia lamblia.
•
Chloroquine is weak local anesthetic, Smooth muscles relaxant, antihistaminic, antiarrythemic.
Adverse effect: Visual disturbance resulting in retinopathy (ethambutol), discoloration of nail beds and mucous
membrane, skin rashes i.e. highly dermatis with phenylbutazone and gold.
Amodiaquine similar to chloroquine but may cause agranulocytosis and hepatitis.
Mefloquine is used for treatment of the acute attack and chloroquine-resistant malaria. Transient CNS
toxicity-giddiness, confusion, dysphoria and insomnia-can occur, and there have been a few reports of aberrant
atrioventricular conduction, bradycardia and serious, but rare, skin diseases. Mefloquine is contraindicated in
pregnant women or in those liable to become pregnant within 3 months of stopping the drug, because of its long
half-life and uncertainty about its teratogenic potential. The drug can cause severe bradycardia with beta blockers,
calcium channel blockers and antidepressant drugs.
Mepacrine is also used for Giardia and tapeworms. It causes discoloration of skin, eyes and permanent
sterility.
60
Page 61
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Quinine is used to treat chloroquine resistant and multidrug resistant strains of P. Falciparum. Quinine is
also used to treat cerebral malaria, diagnostic of myasthenia gravis. Quinine is local anesthetic, bitter taste
stimulates gastric acid secretion, weak analgesic and antipyretic, decreases the Skelton muscles contractility,
lowers the blood sugar level and hence hypoglycemic, also increase the release of insulin from pancreas have
quinidine like effects on CVS. Quinine can cause black water fever and cinchonism.
Proguanil or Chloroguanide The antimalarial activity of proguanil eventually was ascribed to cycloguanil,
a cyclic triazine metabolite and selective inhibitor of the bifunctional plasmodial dihydrofolate reductasethymidylate synthetase. So similar mechanism of action as that of sulfadrugs like pyrimethamine. Proguanil can
cause transient loss of hair and hematuria. Drug is safe in pregnancy.
Pyrimethamine
inhibits
plasmodial
dihydrofolate
reductase enzyme
and
hence
DNA
synthesis.
Pyrimethamine is generally combined with sulfadoxine to increase the antimalarial efficacy. Pyrimethamine
with sulphadiazineis also effective against Toxoplasma gondii. (Clinadamycin)
Primaquine excerts its action on both pre-erythrocytic and gamtocytic stage. But is can cause heamolysis,
cyanosis, methemoglobinemia. Generally level of Glucose- 6-phosphate dehydrogenase is monitored. Passage of
dark urine means heamolysis and stop the drug.
Bulaquine similar to Primaquine but better tolerated in G-6-PD deficient patients.
Artimisnin active against all human malarial parasites and considered to be the most potent one and obtained
naturally. They are even active against quinine resistant strains. They are mainly used for acute attack and cerebral
malaria. They contain a endoperoxide bridge which interact with heme in parasite. The iron mediated
cleavage of the bridge release the highly reactive free radicals that binds to membrane proteins, causes lipid per
oxidation, damages to endoplasmic reticulum, inhibits protein synthesis and ultimately lysis of parasite. Artimisnin
derivates can cause abnormal bleeding, cardiac conduction defects. So they are generally avoided with other drugs
like terfenadine, astemizole, tricyclic antidepressant etc.
Halofantrine is a phenanthrene methanol but can cause severe ventricular tachycardia.
Atovaquone is nephthaquinone derivative. It mainly interferes with ATP production in the parasite. It is
also used in treatment of Toxoplasma gondii (Clinadamycin, Pyrimethamine)
•
Causal prophylaxis: pre-erythrocytic or exoerythrocytic phase is the main target for this purpose. So
generally Primaquine is given.
•
Suppressive prophylaxis: suppress the erythrocytic phase and thus attacks of malarial fever.
So it
includes chloroquine, Proguanil, Mefloquine (in India use of mefloquine for prophylaxis is not allowed
among residents but may be used by travelers.)
61
Page 62
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
•
CONTACT;sahadevparmar_22@yahoo.com
Clinical cure : focus on erythrocytic phase.
a) Fast acting high efficacy drugs : chloroquine, Mepacrine, quinine, mefloquine, halofantrine,
Artimisnin, Atovaquone
b) Slow acting low efficacy drugs: Proguanil, sulfonamides and Tetracyclines.
62
Page 63
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
CHEMOTHERAPY CHART
DRUGS
PENICILLINS
MECHANISM OF
ACTION
ADVERSE EFFECT
SOME FEATURES
Bactericidal, Cell
wall inhibition by
inhibition of
Transpeptidase,
Gram + ve are more
sensitive
Hypersensitivity reactions
mediated via Hapten
formation mainly due to
Penicilloyl moiety
Antibiotic derived from amino acid, all
derivatives of 6-aminopenicillic acid,
Inactivated by β-lactamases
Platelet dysfunction
Nephritis
Hepatitis
Enhanced activity for Pseudomonas
β-lactamases resistant
β-lactamases resistant
Acid resistant
β-lactamase inhibitors
Discoloration of bones
and teeth
Can form unabsorable salt with calcium,
antacids, treat rickettsiae (Rocky Mountain
spotted fever), chlamydiae
(Lymphogranuloma Venereum, brucellosis),
spirochetes (Lyme diseases), mycoplasmas
(Mycoplasma pneumonia), Treponema
pallidum (syphilis), Vibrio cholera, against
some protozoa, e.g. ameobas.
Carbenicillin
Methicillin
Oxacillin
Penicillin V
Clavulanic acid and
Sulbactum
TETRACYCLINES
Bacteriostatic,
Inhibition of amino
acyl t-RNA synthtase
Chlortetracycline
Demeclocycline
Minocycline
Doxycycline
SULFONAMIDES
Phototoxic
Vestibular toxicity
Hepatitis
Bacteriostatic, are
PABA analogue&
inhibit
dihydropteroate
synthetase resulting
in no Nucleic acid
synthesis
Kerniterus, Crystalluria,
Steven-Jonson syndrome,
Hemolytic anemia,
Displacement drug
interactions with drugs
that bind to albumin and
hence increase their free
plasma conc.
Avoid with Procaine (release PABA), Pus
cell
Ulcerative colitis due to 5-aminosalicylate
formed after intestinal m/o degradation
Pseudo sulfonamide, weak carbonic
anhydrase activity, mostly given in burns to
prevent infection
Silver ions are responsible for main
antibacterial activity & given in burns
Minimum tendency to cause Crystalluria
Co-Trimoxazole (Sulphamethoxazole +
Trimethoprim), Bactericidal
Antimalarial (Pyrimethamine +
Sulphamethoxazole)
Eye drops
Sulphasalazine
Mafenide
Silver Sulphadizine
Sulphaisoxazol
Sulphamethoxazole
Sulphadoxine
Sulphacetamide
AMINOGLYCOSIDES
Give green fluorescence
Can cause diabetes insipidus
No alteration of food with its absorption
No alteration of food with its absorption
Misreading in
mRNA, inhibition of
polysomes
Nephrotoxic, Ototoxic
and decrease in skeleton
muscle contractility or
curare like effect i.e.
neuromuscular blockage
Are polycationic in nature & hence given by
I.V route, Therapeutic monitoring,
inactivated by membrane bound enzymes
phosphorylase, adenylate etc.
63
Page 64
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
Netilimicin
Amikacin
CHLORAMPHENICOL
Inhibits Peptidyl
transferase
MACROLIDES
Bacteriostatic,
Inhibits translocation
i.e. transfer of newly
formed peptide chain
fro A site to P site of
the ribosomes
CONTACT;sahadevparmar_22@yahoo.com
Less Ototoxic
Preferred for long term use
Not a substrate for membrane bound
inactivating enzymes
Bone marrow depression
and Gray baby syndrome,
only reserve for life
threatening microbial
infections
Inactivated by acetyl transferase, treat
rickettsiae (Rocky Mountain spotted fever),
chlamydiae (Lymphogranuloma Venereum,
brucellosis), spirochetes (Lyme diseases),
mycoplasmas (Mycoplasma pneumonia),
Treponema pallidum (syphilis), Vibrio
cholera, against some protozoa, e.g.
ameobas.
Alternative to penicillins or the patient who
are hypersensitive to penicillins
Inactivated by gastric contents, estolate salt
improves its bioavailability, inhibits
cytochrome P 450 enzymes and hence raises
the level of terfenadine, astemizole etc
Acid stable
Better pharmacokinetic properties with
respect to absorption, M. aviumintracellulare or mycobacterium avium
complex (MAC) and also used in
tuberculosis and leprosy
Active against Helicobacter pyrroli (Peptic
ulcers), mycobacterium avium complex
(MAC)
Erythromycin
Roxithromycin
Azithromycin
Clarithromycin
FLUOROQUINOLONES
Inhibits DNA gyrase
so DNA replication
Damage to cartilages
First line of drugs to treat UTI, S.Typhi,
gonorrhea
Photoxicity
Can cause glucose impairment
Can serious cause QT prolongation
Glycopeptide
antibiotic, Inhibits
cell wall synthesis by
preventing the release
of D-Ala-D-Ala
dipeptide from park
nucleotide
Lincosamide
antibiotic, Inhibits
protein synthesis by
binding to 50 S
subunit
Oxazolididione
antibiotic, Inhibits
protein synthesis by
inhibiting the
formation of formylMethionine tRNA as
initiation complex
Inhibits cell wall
Nephrotoxic, Histamine
release, Redman
syndrome
Used to treat Methicillin resistant
S.Aureus(MRSA) Beta-lactamases
Sparfloxacin
Gatofloxacin
Moxifloxacin
OTHER ANTIBIOTICS
Vancomycin
Clinadamycin
Linezolid
Baciteracin
Clindamycin,erythromycin,Chloramphenicol
exhibit mutual antagonism as they have
almost same binding site, used to treat
toxoplasmosis in AIDS patients
Weak MAO inhibitor activity, used to treat
Vancomycin resistant S.aureus strains
64
Page 65
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
Polymyxin B and colistin
ANTITUBERCLOSIS
DRUGS
First line of drugs :
Rifampicin, ethambutol,
Pyrazinamide, Isoniazid,
streptomycin
Second line of drugs :
Ethionamide, ofloxacin,
clarithromycin,
Thioacetazone,
Cycloserine, PAS
Isoniazid
synthesis by
preventing the lipid
generation or carrier
lipid C55
Have surfactant like
action on membranes
which results in the
leakage of contents
of the cell
CONTACT;sahadevparmar_22@yahoo.com
Histamine release, kidney
damage, neuromuscular
blockage
Inhibits mycolic acid
synthesis
Neuritis (pyridoxine is
given), hepatitis
Rifampicin
RNA polymerase
inhibition
Hepatitis
Ethambutol
Inhibition of mycolic
acid
Inhibition of mycolic
acid
Retinopathy
Pyrazinamide
Cycloserine
ANTIFUNGAL DRUGS
Amphotericin B
5-Flucytosine
Ketoconazole
Inactivation involves acetylation at 4th
amino grp on the basis of genomics, fast
acetylators (1 hr), slow acetylators (3 hr),
inhibits the metabolism of other drugs,
absorption is effected by antacids, food
Drugs cause pigmentation of urine, tears,
saliva etc, it induce cytochrome P 450
metabolizing enzymes
Hyperuricemia
Pyrazinamide is inactive at neutral pH
but tuberculostatic at acid pH. It is
effective against the intracellular organisms
in macrophages because, after phagocytosis,
the organisms are contained in
phagolysosomes where the pH is low.
Nephrotoxic
Polyene antibiotic, amphipathic
characteristic
Inhibits Recemase
enzymes which
convert L-amino
acids to D-amino
acids.
Inhibits ergosterol
synthesis by spanning
the membrane and
forming the pore
through which leak
out of cellular
components occurs
Deamination
flucytosine to 5fluorouracil then
inhibition of
thymidylate
synthetase
Inhibits 14-α
desmethylase
neutropenia,
thrombocytopenia, and
occasional bone marrow
depression
Antiandrogenic
Absorption is fast and good in acidic
environment, it inhibits Cytochrome P 450
enzymes
65
Page 66
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
Topical azoles:
Clotrimazole,
Miconazole, Econazole
Systemic azoles :
fluconazole,
Ketoconazole,
Itraconazole and
Fluconazole
Griseofulvin
Terbinafine
ANTIMALARIAL
DRUGS
Chloroquine
CONTACT;sahadevparmar_22@yahoo.com
Inhibits microtubule
formation
Inhibits squalene
epoxidase
Inhibits the enzyme
polymerase which
converts heme to
hemozoin, inhibits
DNA synthesis by
incorporated in b / w
DNA strands, also
cause alkalization of
food vacuole or
inactivating the
lysozymes.
Deposited in keratinized tissues, can cause
intolerance with alcoholic patients
Visual disturbance
resulting in retinopathy
(ethambutol),
discoloration of nail beds
and mucous membrane,
skin rashes i.e. highly
dermatis with
phenylbutazone and gold.
Chloroquine is active against Entamoeba
Histolytica, Giardia lamblia, Chloroquine is
weak local anesthetic, Smooth muscles
relaxant, antihistaminic, antiarrythimic.
Mepacrine
Agranulocytosis and
hepatitis
Causes discoloration of
skin, eyes and permanent
sterility
Quinine
Quinine can cause black
Treat chloroquine resistant and multidrug
water
resistant strains of P. Falciparum. Quinine is
Amodiaquine
fever
and
cinchonism, Quinine is
also
local
anesthetic,
diagnostic of myasthenia gravis.
taste
stimulates gastric
acid
secretion,
bitter
used
to
treat
cerebral
malaria,
weak
analgesic and antipyretic,
decreases
the
muscles
Skelton
contractility,
lowers the blood sugar
level
and
hence
hypoglycemic,
also
increase the release of
insulin
have
from
pancreas
quinidine
like
effects on CVS.
Proguanil or
Chloroguanide
plasmodial
dihydrofolate
reductasethymidylate
Proguanil
can
cause
transient loss of hair and
hematuria
66
Page 67
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
synthetase
level
Primaquine
of
Glucose-
6-
phosphate dehydrogenase
Exerts its action on both pre-erythrocytic
and gamtocytic stage
is monitored
Artimisnin
Contain a
endoperoxide bridge
which interact with
heme in parasite. The
iron mediated
cleavage of the
bridge release the
highly reactive free
radicals that binds to
membrane proteins,
causes lipid per
oxidation, damages
to endoplasmic
reticulum, inhibits
protein synthesis and
ultimately lysis of
parasite
cause abnormal bleeding,
cardiac
conduction
defects
severe
Halofantrine
ventricular
tachycardia
ANTICANCER DRUGS
Alkylating Agents
The major site of
alkylation within
DNA is the N7
position of guanine
and forms cross links
Alopecia, bone marrow
depression, mucositis
a
Mechlorethamine
powerful
vesicant
(blistering agent)
Cyclophosphamide &
Ifosphamide
bone marrow depression,
Both Cyclophosphamide and Ifosfamide are
especially
first
leukocytosis,
biotransformed
to
4-hydroxylated
and hemorrhagic cystitis
intermediates by the cytochrome P-450
(Mensa is given), which
system
can lead to fibrosis of the
bladder
Lomustine and
Carmustine
depressive effect on the
Lipid-soluble and cross the blood-brain
bone marrow
barrier, they may be used against tumours of
the brain and meninges.
pulmonary fibrosis and
Busulfan
hyperuricemia
Dacarbazine
Methotrexate
and inhibits RNA and
protein synthesis
Myelotoxicity and severe
Inhibit dihydrofolate
reductase
Deplete
nausea and vomiting.
folate
pool
Immunosuppressant
for
auto
immune
67
Page 68
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
Azathioprine
Cytarabine
Vinca alkaloids
Paclitaxel
Etoposide
CONTACT;sahadevparmar_22@yahoo.com
Inhibits purine
synthesis
(folinic acid is given)
disorders
Hyperuricemia
Converted
to
active
metabolite
6-
dexamethasone
and
Mercaptopurine
inhibits DNA
polymerase
drugs bind to tubulin
and inhibit its
polymerisation into
microtubules,
preventing spindle
formation in dividing
cells and causing
arrest at metaphase
it promotes
polymerization of
microtubules
inhibits
Topoisomerase II
Vincristine
neuropathy.
can
cause
While
Vinblastine is a more
potent myelosuppressant.
Nausea and vomiting,
myelosuppression and
hair loss.
campothecins irinotecan
and topotecan
Doxorubicin and
Daunorubicin
ANTIVIRAL DRUGS
Amantidine, Rimantidine
are anti influenza
inhibit
topoisomerase I
Neuraminidase
Serious
inhibitors
inhibitors
and
of
viral
coat disassembly
hypersensitivity
premedicated
with
reactions, Bone marrow
diphenhydramine
suppression
blocker
and
as well as with an H2
cumulative neurotoxicity
also found.
Antiherpes virus :
Idoxuridine, Acyclovir,
Ganciclovir, Penciclovir,
Foscarnet, Vidarabine,
Trifluuridine
Inhibits
DNA
Zidovudine, Stavudine,
Lamivudine, Zalcitabine,
Didanosine
Reverse transcriptase
polymerase
generally
by
getting
triphosphorylated
inhibitors
68
Page 69
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
CH
HOLINE
ERGIC DRUG
Synthes
sis storage and destru
uction of Ac
ch :
Hemicholiinium: inhibitss the active upttake of cholinee from neuronaal cells.
Vesamicoll: inhibits the entry
e
of Ach innto the synapticc vesicles.
Botulinum
m toxin & β-bu
ungarotoxin: inhibits
i
Ach reelease from synnaptic vesicles.
Black widow spider tox
xin: cause masssive release of Ach from synaaptic vesicles.
Acetylcholline release by
y a nerve impuulse involves thhe entry of Caa2+ into the nerrve terminal; thhe increase in [Ca2+]
2
stimulates exocytosis and
d increases thee rate of quanttal release. Ageents that inhibit Ca2+ entryy include Mg2+
and
69
Page 70
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
various aminoglycoside antibiotics (e.g. streptomycin and neomycin which occasionally produce muscle
paralysis as an unwanted side effect when used clinically.
Two potent neurotoxins, namely botulinum toxin and β-bungarotoxin, act specifically to inhibit ACh release.
Botulinum toxin is a protein produced by the anaerobic bacillus Clostridium botulinum, an organism that can
multiply in preserved food and can cause botulism, an extremely serious type of food poisoning. The potency of
botulinum toxin is extraordinary, the minimum lethal dose in a mouse being less than 10-12g-only a few million
molecules. It belongs to the group of potent bacterial exotoxins that includes tetanus and diphtheria toxins. They
possess two subunits, one of which binds to a membrane receptor and is responsible for cellular specificity. By this
means, the toxin enters the cell, where the other subunit produces the toxic effect. Botulinum toxin
contains
several components (A-G). They are peptidases that cleave specific proteins involved in exocytosis thereby
producing a long-lasting block of synaptic function. Each toxin component inactivates a different functional proteina remarkably coordinated attack by a humble bacterium on a vital component of mammalian physiology.
Botulinum poisoning causes progressive parasympathetic and motor paralysis, with dry mouth, blurred vision and
difficulty in swallowing, followed by progressive respiratory paralysis. Treatment with antitoxin is effective only if
given before symptoms appear, for once the toxin is bound its action cannot be reversed. Mortality is high, and
recovery takes several weeks. Anticholinesterases and drugs that increase transmitter release are ineffective in
restoring transmission.
Botulinum toxin, injected locally into muscles, is used to treat a form of persistent and disabling eyelid spasm
(blepharospasm) as well as other types of local muscle spasm, for example in spasticity. Botox is also fashionable
as a wrinkle remover, removing frown lines by paralysing the superficial muscles that pucker the skin.
Injections must be repeated every few months to sustain the effect. For the same agent to figure as a beauty
treatment as well as a weapon of biological warfare reflects strangely on the modern world.
β-Bungarotoxin is a protein contained in the venom of various snakes of the cobra family, and has a similar
action to botulinum toxin , although its active component is a phospholipase rather than a peptidase. The same
venoms also contain α-bungarotoxin, which blocks postsynaptic ACh receptors, so these snakes evidently cover all
eventualities as far as causing paralysis of their victims is concerned.
Cholinesterases
There are two distinct types of cholinesterase, namely acetylcholinesterase and butyrylcholinesterase (BuChE),
closely related in molecular structure but differing in their distribution, substrate specificity and functions. Both
consist of globular catalytic subunits, which constitute the soluble forms found in plasma (BuChE) and
cerebrospinal fluid (AChE). Certain neuropeptides, such as substance P are inactivated by AChE, but it is not
known whether this is of physiological significance. Butyrylcholinesterase (or pseudocholinesterase) has a
widespread distribution, being found in tissues such as liver, skin, brain and gastrointestinal smooth muscle, as well
as in soluble form in the plasma. It is not particularly associated with cholinergic synapses, and its physiological
70
Page 71
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
function is unclear. It has a broader substrate specificity than AChE. It hydrolyses the synthetic substrate
butyrylcholine more rapidly than ACh, as well as other esters, such as procaine, succinylcholine and propanidid (a
short-acting anaesthetic agent).
Both AChE and BuChE belong to the class of serine hydrolases, which includes many proteases, such as trypsin.
The active site of AChE comprises two distinct regions: an anionic site (glutamate residue), which binds the
basic (choline) moiety of ACh; and an esteratic site (histidine + serine). As with other serine hydrolases, the
acidic (acetyl) group of the substrate is transferred to the serine hydroxyl group, leaving (transiently) an acetylated
enzyme molecule and a molecule of free choline. Spontaneous hydrolysis of the serine acetyl group occurs rapidly,
and the overall turnover number of AChE is extremely high.
Acetylcholine is very rapidly hydrolyzed by cholinesterase so large amounts must be infused intravenously to
achieve concentrations sufficient to produce detectable effects. Methacholine is more resistant to hydrolysis, and the
carbamic acid esters carbachol and bethanechol are still more resistant to hydrolysis by cholinesterase and
have correspondingly longer durations of action. The beta methyl group (methacholine, bethanechol) reduces
the potency of these drugs at nicotinic receptors.
Cholinoreceptors: are two types one is of muscarinic and other is nicotinic. Muscarinic receptors are Gprotein coupled receptors while nicotinic receptors are ligand gated cation channel.
Muscarinic
receptors
M1 ('Neural')
1. Gastric secretion
2. CNS excitation
Antaginist ­Pirenzepine
Agonist ­Oxotremorine
M2 ('Cardiac')
1. Cardiac contractility
decreases
2. Neural inhibition
3. Central muscarinic effects
(e.g. tremor, hypothermia)
Antaginist ­Gallamine.
Triptamine
Agonist ­Methacholine
M3 ('Glandular/ smooth
muscle')
1. Gastric,salivaryand
bronchosecretion
2. smooth muscle contraction
3. Ocular accommodation
4. Vasodilatation via NO
Antaginist ­Darifenacin
Agonist­ Bethanechol
Acetylcholine receptors
71
Page 72
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Main subdivision is into nicotinic (nAChR) and muscarinic (mAChR) subtypes. nAChRs are directly
coupled to cation channels, and mediate fast excitatory synaptic transmission at the neuromuscular junction,
autonomic ganglia, and various sites in the central nervous system (CNS). Muscle and neuronal nAChRs differ
in their molecular structure and pharmacology. mAChRs and nAChRs occur presynaptically as well as
postsynaptically, and function to regulate transmitter release. mAChRs are G-protein-coupled receptors
causing:
o
Activation of phospholipase C (hence formation of inositol trisphosphate and diacylglycerol
as second messengers)
o
Inhibition of adenylyl cyclase
o
Activation of potassium channels or inhibition of calcium channels.
mAChRs mediate acetylcholine effects at postganglionic parasympathetic synapses (mainly heart, smooth
muscle, glands), and contribute to ganglionic excitation. They occur in many parts of the CNS. Three main
types of mAChR occur.
M1 receptors ('neural') producing slow excitation of ganglia. M1 receptors are also involved in the increase
of gastric acid secretion following vagal stimulation. There selective agonist is Oxotremorine. They are
selectively blocked by pirenzepine. Muscarinic agonists that are able to penetrate the blood-brain barrier
produce marked central effects due to activation mainly of M1 receptors in the brain. These include tremor,
hypothermia and increased locomotor activity, as well as improved cognition. M1-selective agonists (e.g.
taclifensine) are being investigated for possible use in treating dementia
M2 receptors ('cardiac') causing decrease in cardiac rate and force of contraction (mainly of atria). They
exert inhibitory effects, mainly by increasing K+ conductance and by inhibiting calcium channels. There
selective agonist is Methacholine. They are selectively blocked by gallamine. M2 receptors also mediate
presynaptic inhibition.
M3 receptors ('glandular') produce mainly excitatory effects, i.e. stimulation of glandular secretions
(salivary, bronchial, sweat, etc.) and contraction of visceral smooth muscle. M3 receptors also mediate
relaxation of smooth muscle (mainly vascular), which results from the release of nitric oxide
from
neighboring endothelial cells. There selective agonist is Bethanechol. They are selectively blocked by
darifenacin.
Nicotinic receptors: are of two types one is one neuromuscular junction and other are on autonomic ganglia.
72
Page 73
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Direct-actting cholinomiimetic agents bind to and activate
a
muscaarinic or nicottinic receptorss. The direct-aacting
cholinomimetic drugs are
a on the basis of chemicaal structure in
nto esters of choline (inclu
uding acetylch
holine)
and alkaloids (such ass muscarine and
a
nicotine. Indirect-actiing agents prroduce their primary
p
effeccts by
inhibiting acetylcholineesterase, whiich hydrolyzees acetylcholin
ne to cholinee and acetic acid. By inhiibiting
acetylcholiinesterase, the indirect actingg drugs increasse the endogenoous acetylcholiine concentratiion in synapticc clefts
and neurooeffector juncttions. The exccess acetylchooline, in turn, stimulates chholinoceptors to evoke incrreased
responses. These drugs act primarily where acetylccholine is physsiologically reeleased and aree thus amplifiiers of
ne. Some cholinnesterase inhibbitors also inhiibit butyrylcholinesterase (psseudocholinesteerase).
endogenouus acetylcholin
However, inhibition of butyrylcholines
b
sterase plays liittle role in thee action of inddirect-acting chholinomimetic drugs
because thhis enzyme iss not importannt in the physiologic termiination of synnaptic acetylchholine action. Some
quaternaryy cholinesterase inhibitors allso have a moodest direct acction as well, eg. neostigmiine, which acttivates
neuromusccular nicotinic cholinoceptorss directly in addition to blockking cholinesterrase.
r
agoniists can be divvided into two groups: (1) ACh
A
and severral synthetic choline
c
Muscarinicc cholinergic receptor
esters, andd (2) the natturally occurriing cholinomiimetic alkaloiids (particularly pilocarpin
ne, muscarinee, and
arecoline) and their synth
hetic congenerrs.
73
Page 74
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Methacholine (acetyl-beta-methylcholine) differs from ACh chiefly in its greater duration and selectivity of action.
Its action is more prolonged because the added methyl group increases its resistance to hydrolysis by
cholinesterase. Its selectivity is manifested by slight nicotinic and a predominance of muscarinic actions and being
manifest in the cardiovascular system i.e. paroxysmal supraventricular tachycardia. Continuous intravenous
infusion of methacholine elicits hypotension and bradycardia.
Carbachol and bethanechol, which are unsubstituted carbamoyl esters, are completely resistant to hydrolysis by
cholinesterase; their half-lives are thus sufficiently long that they become distributed to areas of low blood flow.
Bethanechol has mainly muscarinic actions, showing some selectivity on gastrointestinal tract and urinary
bladder motility. So it is used in postoperative or postpartum nonobstructive urinary retention and
gateroesophageal reflux.
Muscarine acts almost exclusively at muscarinic receptor sites and the classification of the receptors as such is
derived from this fact. Arecoline also acts at nicotinic receptors. Muscarine, a quaternary ammonium compound,
shows more limited absorption. Muscarine and arecoline also are potent diaphoretic agents. Mushroom poisoning
symptoms of intoxication develop within 30 to 60 minutes of ingestion; they include salivation, lacrimation, nausea,
vomiting, headache, visual disturbances, abdominal colic, diarrhea, bronchospasm, bradycardia, hypotension, and
shock. Treatment with atropine effectively blocks these effects. Intoxication produced by A. muscaria and related
Amanita species arises from the neurologic and hallucinogenic properties of muscimol, ibotenic acid, and other
isoxazole derivatives. These agents stimulate excitatory and inhibitory amino acid receptors. Symptoms range from
irritability, restlessness, ataxia, hallucinations, and delirium to drowsiness and sedation. Treatment is mainly
supportive; benzodiazepines are indicated when excitation predominates, whereas atropine often exacerbates
the delirium.
Pilocarpine has a dominant muscarinic action, but it causes anomalous cardiovascular responses; the sweat
glands are particularly sensitive to the drug. Arecoline and pilocarpine are tertiary amines. Muscarinic agonists
mainly Pilocarpine cause contraction of the smooth muscle of the iris sphincter (resulting in miosis) and of the
ciliary muscle (resulting in accommodation). Both effects facilitate aqueous humor outflow into the canal of
Schlemm, which drains the anterior chamber results in fall of intraocular tension and so used for treatment of
glaucoma.
Asthmatic patients respond with intense bronchoconstriction, secretions, and a reduction in vital capacity due
to M3 receptor stimulation.
Oxotremorine is a synthetic compound which stimulates central muscarinic receptors and produces tremors
and other parkinsonian like extrapyramidal effects.
74
Page 75
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Anticholineesterases
Reversible
1.
Carbamates : Physostigmine (Eserine, tertiary amine), Neostigmine, Edrophonium (shortest acting),
Pyridostigmine, Rivastigmine, Donepezil
2.
Acridine : Tacrine
Irreversible
1.
Organophosphates (Never gas and insecticides) : Parathion, Malathion, Echothiophate, Dyflos, Tabun,
Sarin, Soman
2.
Carbamates : Carbaryl
Edrophonium has a brief duration of action because its quaternary structure facilitates renal elimination and it
binds reversibly to the AChE active center. Edrophonium, a quaternary drug whose activity is limited to peripheral
nervous system synapses, has a moderate affinity for AChE. So, Edrophonium mainly used as a diagnostic agent
for myasthenia gravis. Its volume of distribution is limited and renal elimination is rapid, accounting for its short
duration of action. By contrast, tacrine, galantamine, rivastigmine and donepezil have higher affinities for
AChE, are more hydrophobic, and readily cross the blood-brain barrier to inhibit AChE in the central
nervous system (CNS) and hence used in the treatment of Alzheimer’s diseases. Drugs that have a carbamoyl
ester linkage, such as physostigmine and neostigmine, are hydrolyzed by AChE, but much more slowly than is ACh.
The quaternary amine neostigmine and the tertiary amine physostigmine exist as cations at physiological pH.
Echothiophate, Edrophonium and tacrine will bind to the anionic site while remaining anticholinesterase bind
to the esteric site.
Because of their low volatility and stability in aqueous solution, parathion and methylparathion were widely used
as insecticides. These compounds are inactive in inhibiting AChE in vitro; paraoxon is the active metabolite. The
phosphoryl oxygen for sulfur substitution is carried out predominantly by hepatic CYPs. This reaction also occurs in
the insect, typically with more efficiency.
Organophosphate or anticholinesterase poisoning:
It Includes Lacrimation, salivation, sweating, bronchial secretion, urination, respiratory paralysis, cardiac
arrhythmia.
Treatment:
1.
Gastric lavage to prevent more absorption of insecticides
2.
Atropine:
75
Page 76
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
3.
CONTACT;sahadevparmar_22@yahoo.com
Cholinesterase reactivators: when organophosphate bind to esteric site of the cholinesterase than
phosphorylated CHE react very slowly or not at all with water. However, if more reactive OH grps of
oximes (R-CH= N-OH) are provided then reactivation occurs million times faster.
Pralidoxime (PAM) and obidoxime is antidote for organophosphates but it is ineffective as an antidote to
carbamate anti CHEs (Physostigmine, neostigmine, carbaryl) as in this case anionic site of enzyme is not free to
provide attachment to pralidoxime.
DAM (Diacetyl- monoxime) lacks quaternary N and is lipophilic. It combines with free organophosphates
molecule in body fluids rather than the bound to CHE.
Treatment of Glaucoma:
Ciliary body has receptors for
1.
α1 adrenoreceptors constrict ciliary vessels and reduce aqueous humor production
2.
α2 adrenoreceptors located on ciliary epithelium reduce aqueous humor secretion. Aqueous humour is
secreted slowly and continuously by the cells of the epithelium covering the ciliary body and it drains into
the canal of Schlemm.
76
Page 77
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
3.
CONTACT;sahadevparmar_22@yahoo.com
β adrenoreceptors located on ciliary epithelium enhance aqueous secretion via cAMP. Their blockage
reduces the secretion.
4.
Carbonic anhydrase present within ciliary epithelial cells generates HCO3- ion which is secreted into
aqueous humor.
DRUG USED:
A. Miotic: Pilocarpine 0.5 % cause contraction of the smooth muscle of the iris sphincter (resulting in miosis)
and of the ciliary muscle (resulting in accommodation). Both effects facilitate aqueous humor outflow into
the canal of Schlemm, which drains the anterior chamber resulting in lowering of intraocular tension. For
pilocarpine a long acting sustained delivery system ‘ocusert’ has been used and 4% gel formulation has
been introduced for once daily bed time. Physostigmine 0.1 % is only used to supplement to
pilocarpine. Potent and long acting miotics like ecothiophate and demecarium are hardly used because
they accelerate cataract development.
B. β2 adrenergic blockers : are first choice of drugs. They donot effect pupil size, tone of ciliary muscle
or outflow facility. They lower i.o.t by reducing aqueous formation. They down regulate adenylcyclase
in the ciliary muscles due to blockage of β2 receptor blockage. Significant systemic absorption of ocular
β2 can cause life threatening bronchoconstriction in asthmatics, bradycardia and heart block for
CHF patients.
•
Timolol: nonselective (β1 + β2 blocker)
•
Levobunolol: similar to Timolol but longer duration of action.
•
Betaxolol (β1 blocker) have less bronchopulmonary, less cardiac and metabolic side effects.
•
Cartiolol: β blocker with internsic sympathomimetic activity.
•
Metipranolol: have weak corneal anaesthetic property.
C. α adrenergic agonists includes
•
Adrenaline
•
Dipivefrine (prodrug of Adr, penetrates cornea and hydrolyzed by esterases present there into
Adr),
•
Apraclonidine and bromonidine (more α2 selective, analogue of clonidine and much more
lipophilic than apraclonidine)
D. Carbonic anhydrase inhibitors: Acetazolamide, Dolazolamide, Brinzolamide.
E. Prostagladins: mainly PGF2α derivative latanoprost.
Presently first choice of drug for treatment of glaucoma is beta blockers then second choice of drug is
bromonidine / latanoprost.
77
Page 78
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Myasthenia gravis:
•
Treatment is usually started with neostigmine and alternative is pyridostigmine.
•
Corticosteroids and immunosuppressant: Prednisolone, Azathioprine, cyclosporine
Cholinergic drugs with their clinical applications:
Preferred Miotic
Pilocarpine (0.5 %)
Systemic effects cause sweating,
bronchospasm, diarrhea
Treatment of Myasthenia gravis
Neostigmine
Alternative to neostigmine for
Pyridostigmine
myasthenia gravis
Diagnostic for myasthenia gravis due
Edrophonium
to short action
Belladonna poisoning
Physiostigmine
As it penetrates BBB and antagonize
both central and peripheral actions.
Alzheimer’s diseases
Tacrine, Donepezil, Galantamine,
Due to more penetration in brain
Rivastigmine
Overdoses of TCA, Phenothiazines and
Physostigmine
antihistaminics as they have additional
as it penetrates BBB and antagonize
both central and peripheral actions.
anticholinergic property.
Cobra bite which have curare like
Neostigmine + atropine
To prevent respiratory paralysis
neurotoxin
78
Page 79
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
MUSCARINIC ANTAGONISTS
Classification :
1. Natural alkaloids: Atropine and Hyoscine (scopolamine)
2. Semisynthetic derivatives: Homatropine, Ipratropium, Tiotropium
3. Synthetic compounds:
a.
Mydriatics: Cyclopentolate, Tropicamide
b. Antisecretory-antispasmodic:
i.
Quaternary compounds: Propantheline, Oxyphenonium, Clinidium, Glycoprrolate
ii.
Tertiary amines: Dicyclomine, Pirenzepine, Oxybutynin, Flevoxate
c. Antiparkinsonian: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden, Benztropine
Muscarinic receptor antagonists (parasympatholytic drugs) are competitive antagonists whose chemical
structures usually contain ester and basic groups in the same relationship as ACh, but they have a bulky
aromatic group in place of the acetyl group. The two naturally occurring compounds, atropine and scopolamine
, are alkaloids found in solanaceous plants. The deadly nightshade (Atropa belladonna) contains mainly atropine,
whereas the thorn apple (Datura stramonium) contains mainly scopolamine . These are tertiary ammonium
compounds that are sufficiently lipid-soluble to be readily absorbed from the gut or conjunctival sac and,
importantly, to penetrate the blood-brain barrier. The quaternary derivative of atropine, atropine methonitrate, has
peripheral actions very similar to those of atropine but, because of its exclusion from the brain, lacks central
actions. Ipratropium, another quaternary ammonium compound, is used by inhalation as a bronchodilator and
used in the treatment of COPD and asthma. Cyclopentolate and tropicamide are tertiary amines developed for
ophthalmic use and administered as eye drops. Pirenzepine is a relatively selective M1 receptor antagonist.
Oxybutynin , tolterodine and darifenacin (M3-selective) are new drugs that act on the bladder to inhibit
micturition, and are used for treating urinary incontinence. They produce unwanted effects typical of
muscarinic antagonists, such as dry mouth, constipation and blurred vision, but these are less severe than
with earlier drugs.
The main effects of atropine are as follow:
Main effects are inhibition of secretions; tachycardia, pupillary dilatation and paralysis of accommodation;
relaxation of smooth muscle (gut, bronchi, biliary tract, bladder); inhibition of gastric acid secretion (especially
pirenzepine); central nervous system effects (mainly excitatory with atropine; depressant, including amnesia, with
scopolamine ), including antiemetic effect and antiparkinsonian effect
Inhibition of secretions. Salivary, lacrimal, bronchial and sweat glands are inhibited by very low doses of
atropine, producing an uncomfortably dry mouth and skin. Gastric secretion is only slightly reduced. Mucociliary
clearance in the bronchi is inhibited, so that residual secretions tend to accumulate in the lungs. Ipratropium lacks
79
Page 80
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
this effect.
Effects on heart rate. Atropine causes tachycardia through block of cardiac mAChRs. The tachycardia is
modest, up to 80-90 beats/min in humans. Tachycardia is most pronounced in young people, in whom vagal tone at
rest is highest; it is often absent in the elderly.
Effects on the eye. The pupil is dilated (mydriasis) by atropine administration, and becomes unresponsive to
light. Relaxation of the ciliary muscle causes paralysis of accommodation (cycloplegia), so that near vision is
impaired. Intraocular pressure may rise; although this is unimportant in normal individuals, it can be dangerous in
patients suffering from narrow-angle glaucoma.
Effects on the gastrointestinal tract. Gastrointestinal motility is inhibited by atropine.
Effects on other smooth muscle. Bronchial, biliary and urinary tract smooth muscle are all relaxed by
atropine.
Reflex
bronchoconstriction
(e.g.
during
anaesthesia)
is
prevented
by
atropine,
whereas
bronchoconstriction caused by local mediators, such as histamine and leukotrienes (e.g. in asthma) is unaffected.
Effects on the CNS. Atropine produces mainly excitatory effects on the CNS. At low doses, this causes mild
restlessness; higher doses cause agitation and disorientation. In atropine poisoning, which occurs mainly in young
children who eat deadly nightshade berries, marked excitement and irritability result in hyperactivity and a
considerable rise in body temperature, which is accentuated by the loss of sweating? These central effects are the
result of blocking mAChRs in the brain, and they are opposed by anticholinesterase drugs such as
physostigmine, which is an effective antidote to atropine poisoning. Atropine is recemic while scopolamine is
levo isomer. The levo isomer is 100 times more potent than the dextro isomer. Scopolamine in low doses
causes marked sedation, but has similar effects in high dosage. Scopolamine also has a useful antiemetic effect
and is used in treating motion sickness.
Muscarinic antagonists also affect the extrapyramidal system, reducing the involuntary movement and
rigidity of patients with Parkinson's disease and counteracting the extrapyramidal side effects of many
antipsychotic drugs.
80
Page 81
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Anticholinergic drugs with their clinical applications:
•
Ipratropium and Tiotropium: mainly for COPD (chronic obstructive pulmonary diseases) and asthma
•
Propantheline and Oxyphenonium: For treatment of peptic ulcers
•
Glycoprrolate: potent and rapidly acting antimuscarinic agent lacking CNS effects. Mainly used for
preanesthetic medication and during anesthesia.
•
Hyoscine: As a lie detector and motion sickness.
•
Dicyclomine: Directly acting smooth muscle relaxant mainly exerts antispasmodic action.
•
Drotaverine: A novel non anticholinergic smooth muscle antispasmodic which acts by inhibiting PDE
4 selective for smooth muscles. Elevation of intracellular cAMP / cGMP attends smooth muscle
relaxation.
•
Oxybutynin somewhat selective for M3 receptors is used to relieve bladder spasm after urologic
surgery, eg, prostatectomy. It is also valuable in reducing involuntary voiding in patients with neurologic
disease, eg, children with meningomyelocele.
•
Darifenacin and solifenacin are recently approved antagonists that have greater selectivity for M3
receptors than oxybutynin or trospium. Their advantages include once daily dosing because of their long
half-lives and a reduced incidence of xerostomia and constipation. Tolterodine, another M3-selective
antimuscarinic, is available for use in adults with urinary incontinence.
•
Imipramine, a tricyclic antidepressant drug with strong antimuscarinic actions, has long been used to
reduce incontinence in institutionalized elderly patients. It is moderately effective but causes significant
central nervous system toxicity. Propiverine, a newer antimuscarinic agent, has been approved for this
purpose.
81
Page 82
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
GANGLION-BLOCKING DRUGS
These drugs mainly act by:
1.
By interference with ACh release, as at the neuromuscular junction. Botulinum toxin
and
hemicholinium work in this way.
2.
By prolonged depolarisation. Nicotine can block ganglia, after initial stimulation, in this way, as can
ACh itself if cholinesterase is inhibited so that it can exert a continuing action on the postsynaptic
membrane.
3.
By interference with the postsynaptic action of ACh. The few ganglion-blocking drugs of practical
importance act by blocking neuronal nAChRs (in large doses) or the associated ion channels.
Compounds with five or six carbon atoms (hexamethonium in the methylene chain linking the two quaternary
groups produced ganglionic block, whereas compounds with nine or ten carbon atoms (decamethonium)
produced neuromuscular block. Hexamethonium, Mecamylamine, pempidine, although no longer used,
deserves recognition as the first effective antihypertensive agent. The only ganglion-blocking drug currently in
clinical use is trimetaphan. It is a very short- acting drug that can be administered as an intravenous infusion for
certain types of anaesthetic procedure results in controlled hypotension, used to minimize bleeding during
certain kinds of surgery. Trimetaphan can also be used to lower blood pressure as an emergency procedure
as it is ultra short acting.
NEUROMUSCULAR‐BLOCKING DRUGS
Drugs can block neuromuscular transmission either by acting presynaptically to inhibit ACh synthesis or release,
or by acting postsynaptically, the latter being the site of action of all the clinically important drugs. Clinically,
neuromuscular block is used only as an adjunct to anaesthesia. The drugs that are used all work by interfering
with the postsynaptic action of ACh. They fall into two categories:
•
Non-depolarising blocking agents all act as competitive antagonists at the ACh receptors of the
endplate (and, in some cases, also by blocking ion channels)
•
Depolarising blocking agents, which are agonists at ACh receptors.
NON-DEPOLARISING BLOCKING AGENTS
'Curare' causes paralysis by blocking neuromuscular transmission, rather than by abolishing nerve conduction or
muscle contractility. Curare is a mixture of naturally occurring alkaloids found in various South American plants
and used as arrow poisons by South American Indians. The most important component is tubocurarine. The
most important are pancuronium, vecuronium and atracurium which differ mainly in their duration of action.
Gallamine was the first useful synthetic successor to tubocurarine, but has been replaced by compounds with fewer
side effects. These substances are all quaternary ammonium compounds, which means that they are poorly
82
Page 83
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
absorbed and generally rapidly excreted. They also fail to cross the placenta, which is important in relation to
their use in obstetric anaesthesia.
Mechanism of action
Non-depolarising blocking agents all act as competitive antagonists at the ACh receptors of the endplate. The
amount of ACh released by a nerve impulse normally exceeds by several-fold what is needed to elicit an action
potential in the muscle fibre. It is therefore necessary to block 70-80% of the receptor sites before transmission
actually fails. The effects of non-depolarising neuromuscular-blocking agents are mainly due to motor paralysis,
although some of the drugs also produce clinically significant autonomic effects. The first muscles to be affected
are the extrinsic eye muscles (causing double vision) and the small muscles of the face, limbs and pharynx (causing
difficulty in swallowing). Respiratory muscles are the last to be affected and the first to recover.
The main side effect of tubocurarine is a fall in arterial pressure, chiefly due to ganglion block. An additional
cause is the release of histamine from mast cells which can also give rise to bronchospasm in sensitive
individuals. This is unrelated to nAChRs but also occurs with atracurium and mivacurium. The other nondepolarising blocking drugs lack these side effects, and hence cause less hypotension. Gallamine, and to a lesser
extent pancuronium, block mAChRs, particularly in the heart, which results in tachycardia.
Most of the non-depolarising blocking agents are metabolised by the liver or excreted unchanged in the
urine, exceptions being atracurium (undergo Hofmann’s degradation), which hydrolyses spontaneously in
plasma, and mivacurium, which, like succinylcholine, is hydrolysed by plasma cholinesterase.
Pancuronium is vagolytic so can increase heart rate. Pancuronium, Vecuronium, rocuronium (longest
acting) are amino steroid.
DEPOLARISING BLOCKING AGENTS
Symmetrical bisquaternary ammonium compounds like decamethonium cause a maintained depolarisation at
the endplate region of the muscle fibre, which led to a loss of electrical excitability is called as depolarisation
block.
Decamethonium itself was used clinically but has the disadvantage of too long a duration of action.
Succinylcholine is closely related in structure to both decamethonium and ACh (consisting of two ACh molecules
linked by their acetyl groups). Its action is shorter than that of decamethonium, because it is quickly hydrolysed
by plasma cholinesterase. Succinylcholine and decamethonium act-like ACh-as agonists on the receptors of the
motor endplate. However, when given as drugs, they diffuse relatively slowly to the endplate and remain there for
long enough that the depolarisation causes loss of electrical excitability. ACh, in contrast, when released from the
nerve, reaches the endplate in very brief spurts and is rapidly hydrolysed in situ, so it never causes sufficiently
prolonged depolarisation to result in block. If cholinesterase is inhibited, however. it is possible for the circulating
83
Page 84
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ACh concentration to reach a level sufficient to cause depolarisation block.
Anticholinesterase drugs are very effective in overcoming the blocking action of competitive agents. This is
because the released ACh, protected from hydrolysis, can diffuse further within the synaptic cleft, and so gains
access to a wider area of postsynaptic membrane than it normally would. The chances of an ACh molecule finding
an unoccupied receptor before being hydrolysed are thus increased. In contrast, depolarisation block is unaffected,
or even increased, by anticholinesterase drugs.
Unwanted effects and dangers of depolarising drugs
Succinylcholine, the only drug of this type in clinical use, can produce a number of important adverse effects.
Bradycardia. This is preventable by atropine and is probably due to a direct muscarinic action.
Potassium release. The increase in cation permeability of the motor endplates causes a net loss of K+ from muscle,
and thus a small rise in plasma K+ concentration. In normal individuals, this is not important, but in cases of
trauma, especially burns or injuries causing muscle denervation, it may be. The resulting hyperkalaemia can be
enough to cause ventricular dysrhythmia or even cardiac arrest.
Increased intraocular pressure. This results from contracture of extraocular muscles applying pressure to the
eyeball. It is particularly important to avoid this if the eyeball has been injured.
Malignant hyperthermia. This is a rare inherited condition, due to a mutation of the Ca2+ release channel of the
sarcoplasmic reticulum (the ryanodine receptor which results in intense muscle spasm and a dramatic rise in
body temperature when certain drugs are given. The most commonly implicated drugs are succinylcholine and
halothane , although it can be precipitated by a variety of other drugs. It
is treated by administration of
2+
release from the sarcoplasmic
dantrolene, a drug that inhibits muscle contraction by preventing Ca
reticulum.
84
Page 85
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
AD
DRENER
RGIC SY
YSTEM
M
Noradrenaaline (norepinephrine), a transmitter released byy sympatheticc nerve term
minals, Adren
naline
(epinephriine) , a hormo
one secreted by the adrenal medulla
m
, Dopamine, the meetabolic precurrsor of noradreenaline
and adrenaline, also a transmitter/neuromodulator in the centraal nervous sysstem , Isoprooterenol (prevviously
isoprenaline), a synthetic derivative off noradrenalinee, not present inn the body.
Classificattion
85
Page 86
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
a.
CONTACT;sahadevparmar_22@yahoo.com
Nonselective (β1and β2) antagonist
™ Without intrinsic sympathomimetic activity: propranolol, Nadolol (long-acting antagonist),
Timolol and Penbutolol
9
With intrinsic sympathomimetic activity:
Pindolol, Acebutolol (in higher dose can stimulate the
release of NA)
™ With additional α locking activity : labetalol, Carvedilol
b.
Cardioselective (β1) : Nabivolol (also have vasodilating activity), metoprolol, atenolol, Acebutolol,
esmolol, betaxolol
c.
Selective β2 blocker : butoxamine
Direct-acting sympathomimetic drugs act directly on one or more of the adrenergic receptors. These agents may
exhibit considerable selectivity for a specific receptor subtype (e.g., phenylephrine for a1, terbutaline for b2) or may
have no or minimal selectivity and act on several receptor types (e.g., epinephrine for α1, α2, β1, β2, β3 receptors;
norepinephrine for α1, β2, β1 receptors).
Indirect-acting drugs increase the availability of norepinephrine or epinephrine to stimulate adrenergic
receptors. This can be accomplished in several ways:
(1) By releasing or displacing norepinephrine from sympathetic nerve varicosities e.g. amphetamine, tyramine,
dopamine
(2) By blocking the transport of norepinephrine into sympathetic neurons (e.g., cocaine); or
(3) By blocking the metabolizing enzymes, monoamine oxidase (MAO) (e.g., pargyline) or catechol-Omethyltransferase (COMT) (e.g., entacapone).
Mixed-acting sympathomimetic drugs that indirectly release norepinephrine and also directly activate
receptors (e.g., ephedrine, Mephentramine, dopamine).
α2-selective adrenergic receptor agonists
α2-Selective adrenergic agonists are used primarily for the treatment of systemic hypertension as many blood vessels
contain postsynaptic α2 adrenergic receptors that promote vasoconstriction. In addition, a2 agonists reduce
intraocular pressure by decreasing the production of aqueous humor. This action first was reported for
clonidine and suggested a potential role for a2 receptor agonists in the management of ocular hypertension and
glaucoma. Unfortunately, clonidine lowered systemic blood pressure even if applied topically to the eye. Two
derivatives of clonidine, apraclonidine and brimonidine, have been developed that retain the ability to
decrease intraocular pressure with little or no effect on systemic blood pressure.
86
Page 87
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
Type
Sympathomimetic
Drug
CONTACT;sahadevparmar_22@yahoo.com
Main action
NA
α/βAgonist
Epinephrine
α/βAgonist
Dobutamine
β1 Agonist (nonselective)
Salbutamol,
terbutaline
Selective β2 Agonist
Clenbuterol
β2 Agonist
Ritodrine,
isosuxpine
β2 Agonist
Phenylephrine
α1 Agonist
Methoxamine
αAgonist (nonselective)
α2 Partial agonist
(directly acting)
Clonidine
(imidazoline
derivative)
methyldopa,
guanfacine,
guanabenz
Sympathomimetic
(indirectly acting)
α2 Partial agonist
Uses/function
Not used clinically
Transmitter at
postganglionic sympathetic
neurons, and in CNS
Hormone of adrenal medulla
Asthma (emergency
treatment),
anaphylactic shock,
cardiac arrest,
Added to local
anaesthetic solutions,
glaucoma,
Main hormone of adrenal
medulla
Cardiogenic shock,
strokes-Adam syndrome
Asthma, premature labour
'Anabolic' action to
increase muscle
strength
Delay of parturition
(uterine relaxant),
Ritodrine and related
drugs can prolong
pregnancy.
Nasal decongestion
Nasal decongestion
Unwanted effects
Hypertension,
vasoconstriction,
tachycardia (or reflex
bradycardia), ventricular
dysrhythmias
As norepinephrine
Dysrhythmias
Tachycardia,
dysrhythmias, tremor,
peripheral vasodilatation
As salbutamol
As salbutamol
Hypertension, reflex
bradycardia
As phenylephrine
Hypertension, migraine,
minimize withdrawal
symptoms of opiates
and benzodiazepines
Hypertension
Drowsiness, orthostatic
hypotension, oedema and
weight gain, rebound
hypertension
Tyramine
NA release
No clinical uses
Present in various foods
As norepinephrine
Amphetamine
NA release,
MAO inhibitor, uptake
1 inhibitor, CNS
stimulant
Hypertension,
tachycardia, insomnia
Acute psychosis with
overdose
Dependence
Ephedrine
NA release, βagonist,
weak CNS stimulant
Used as CNS stimulant
in narcolepsy, also
(paradoxically) in
hyperactive children
Appetite suppressant
Drug of abuse (DOP
test), weak analgesic,
antiemetic, weak
anticonvulsant
Nasal decongestion,
prophylactic in
As amphetamine but less
pronounced
87
Page 88
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
Antagonists
Phenoxybenza
mine
Phentolamine
Prazosin
CONTACT;sahadevparmar_22@yahoo.com
αAntagonist (nonselective, irreversible)
Uptake 1 inhibitor
αAntagonist (nonselective), vasodilator
α1 Antagonist
Tamsulosin
α1 Antagonist
('uroselective')
Yohimbine
α2 Antagonist
Propranolol
Βeta Antagonist (nonselective)
Nebivolol
β1 Antagonist
Enhances nitric
oxide-mediated
transmission
β1 Antagonist
Metoprolol,
Atenolol
Labetalol
Carvedilol
treatment in chronic
asthma
Phaeochromocytoma
Rarely used
Hypotension, flushing,
tachycardia, nasal
congestion, impotence
As phenoxybenzamine
Hypertension
As phenoxybenzamine
Prostatic hyperplasia
(another drug is 5α
reductase inhibitor
finastride can be used}
Not used clinically
Claimed to be
aphrodisiac
Angina, hypertension,
cardiac dysrhythmias,
anxiety tremor, glaucoma,
migraine , hyperthyroidism,
myocardial infraction
Failure of ejaculation
Hypertension
Bronchoconstriction,
cardiac failure, cold
extremities, fatigue
and depression,
hypoglycaemia,
increase in LDL and
depletion of HDL
Fatigue, headache
Angina, hypertension,
dysrhythmias
As propranolol, less risk of
bronchoconstriction
Postural hypotension,
bronchoconstriction
α/βAntagonist
Hypertension in
pregnancy
Heart failure
Inhibits tyrosine
hydroxylase
Occasionally used in
phaeochromocytoma
False transmitter
precursor
Hypertension in pregnancy
Depletes NA
stores by
inhibiting
vesicular uptake
of NA
Inhibits NA release
Also causes NA
depletion and can
damage NA neurons
irreversibly
Blocks uptake 1
Also has atropinelike action
Local anaesthetic;
Hypertension (obsolete)
α/βAntagonist
(antioxidant)
Drugs affecting
NA synthesis
α-Methyl- ptyrosine
α-Methyl-dopa
Reserpine
Guanethidine
Drugs affecting
NA uptake
Imipramine
Cocaine
Excitement, hypertension
As for other β-blockers
Initial exacerbation of
heart failure
Renal failure
Hypotension, sedation
Hypotension, drowsiness,
diarrhoea, impotence,
hypersensitivity reactions
As methyldopa Also
depression, parkinsonism,
gynaecomastia
Hypertension (obsolete)
As methyldopa
Hypertension on first
administration
Depression
Atropine-like side effects
Cardiac dysrhythmias in
overdose
Rarely used local
Hypertension, excitement,
88
Page 89
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
blocks uptake 1 CNS
stimulant
anaesthetic
Major drug of abuse
convulsions, dependence
Anorectics (in obesity i.e. decrease apatite): Fenfluramine, Desfluramine
Biosynthesis of NA
The metabolic precursor for noradrenaline is L-tyrosine, an aromatic amino acid that is present in the body fluids,
and is taken up by adrenergic neurons.
1.
Tyrosine
hydroxylase,
a
cytosolic
enzyme
that
catalyses
the
conversion
of
tyrosine
to
dihydroxyphenylalanine (dopa) is found only in catecholamine-containing cells. It is a rather selective
enzyme; unlike other enzymes involved in catecholamine metabolism, it does not accept indole derivatives
as substrates, and so is not involved in 5-hydroxytryptamine (5-HT) metabolism. This first hydroxylation
step is the main control point for noradrenaline synthesis. The tyrosine analogue α-methyl
tyrosine strongly inhibits tyrosine hydroxylase and may be used experimentally to block
noradrenaline synthesis.
2.
Dopa decarboxylase converts of dopa to dopamine by decarboxylation, is catalysed by, a cytosolic enzyme
that is by no means confined to catecholamine-synthesising cells. Carbidopa , a hydrazine derivative of
89
Page 90
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
dopa, which inhibits dopa decarboxylase and is used in the treatment of Parkinsonism.
3.
Dopamine-β-hydroxylase (DBH) is also a relatively non-specific enzyme, but is restricted to
catecholamine-synthesising cells incorporates hydroxyl grp at β position in dopamine. It is located in
synaptic vesicles, mainly in membrane-bound form. A small amount of the enzyme is released from
adrenergic nerve terminals in company with noradrenaline, representing the small proportion in a soluble
form within the vesicle. Unlike noradrenaline, the released DBH is not subject to rapid degradation or
uptake, so its concentration in plasma and body fluids can be used as an index of overall sympathetic nerve
activity. Many drugs
inhibit DBH, including copper-chelating agents and
disulfiram. Such drugs can cause a partial depletion of noradrenaline stores and interference
with sympathetic transmission.
4.
Phenylethanolamine N-methyl transferase (PNMT) catalyses the N-methylation of noradrenaline to
adrenaline.
Transmitter storage, release and uptake: noradrenaline is stored at high concentration in
synaptic vesicles, together with ATP, and DBH, all of which are released by exocytosis. Transport of
noradrenaline into vesicles occurs by a reserpine -sensitive transporter. Reserpine also
inhibits the transport of dopamine and 5 HT to synaptic vesicles. Noradrenaline content of cytosol is normally low
due to monoamine oxidase in nerve terminals. Transmitter release occurs normally by Ca2+-mediated exocytosis
from varicosities on the terminal network. Non-exocytotic release occurs in response to
indirectly acting sympathomimetic drugs (e.g. amphetamine), which displace
noradrenaline from vesicles. Noradrenaline escapes via uptake 1 (reverse transport). Transmitter action is
terminated mainly by transporter-mediated reuptake of noradrenaline into nerve terminals (uptake 1). Uptake 1
is blocked by tricyclic antidepressant drugs and cocaine. Noradrenaline release is controlled
by autoinhibitory feedback mediated by α2 receptors.
DRUGS THAT AFFECT NORADRENALINE SYNTHESIS
Methyldopa used in the treatment of hypertension during pregnancy is taken up by noradrenergic neurons, where it
is converted to the false transmitter α-Methylnoradrenaline. This substance is not deaminated within
the neuron by MAO, so it accumulates and displaces noradrenaline from the synaptic vesicles. αMethylnoradrenaline is released in the same way as noradrenaline, but is less active than noradrenaline on α1receptors and thus is less effective in causing vasoconstriction. On the other hand, it is more active on presynaptic
(α2) receptors, so the autoinhibitory feedback mechanism operates more strongly than normal, thus reducing
transmitter release below the normal levels.
90
Page 91
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Tyramine (indirectly acting) These drugs have only weak actions on adrenoceptors, but sufficiently resemble
noradrenaline to be transported into nerve terminals by uptake 1. They are taken up into the vesicles by the
vesicular monoamine transporter, in exchange for noradrenaline, which escapes into the cytosol. Some of the
cytosolic noradrenaline is degraded by MAO, while the rest escapes via uptake 1, in exchange for the foreign
monoamine, to act on postsynaptic receptors. Exocytosis is not involved in the release process, so their actions do
not require the presence of Ca2+. They are not completely specific in their actions, and act partly by a direct effect
on adrenoceptors, partly by inhibiting uptake 1 (thereby enhancing the effect of the released noradrenaline), and
partly by inhibiting MAO.
Phenylethylamines normally are synthesized in the GI tract as a result of the action of bacterial tyrosine
decarboxylase. The tyramine formed in this fashion usually is oxidatively deaminated in the GI tract and the liver,
and the amine does not reach the systemic circulation in significant concentrations. However, when an MAO
inhibitor is administered, tyramine may be absorbed systemically and transported into sympathetic nerve
terminals, where its catabolism again is prevented because of the inhibition of MAO at this site; the tyramine then is
beta-hydroxylated to octopamine and stored in the vesicles in this form. As a consequence, norepinephrine gradually
is displaced, and stimulation of the nerve terminal results in the release of a relatively small amount of
norepinephrine along with a fraction of octopamine. Patients who have received MAO inhibitors may experience
severe hypertensive crises if they ingest cheese, beer, or red wine. These and related foods, which are produced by
fermentation, contain a large quantity of tyramine, and to a lesser degree, other phenylethylamines. When
gastrointestinal and hepatic MAO are inhibited, the large quantity of tyramine that is ingested is absorbed rapidly
and reaches the systemic circulation in high concentration. A massive and precipitous release of norepinephrine can
result, with consequent hypertension that can be severe enough to cause myocardial infarction or a stroke. This
overall effect is called as cheese reaction.
6-Hydroxydopamine (identical with dopamine except that it possesses an extra ring hydroxyl group) is a
neurotoxin of the Trojan horse kind. It is taken up selectively by noradrenergic nerve terminals, where it is
converted to a reactive quinone, which destroys the nerve terminal, producing a 'chemical sympathectomy'.
MPTP (1-methyl-4-phenyl-1,2,3,5-tetrahydropyridine is a rather similar selective neurotoxin.
Metabolic degradation of catecholamines
Endogenous and exogenous catecholamines are metabolised mainly by two enzymes: monoamine oxidase (MAO)
and catechol-O-methyl transferase (COMT). MAO occurs within cells, bound to the surface membrane of
mitochondria. It is abundant in noradrenergic nerve terminals but is also present in many other places, such as liver
91
Page 92
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
and intestinal epithelium. MAO converts catecholamines to their corresponding aldehydes, which, in the
periphery, are rapidly metabolised by aldehyde dehydrogenase to the corresponding carboxylic acid (3,4dihydroxyphenylglycol being formed from noradrenaline. MAO A predominately acts on 5 HT substrate while
MAO B substrate are dopamine and other catecholamines i.e. NA etc. Within sympathetic neurons, MAO
controls the content of dopamine and noradrenaline, and the releasable store of noradrenaline increases if the
enzyme is inhibited.
Catechol-O-methyl transferase (COMT) metabolism involves methylation of one of the catechol hydroxyl
groups to give an o-methoxy derivative. Amphetamine, ephedrine and mephentramine are not substrate for
COMT as they does not have OH grps.
SAR OF CATECHOLAMINES (β-PHENYLETHANOLAMINES)
A.
SUBSTITUTION ON THE AMINO GROUP
Increasing the size of alkyl substituent’s on the amino group tends to increase β-receptor activity e.g. Isopropyl
substitution at the amino nitrogen (isoproterenol). Beta2-selective agonists generally require a large amino
substituent group. Norepinephrine has, no β2 activity; this activity is greatly increased in epinephrine by the addition
of a methyl group. A notable exception is phenylephrine, which has an N-methyl substituent but is α-selective
agonist.
B. SUBSTITUTION ON THE BENZENE RING
Maximal αand βactivity is found with catecholamines (drugs having –OH groups at the 3 and 4 positions).
1.
The absence of one or the other of these groups, particularly the hydroxyl at C3, without other
substitutions on the ring may dramatically reduce the potency of the drugs. For example,
phenylephrine is much less potent than epinephrine; indeed, α-receptor affinity is decreased about 100-fold
and βactivity is almost negligible except at very high concentrations.
2.
Catecholamines are subject to inactivation by catechol-O-methyltransferase (COMT), an enzyme
found in gut and liver. Therefore, absence of one or both –OH groups on the phenyl ring increases
the bioavailability after oral administration and prolongs the duration of action.
3.
Absence of ring –OH groups tends to increase the distribution of the molecule to the central nervous
system. For example, ephedrine and amphetamine are orally active, have a prolonged duration of action,
and produce central nervous system effects not typically observed with the catecholamines.
4.
Hydroxyl groups in positions 3 and 5 confer β2 receptor selectivity on compounds with large amino
substituents. Thus, metaproterenol, terbutaline, and other similar compounds relax the bronchial
musculature in patients with asthma, but cause less direct cardiac stimulation than do the nonselective
drugs.
92
Page 93
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
C. SUBSTITUTION ON THE ALPHA CARBON
9
Substitutions at the carbon block oxidation by monoamine oxidase (MAO) and prolong the action of
such drugs, particularly the noncatecholamines. Ephedrine and amphetamine are examples of αsubstituted compounds. Alpha-methyl compounds are also called phenylisopropylamines.
9
In addition to their resistance to oxidation by MAO, some phenylisopropylamines have an enhanced
ability to displace catecholamines from storage sites in noradrenergic nerves. Therefore, a portion of
their activity is dependent on the presence of normal norepinephrine stores in the body; they are indirectly
acting sympathomimetics.
Mixed-action adrenergic agonists (ephedrine,
metaraminol)
they not only releases stored
norepinephrine from nerve endings (indirectly acting) but also directly stimulate both α and β receptors. The
indirectly acting adnergic agonistic itself does not have any effects on α and β receptors. Ephedrine is not a
catechol and is a poor substrate for COMT and MAO. Ephedrine produces bronchodilation, but it is less potent
than epinephrine or isoproterenol in this regard and produces its action more slowly. It is therefore some- times
used prophylactically in chronic treatment of asthma to pre vent attacks, rather than to treat the acute
attack. Ephedrine enhances contractility and improves motor function in myasthenia gravis, particularly
when used in conjunction with anticholinesterases. Ephedrine produces a mild stimulation of the CNS. This
93
Page 94
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
increases alertness, decreases fatigue, and prevents sleep. It also improves athletic performance. Ephedrine has been
used to treat asthma, as a nasal decongestant (due to its local vasoconstrictor action), and to raise blood pressure.
Metaraminol is other mixed-action adrenergic agonists; this agent has been used in the treatment of shock (when
an infusion of norepinephrine or dopamine is not possible) and to treat acute hypotension. It is given
parenterally as a single injection. It enhances cardiac activity and produces mild vasoconstriction.
94
Page 95
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ADRENERGIC DRUGS
1.
Epinephrine
Epinephrine interacts with both α and β receptors. At low doses, β effects (vasodilation) on the vascular system
predominate, whereas at high doses, α effect (vasoconstrictor) is strongest.
Cardiovascular: Epinephrine strengthens the contractility of the myocardium (positive inotropic) and increases its
rate of contraction. Cardiac output therefore increases. With these effects come increased oxygen demands on the
myocardium. Epinephrine constricts arterioles in the skin, mucous membranes, and viscera (α effect) and dilates
vessels going to the liver and skeletal muscle (β effects). Renal blood flow is decreased.
Respiratory: Epinephrine causes powerful bronchodilation by acting directly on bronchial smooth muscle (β
action). This action relieves all known allergic or histamine-induced bronchoconstriction. In the case of
anaphylactic shock, this can be life-saving. In individuals suffering from an acute asthmatic attack,
epinephrine rapidly relieves the dyspnea (labored breathing) and increases the tidal volume (volume of gases
inspired and expired).
Hyperglycemia: Epinephrine has a significant hyperglycemic effect because of increased glycogenolysis in liver
(β2), increased release of glucagon (β effect), and a decreased release of insulin (α2 effect). These effects are
mediated via the cyclic AMP mechanism.
Lipolysis: Epinephrine initiates lipolysis through its agonist activity on the β receptors of adipose tissue, which
upon stimulation; activate adenylyl cyclase to increase cyclic AMP levels. Cyclic AMP stimulates a hormonesensitive lipase, which hydrolyzes triacylglycerol to free fatty acids and glycerol.
Interactions
a. Hyperthyroidism: Epinephrine may have enhanced cardiovascular actions in patients with hyperthyroidism. If
epinephrine is required in such an individual, the dose must be reduced. The mechanism appears to involve
increased production of adrenergic receptors on the vasculature of the hyperthyroid individual leading to a
hypersensitive response.
b. Cocaine: In the presence of cocaine, epinephrine produces exaggerated cardiovascular actions. This is due to the
ability of cocaine to prevent re-uptake of catecholamines into the adrenergic neuron; thus, like norepinephrine,
epinephrine remains at the receptor site for longer periods of time
95
Page 96
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
2.
CONTACT;sahadevparmar_22@yahoo.com
Metaproterenol is not a catecholamine and is resistant to methylation by COMT. It can be administered
orally or by inhalation. The drug acts primarily at β2 receptors, producing little effect on the heart.
Metaproterenol produces dilation of the bronchioles and improves airway function. The drug is
useful as a bronchodilator in the treatment of asthma and to reverse bronchospasm
3.
Methoxamine Because of its effects on the vagus, methoxamine is used clinically to relieve attacks of
paroxysmal supraventricular tachycardia. It is also used to overcome hypotension during surgery
involving halothane anesthetics. In contrast to most other adrenergic drugs, methoxamine does not
tend to trigger cardiac arrhythmias in the heart that is sensitized by these general anesthetics.
Adverse effects include hypertensive headache and vomiting.
4.
Dopamine can activate α- and β-adrenergic receptors. For example, at higher doses it can cause
vasoconstriction by activating receptors, whereas at lower doses, it stimulates β1 cardiac receptors. In
addition, D1 and D2 dopaminergic receptors, distinct from α and β adrenergic receptors occur in the
peripheral mesenteric and renal vascular beds, where binding of dopamine produces vasodilatation. D2
receptors are also found on presynaptic adrenergic neurons, where their activation interferes with
norepinephrine release.
5.
Dobutamine (β1 agonist) is used to increase cardiac output in congestive heart failure. Dobutamine has
relatively more prominent inotropic than chronotropic effects on the heart compared to isoproterenol. The
drug increases cardiac output with little change in the heart rate and does not significantly elevate oxygen
demands of the myocardium--a major advantage over other sympathomimetic drugs. The (-) isomer
of dobutamine is a potent agonist at α1 receptors and is capable of causing marked pressor responses.
In contrast. The (+) isomer is a more potent β receptor agonist than the (-) isomer (approximately
tenfold). Both isomers appear to be full agonists.
6.
Salmeterol (β2) also have anti-inflammatory activity. It provides symptomatic relief and improves lung
function and quality of life in patients with COPD; in this setting, it is as effective as the cholinergic
antagonist ipratropium and more effective than oral theophylline.
7.
Midodrine (α1) is a prodrug; its activity is due to its conversion to an active metabolite,
desglymidodrine, raises blood pressure that is associated with both arterial and venous smooth muscle
contraction.
8.
96
Page 97
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ADRENERGIC ANTAGONISTS
Propranolol or Adverse effect of nonselective beta blocker
The principal toxicities of propranolol result from blockade of cardiac, vascular, or bronchial β receptors. The most
important of these predictable extensions of the β-blocking action occur in patients with bradycardia or cardiac
conduction disease, asthma, peripheral vascular insufficiency, and diabetes.
a.
Bronchoconstriction: Propranolol has a serious and potentially lethal side effect when administered to an
asthmatic. An immediate contraction of the bronchiolar smooth muscle prevents air from entering the
lungs. Deaths by asphyxiation have been reported for asthmatics who were inadvertently administered the
drug. Therefore, propranolol must never be used in treating any individual with obstructive pulmonary
disease.
b.
Arrhythmias: Treatment with the β-blockers must never be stopped quickly because of the risk of
precipitating cardiac arrhythmias, which may be severe. The β-blockers must be tapered off gradually for 1
week. Long-term treatment with a antagonist leads to up-regulation of the β-receptor. On suspension of
therapy, the increased receptors can worsen angina or hypertension.
c.
Disturbances in metabolism: The β-blockers may disturb lipid metabolism, decreasing high-density
lipoproteins (HDL) and increasing plasma triacylglycerol. β-Blockade leads to decreased glycogenolysis
and decreased glucagon secretion. Fasting hypoglycemia may occur. So, Cardioselective β-blockers are
preferred in treating insulin-dependent asthmatics.
97
Page 98
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Esmolol administered intravenously and is used when beta blockade of short duration is desired or in critically ill
patients in whom adverse effects of bradycardia, heart failure or hypotension may necessitate rapid withdrawal of
the drug. Esmolol has a half-life of about 8 minutes. The drug contains an ester linkage, and it is hydrolyzed
rapidly by esterases in erythrocytes.
Adrenergic drugs:
Adrenoceptors agonists
•
Noradrenaline and adrenaline show relatively little receptor selectivity.
•
Selective α1 agonists include phenylephrine and oxymetazoline.
•
Selective α2 agonists include clonidine and α-methylnoradrenaline. They cause a fall in blood
pressure, partly by inhibition of noradrenaline release and partly by a central action.
Methylnoradrenaline is formed as a false transmitter from methyldopa
, developed as a
Hypotensive drug (now largely obsolete).
•
Selective β1 agonists include dobutamine. Increased cardiac contractility may be useful
clinically, but all β1 agonists can cause cardiac dysrhythmias.
•
Selective β2 agonists include Salbutamol, terbutaline and Salmeterol, used mainly for their
bronchodilator action in asthma.
•
Selective β3 agonists may be developed for the control of obesity.
Classification of adrenergic drugs:
1.
Pressor agents: NA, Ephedrine, Phenylephrine, Methoxamine, Mephentermine
2.
Cardiac stimulants: Dobutamine, Adrenaline, Isoprenaline
3.
Bronchodilators: Salbutamol (Albuterol), Salmeterol, Terbutaline, Isoprenaline, Adrenaline
4.
Nasal decongestant: Phenylephrine, Pseudoephedrine, Phenylpropanolamine, Naphthazoline,
Xylometazoline, oxymetazoline
5.
CNS stimulants: Amphetamine, Dexamphetamine, Methamphetamine
6.
Anorectics (Suppress apatite): Fenfluramine, Dexfenfluramine
7.
Anti obesity: Sibutramine
8.
Uterine smooth muscle relaxant to delay the premature labour: Ritodrine, Isosuxpine,
Salbutamol, terbutaline
1.
Dopamine:
98
Page 99
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
•
CONTACT;sahadevparmar_22@yahoo.com
At low doses D1 stimulation causes renal and mesenteric blood vessels dilation and thus
increasing GFR.
•
At high doses Ionotopic effect (β1 stimulation)
•
Large doses vasoconstriction (α1 stimulation)
Dopamine is used for the patients of cardiogenic or septic shock and severe CHF as due to its
Ionotopic and increased urine flow activity.
2.
Dobutamine: lacks D1 & D2 agnostic activity but have effect on α &β1 receptors.
3.
Ephedrine: mixed acting, repeated injections produce tachyphylaxis primarily because of displacement of
NA from neuronal pool. It is resistant to MAO and COMT. Mainly used as prophylactic in asthma. Its
analogue pseudoephedrine which is L-stereoisomer of ephedrine has poor β2 agonistic activity, so
used as nasal decongestant. Ephedrine is also used to prevent hypotension during spinal anesthesia
and surgical procedures.
4.
Mephentermine: is mixed acting have both cardiac stimulation and vasoconstriction by direct acting on α
& β, also cause displacement of NA. Mephentermine is not a substrate of MAO & COMT. It is used to treat
hypotension due to spinal anesthesia and surgical procedures.
5.
Amphetamine: increases the mental alertness, athletic performance, so it is drug comes under dope
test for athletes, suppress hunger. Amphetamines are the drug of abuse. To treat the toxicity of
amphetamine, chlorpromazine is given which controls both central and peripheral α adrenergic effects.
Central actions of amphetamine are mediated by release of NA in brain. However, certain actions are
probably due to DA and 5-HT release. It also inhibits neuronal uptake of DA so also found useful in
parkinsonian to reduce rigidity but not tremors. Amphetamine is weak analgesic, antiemetic, weak
anticonvulsant
6.
Phenylephrine: it is selective α1 agonist with minimum β activity. it raises BP by causing
vasoconstriction. Orally it is used as nasal decongestant. It is also used in glaucoma to reduce the
intraocular tension by constricting the ciliary body blood vessels.
7.
Methoxamine: selective α1 agonist with no β actions.
99
Page 100
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
8.
CONTACT;sahadevparmar_22@yahoo.com
Anorectics: They mainly act on feeding center but have little or no CNS stimulant action. All of them act
by inhibiting the reuptake of NA /DA or 5-HT enhancing monoaminergic transmission in the brain. They
can be
•
Noradrenergic agents: Phenteramine, Phenylpropanolamine
•
Serotonergic agents: Fenfluramine, Dexfenfluramine
•
Noradrenergic / Serotonergic agents: Sibutramine
Therapeutic uses of adrenergic drugs:
A. Anaphylactic shock due to allergic disorder like histamine release: Adrenaline
Cardiac uses:
B. Cardiac arrest: Adrenaline
C. Stokes-Adams syndrome: Adrenaline or Isoprenaline (a synthetic derivative of noradrenaline, not present
in the body)
D. CHF: Dobutamine / DA
E. Hypotensive shock: Dobutamine alternative ephedrine
F. Along with local anasethetics: Adr. In 1: 100,000 to prolong the duration of action of local anasethetics
and to minimize the systemic toxicity of local anaesthetics.
G. Nasal decongestant: Phenylephrine, Pseudoephedrine, Phenylpropanolamine
H. Bronchial asthma: Salbutamol, Terbutaline, Salmeterol
I.
Mydriatic: Phenylephrine
Central uses:
J.
Narcolepsy(is sleep occurring in fits): Amphetamine
K. Epilepsy: Amphetamines are occasionally used as adjuvant to counteract sedation caused by antiepileptics.
L. Parkinsonian: Amphetamine to inhibit DA reuptake. It mainly reduces the rigidity but not tremors.
M. Hyperkinetic children: are recognized by mental retardation or reduction in ability to concentrate.
Amphetamine is used.
N. Uterine relaxant: Selective β2 stimulants like Ritodrine, Isosuxpine
O. Antiobesity: Sibutramine
Orlistat: Inhibits gastric and pancreatic lipase, so interferes with digestion and absorption of dietary TGs.
Olestra: Sucrose polyester which can be used as cooking medium in place of fat but it is neither digested nor
absorbed.
Other drugs for future are Leptin: is slimming peptide and β3 agonist.
100
Page 101
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Antiadrenergic drugs:
Classification of α blockers:
Non equilibrium type: β- Haloalkylamines i.e. Phenoxybenzamine
I.
II.
Equilibrium type (Competitive):
A. Nonselective α blockers
1.
Ergot alkaloids: Ergotamine, Ergotoxine
2.
Hydrogenated ergot alkaloids: Dihydroergotamine and Dihydroergotoxine
3.
Imidazolines: Tolazoline, Phentolamine
4.
Miscellaneous: Chlorpromazine, Ketanaserin
B. α1 selective antagonist: Prazocin, Terazocin, Doxazosin, Tamsulosin
C. α2 selective antagonist: Yohimbine, Idazoxan
Clinical uses of α-adrenoceptor antagonists
•
Severe hypertension: α1-selective antagonists (e.g. doxazosin due to longest acting) in combination with
other drugs.
•
Benign prostatic hypertrophy i.e. increases in prostate size causes urinary obstruction (e.g. tamsulosin, a
selective α1A-receptor antagonist, Prazocin and 5α reductase inhibitor- Finastride).
•
Phaeochromocytoma: Phenoxybenzamine (irreversible antagonist) in preparation for surgery.
•
Phenoxybenzamine and Phentolamine are great value in controlling episodes of rise in BP during
clonidine withdrawal and cheese reactions in patients with MAO inhibitors.
•
Drugs that block α1 and α2 adrenoceptors (e.g. Phenoxybenzamine and Phentolamine) were once used to
produce vasodilatation in the treatment of peripheral vascular disease, but this use is now largely obsolete.
•
Selective α1 antagonists (e.g. prazosin, doxazosin, terazosin) are used in treating hypertension. Postural
hypotension and impotence are unwanted effects.
•
Ergotamine is one of the most effective drug to abort / terminate moderate to severe migraine
attacks.
•
Yohimbine, probably by virtue of its vasodilator effect, historically enjoyed notoriety as an aphrodisiac,
but they are not used therapeutically. Now a day’s sildenafile which is a PDE 5 inhibitor is used.
•
Some drugs (e.g. labetolol, carvedilol ) block both α and β adrenoceptors and used in hypertension.
101
Page 102
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Phaeochromocytoma is a catecholamine-secreting tumour of chromaffin tissue, which causes episodes of severe
hypertension. A combination of α- and β-receptor antagonists is the most effective way of controlling the blood
pressure. The tumour may be surgically removable, and it is essential to block α- and β- receptors before surgery is
begun, to avoid the effects of a sudden release of catecholamines when the tumour is disturbed. A combination of
phenoxybenzamine and atenolol is effective for this purpose.
Phenoxybenzamine is not specific for α-receptors, and also antagonises the actions of acetylcholine, histamine and
5-HT. It is long-lasting because it binds covalently to the receptor. It cyclize spontaneously to ethyliniminium
intermediate which reacts with alpha receptors and forming a covalent bond. Phentolamine is more selective,
but it binds reversibly and its action is short-lasting. In humans, these drugs cause a fall in arterial pressure (because
of block of α-receptor-mediated vasoconstriction) and postural hypotension. The cardiac output and heart rate are
increased. This is a reflex response to the fall in arterial pressure, mediated through β-receptors. The concomitant
block of α2-receptors tends to increase noradrenaline release, which has the effect of enhancing the reflex
tachycardia that occurs with any blood pressure-lowering agent. Phenoxybenzamine retains a niche (but vital) use in
preparing patients with phaeochromocytoma for surgery; its irreversible antagonism and the resultant depression in
the maximum of the agonist dose -response curve are desirable in a situation where surgical manipulation of the
tumour may release a large bolus of pressor amine into the circulation.
Partial agonist
Several drugs that act on adrenoceptors have the characteristics of partial agonists, i.e. they block receptors and thus
antagonise the actions of full agonists, but also have a weak agonist effect of their own. When both a full agonist
and partial agonist are present, the partial agonist actually acts as a competitive antagonist, competing with
the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with
the full agonist alone. Clinically partial agonists can activate receptors to give a desired submaximal response when
inadequate amounts of the endogenous ligand are present, or they can reduce the overstimulation of receptors when
excess amounts of the endogenous ligand are present. Examples include ergotamine (α1-receptors) and clonidine
(α2-receptors). Some β-adrenoceptor-blocking drugs (e.g. alprenolol, oxprenolol) cause, under resting conditions,
an increase of heart rate while at the same time opposing the tachycardia produced by sympathetic stimulation.
Other partial agonist includes such as buspirone, buprenorphine, or norclozapine.
α2 agonists (e.g. clonidine): to lower blood pressure and intraocular pressure; as an adjunct during drug
withdrawal in addicts to reduce menopausal flushing; and to reduce frequency of migraine attacks .
102
Page 103
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Classification of β blockers:
1.
Nonselective (β1and β2) antagonist
™ Without intrinsic sympathomimetic activity: Propranolol, Nadolol (long-acting antagonist),
Timolol and Penbutolol
2.
With intrinsic sympathomimetic activity:
Pindolol, Acebutolol (in higher dose can stimulate the
release of NA)
3.
Membrane stabilizing activity (used in arrhythmias) : Acebutolol, Propranolol, oxprenolol
™ With additional α locking activity : labetalol, Carvedilol
4.
Cardioselective (β1) : Nabivolol (also have vasodilating activity), metoprolol, atenolol, Acebutolol,
esmolol, betaxolol
5.
Selective β2 blocker : butoxamine
Adverse effects of nonselective beta blockers:
1. Bronchoconstriction. This is of little importance in the absence of airways disease, but in asthmatic patients the
effect can be dramatic and life-threatening. It is also of clinical importance in patients with other forms of
obstructive lung disease (e.g. chronic bronchitis, COPD).
2. Cardiac depression. Cardiac depression can occur, leading to signs of heart failure, particularly in elderly people.
Patients suffering from heart failure who are treated with β-receptor antagonists (see above) often deteriorate in the
first few weeks before the beneficial effect develops.
3. Bradycardia. This side effect can lead to life-threatening heart block and can occur in patients with coronary
disease, particularly if they are being treated with antiarrhythmic drugs that impair cardiac conduction.
4. Hypoglycaemia. Glucose release in response to adrenaline is a safety device that may be important to diabetic
patients and to other individuals prone to hypoglycaemic attacks. The sympathetic response to hypoglycaemia
produces symptoms (especially tachycardia) that warn patients of the urgent need for carbohydrate (usually in the
form of a sugary drink). β-Receptor antagonists reduce these symptoms, so incipient hypoglycaemia is more likely
to go unnoticed by the patient. The use of β-receptor antagonists is generally to be avoided in patients with poorly
controlled diabetes. There is a theoretical advantage in using β1-selective agents, because glucose release from the
liver is controlled by β2-receptors.
5. Fatigue. This is probably due to reduced cardiac output and reduced muscle perfusion in exercise. It is a frequent
complaint of patients taking β receptor-blocking drugs.
6. Cold extremities. These are presumably due to a loss of β-receptor-mediated vasodilatation in cutaneous vessels,
and are a common side effect. Theoretically, β1-selective drugs are less likely to produce this effect, but it is not
clear that this is so in practice.
103
Page 104
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Other side effects associated with β-receptor antagonists are not obviously the result of β-receptor blockade. One is
the occurrence of bad dreams, which occur mainly with highly lipid-soluble drugs such as propranolol, which enter
the brain easily.
Propranolol: bronchoconstriction (avoid in asthmatic patients), decreases heart rate and force of contraction (avoid
with other drug which have effect on heart like digitalis, verapamil, diltiazam to prevent cardiac arrest but
nafedipine donot have direct action on heart so it can be used), hypoglycemia (avoid with oral hypoglycemic drugs),
cause increase in total LDL-Cholesterol and fall in HDL- cholesterol, fatigue, propranolol also have local
anaesthetic property, reduces the aqueous humor production and lowers the i.o.t, inhibits adrenergic
provoked tremors in parkinsonian, relaxation of uterus is blocked. Propranolol is extensively metabolised in
liver by glucuronides conjugation.
Celiprolol: is a selective β1 blocker having additional weak β2 agonistic activity which reduces the vascular
resistance and holds promise of safety in asthmatics.
Esmolol administered intravenously and is used when beta blockade of short duration is desired or in critically ill
patients in whom adverse effects of bradycardia, heart failure or hypotension may necessitate rapid withdrawal of
the drug. Esmolol has a half-life of about 8 minutes. The drug contains an ester linkage, and it is hydrolyzed
rapidly by esterases in erythrocytes.
Clinical uses of β-adrenoceptor antagonists
•
Cardiovascular :
o
Angina pectoris
o
Myocardial infarction
o
Dysrhythmias like extra systoles and tachycardia which are mediated by adrenergically like
during anaesthesia. Esmolol for Paroxysmal supraventricular tachycardia. Sotalol have
additional K + channel blocking activity.
o
•
Hypertension only selective like atenolol
Other uses:
o
Glaucoma (e.g. timolol eye drops)
o
Thyrotoxicosis: propranolol as it inhibits peripheral conversion of T4 to T3 and highly valuable
in thyroid storm.
o
Anxiety Propranolol is used to control palpitations, tremor.
o
Migraine prophylaxis by Propranolol
o
Phaeochromocytoma β blockers are used to control tachycardia and arrhythmia. They also
suppress cardiomyopathy caused by excess of catecholamines.
104
Page 105
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ANS CHART AND TABLE
Classification of Cholinergic agonists:
M1: Increased gastric acid secretion, M2: Decrease in cardiac contractility, bradycardia (Vagal stimulation) M3: Vascular
smooth muscle contraction i.e. bronchoconstriction, increase glandular secretion which includes sweating, Lacrimation,
salivation, urination and miotic as contraction of ciliary and iris muscles resulting in reduction in size of pupil.
Choline esters: Acetylcholine, Methacholine, Carbachol, Bethanechol
Alkaloids: Pilocarpine, Muscarine, Arecoline
Anticholineesterases
Reversible
3.
Carbamates : Physostigmine (Eserine, tertiary amine), Neostigmine, Edrophonium (shortest acting),
Pyridostigmine, Rivastigmine, Donepezil
4.
Acridine : Tacrine
Irreversible
3.
Organophosphates (Never gas and insecticides) : Parathion, Malathion, Echothiophate, Dyflos, Tabun,
Sarin, Soman
4.
Carbamates : Carbaryl
Cholinergic drugs with their clinical applications:
Preferred Miotic
Pilocarpine (0.5 %)
Systemic effects cause sweating,
bronchospasm, diarrhea
Treatment of Myasthenia gravis
Neostigmine
Alternative to neostigmine for myasthenia
Pyridostigmine
gravis
Diagnostic for myasthenia gravis due to
Edrophonium
short action
Belladonna poisoning
Physiostigmine
As it penetrates BBB and antagonize both
central and peripheral actions.
Alzheimer’s diseases
Tacrine, Donepezil, Galantamine,
Due to more penetration in brain
Rivastigmine
Overdoses of TCA, Phenothiazines and
Physostigmine
as it penetrates BBB and antagonize both
105
Page 106
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
antihistaminics as they have additional
central and peripheral actions.
anticholinergic property.
Cobra bite which have curare like
To prevent respiratory paralysis
Neostigmine + atropine
neurotoxin
Classification of anticholinergic drugs:
Atropine causes tachycardia (M2 blockage), vascular smooth muscles relaxation i.e. bronchodilation (M3 blockage),
blockage of salivary, lacrimal, sweat secretion (M3 blockage), rise in body temperature, Mydriasis i.e. dilation of pupil
results in increased size of pupil.
4. Natural alkaloids: Atropine and Hyoscine (scopolamine)
5. Semisynthetic derivatives: Homatropine, Ipratropium, Tiotropium
6. Synthetic compounds:
d.
Mydriatics: Cyclopentolate, Tropicamide
e.
Antisecretory-antispasmodic:
iii.
Quaternary compounds: Propantheline, Oxyphenonium, Clinidium, Glycoprrolate
iv.
Tertiary amines: Dicyclomine, Pirenzepine, Oxybutynin, Flevoxate
Antiparkinsonian: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden, Benztropine
Therapeutic uses of anticholinergic drugs:
Dilate the pupil
Tropicamide or Cyclopentolate eye drops
Prevention of motion sickness
Scopolamine (orally or transdermally).
Asthma and chronic obstructive pulmonary disease
Ipratropium or Tiotropium by inhalation
Antispasmodic in irritable bowel syndrome
Dicycloverine (dicyclomine)
Peptic ulcer disease by suppressing gastric acid secretion
Pirenzepine (M1-selective antagonist)
Bladder spasm
Oxybutynin
Preanesthetic medication and during anesthesia
Glycoprrolate
106
Page 107
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Urinary incontinence
Darifenacin and solifenacin (Selective M3
antagonist)
Classification of adrenergic drugs:
α1: Smooth muscle contraction, vasoconstriction and increased peripheral resistance resulting in increased B.P, α2:
Inhibition of transmitter release, decreased insulin release, platelet aggregation, β1: Increased myocardial contractility,
tachycardia, β2: vasodilation, bronchodilation, relaxation of uterine muscles, increased gluconeogenesis, lipolysis in
liver, increased release of glucagon, β3:
9.
Pressor agents: NA, Ephedrine, Phenylephrine, Methoxamine, Mephentermine
10. Cardiac stimulants: Dobutamine, Adrenaline, Isoprenaline
11. Bronchodilators: Salbutamol (Albuterol), Salmeterol, Terbutaline, Isoprenaline, Adrenaline
12. Nasal decongestant: Phenylephrine, Pseudoephedrine, Phenylpropanolamine, Naphthazoline,
Xylometazoline, oxymetazoline
13. CNS stimulants: Amphetamine, Dexamphetamine, Methamphetamine
14. Anorectics (Suppress apatite): Fenfluramine, Dexfenfluramine
15. Anti obesity: Sibutramine
16. Uterine smooth muscle relaxant to delay the premature labour: Ritodrine, Isosuxpine,
Salbutamol, terbutaline
Therapeutic uses of adrenergic drugs:
Anaphylactic shock due to allergic disorder like
Adrenaline
histamine release
Cardiac arrest
Stokes-Adams syndrome
CHF
Hypotensive shock
Along with local anasethetics
Adrenaline
Adrenaline or Isoprenaline
Dobutamine / DA
Dobutamine alternative is ephedrine
Adrenaline in 1: 100,000 to prolong the duration of action of local
anasethetics and to minimize the systemic toxicity of local anaesthetics.
Nasal decongestant
Bronchial asthma
Phenylephrine, Pseudoephedrine, Phenylpropanolamine
Salbutamol, Terbutaline, Salmeterol
Mydriatic
Phenylephrine
Narcolepsy (is sleep occurring in fits)
Amphetamine
Epilepsy
Amphetamines are occasionally used as adjuvant to counteract sedation
107
Page 108
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
caused by antiepileptics.
Amphetamine to inhibit DA reuptake. It mainly reduces the rigidity but
Parkinsonian
not tremors.
Hyperkinetic children: are recognized by mental
Amphetamine
retardation or reduction in ability to concentrate
Selective β2 stimulants like Ritodrine, Isosuxpine
Uterine relaxant
Antiobesity
Sibutramine
Antiadrenergic drugs:
Classification of α blockers:
III.
Non equilibrium type: β- Haloalkylamines i.e. Phenoxybenzamine
IV.
Equilibrium type (Competitive):
D. Nonselective α blockers
5.
Ergot alkaloids: Ergotamine, Ergotoxine
6.
Hydrogenated ergot alkaloids: Dihydroergotamine and Dihydroergotoxine
7.
Imidazolines: Tolazoline, Phentolamine
8.
Miscellaneous: Chlorpromazine (To treat amphetamine overdose), Ketanaserin
E. α1 selective antagonist: Prazocin, Terazocin, Doxazosin, Tamsulosin
F. α2 selective antagonist: Yohimbine, Idazoxan
Clinical uses of alpha blockers:
Severe hypertension
Doxazosin due to longest acting, Prazocin
Benign prostatic hypertrophy
Uroselective α1A blocker Tamsulosin, Finastride (5α reductase inhibitor), Prazocin
Phaeochromocytoma
Phenoxybenzamine
Migraine attacks
Prophylaxis by propranolol & treatment by ergotamine
Classification of β blockers:
Propranolol: bronchoconstriction (avoid in asthmatic patients), decreases heart rate and force of contraction (avoid with
other drug which have effect on heart like digitalis, verapamil, diltiazam to prevent cardiac arrest but nafedipine donot
antagonist
Nonselective
(β1and
have6.direct
action on heart
soβit2) can
be used), hypoglycemia (avoid with oral hypoglycemic drugs), cause increase in
™ Without
intrinsic
sympathomimetic
activity: Propranolol, Nadolol (long-acting antagonist),
total LDL-Cholesterol
and fall
in HDLcholesterol, fatigue.
Timolol and Penbutolol
108
Page 109
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
7.
CONTACT;sahadevparmar_22@yahoo.com
With intrinsic sympathomimetic activity:
Pindolol, Acebutolol (in higher dose can stimulate the
release of NA)
8.
Membrane stabilizing activity (used in arrhythmias) : Acebutolol, Propranolol, oxprenolol
™ With additional α locking activity or α + β blocker : labetalol, Carvedilol (also have
antioxidant property)
9.
Cardioselective (β1) : Nabivolol (also have vasodilating activity), metoprolol, atenolol, Acebutolol,
esmolol (rapidly degraded in plasma by esterases), betaxolol, Celiprolol
10. Selective β2 blocker : Butoxamine
Clinical uses of beta blockers:
Glaucoma
Betaxolol, Timolol,
Thyrotoxicosis
Propranolol as it inhibits peripheral conversion of T4 to T3
Anxiety and tremors
Propranolol
Migraine attacks
Prophylaxis by propranolol
Paroxysmal supraventricular tachycardia
Esmolol
Hypertension
Selective β1 blocker like Atenolol, Metoprolol
Angina pectoris, Myocardial infarction , Dysrhythmias
Classification of anti peptic ulcer
A. Reduction in gastric acid secretion
I.
II.
H2 blockers : Cimetidine, Ranitidine, Roxatidine, Famotidine, Loxatidine
Proton pump inhibitors : Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole
III.
Anticholinergics : Pirenzepine, Propantheline, Oxyphenonium
IV.
Prostaglandin analogue : Misoprostol, Enaprostil
B. Ulcer protective : Sucralfate, Colloidal bismuth sub citrate
C. Ulcer healing : Carbenoxlone sodium
D. Antimicrobial : Clarithromycin, Metronidazole, Tetracycline, Amoxicillin, Colloidal bismuth sub citrate
E. Neutralization of gastric acid
I.
II.
systemic : sodium bicarbonate, sodium citrate
Nonsystemic : Magnesium hydroxide, aluminum hydroxide gel
NASIDS induced peptic ulcer
Misoprostol, Enaprostil
Nocturnal acid secretion
Ranitidine
Zollinger-Ellison syndrome (gastric hypersecretory state due to
Omeprazole, Ranitidine
Tumor secretion gastrin)
109
Page 110
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Gastroesophageal reflux
Omeprazole, Ranitidine
Classification of antiemetics drugs:
A. Anticholinergics: Hyoscine, Dicyclomine
B. H1 antihistaminics: Promethazine, Diphenhydramine, Cyclizine, Meclozine, Cinnarizine
C. Neuroleptics or antipsychotic drugs: Chlorpromazine, Prochlorperazine, Haloperidol
D. Prokinetics: Metoclopramide, Domperidone, Cisapride, Mosapride
E. 5-HT3 antagonists: ondansetron, Granisetron
F. Adjuvant antiemetics: Benzodiazepines, Dexamethasone, Cannabinoids
Prophylaxis of vomiting
Metoclopramide
Vestibular disorders (e.g. Ménière's disease)
Misoprostol, Enaprostil
Severe morning sickness of pregnancy
Promethazine
Cytotoxic drugs or radiation caused vomiting
Ondansetron, Omeprazole
Gastroesophageal reflux
Omeprazole, Ranitidine
110
Page 111
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Neurotransmitter, Neuromodulator, Neurotrophic factors
Conventional
small-molecule
mediators
include
Glutamate,
GABA,
acetylcholine,
dopamine,
5-
hydroxytryptamine, glycine etc. neurotransmitters are released by presynaptic terminals and produce rapid
excitatory or inhibitory responses in postsynaptic neurons. Fast neurotransmitters (e.g. glutamate, GABA) operate
through ligand-gated ion channels while slow neurotransmitters and neuromodulators (e.g. dopamine, neuropeptides,
and prostanoids) operate mainly through G-protein-coupled receptors. The same agent (e.g. glutamate, 5hydroxytryptamine, and acetylcholine) may act through both ligand-gated channels and G-protein-coupled receptors
and function as both neurotransmitter and neuromodulator.
Excitatory transmitter are glutamate (excitatory transmitter in the CNS), aspartate in some regions of brain.
Glutamate is widely and fairly uniformly distributed in the CNS, where its concentration is much higher than
in other tissues. Glutamate uptake is coupled to Na+ entry. Glutamate is stored in synaptic vesicles and released by
Ca2+-dependent exocytosis; specific transporter proteins account for its uptake by neurons and other cells, and for its
accumulation by synaptic vesicles.
Inhibitory transmitters are GABA (in brain) and glycine (in spinal cord)
GABA is formed from glutamate by the action of glutamic acid decarboxylase (GAD), an enzyme found only in
GABA-synthesizing neurons in the brain. GABA is destroyed by a transamination reaction catalysed by GABA
transaminase, which is inhibited by vigabatrine, a compound used to treat epilepsy. GABAergic neurons and
astrocytes take up GABA via specific transporters. GABA transport is inhibited by guvacine and nipecotic acid.
GABA acts on two distinct types of receptor, one (the GABAA receptor) being a ligand-gated channel, the other
(GABAB) is a G-protein-coupled receptor. GABAA receptors belong to the same structural class as nicotinic
acetylcholine receptor. They are pentamers, most of them composed of three different subunits (α, β, γ), each of
which can exist in three to six molecular subtypes. GABAA receptors located postsynaptically mediate fast
postsynaptic inhibition as the channel being selectively permeable to Cl- which hyperpolarizes the cell,
thereby reducing its excitability.
Muscimol, derived from a hallucinogenic mushroom, resembles GABA chemically and is a powerful GABAA
receptor agonist. Benzodiazepines, which have powerful sedative and anxiolytic effects, selectively potentiate the
effects of GABA on GABAA receptors. They bind with high affinity to an accessory site (the 'benzodiazepine
receptor') on the GABAA receptor, in such a way that the binding of GABA is facilitated and its agonist effect is
enhanced. Barbiturates and some general anaesthetic agents, which facilitate the action of GABA.
Bicuculline, a naturally occurring convulsant compound, is a specific GABAA receptor antagonist that blocks the
111
Page 112
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
fast inhibitory synaptic potential in most CNS synapses. Gabazine, a synthetic GABA analogue, is another
antagonist. Convulsants such as picrotoxin, which block the anion channel.
GABAB receptors are located pre- and postsynaptically, and they are typical G-protein-coupled receptors, but
unusual in that the functional receptor is a dimer consisting of two different subunits. GABAB receptors exert their
effects by inhibiting voltage-gated calcium channels (thus reducing transmitter release) and by opening
potassium channels (thus reducing postsynaptic excitability), these actions resulting from inhibition of
adenylyl cyclase.
Baclofen is selective GABAB agonist while saclofen is GABAB antagonist.
Glycine is present in particularly high concentration in the grey matter of the spinal cord. Strychnine a
convulsant poison that acts mainly on the spinal cord, blocks both the synaptic inhibitory response and the response
to glycine. β-Alanine has pharmacological effects and a pattern of distribution very similar to those of glycine ,
but its action is not blocked by strychnine. The inhibitory effect of glycine
is quite distinct from its role in
facilitating activation of NMDA receptors. Tetanus toxin, a bacterial toxin resembling botulinum toxin acts
selectively to prevent glycine release from inhibitory interneurons in the spinal cord, causing excessive
reflex hyperexcitability and violent muscle spasms.
Dopamine is a neurotransmitter as well as being the precursor for noradrenaline. It is degraded in a similar
fashion to noradrenaline, giving rise mainly to dihydroxyphenylacetic acid and homovanillic acid, which are
excreted in the urine. There are three main dopaminergic pathways:
1.
Nigrostriatal pathway, important in motor control. Parkinson's disease is associated with a
deficiency of nigrostriatal dopaminergic neurons. Many antipsychotic drugs are D2 receptor antagonists,
whose major side effect is to cause movement disorders, probably associated with block of D2 receptors in
the nigrostriatal pathway.
2.
Mesolimbic/mesocortical pathways are involved in emotion or behavior and drug-induced reward
systems.
3.
Tuberohypophyseal neurons running from the hypothalamus to the pituitary gland which control the
prolactin secretions. Hormone release from the anterior pituitary gland is regulated by dopamine,
especially prolactin release (inhibited) and growth hormone release (stimulated).
There are five dopamine receptor subtypes. D1 and D5 receptors are linked to stimulation of adenylyl cyclase. D2, D3
and D4 receptors are linked to inhibition of adenylyl cyclase. Most known functions of dopamine appear to be
mediated mainly by receptors of the D2 family.
112
Page 113
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Receptors of the D2 family may be implicated in schizophrenia. The D4 receptor shows marked polymorphism in
humans, but no clear relationship with disease has been established.
Behavioural effects of an excess of dopamine activity consist of stereotyped behaviour patterns and can be produced
by dopamine-releasing agents (e.g. amphetamine) and dopamine agonists (e.g. apomorphine).
Dopamine acts on the chemoreceptor trigger zone to cause nausea and vomiting. Thus nearly all dopamine
receptor agonists (e.g. bromocriptine, a dopamine receptor agonist derived from ergot, is used clinically to
suppress prolactin secretion by tumours of the pituitary gland) and other drugs that increase dopamine release in
the brain cause nausea and vomiting as side effects, while many dopamine antagonists (e.g. phenothiazines,
metoclopramide) have antiemetic activity. D2 receptors occur in the area of the medulla (chemoreceptor trigger
zone) associated with the initiation of vomiting and are assumed to mediate this effect.
6-hydroxydopamine, which selectively destroys dopaminergic nerve terminals, is commonly used as a research
tool. It is taken up by the dopamine transporter and converted to a reactive metabolite that causes oxidative
cytotoxicity.
5-hydroxytriptamine / Serotonin its precursor is tryptophan, an amino acid derived from dietary
protein, the plasma content of which varies considerably according to food intake and time of day. Tryptophan is
actively taken up into neurons, converted by tryptophan hydroxylase to 5-hydroxytryptophan, and then
decarboxylated by a non-specific amino acid decarboxylase to 5-HT. Tryptophan hydroxylase can be selectively and
irreversibly inhibited by p-chlorophenylalanine (PCPA). Following release, 5-HT is largely recovered by
neuronal uptake, this mechanism being inhibited by many of the same drugs (e.g. tricyclic antidepressants)
that inhibit catecholamine uptake. The carrier is not identical, however, and inhibitors show varying degrees of
specificity between the two. Selective serotonin reuptake inhibitors constitute an important group of
antidepressant drugs. 5-HT is degraded almost entirely by monoamine oxidase A, which converts it to 5hydroxyindole acetaldehyde, most of which is dehydrogenated to form 5-hydroxyindole acetic acid , which is
excreted in the urine. Serotonin is involved in hallucinations and behavioral changes, sleep (induces sleep),
wakefulness mood, feeding behaviour (increased apatite or hyperphagia, leading to obesity) and vomiting.
There are different classes of 5-HT receptors1.
5-HT1 receptors are predominantly inhibitory in their effects. 5-HT1A receptors are believed to be the
main target of drugs used to treat anxiety and depression e.g. buspirone. 5-HT1D constricts cranial blood
vessels and inhibits release of inflammatory neuropeptides in them. Agonists acting on peripheral 5-HT1D
receptors are used to treat migraine e.g. sumatriptan
2.
5-HT2 receptors (mostly 5-HT2A in the brain) exert an excitatory postsynaptic effect, and are abundant in
the cortex and limbic system. They are believed to be the target of various hallucinogenic drugs e.g. LSD
113
Page 114
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
(lysergic acid diethyl amide) is a non selective 5-HT agonist. The use of 5-HT2 receptor antagonists
such as methysergide in treating migraine. 5-HT2A causes change in shape of platelets and is a weak
aggregator. Ketanserin is 5-HT2A antagonist and will antagonise the vasoconstriction, platelet
aggregation and contraction of airway of smooth muscles.
3.
5-HT3 receptors are involved in vomiting. They are excitatory ionotropic receptors while remaining 5HT receptors are G-protein coupled receptors and specific antagonists e.g. ondansetron is used to treat
nausea and vomiting. They may also have anxiolytic affects, but this is less clear.
4.
5-HT4 receptors are important in the gastrointestinal tract, and are also expressed in the brain. They exert a
presynaptic facilitatory effect, particularly on ACh release, which increases the peristalsis e.g.
prokinetic drug cisapride. This receptor in brain is also involved in thus enhancing cognitive
performance.
5.
5-HT6 receptors occur only in the CNS, particularly in the hippocampus, cortex and limbic system. They
are considered potential targets for drugs to improve cognition or relieve symptoms of schizophrenia,
although no such drugs are yet available.
6.
5-HT7 receptors occur in the hippocampus, cortex, thalamus and hypothalamus, and also in blood vessels
and the gastrointestinal tract. Likely CNS functions include thermoregulation and endocrine
regulation, as well as suspected involvement in mood, cognitive function, and sleep. Selective
antagonists are being developed for clinical use in a variety of potential indications e.g. clozapine (atypical
neuroleptic which have high affinity for 5-HT6 , 5-HT7 in addition 5-HT2A antagonist.)
Several classes of drugs used clinically influence 5-HT-mediated transmission. They include:
•
Serotonin reuptake inhibitors, such as fluoxetine, used as antidepressants
•
5-HT1D receptor agonists, such as sumatriptan used to treat migraine
•
Buspirone, a 5-HT1A receptor agonist used in treating anxiety
•
5-HT3 receptor antagonists, such as ondansetron, used as antiemetic agents which are also active in animal
models of anxiety
•
Antipsychotic drugs e.g. clozapine which owe their efficacy partly to an action on 5-HT receptors
Neuromodulator covers neuropeptide (Substance P, neuropeptide Y, corticotrophin-releasing factor, etc.), nitric
oxide and arachidonic acid metabolites, Steroids (Androgens, oestrogens) which are not stored and released like
conventional neurotransmitters, and may come from non-neuronal cells, particularly glia, as well as neurons. In
general, neuromodulation relates to synaptic plasticity, including short-term physiological events such as the
regulation of presynaptic transmitter release or postsynaptic excitability.
114
Page 115
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Neurotrophic factor are released mainly by non-neuronal cells and act on tyrosine kinase-linked receptors that
regulate gene expression and control neuronal growth and phenotypic characteristics or morphology of neurons, as
well as their functional properties.
115
Page 116
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
OPIOID ANALGESICS
Synthetic derivatives with structures unrelated to morphine:
o
Phenylpiperidine series (e.g. pethidine and fentanyl)
o
Methadone series (e.g. methadone and dextropropoxyphene)
o
Benzomorphan series (e.g. pentazocine and cyclazocine)
o
Semi synthetic thebaine derivatives (e.g. etorphine and buprenorphine)
loperamide, an opiate that does not enter the brain and therefore lacks analgesic activity. Like other opiates, it
inhibits peristalsis, and it is used to control diarrhea.
Fentanyl and sufentanil are more potent and shorter-acting derivatives that are used intravenously, or for chronic pain
via patches applied to the skin, to treat severe pain or as an adjunct to anaesthesia.
Dextropropoxyphene is very similar and was used clinically for treating mild or moderate pain (no longer
recommended on account of cardiotoxicity).
All opioid receptors are linked through G-proteins to inhibition of adenylate cyclase. They also facilitate opening of
potassium channels (causing hyperpolarisation) and inhibit opening of calcium channels (inhibiting transmitter release).
These membrane effects are not linked to the decrease in cAMP formation. Three families of endogenous opioid peptides
are endorphins, the pentapeptides enkephalin and dynorphins. The three families of opioid receptors have overlapping
affinities for these endogenous peptides.
μ-Receptors are thought to be responsible for most of the analgesic effects of opioids, and for some major unwanted
effects (e.g. respiratory depression, euphoria, sedation and dependence). Most of the analgesic opioids are μ-receptor
agonists.
δ-Receptors are probably more important in the periphery but may also contribute to analgesia.
κ-Receptors contribute to analgesia at the spinal level and may elicit sedation and dysphoria, but produce relatively few
unwanted effects and do not contribute to dependence. Some analgesics are relatively κ-selective.
Partial agonists and mixed agonist-antagonists. Nalorphine and Pentazocine are antagonists at μ-receptors but partial
agonists on δ and κ-receptors. Most of the drugs in this group tend to cause dysphoria rather than euphoria, probably by
acting on the κ-receptor.
Antagonists. Naloxone and Naltrexone (to overcome respiratory depression caused by opiates)
116
Page 117
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
The main pharmacological effects of morphine are
1. .Analgesia
2. Euphoria and sedation
3. Respiratory depression and suppression of cough
4. Pupillary constriction (pinpoint pupil, characteristic of morphine use, results from stimulation of μ and κ: receptors.)
5. Reduced gastrointestinal motility, causing constipation
6. Histamine release, causing bronchoconstriction and hypotension
7. Tolerance and dependence to opiates (i.e. an increase in the dose needed to produce a given pharmacological effect) develops
within a few days.
8. Morphine directly stimulates the chemoreceptor trigger zone in that causes vomiting.
9. Morphine inhibits release of gonadotropin- releasing hormone and corticotropin-releasing hormone and decreases the
concentration of luteinizing hormone, follicle- stimulating hormone, adrenocorticotropic hormone. Testosterone and cortisol levels
decrease. Morphine increases prolactin and growth hormone release by diminishing dopaminergic inhibition. It increases
antidiuretic hormone (ADH) and thus leads to urinary retention
117
Page 118
vPHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
The most troublesome unwanted effects are constipation and respiratory depression. Hepatic metabolism is the main
mode of inactivation, usually by conjugation with glucuronide. This occurs at the 3- and 6-OH groups, Morphine is
metabolised to morphine-6-glucuronide, which is four to six times more potent than that of its parent compound.
while morphine -3-glucuronide derivative is inactive or even can antagonize the analgesic effect of morphine and also
found to be neuroexcitatory properties. Analogues that have no free hydroxyl group in the 3-position (i.e. diamorphine,
codeine) are metabolised to morphine, which accounts for all or part of their pharmacological activity. Morphine and
morphine-6-glucuronide are the active metabolites of diamorphine and codeine.
Pethidine or Meperidine is very similar to morphine in its pharmacological effects, except that it tends to cause
restlessness rather than sedation, and it has an additional antimuscarinic action that may cause dry mouth,
taccycardia and blurring of vision as side effects. Meperidine does not cause pinpoint pupils, but rather causes the
pupils to dilate because of an atropine-like activity. It produces a very similar euphoric effect and is equally liable to
cause dependence. Pethidine is partly N-demethylated in the liver to norpethidine, which has a hallucinogenic and
convulsant effect. Pethidine is preferred to morphine for analgesia during labour, because it does not reduce the
force of uterine contraction. Pethidine is only slowly eliminated in the neonate and naloxone may be needed to reverse
respiratory depression in the baby. (Morphine is even more problematic in this regard, because the conjugation reactions
on which the excretion of morphine, but not of pethidine, depends are deficient in the newborn). Severe reactions,
consisting of excitement, hyperthermia and convulsions, have been reported when pethidine is given to patients receiving
monoamine oxidase inhibitors. This seems to be due to inhibition of an alternative metabolic pathway, leading to
increased norpethidine formation.
Fentanyl and sufentanil are highly potent phenylpiperidine derivatives, with actions similar to those of morphine but
with a more rapid onset and shorter duration of action, particularly sufentanil. Their main use is in anaesthesia, and
they may be given intrathecally. They are also used in patient-controlled infusion systems, where a short duration of
action is advantageous, and in severe chronic pain, when they are administered via patches applied to the skin.
Etorphine is a morphine analogue of remarkable potency, more than 1000 times that of morphine, but otherwise very
similar in its actions. Its high potency confers no particular clinical advantage, but it is used to immobilise wild animals
for trapping and research purposes, because the required dose, even for an elephant, is small enough to be
incorporated into a dart or pellet.
Methadone is also pharmacologically similar to morphine, the main difference being that its duration of action is
considerably longer (plasma half-life > 24 hours) as it accumulates in tissues, where it remains bound to protein from
which it is slowly released. Methadone exhibits strong analgesic action when administered orally, in contrast to
morphine, which is only partially absorbed from the gastrointestinal tract. The increased duration seems to occur because
the drug is bound in the extravascular compartment and slowly released. Methadone (and buprenorphine) is widely
used as a means of treating morphine and diamorphine addiction. Methadone is not only a potent μ -receptor
118
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
agonist but its racemic mixture of D- and L-methadone isomers can also block both NMDA receptors and
monoaminergic reuptake transporters. These nonopioid receptor properties may help neuropathic, cancer pain,
especially when a previous trial of morphine has failed. In the presence of methadone, an injection of morphine does not
cause the normal euphoria, and the lack of a physical abstinence syndrome makes it possible to wean addicts from
morphine or diamorphine by giving regular oral doses of methadone-an improvement if not a cure.
Propoxyphene is a derivative of methadone. The dextro isomer is used as an analgesic to relieve mild to
moderate pain. The levo isomer is not analgesic but has antitussive action. Propoxyphene is often used in
combination with aspirin or acetaminophen for a greater analgesia than that obtained with either drug alone.
When toxic doses are taken, a very serious problem can arise in some individuals, with resultant cardiotoxicity and
pulmonary edema. [Note: When used with alcohol and sedatives, a severe CNS depression is produced and death by
respiratory depression and cardiotoxicity can result. The respiratory depression and sedation can be antagonized by
naloxone, but the cardiotoxicity cannot.]
Buprenorphine is a partial agonist on μ receptors. It is less liable to cause dysphoria than pentazocine but more
liable to cause respiratory depression. It has a long duration of action. Its abuse liability is probably less than that of
morphine. Buprenorphine was approved by the US Food and Drug Administration (FDA) in 2002 for the management
of opioid dependence.
Meptazinol It is seems to be relatively free of morphine-like side effects, causing neither euphoria nor dysphoria, nor severe
respiratory depression. It does, however, produce nausea, sedation and dizziness, and has atropine-like side effects. B /cuse of its
short duration of action and lack of respiratory depression, it may have advantages for obstetric analgesia.
Tramadol, a metabolite of the antidepressant trazodone, is widely used as an analgesic for postoperative pain. It is a
weak agonist at μ-opioid receptors, and also a weak inhibitor of noradrenaline reuptake. Tramadol is a centrally
acting analgesic whose mechanism of action is predominantly based on blockade of serotonin reuptake. Tramadol has
also been found to inhibit norepinephrine transporter function.
OPIOID ANTAGONISTS
Nalorphine in low doses, it is a competitive antagonist and blocks most actions of morphine in whole animals or
isolated tissues. Higher doses, however, are analgesic and mimic the effects of morphine. So it is a partial agonist. These
effects probably reflect an antagonist action on μ-receptors, coupled with a partial agonist action on δ and κreceptors, the latter causing dysphoria, which makes it unsuitable for use as an analgesic. Nalorphine can itself
produce physical dependence, but can also precipitate a withdrawal syndrome in morphine or diamorphine addicts.
Pentazocine is a mixed agonist-antagonist with analgesic properties similar to those of morphine. It is an agonist on
119
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
κ receptors and is a weak antagonist at μ- and δ receptors. Pentazocine does not antagonize the respiratory
depression of morphine. Pentazocine should not be used with agonists such as morphine, since the antagonist
action of pentazocine may block the analgesic effects of morphine. However, it causes marked dysphoria, with
nightmares and hallucinations, rather than euphoria, and is now rarely used.
Nalbuphine is a strong κ-receptor agonist and a μ receptor antagonist; it is given parenterally.
Naloxone was the first pure opioid antagonist, with affinity for all three opioid receptors. It blocks the actions of
endogenous opioid peptides as well as those of morphine-like drugs, and has been extensively used as an experimental
tool to determine the physiological role of these peptides, particularly in pain transmission. The main clinical uses of
naloxone are to treat respiratory depression caused by opiate overdosage, and occasionally to reverse the effect of
opiate analgesics, used during labour, on the respiration of the newborn baby. It is usually given intravenously, and
its effects are produced immediately. Naloxone has no important unwanted effects of its own but precipitates withdrawal
symptoms in addicts. It can be used to detect opiate addiction.
Naltrexone is very similar to naloxone but with the advantage of a much longer duration of action (half-life about 10
hours. Naltrexone is also being beneficial in treating chronic alcoholism.
DRUGS FOR NEUROPATHIC PAIN
Several other drugs are used as analgesics, particularly to treat neuropathic pain states, which respond poorly to
conventional analgesic drugs and pose a major clinical problem. This group includes the following.
Tricyclic antidepressants, particularly imipramine and amitriptyline. These drugs act centrally by inhibiting
noradrenaline reuptake and are highly effective in relieving neuropathic pain in some, but not all, cases. Their action is
independent of their antidepressant effects, and selective serotonin reuptake inhibitors are not effective.
Antiepileptic drugs. Carbamazepine , gabapentin and occasionally phenytoin are sometimes effective in neuropathic
pain. Carbamazepine and phenytoin act on voltage-gated sodium channels. The target for gabapentin is the α2δ
subunit of the L-type calcium channel.
Ketamine, a dissociative anaesthetic that works by blocking NMDA receptor channels, has analgesic properties
probably directed at the wind-up phenomenon in the dorsal horn. Given intrathecally, its effects on memory and
cognitive function are largely avoided.
Lidocaine Intravenous a local anaesthetic drug with a short plasma half-life, can give long-lasting relief in neuropathic
pain states. It probably acts by blocking spontaneous discharges from damaged sensory nerve terminals.
120
ANTIPSYCHOTIC DRUGS
SCHIZOPHRENIA is characterized by positive symptoms like Delusions, hallucinations, usually in the form of
voices which are often exhortatory in their message, abnormal behaviours, such as stereotyped movements and
occasionally aggressive behaviours and negative symptoms like withdrawal from social contacts.
Pharmacological evidence is generally consistent with dopamine overactivity/glutamate underactivity hypothesis
and there is also evidence for involvement of 5-hydroxytryptamine. Excessive dopamine synthesis or release or an
increase in dopamine receptor density in schizophrenia. NMDA receptor antagonists such as phencyclidine, ketamine
and dizocilpine produce psychotic symptoms (e.g. hallucinations, thought disorder) in humans, and reduced glutamate
concentrations and glutamate receptor densities in schizophrenic brains.
Amphetamine releases dopamine in the brain and can produce in humans a behavioral syndrome indistinguishable
from an acute schizophrenic episode-very familiar to doctors who treat drug users. Potent D2-receptor agonists (e.g.
apomorphine and bromocriptine; produce similar effects in animals, and these drugs, like amphetamine, exacerbate the
symptoms of schizophrenic patients. Furthermore, dopamine antagonists and drugs that block neuronal dopamine storage
(e.g. reserpine ) are effective in controlling the positive symptoms of schizophrenia, and in preventing amphetamineinduced behavioral changes.
Dopamine has five receptors i.e. D1 and D5 receptors activate adenylyl cyclase, whereas D2, D3 and D4 receptors
inhibit adenylyl. Antipsychotic drugs owe their therapeutic effects mainly to blockade of D2-receptors but most
also block other monoamine receptors, especially 5-HT2. Effects on the mesolimbic/mesocortical dopamine pathways
are believed to correlate with antipsychotic effects, whereas effects on the nigrostriatal pathways (extrapyramidal side
effects i.e. acute dystonias and tardive dyskinesias) are responsible for the unwanted motor effects (Parkinson’s
symptoms) produced by antipsychotic drugs. The actions of the neuroleptic drugs are antagonized by agents that
raise dopamine concentration, for example, L-dopa and amphetamines.
Acute dystonias are involuntary movements (restlessness, muscle spasms, protruding tongue, fixed upward gaze,
torticollis, i.e. involuntary spasm of neck muscles resulting in turning of the head, etc.), often accompanied by symptoms
of Parkinson's disease.
Tardive dyskinesia comprises mainly involuntary movements of face and limbs, appearing after months or years of
antipsychotic treatment. Tardive dyskinesia is postulated to result from an increased number of dopamine receptors that
are synthesized in response to long-term dopamine receptor blockade. This makes the neuron supersensitive to the
actions of dopamine and allows the dopaminergic input to this structure to overpower the cholinergic input, causing
excess movement in the patient. . Incidence of extrapyramidal side effects is less in atypical group antipsychotic
121
"Atypical" antipsychotic drugs like clozapine, respiridone appear to owe their unique activity to blockade of
serotonin receptors. Incidence of extrapyramidal side effects is less in atypical group antipsychotic drugs.
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
drugs.
Classification of neuroleptic drugs
A. Phenothiazines
1.
Aliphatic (propyl amino) side chain e.g. Chlorpromazine (also α adrenergic blockage , results in hypotension)
2.
Piperidine side chain
e.g. Thioridazine (potent antimuscarinic active cause cardiotoxicity, retinal deposits)
3.
Piperazine side chain
e.g. Fluphenazine (Severe extrapyramidal syndrome)
¾
Thioxanthene
e.g. Thiothixene
¾
Butyrophenone
e.g. Haloperidol (Severe extrapyramidal syndrome)
¾
Dibenzodiazepine
e.g. Clozapine (leucopenia and agranulocytosis)
¾
Dibenzoxazepine
e.g. Loxapine
¾
Benzisoxazole
e.g. Respiridone
¾
Thienobenzodiazepine
e.g. Olanzapine
122
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Like many neuroactive compounds, take several weeks to take effect, even though their receptor-blocking action is
immediate.4 When antipsychotic drugs are administered chronically, the increase in activity of dopaminergic neurons is
transient and gives way after about 3 weeks to inhibition, at which time both the biochemical and electrophysiological
markers of activity decline The first-generation compounds show some preference for D2 over D1-receptors, whereas
some of the newer agents (e.g. sulpiride, amisulpride, remoxipride) are highly selective for D2-receptors. Clozapine
is relatively non-selective between D1- and D2-, but has high affinity for D4.
9
Endocrine effects
Dopamine, released in the median eminence by neurons of the tuberohypophyseal pathway, acts physiologically to
inhibit prolactin secretion via D2-receptors. Blocking D2-receptors by antipsychotic drugs can therefore increase the
plasma prolactin concentration, resulting in breast swelling, pain and lactation, which can occur in men as well as
in women. Other less pronounced endocrine changes have also been reported, including a decrease of growth hormone
secretion, but these, unlike the prolactin response, are believed to be unimportant clinically.
9
Other actions of antipsychotic drugs
Antipsychotic drugs block a variety of receptors other than D2 blockage particularly 9
Antimuscarinic e.g. clozapine, thioridazine, chlorpromazine
9
Antihistamine (H1) e.g. phenothiazines
9
Antinoradnergic (α receptor blockage) e.g. chlorpromazine can cause orthostatic hypotension
9
5-HTreceptor blockage e.g. clozapine, respiridone
123
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Antihistamine (H1) activity is a property of phenothiazines and contributes to their sedative and antiemetic
properties. Phenothiazines and, to a variable extent, other Blocking muscarinic receptors produces a variety of
peripheral effects, including blurring of vision and increased intraocular pressure, dry mouth and eyes, constipation and
urinary retention. It may, however, also be beneficial in relation to extrapyramidal side effects as acetylcholine opposes
dopamine in the basal ganglia. Clozapine and thioridazine is due to their high antimuscarinic potency results in lack
of extrapyramidal side effects due to inhibition of both acetylcholine (excitatory) and dopamine (inhibitory i.e. D2
blockage) .
Clozapine can leucopenia and agranulocytosis is common and requires routine monitoring. Olanzapine appears
to be free of this disadvantage. Clozapine can produce bone marrow suppression and cardiovascular side effects.
Clozapine is also effective against 'negative' features of schizophrenia like withdrawal from social contacts, lack of
motivation while typical antipsychotic drugs can only improve positive symptoms like Delusions, hallucinations.
9
Haloperidol is also used in Huntington's chorea
9
Weight gain is a common and troublesome side effect, particularly associated with some of the atypical drugs,
and probably related to 5-HT antagonism.
124
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
GENERAL ANAESTHETICS
General anaesthetics are used to render patients unaware of, and unresponsive to, painful stimulation (analgesia)
during surgical procedures. General anesthetics typically include analgesia, amnesia, loss of consciousness,
inhibition of sensory and autonomic reflexes, and skeletal muscle relaxation. The drug would also possess a
wide margin of safety and be devoid of adverse effects. No single anesthetic agent is capable of achieving all of
these desirable effects without some disadvantages when used alone. High concentrations of any general anaesthetic
affect all parts of the CNS, causing complete shut-down and, in the absence of artificial respiration, death from
respiratory failure. The margin between surgical anaesthesia and potentially fatal respiratory and circulatory
depression is quite narrow, requiring careful monitoring by the anaesthetist and rapid adjustment of the level of
anaesthesia, as required. With the exception of nitrous oxide and Ketamine, all anaesthetics depress respiration
markedly. General anesthetics are usually administered by intravenous injection or by inhalation. They are given
systemically and exert their main effects on the central nervous system (CNS), in contrast to local anaesthetics,
which work by blocking conduction of impulses in peripheral sensory nerves. For a drug to be useful as an
anaesthetic, it must be readily controllable, so that induction and recovery are rapid. Generally for induction
of anaesthesia intravenous anaesthetics while for maintenance of surgical anesthesia inhalational anesthetic
are used. Although all parts of the nervous system are affected by anaesthetic agents, the main targets appear
to be the thalamus, cortex and hippocampus.
STAGES OF ANESTHESIA
The traditional description of the stages of anesthesia was derived from observations of the effects of diethyl
ether, which has a slow onset of central action owing to its high solubility in blood. Using these signs, anesthetic
drug effects can be divided into four stages of increasing depth of central nervous system depression:
I. Stage of analgesia: The patient initially experiences analgesia without amnesia. Later in Stage I, both
analgesia and amnesia are produced.
II. Stage of excitement: The patient experiences delirium and violent combative behavior. There is a rise
and irregularity in blood pressure. The respiratory rate may be increased. To avoid this stage of anesthesia,
a short-acting barbiturate, such as sodium pentothal, is given intravenously before inhalation anesthesia is
administered.
III. Stage of surgical anesthesia: This stage begins with the recurrence of regular respiration and extends
to complete cessation of spontaneous respiration (apnea). Four planes of stage III have been described in
terms of changes in ocular movements, eye reflexes, and pupil size, which under specified conditions may
represent signs of increasing depth of anesthesia.
IV. Stage of medullary depression: This deep stage of anesthesia includes severe depression of the
vasomotor center in the medulla, as well as the respiratory center. Without circulatory and respiratory
support, death rapidly ensues.
125
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
In current anesthesia practice, the distinctive signs of each of the four stages described above are usually obscured
because of the more rapid onset of action of modern intravenous and inhaled anesthetics (compared with ether), and
the fact that ventilation is often controlled mechanically.
Quite often, surgical patients receive one or more of the following preanesthetic medications: benzodiazepines
(for example, diazepam) to relieve anxiety and facilitate amnesia; barbiturates (for example, pentobarbital)
for sedation; antihistamines for prevention of allergic reactions (for example, diphenhydramine) or to reduce
gastric acidity (cimetidine); antiemetics (for example, droperidol); opioids (for example, fentanyl) for
analgesia; and/or anticholinergics (for example, glycopyrrolate scopolamine) to prevent bradycardia and
secretion of fluids into the respiratory tract, they also dilate the pupils. These agents facilitate smooth induction
of anesthesia, and when continuously administered, they also lower the dose of anesthetic required to maintain the
desired level of surgical (Stage III) anesthesia.
Anesthesia can be divided into three stages: induction (by intravenous anaesthetics), maintenance (by gases
or volatile anesthetics, since these agents offer good minute-to-minute control over the depth of anesthesia.)
and recovery. Induction is defined as the period of time from onset of administration of the anesthetic to the
development of effective surgical anesthesia in the patient. Maintenance provides a sustained surgical anesthesia.
Recovery is the time from discontinuation of administration of anesthesia until consciousness is regained. Induction
126
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
of anesthesia depends on how fast effective concentrations of the anesthetic drug reach the brain; recovery is the
reverse of induction and depends on how fast the anesthetic drug is removed from the brain.
Mechanism of Action
Both the inhaled and the intravenous anesthetics have nonspecific interactions with the lipid matrix of the nerve
membrane (the Meyer-Overton principle)—interactions that were thought to lead to secondary changes in ion flux.
The ionic mechanisms involved for different anesthetics may vary, but at clinically relevant concentrations they
appear to involve interactions with members of the ligand-gated ion channel family. Primary molecular target of
general anesthetics is the GABAA receptor-chloride channel, a major mediator of inhibitory synaptic transmission.
Inhaled anesthetics, barbiturates, benzodiazepines, etomidate, and propofol facilitate GABA-mediated inhibition at
GABAA receptor sites. Ketamine does not produce its effects via facilitation of GABAA receptor functions, but
it may function via antagonism of the action of the excitatory neurotransmitter glutamic acid on the Nmethyl-D-aspartate (NMDA) receptor. This receptor may also be a target for nitrous oxide. In addition to their
action on GABAA chloride channels, certain general anesthetics have been reported to cause membrane hyper
polarization (i.e, an inhibitory action) via their activation of potassium channels. The strychnine-sensitive glycine
receptor is another ligand-gated ion channel that may function as a target for inhaled anesthetics, which can elicit
channel opening directly and independently of their facilitatory effects on neurotransmitter binding. Many
anaesthetics inhibit activation of excitatory receptors such as glutamate and nicotinic acetylcholine receptors.
Classification of anaesthetics:
A. Inhalational: Nitrous oxide (gas), Ether, Halothane, Enflurane, Isoflurane, Desflurane, Sevoflurane
B. Intravenous:
i.
Induction: Thiopentone sod, Profol, Etomidate, Methohexitone
ii.
Slower acting: Diazepam, Lorazepam, Midazolam
iii.
Dissociative anaesthesia: Ketamine
iv.
Opioid analgesia: Fentanyl
Inhalational anaesthetics
The anaesthetic state consists of three main components, namely loss of consciousness, analgesia and muscle
relaxation. In practice, these effects are produced with a combination of drugs. A common approach for a major
surgical operation would be to produce unconsciousness rapidly with an intravenous induction agent (e.g. propofol
); to maintain unconsciousness and produce analgesia with one or more inhalation agents (e.g. nitrous oxide and
halothane ), which might be supplemented with an intravenous analgesic agent (e.g. an opiate; and to produce
127
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
muscle paralysis with a neuromuscular-blocking drug (e.g. atracurium). Such a procedure results in much faster
induction and recovery, avoiding long (and hazardous) periods of semi consciousness.
The rate at which an effective brain concentration is achieved (ie, time to induction of general anesthesia) depends
on multiple pharmacokinetic factors that influence the brain uptake and tissue distribution of the anesthetic agent.
The concentration of an inhaled anesthetic in a mixture of gases is proportional to its partial pressure (or tension).
Achievement of a brain concentration of an inhaled anesthetic to provide adequate anesthesia requires transfer of
the anesthetic from the alveolar air to the blood and from the blood to the brain. The rate at which a
therapeutic concentration of the anesthetic is achieved in the brain depends on the solubility properties of the
anesthetic, its concentration in the inspired air, the volume of pulmonary ventilation, the pulmonary blood flow, and
the partial pressure gradient between arterial and mixed venous blood anesthetic concentrations.
MAC (Minimal alveolar concentration) is the lowest concentration of anaesthetic in pulmonary alveoli needed to
produce immobility in response to a painful stimulus (surgical incision) in 50 % individuals. MAC (inversely
proportional to potency) and lipid solubility, expressed as oil: water partition coefficient.
Solubility is one of the most important factors influencing the transfer of an anesthetic from the lungs to the
arterial blood is its solubility characteristics. The blood: gas partition coefficient is a useful index of solubility
and defines the relative affinity of an anesthetic for the blood compared with that of inspired gas. Blood: gas
partition coefficient is the ratio of the total amount of gas in the blood relative to the gas equilibrium phase. Drugs
with low versus high solubility in blood differ in their speed of induction of anesthesia. For example, when an
anesthetic gas with low blood solubility, such as nitrous oxide, diffuses from the alveoli into the circulation, little of
the anesthetic dissolves in the blood. Therefore, the equilibrium between the inhaled anesthetic and arterial blood
occurs rapidly. The partition coefficients for desflurane and nitrous oxide, which are relatively insoluble in
blood, are extremely low. Conversely, for anesthetics with moderate-to-high solubility (eg, halothane, isoflurane),
more molecules dissolve before partial pressure changes significantly, and arterial tension of the gas increases less
rapidly. Nitrous oxide, with low solubility in blood, reaches high arterial tensions rapidly, which in turn results in
rapid equilibration with the brain and fast onset of action. A rapid onset of anesthetic action is also characteristic of
desflurane and, to a lesser extent, sevoflurane, volatile anesthetics that have low blood: gas partition coefficients.
Tissue uptake The transfer of anaesthetic between blood and tissues also affects the kinetics of equilibration
and is inversely proportional to the blood flow to that tissue (faster flow results in a more rapidly achieved
steady-state), and directly proportional to the capacity to store anesthetic (larger capacity results in a longer time to
achieve steady-state). Capacity, in turn, is directly proportional to the tissue's volume, and the tissue/blood solubility
coefficient of the anesthetic molecule. On the basis of these considerations, four major compartments determine the
time course of anesthetic uptake:
1.
Brain, heart, liver, and kidney, endocrine glands: These highly perfused tissues rapidly attain a steadystate with the partial pressure of the anesthetic in blood.
128
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
2.
CONTACT;sahadevparmar_22@yahoo.com
Skeletal muscles: These are poorly perfused during anesthesia. This and the fact that they have a large
volume, prolong the time required to achieve steady-state.
3.
Fat: This tissue is also poorly perfused. However, potent general anesthetics are very lipid soluble.
Therefore, fat has a large capacity to store anesthetic. This combination of slow delivery to a high capacity
compartment prolongs the time required to achieve steady state.
4.
Bone, ligaments, and cartilage: These are poorly perfused and have a relatively low capacity to store
anesthetic. Therefore, these tissues have only a slight impact on the time course of anesthetic distribution in
the body.
Alveolar ventilation greater the ventilation rate, the faster is equilibration, particularly for drugs that have
high blood: gas partition coefficients. Respiratory depressant drugs, such as morphine, can thus retard recovery
from anaesthesia.
Elimination The time to recovery from inhalation anesthesia depends on the rate of elimination of anesthetics
from the brain. Factors controlling rate of recovery include the pulmonary blood flow, the magnitude of
ventilation, and the tissue solubility of the anesthetic. If anaesthesia with a highly fat-soluble drug has been
maintained for a long time, so that the fat has had time to accumulate a substantial amount of the anaesthetic, this
hangover can become very pronounced and the patient may remain drowsy for some hours. Inhaled anesthetics that
are relatively insoluble in blood (ie, low blood: gas partition coefficient) and brain are eliminated at faster rates than
more soluble anesthetics. The washout of nitrous oxide, desflurane, and sevoflurane occurs at a rapid rate, which
leads to a more rapid recovery from their anesthetic effects compared with halothane and isoflurane. Halothane is
approximately twice as soluble in brain tissue and five times more soluble in blood than nitrous oxide and
desflurane; its elimination therefore takes place more slowly, and recovery from halothane anesthesia is predictably
less rapid.
Metabolism of inhalational anaesthetics
Metabolism, although not quantitatively important as a route of elimination of inhalation anaesthetics, can generate
toxic metabolites. Chloroform (now obsolete) cause’s hepatotoxicity associated with free radical formation in liver
cells.
Methoxyflurane, halogenated ether, is no longer used because about 50% is metabolised to fluoride and oxalate,
which cause renal toxicity or nephrotoxic.
Enflurane and sevoflurane also generate fluoride, but at much lower (non-toxic) concentrations.
129
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Halothane is the only volatile anaesthetic in current use that undergoes substantial metabolism, about 30% being
converted to bromide, trifluroacetic acid and other metabolites that are implicated in instances of liver toxicity.
In terms of the extent of hepatic metabolism, the rank order for the inhaled anesthetics is methoxyflurane
> halothane > enflurane > sevoflurane > isoflurane > desflurane > nitrous oxide. Nitrous oxide is not metabolized
by human tissues. However, bacteria in the gastrointestinal tract may be able to break down the nitrous oxide
molecule.
Sevoflurane is degraded by contact with the carbon dioxide absorbent in anesthesia machines, yielding vinyl ether
called "compound A," which can cause renal damage if high concentrations are absorbed.
Halothane
Halothane is a potent anesthetic; it is a relatively weak analgesic and not a good muscle relaxant.
1.
Liver damage: Halothane metabolism yields trifluroacetic acid, which reacts covalently with protein,
especially in liver cells where halothane metabolism occurs. Fluoroacetylated liver proteins are believed
to initiate an immune response.
2.
Malignant hyperthermia. This is caused by heat production in skeletal muscle, due to excessive release of
Ca2+ from the sarcoplasmic reticulum. The result is muscle contracture, acidosis, increased metabolism, and
an associated dramatic rise in body temperature that can be fatal unless treated promptly. Neuromuscularblocking drugs succinylcholine also has this effect. Susceptibility has a genetic basis, being associated with
mutations in the gene encoding the ryanodine receptor, which controls Ca2+ release from the sarcoplasmic
reticulum. Malignant hyperthermia is treated with dantrolene, a muscle relaxant drug that blocks these
calcium channels.
3.
Cardiac dysrhythmias: Like other halogenated hydrocarbons, halothane is vagomimetic and will cause
atropine-sensitive bradycardia. It causes the depression of myocardium by reducing intracelleur
calcium ion concentration. Even sympathetic activity fails to increase it and cardiac output is decreased
with deepening of anaesthesia. It tends to sensitize the heart to arrhythmogenic action of Adr or
catecholamines. Halothane produces hypotension. Should it become necessary to counter excessive
hypotension during halothane anesthesia, it is recommended that a direct-acting vasoconstrictor (for
example, phenylephrine) be given.
Halothane also relaxes the uterine muscles so avoided for pregnant women going for anaesthesia.
Nitrous oxide is good analgesic but poor muscle relaxant. It is rapid in action because of its low blood: gas
partition coefficient, and is an effective analgesic in concentrations too low to cause unconsciousness. It is used in
this way to reduce pain during childbirth. Its potency is low; even at 80% in the inspired gas mixture; nitrous oxide
does not produce surgical anaesthesia. It is not therefore used on its own as an anaesthetic, but is very often used (as
70% nitrous oxide in oxygen) as adjunct to volatile anaesthetics, allowing them to be used at lower
130
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
concentrations. Second gas effect and diffusion hypoxia occurs with nitrous oxide only. Given for brief periods,
nitrous oxide is devoid of any serious toxic effects, but prolonged exposure (> 6 hours) causes inactivation of
methionine
synthase, an enzyme required for DNA and protein synthesis, resulting in bone marrow
depression that may cause anaemia and leucopenia, so its use should be avoided in patients with anaemia related
to vitamin B12 deficiency. Bone marrow depression does not occur with brief exposure to nitrous oxide, but
prolonged or repeated use should be avoided. Nitrous oxide 'sniffers' are subject to this danger.
Enflurane is halogenated ether similar to halothane in its potency and moderate speed of induction. It was
introduced as an alternative to methoxyflurane , its advantages being that at therapeutic levels it produces less
fluoride (and hence less renal toxicity) than methoxyflurane and is less fat-soluble so that onset and recovery are
faster. Its main drawback is that it can cause seizures (powerful convulsant agent), either during induction or
following recovery from anaesthesia. Enflurane can induce malignant hyperthermia.
Isoflurane is now the most widely used volatile anaesthetic. It is expensive to manufacture because of the
difficulty in separating isomers formed during synthesis. It can cause hypotension and is a powerful coronary
vasodilator. This can exacerbate cardiac ischaemia in patients with coronary disease, because of the 'steal'
phenomenon.
Desflurane is chemically similar to isoflurane , but its lower solubility in blood and fat means that induction
and recovery are faster, so it is increasingly used as an anaesthetic for day case surgery. Desflurane causes some
respiratory tract irritation, which can lead to coughing and bronchospasm.
Sevoflurane resembles desflurane but is more potent and does not cause respiratory irritation. It is partially
(about 3%) metabolised, and detectable levels of fluoride are produced, although this does not appear to be sufficient
to cause toxicity. Like other halogenated anaesthetics, sevoflurane can cause malignant hyperthermia in genetically
susceptible individuals. It does not cause sympathetic stimulation like halothane and no airway secretions like
enflurane during the rapid induction
Many inhalation anaesthetics have been introduced and gradually superseded, mainly because of their inflammable
nature or because of toxicity. They include chloroform (hepatotoxicity and cardiac dysrhythmias), diethyl ether
(explosive and highly irritant to the respiratory tract, leading to postoperative complications), vinyl ether
(explosive), cyclopropane (explosive, strongly depressant to respiration, and hypotensive), trichloroethylene
(chemically unstable, no special advantages), and methoxyflurane (slow recovery and renal toxicity).
131
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Intravenous anaesthetics
Even the fastest-acting inhalation anaesthetics, such as nitrous oxide, take a few minutes to act and cause a period
of excitement before anaesthesia is produced. Intravenous anaesthetics act much more rapidly, producing
unconsciousness in about 20 seconds, as soon as the drug reaches the brain from its site of injection. These drugs
(e.g. thiopental, etomidate , propofol, methohexitol ) are normally used for induction of anaesthesia. They are
preferred by patients because injection generally lacks the menacing quality associated with a face mask in an
apprehensive individual.
Other drugs used as intravenous induction agents include certain benzodiazepines such as diazepam
and
midazolam (water soluble and potent amnesic), which act rather less rapidly than the drugs listed above. BZDs
are poor anaesthetics an opioid or nitrous oxide is usually added. They do not provoke postoperative nausea and
vomiting. The anaesthetic action of BZDs can be reversed by flumazenil. Although intravenous anaesthetics on
their own are generally unsatisfactory for producing maintained anaesthesia because their elimination from the body
is relatively slow compared with that of inhalation agents, propofol can be used in this way, and the duration of
action of ketamine is sufficient that it can be used for short operations without the need for an inhalation agent.
The combined use of droperidol , a dopamine antagonist related to antipsychotic drugs and an opiate analgesic such
as fentanyl can produce a state of deep sedation and analgesia (known as neuroleptanalgesia) in which the patient
remains responsive to simple commands and questions, but does not respond to painful stimuli or retain any memory
of the procedure. This is used for minor procedures such as endoscopy.
Propanidid and althesin were withdrawn because of allergic reactions including hypotension and
bronchoconstriction.
Thiopental is the only remaining barbiturate used as an anaesthetic. It is ultra short acting barbiturate. It has
no analgesic effect and can cause profound respiratory depression even in amounts that fail to abolish reflex
responses to painful stimuli. It is generally combined with nitrous oxide or opioids for analgesic effect. The free acid
is insoluble in water, so thiopental is given as the sodium salt. This solution is strongly alkaline and is unstable, so
the drug must be dissolved immediately before it is used. On intravenous injection, thiopental causes
unconsciousness within about 20 seconds and lasts for 5-10 minutes. The anaesthetic effect closely parallels the
concentration of thiopental in the blood reaching the brain, because its high lipid solubility allows it to cross the
blood-brain barrier without noticeable delay. The blood concentration of thiopental declines rapidly, by about 80%
within 1-2 minutes, following the initial peak after intravenous injection, because the drug is redistributed, first to
tissues with a large blood flow (liver, kidneys, brain, etc.) and more slowly to muscle. Uptake into body fat,
although favoured by the high lipid solubility of thiopental, occurs only slowly, because of the low blood flow to
this tissue. After several hours, however, most of the thiopental present in the body will have accumulated in body
fat, the rest having been metabolised. Recovery from the anaesthetic effect occurs within about 5 minutes,
governed entirely by redistribution of the drug to well-perfused tissues; very little is metabolised in this time.
132
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
After the initial rapid decline, the blood concentration drops more slowly, over several hours, as the drug is taken up
by body fat and metabolised. Consequently, thiopental produces a long-lasting hangover; furthermore, repeated
intravenous doses cause progressively longer periods of anaesthesia, because the plateau in blood concentration
becomes progressively more elevated as more drug accumulates in the body. For this reason, thiopental is not used
to maintain surgical anaesthesia but only as an induction agent.
Etomidate has gained favour over thiopental on account of the larger margin between the anaesthetic dose and
the dose needed to produce respiratory and cardiovascular depression. It is also more rapidly metabolised than
thiopental, and thus less likely to cause a prolonged hangover. In other respects, etomidate is very similar to
thiopental, although it appears more likely to cause involuntary movements during induction, postoperative nausea
and vomiting, and pain at the injection site. Etomidate , particularly with prolonged use, suppresses the
production of adrenal steroids. It should therefore not be used in patients with adrenal insufficiency. It is
preferable to thiopental in patients at risk of circulatory failure.
Propofol is oily liquid and employed as 1 % emulsion. It is also similar in its properties to thiopental, but it has
the advantage of being very rapidly metabolised and therefore giving rapid recovery without any hangover effect.
This enables it to be used as a continuous infusion to maintain surgical anaesthesia without the need for any
inhalation agent. It additionally has antiemetic activity. Propofol
lacks the tendency to cause involuntary
movement and adrenocortical suppression seen with etomidate. It is particularly useful for day case surgery.
Ketamine closely resembles, both chemically and pharmacologically, phencyclidine, which is a 'street drug' with
a pronounced effect on sensory perception. Both drugs are believed to act by blocking activation of one type of
excitatory amino acid receptor (the NMDA receptor). Given intravenously, ketamine takes effect more slowly
(2-5 minutes) than thiopental, and produces a different effect, known as 'dissociative anaesthesia', in which there
is a marked sensory loss and analgesia, as well as amnesia and paralysis of movement, without actual loss of
consciousness. Ketamine does not act simply as a depressant and it produces cardiovascular and respiratory
effects quite different from those of most anaesthetics. Blood pressure and heart rate are usually increased, and
respiration is unaffected by effective anaesthetic doses. Ketamine, unlike other intravenous anaesthetic drugs,
increases intracranial pressure, so it should not be given to patients with raised intracranial pressure or at
risk of cerebral ischaemia. The main drawback of ketamine, despite the safety associated with a lack of overall
depressant activity, is that hallucinations, and sometimes delirium and irrational behaviour, are common during
recovery. These after-effects limit the usefulness of ketamine but are said to be less marked in children, therefore
ketamine, often in conjunction with a benzodiazepine, is sometimes still used for minor procedures in paediatrics.
133
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
General anesthetic at a glance
•
Intravenous anaesthetic generally used to produce unconsciousness while lack analgesic effect so combine
either with nitrous oxide or opioids, mainly used to induce anesthesia. Inhalational agents are given to
maintain anaesthesia. Nitrous oxide is the one of the inhalational anesthetic which has good analgesic
activity.
•
The potency of inhalational anesthetic is measured by MAC which is inversely proportional to potency. The
recovery of anesthetic mainly occurs by redistribution.
•
Most anaesthetics enhance the activity of inhibitory GABAA receptors, and many inhibit activation of
excitatory receptors such as glutamate and nicotinic acetylcholine receptors.
•
With the exception of nitrous oxide and Ketamine, all anaesthetics depress respiration.
•
Most anaesthetic agents cause cardiovascular depression by effects on the myocardium and blood vessels, as
well as on the nervous system. Halogenated anaesthetic agents are likely to cause cardiac dysrhythmias,
accentuated by circulating catecholamines.
•
Halothane (malignant hyperthermia, heaptotoxicity, cardiac dysrhythmias), Nitrous oxide (risk of bone
marrow depression and anemia), Enflurane (risk of epilepsy-like seizures), Isoflurane (may precipitate
myocardial ischaemia in patients with coronary disease, irritant to respiratory tract), Desflurane (respiratory
irritant, so liable to cause coughing and laryngospasm)
•
Thiopental sodium (redistribution is very fast, Cardiovascular and respiratory depression), Etomidate
(Adrenocortical suppression), Propofol (Cardiovascular and respiratory depression, rapidly metabolised
Possible to use as continuous infusion), Ketamine (Produces good analgesia and amnesia, dissociative
anaesthesia, raised intracranial pressure), Midazolam (Little respiratory or cardiovascular depression)
•
Neuroleptanalgesia Droperidol, a dopamine antagonist related to antipsychotic drugs and an opiate
analgesic such as fentanyl can produce a state of deep sedation and analgesia
134
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ANTIPARKINSONIAN DRUGS
Parkinsonism is a progressive neurologic disorder occurring due to imbalance between excitatory acetylcholine and
inhibitory dopamine level in substantia nigra. The symptoms includes of muscle movement, characterized by
tremors at rest, muscular rigidity, bradykinesia or hypokinesis (slowness in initiating and carrying out voluntary
movements) and postural and gait. The symptom most clearly related to dopamine deficiency. But these
symptoms can also be
1.
Drug-induced, the main drugs involved being those that reduce the amount of dopamine in the brain (e.g.
reserpine)
2.
Block dopamine receptors (e.g. antipsychotic drugs such as chlorpromazine).
3.
Rare instances of early-onset PD that runs in families, and several gene mutations have been identified, the
most important being synuclein and parkin.
4.
Neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), which was a contaminant in a
preparation used as a heroin substitute. MPTP causes irreversible destruction of nigrostriatal dopaminergic
neurons in various species, and produces a PD-like state in primates. MPTP acts by being converted to a
toxic metabolite, MPP+, by the enzyme monoamine oxidase (MAO, specifically by the MAO-B subtype.
MPP+ is taken up by the dopamine transport system, and thus acts selectively on dopaminergic neurons; it
inhibits mitochondrial oxidation reactions, producing oxidative stress. MPTP appears to be selective in
destroying nigrostriatal neurons and does not affect dopaminergic neurons elsewhere.
Selegiline , a selective MAO-B inhibitor prevents MPTP-induced neurotoxicity by blocking its
conversion to MPP+.
Various herbicides, such as rotenone, that selectively inhibit mitochondrial function cause a PD-like
syndrome in animals, suggesting that environmental toxins could be a factor in human PD, because
impaired mitochondrial function is a feature of the disease in humans.
Dopamine Receptors: The actions of dopamine in the brain are mediated by a family of dopamine-receptor
proteins. Two types of dopamine receptors were identified in the mammalian brain using pharmacological
techniques: D1 receptors, which stimulate the synthesis of the intracellular second messenger cyclic AMP, and
D2 receptors, which inhibit cyclic AMP synthesis as well as suppress Ca2+ currents and activate receptoroperated K+ currents.
The five dopamine receptors can be divided into two groups on the basis of their pharmacological and structural
properties. The D1 and D5 proteins have a long intracellular carboxy-terminal tail and are members of the class
defined pharmacologically as D1; they stimulate the formation of cyclic AMP and phosphatidyl inositol hydrolysis.
The D2, D3, and D4 receptors share a large third intracellular loop and are of the D2 class. They decrease cyclic AMP
formation and modulate K+ and Ca2+ currents. Each of the five dopamine receptor proteins has a distinct anatomical
pattern of expression in the brain. The D1 and D2 proteins are abundant in the striatum and are the most
135
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
important receptor sites with regard to the causes and treatment of PD. The D4 and D5 proteins are largely
extrastriatal, whereas D3 expression more abundant in olfactory tubercle.
Classification of antiparkinsonian drugs1.
Dopamine precursor: levodopa
2.
Dopamine facilitator (enhance dopamine release): Amantadine
3.
Dopaminergic agonist: Bromocriptine, Pergolide, Ropinirole, Pramipexol, Piribedil
4.
Peripheral decarboxylase inhibitors: Carbidopa, Benzserazide
5.
Selective MAO-B inhibitor: Selegiline or deprenyl
6.
COMT (catechol-O-methyl transferase) inhibitors: Entacapone, Tolcapone
7.
Anticholinergic agents: Trihexyphenidyl, Benztropine, Procyclidine, Biperiden, Promethazine
Levodopa
Dopamine itself does not cross the blood-brain barrier, but its immediate precursor levodopa is readily
transported into the CNS (via an L-amino acid transporter, LAT), where it is decarboxylated to dopamine. Levodopa
is almost always administered in combination with a peripherally acting inhibitor of aromatic L-amino acid
decarboxylase, such as carbidopa or benserazide that do not penetrate well into the CNS. If levodopa is
administered alone, the drug is largely decarboxylated by enzymes in the intestinal mucosa and other peripheral sites
so that relatively little unchanged drug reaches the cerebral circulation and probably less than 1% penetrates the
CNS. In addition, dopamine release into the circulation by peripheral conversion of levodopa produces undesirable
effects, particularly nausea vomiting, cardiac arrhythmias, hypotension. Inhibition of peripheral decarboxylase
markedly increases the fraction of administered levodopa that remains unmetabolized and available to cross the
blood-brain barrier and reduces the incidence of gastrointestinal side effects. Carbidopa or benserazide, which
reduces the dose needed by about 10-fold and diminishes the peripheral side effects.
Initial improvements with levodopa are particularly of rigidity and hypokinesia. Levodopa can inhibits
prolactin release and increase GH release.
The benefits of dopaminergic antiparkinsonism drugs appear to depend mostly on stimulation of the D2
receptors, but D1-receptor stimulation may also be required for maximal benefit and one of the newer drugs is D3selective. Dopamine agonist or partial agonist ergot derivatives such as lergotrile and bromocriptine that are
powerful stimulators of the D2 receptors have antiparkinsonism properties, whereas certain dopamine blockers
that are selective D2 antagonists like chlorpromazine can induce Parkinsonism.
The levodopa is absorbed rapidly from the small intestine (when empty of food), although much of it is inactivated
by MAO in the wall of the intestine. The plasma half-life is short (about 2 hours). Levodopa has an extremely
short half-life (1 to 2 hours), which causes fluctuations in plasma concentration. This may produce fluctuations in
motor response ("on-off" phenomenon), which may cause the patient to suddenly lose normal mobility and
136
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
experiencee tremors, cram
mps, and immoobility. Ingestiion of meals, particularly
p
if high in proteiin content, inteerferes
with the trransport of levodopa into thee CNS. Large,, neutral amin
no acids (for example, leuccine and isoleu
ucine)
compete with
w levodopa for absorptionn from the gut and for transpoort across the blood-brain
b
baarrier. Thus levvodopa
should be taken on an empty
e
stomachh, typically 455 minutes befoore a meal. Withdrawal
W
from
m the drug must
m
be
gradual.
137
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
There are two main types of unwanted effect.
1.
Involuntary writhing movements (dyskinesia), which do not appear initially but develop in the majority
of patients within 2 years of starting levodopa therapy. These movements usually affect the face and
limbs, and can become very severe. Levodopa
is short acting, and the fluctuating plasma
concentration of the drug may favour the development of dyskinesias, as longer-acting dopamine
agonists may be less problematic in this regard.
2.
Rapid fluctuations in clinical state, where hypokinesia and rigidity may suddenly worsen for anything from
a few minutes to a few hours, and then improve again. This 'on-off effect' is not seen in untreated PD
patients or with other anti-PD drugs. The 'off effect' can be so sudden that the patient stops while walking
and feels rooted to the spot, or is unable to rise from a chair in which he or she had sat down normally a
few moments earlier. As with the dyskinesias, the problem seems to reflect the fluctuating plasma
concentration of levodopa , and it is suggested that as the disease advances, the ability of neurons to store
dopamine is lost, so the therapeutic benefit of levodopa depends increasingly on the continuous formation
of extraneuronal dopamine, which requires a continuous supply of levodopa . The use of sustained-release
preparations, or coadministration of COMT inhibitors such as entacapone , may be used to counteract
the fluctuations in plasma concentration of levodopa.
In addition to these slowly developing side effects, levodopa produces several acute effects, which are experienced
by most patients at first but tend to disappear after a few weeks. The main ones are as follow.
3.
Nausea and anorexia. Domperidone, a dopamine antagonist that works in the chemoreceptor trigger
zone (where the blood-brain barrier is leaky) but does not gain access to the basal ganglia, may be useful in
preventing this effect.
4.
Hypotension: postural hypotension is a problem in a few patients.
5.
Psychological effects. Levodopa
, by increasing dopamine activity in the brain, can produce a
schizophrenia-like syndrome with delusions and hallucinations. More commonly, in about 20% of patients,
it causes confusion, disorientation, insomnia or nightmares.
Interactions
i.
The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its
effectiveness as pyridoxine is coenzyme for peripheral decarboxylase.
ii.
Peripheral decarboxylation of levodopa and release of dopamine into the circulation may activate vascular
dopamine receptors and produce orthostatic hypotension. The actions of dopamine at α and β adrenergic
receptors may induce cardiac arrhythmias, especially in patients with pre-existing conduction
disturbances. Administration of levodopa with nonspecific inhibitors of MAO, such as phenelzine and
tranylcypromine, markedly accentuates the actions of levodopa and may precipitate life-threatening
hypertensive crisis and hyperpyrexia; nonspecific MAO inhibitors always should be discontinued at least
138
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
14 days before levodopa is administered (note that this prohibition does not include the MAO-B subtypespecific inhibitor selegiline, often is administered safely in combination with levodopa).
iii.
Phenothiazines, butyrophenones, metoclopramide reverse the therapeutic effect of levodopa by
blocking DA receptors.
iv.
Reserpine abolishes levodopa action by preventing entry of DA into synaptic vesicles.
v.
Abrupt withdrawal of levodopa or other dopaminergic medications may precipitate the neuroleptic
malignant syndrome more commonly observed after treatment with dopamine antagonists.
COMT inhibitors adverse effects include diarrhea, abdominal pain, orthostatic hypotension, sleep
disturbances, and an orange discoloration of the urine. Tolcapone may cause an increase in liver enzyme levels
and has been rarely associated with death from acute hepatic failure.
Selegiline or deprenyl
Selegiline is a MAO inhibitor that is selective for MAO-B, which predominates in dopamine-containing regions of
the CNS. It therefore lacks the unwanted peripheral effects of non-selective MAO inhibitors used to treat
depression and, in contrast to them, does not provoke the 'cheese reaction' or interact so frequently with
other drugs. Inhibition of MAO-B protects dopamine from intraneuronal degradation and was initially used as an
adjunct to levodopa.
Rasagiline, another monoamine oxidase B inhibitor, is more potent than selegiline in preventing MPTP-induced
parkinsonism and is being used as a neuroprotective agent and for early symptomatic treatment.
Dopamine-Receptor Agonists. An alternative to levodopa is the use of drugs that are direct agonists of striatal
dopamine receptors, an approach that offers several potential advantages.
1.
Longer in duration of action (8 to 24 hours)as compared to levodopa (3-4 hr) and hence no on-off
fluctuations.
2.
No enzymatic conversion in brain is required as compare to the levodopa.
3.
No peripheral side effects as compared to release of dopamine in peripheral.
Four orally administered dopamine-receptor agonists are available for treatment of PD: two older agents,
bromocriptine and pergolide and two newer, more selective compounds, ropinirole and pramipexole.
Bromocriptine is a strong agonist of the D2 class of dopamine receptors and a partial antagonist of the D1
receptors, whereas pergolide is an agonist of both classes. Ropinirole and pramipexole have selective activity
at D2 class sites (specifically at the D2 and D3 receptor proteins) and little or no activity at D1 class sites.
Bromocriptine inhibits the release of prolactin from the anterior pituitary gland, and was first introduced for
the treatment of galactorrhoea and gynaecomastia, but is effective also in PD. The main side effects of
bromocriptine are nausea and vomiting, and (rarely but seriously) peritoneal fibrosis, as seen with other ergot
derivatives. Newer dopamine receptor agonists include lisuride, pergolide, ropinirole, cabergoline
and
139
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
pramipexole. They are longer acting than levodopa and need to be given only once or twice daily, with less
tendency to cause dyskinesias and on-off effects. Their main side effects are confusion and occasionally delusions,
and sleep disturbances. Pramipexole have antioxidant effects, as well as a protective effect on mitochondria.
Apomorphine
Subcutaneous injection of apomorphine hydrochloride a potent dopamine agonist, is effective for the temporary
relief of off-periods of akinesia in patients on dopaminergic therapy. It is rapidly taken up in the blood and then
the brain, leading to clinical benefit that begins within about 10 minutes of injection and persists for up to 2 hours.
Nausea is often troublesome, especially at the initiation of apomorphine treatment; accordingly, pretreatment with
the antiemetic trimethobenzamide for 3 days is recommended before apomorphine is introduced and is then
continued for at least 1 month, if not indefinitely. Other potentially serious side effects of apomorphine include QT
prolongation, injection-site reactions, and the development of a pattern of abuse characterized by increasingly
frequent dosing leading to hallucinations, dyskinesia, and abnormal behavior. Because of these potential adverse
effects, use of apomorphine is appropriate only when other measures, such as oral dopamine agonists or COMT
inhibitors, have failed to control the "off" episodes.
Amantidine
It was accidentally discovered that the antiviral drug, amantadine effective in the treatment of influenza has
antiparkinsonism action. It appears to enhance the synthesis, release, or re-uptake of dopamine from the surviving
neurons. [Note: If dopamine release is already at a maximum, amantadine has no effect.] The drug may cause
restlessness, agitation, confusion, and hallucinations, and at high doses it may induce acute toxic psychosis.
Orthostatic hypotension, urinary retention, peripheral edema, and dry mouth also may occur. Amantadine is less
efficacious than levodopa and tolerance develops more readily, but it has fewer side effects. The drug has little
effect on tremor but is more effective than the anticholinergics against rigidity and bradykinesia.
Anticholinergic agents
Muscarinic acetylcholine receptors exert an inhibitory effect on dopaminergic nerve terminals, suppression of which
compensates for a lack of dopamine. Generally tremors are more benefited than rigidity and hypokinesia with
anticholinergic therapy (Trihexyphenidyl, Procyclidine, Biperiden, and Promethazine). These are the only
drugs effective in drug induced parkinsonian e.g. reserpine and the related drug tetrabenazine deplete
biogenic monoamines from their storage sites, whereas haloperidol and the phenothiazines block dopamine
receptors. These drugs may therefore produce a parkinsonian syndrome, usually within 3 months after introduction.
This is related to high dosage and clears over a few weeks or months after withdrawal. If treatment is necessary,
antimuscarinic agents are preferred. The side effects of muscarinic antagonists-dry mouth, constipation, impaired
vision, urinary retention-are troublesome, and they are now rarely used, except to treat parkinsonian symptoms in
patients receiving antipsychotic drugs (which are dopamine antagonists and thus nullify the effect of L-dopa).
140
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ANTIEPILEPTIC DRUGS
The characteristic event in epilepsy is the seizure (neuronal firing), which is associated with the episodic highfrequency discharge of impulses by a group of neurons in the brain. Seizures are finite episodes of brain dysfunction
resulting from abnormal discharge of cerebral neurons. The causes of seizures are many and include the full range of
neurologic diseases—from infection to neoplasm and head injury. Abnormal electrical activity during and following
a seizure can be detected by electroencephalography (EEG) recording from electrodes distributed over the surface of
the scalp. What starts as a local abnormal discharge may then spread to other areas of the brain. The site of the
primary discharge and the extent of its spread determine the symptoms that are produced. Thus involvement of the
motor cortex causes convulsions; involvement of the hypothalamus causes peripheral autonomic discharge,
and involvement of the reticular formation in the upper brain stem leads to loss of consciousness.
Epileptogenesis can arise if excitatory transmission is facilitated or inhibitory transmission is reduced. The
neurotransmitters mediating the bulk of synaptic transmission in the mammalian brain are amino acids, with
γ-aminobutyric acid (GABA) and glutamate being the principal inhibitory and excitatory neurotransmitters,
respectively. In certain respects, epileptogenesis resembles long-term potentiation and similar types of usedependent synaptic plasticity may be involved. Convulsant drugs such as pentylenetetrazol (PTZ) are often
used, particularly in the testing of antiepileptic agents, and seizures caused by electrical stimulation of the whole
brain are used for the same purpose. It has been found empirically that drugs that inhibit PTZ-induced convulsions
and raise the threshold for production of electrically induced seizures are generally effective against absence
seizures, whereas those that reduce the duration and spread of electrically induced convulsions are effective in focal
types of epilepsy such as tonic-clonic seizures.
Types of epilepsy
The clinical classification of epilepsy defines two major categories, namely partial and generalised seizures,
although there is some overlap and many varieties of each. Either form is classified as simple (if consciousness is
not lost) or complex (if consciousness is lost).
Partial seizures are those in which the discharge begins locally and often remains localised. The symptoms
depend on the brain region or regions involved, and include involuntary muscle contractions, abnormal sensory
experiences or autonomic discharge, or effects on mood and behaviour, often termed psychomotor epilepsy.
An epileptic focus in the motor cortex results in attacks, sometimes called Jacksonian epilepsy, consisting of
repetitive jerking of a particular muscle group, beginning on one side of the body, often in the thumb, big toe or
angle of the mouth, which spreads and may involve much of the body within about 2 minutes before dying out.
Generalised seizures involve the whole brain, including the reticular system, thus producing abnormal
electrical activity throughout both hemispheres. Immediate loss of consciousness is characteristic of generalised
141
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
seizures. Two important categories are tonic-clonic seizures (grand mal) and absence seizures (petit mal) and
myoclonic.
A tonic-clonic seizure consists of an initial strong contraction of the whole musculature, causing a rigid extensor
spasm and an involuntary cry. Respiration stops, and defecation, micturition and salivation often occur. This tonic
phase lasts for about 1 minute, during which the face is suffused and becomes blue (an important clinical distinction
from syncope, the main disorder from which fits must be distinguished, where the face is ashen pale), and is
followed by a series of violent, synchronous jerks that gradually die out in 2-4 minutes. The patient stays
unconscious for a few more minutes and then gradually recovers, feeling ill and confused. Injury may occur during
the convulsive episode. The EEG shows generalised continuous high-frequency activity in the tonic phase and an
intermittent discharge in the clonic phase.
Absence seizures occur in children; they are much less dramatic but may occur more frequently (many seizures
each day) than tonic-clonic seizures. The patient abruptly ceases whatever he or she was doing, sometimes stopping
speaking in mid-sentence, and stares vacantly for a few seconds, with little or no motor disturbance. Patients are
unaware of their surroundings and recover abruptly with no after-effects. The drugs used specifically to treat
absence seizures act mainly by blocking calcium channels, whereas drugs effective against other types of epilepsy
act mainly by blocking sodium channels or enhancing GABA-mediated inhibition.
Classification of antiepileptic drugs:
A. Barbiturates: Phenobarbitone, Mephobarbitone
B. Deoxybarbitutares : Primidones
C. Hydantoin: Phenytoin
D. Iminostilbene : Carbamazepine
E. Succinimide : Ethosuximide
F. Aliphatic carboxylic acid : Valporic acid
G. Benzodiazepines : Clonazepam, Diazepam, Clobazam
H. Phenyltriazine : Lamotrignine
I.
Cyclic GABA analogue : Gabapentin
J.
Newer drugs : Vigabatrin, Topiramate, Tiagabine, Levetiracetam
142
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Three main mechanisms appear to be important in the action of antiepileptic drugs
1.
Enhancement of GABA action e.g.
•
Barbiturates & Benzodiazepines (enhance the activation of GABAA receptors, thus facilitating
the GABA-mediated opening of chloride channels),
•
Vigabatrin (acts by inhibiting the enzyme GABA transaminase, which is responsible for
inactivating GABA),
2.
•
Tiagabine( inhibits GABA uptake)
•
Gabapentin (an agonist at GABAA receptors)
•
Valporate
Inhibition of sodium channel function affects membrane excitability by an action on voltagedependent sodium channels, which carry the inward membrane current necessary for the generation of an
action potential. they block preferentially the excitation of cells that are firing repetitively e.g. Phenytoin,
Carbamazepine, Lamotrignine, Valporate
3.
Inhibition of calcium channel function (T-type calcium channel,) e.g. Ethosuximide,
Trimethadione, Valporate
143
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Phenobarbital is a barbiturate that has a greater antiepileptic effect and relatively less sedative action than
other barbiturates, although it’s GABA-potentiating action is similar. Other barbiturates have severe respiratory
depression their main adverse effect but it lacks . However, phenobarbital is as effective against electrically
induced convulsions as it is against PTZ-induced convulsions in rats or mice, whereas benzodiazepines, which
act similarly on GABA-mediated transmission, are without effect on electrically induced convulsions.
Phenobarbital reduces the electrical activity of neurons within a chemically induced epileptic focus within the
cortex, whereas diazepam (a benzodiazepine) does not suppress the focal activity but prevents it from spreading.
The drug has been regarded as the first choice in treating recurrent seizures in children, including febrile seizures.
However, phenobarbital can depress cognitive performance in children treated for febrile seizures, and the drug
should be used cautiously. Phenobarbital is a potent inducer of the P-450 system, and when given chronically,
it enhances the metabolism of other agents.
Primidone is a prodrug. The deoxybarbiturate efficacy comes from its metabolites by liver to
phenobarbital and phenylethylmalonamide which have longer half- lives than the parent drug. Phenobarbital is
effective against tonic-clonic and simple partial seizures, and phenylethylmalonamide is effective against complex
partial seizures.
Phenytoin is well absorbed when given orally, and about 80-90% of the plasma content is bound to albumin.
1.
Chloramphenicol, isoniazid, cimetidine etc inhibits the metabolism of phenytoin can lead to toxicity.
2.
Other drugs, such as salicylates, phenylbutazone and valproate, inhibit this binding competitively.
3.
Phenytoin causes enzyme induction, and thus increases the rate of metabolism of other drugs (e.g. oral
anticoagulants, steroids, digoxin, and theophylline).
4.
Phenobarbitone competitively inhibits phenytoin metabolism while by enzyme induction both enhance
each other metabolism.
5.
Sucralfate binds to phenytoin in git and decreases its absorption.
Adverse effects includes:
1.
Nystagmus and ataxia.
2.
Gingival hyperplasia may cause the gums to grow over teeth, particularly in children. This hyperplasia
slowly regresses after termination of drug therapy.
3.
Hirsuitism
4.
Megaloblastic anemia occurs because the drug interferes with vitamin B12 metabolism.
5.
Osteomalaceia as it desensitizes target tissue to vit D and interferes with calcium metabolism.
6.
Inhibition of antidiuretic hormone release occurs as well as hyperglycemia and glycosuria caused by
inhibition of insulin secretion.
7.
If used during pregnancy can cause hydantoin syndrome.
8.
Behavioral changes, such as confusion, hallucination, and drowsiness are common.
144
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Phenytoin is also an antiarrhythmic drug.
Carbamazepine, one of the most widely used antiepileptic drugs, is chemically derived from the tricyclic
antidepressant drugs i.e. imipramine. Carbamazepine has antidiuretic action and so causes water retention.
Carbamazepine in liver gets metabolized to 10-11 epoxycarbmazepine an active metabolite and hydroxylation to
give inactive metabolites. Carbamazepine is also enzyme inducer so by induction it reduces the efficacy of
haloperidol and oral contraceptives. This drug has the potential for inducing serious liver toxicity. Carbamazepine
can cause stupor, coma, and respiratory depression, along with drowsiness, vertigo, ataxia, and blurred vision.
Diazepam given intravenously or rectally is used to treat status epilepticus, a life-threatening condition in
which epileptic seizures occur almost without a break. Its advantage in this situation is that it acts very rapidly
compared with other antiepileptic drugs. With most benzodiazepines the sedative effect is too pronounced for them
to be used for maintenance therapy. Clonazepam and the related compound clobazam are claimed to be relatively
selective as antiepileptic drugs. Sedation is the main side effect of these compounds, and an added problem may be
the withdrawal syndrome, which results in an exacerbation of seizures if the drug is stopped abruptly.
Valproate is a simple monocarboxylic acid act by all three mechanisms. Besides this it have a significant
increase in the GABA content of the brain and is a weak inhibitor of two enzyme systems that inactivate GABA,
namely GABA transaminase and succinic semialdehyde dehydrogenase, but in vitro studies suggest that these
effects would be very slight at clinical dosage. Valporate can inhibit the metabolism of Phenobarbitone. It
displaces phenytoin from plasma protein binding site and increases phenytoin toxicity. It causes thinning and
curling of the hair in about 10% of patients. Valproic acid can cause nausea and vomiting; sedation, ataxia, and
tremor are common. Hepatic toxicity may cause a rise in hepatic enzymes in plasma, which should be monitored
frequently. In some individuals, a rash and alopecia may occur. Bleeding times may increase because of both
thrombocytopenia and an inhibition of platelet aggregation.
Ethosuximide, which belongs to the succinimide class, is another drug developed empirically by modifying the
barbituric acid ring structure. It acts by blocking T-type calcium channels. It supplanted trimethadione , the first
drug found to be effective in absence seizures, which had major side effects. Ethosuximide is used clinically for
its selective effect on absence seizures. Its main side effects are nausea and anorexia, sometimes lethargy and
dizziness. In sensitive individuals, a Stevens - Johnson syndrome or urticaria may occur, as well as leukopenia,
aplastic anemia, and thrombocytopenia. This drug is not plasma bound. Ethosuximide does not induce P-450
enzyme synthesis.
Topiramate also have weak carbonic anhydrase activity and is board spectrum anticonvulsant activity. It
appears to act via phenytoin sodium channel inactivation, GABA potentiation by postsynaptic effect and antagonism
of certain glutamate receptors. Its main drawback is that (like many antiepileptic drugs) it is teratogenic in animals,
so it should not be used in women of child-bearing age.
145
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Lamotrignine is broad spectrum antiepileptic. it resembles phenytoin
and carbamazepine
in its
pharmacological effects, acting on sodium channels and inhibiting the release of excitatory amino acids Its main side
effects are nausea, dizziness and ataxia, and hypersensitivity reactions
Levetiracetam was developed as an analogue of piracetam, a drug used to improve cognitive function. It is
used for kindled seizures.
Felbamate is an analogue of an obsolete anxiolytic drug, meprobamate. It has only a weak effect on sodium
channels and little effect on GABA, but causes some block of the NMDA receptor channel. Its acute side effects are
mild, mainly nausea, irritability and insomnia, but it occasionally causes severe reactions resulting in aplastic
anaemia or hepatitis.
Zonisamide is a sulfonamide compound originally intended as an antibacterial drug and found accidentally to
have antiepileptic properties. It is believed to act by blocking sodium channels but may well have other effects. It is
free of major unwanted effects, although it causes drowsiness, and of serious interaction with other drugs. It tends
to suppress appetite and cause weight loss, and is sometimes used for this purpose
Clinical uses of antiepileptic drugs:
A. Tonic-clonic (grand mal) seizures: first choice of drugs are Carbamazepine (preferred because of a
relatively favorable effectiveness: risk ratio), phenytoin , valproate. use of a single drug is preferred,
when possible, to avoid pharmacokinetic
B. Partial (focal) seizures: Carbamazepine, valproate; alternatives are Clonazepam or phenytoin
C. Absence seizures (petit mal): Ethosuximide or valproate
D. Myoclonic seizures: Diazepam intravenously or (in absence of accessible veins) rectally.
E. Febrile seizures: Diazepam via rectal route
F. Status epileptics: Diazepam alternative is Phenobarbitone
G. Neuropathic pain: Carbamazepine , gabapentin
H. Trigeminal neuralgia: Carbamazepine
I.
To stabilize mood in mono- or bipolar affective disorder or manic depressive illness (as an alternative
to lithium ): Carbamazepine , valproate
Other uses of antiepileptic drugs:
A. Cardiac dysrhythmias e.g. phenytoin
B. Neuropathic pain e.g. gabapentin , Carbamazepine , lamotrigine
C. Anxiety disorders (gabapentin
D. Migraine prophylaxis (valproate, gabapentin )
146
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
E. Bipolar disorder (valproate, Carbamazepine , oxcarbazepine , lamotrigine , topiramate
147
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Drugs used in treatment of hypertension
Hypertension is defined conventionally as a sustained increase in blood pressure ≥140/90 mm Hg.
Arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the
resistance to passage of blood through precapillary arterioles (peripheral vascular resistance, PVR):
BP = CO × PVR
In most cases, elevated blood pressure is associated with an overall increase in
1.
Resistance to flow of blood through arterioles, while cardiac output is usually normal.
2.
The renin-angiotensin-aldosterone system
3. Autonomic nervous system function, baroreceptor reflexes (Baroreflexes, mediated by autonomic nerves, act
in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system. The kidney
contributes to maintenance of blood pressure by regulating the volume of intravascular fluid. In addition,
decreased pressure in renal arterioles as well as sympathetic neural activity (via βadrenoceptors) stimulates
production of renin, which increases production of angiotensin II.
148
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Classification of antihypertensive drugs
A. ACE inhibitors : captopril, enalapril, ramipril, lisinopril
B. Angiotensin II receptor(type AT1) antagonist : losartan, candesatan, irbesartan
C. Calcium channel blockers :
i.
Phenyl alkylamines : verapamil,
ii.
Benzodiazepine : diltiazam,
iii.
Dihydropyridines : nifedipine, felodipine
D. Diuretics :
i.
Thiazides : hydrochlorothiazide, Chlorthalidone (nonbenzothiazide), indepamide
ii.
High ceiling : furosemide
iii.
K+ sparing : Spironolactone, tramterene,amiloride
E. β adrenergic blockers : propranolol, metoprolol, atenolol
F. β + α blockers : labetalol, carvedilol
G. α adrenergic blockers : prazosin, terazosin,phenetolamine, phenoxybenzamine
H. vasodilators : arterial (hydralazine,minoxidil,diazoxide) and
Arterial + venous (sodium nitroprusside)
I.
central sympatholytics : clonidine, methyldopa
149
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
150
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
151
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Inhibitors of Angiotensin II (also given in CHF as first choice)
Renin, angiotensin, and aldosterone play important roles in at least some individuals with essential hypertension.
Blood pressure of patients with high-renin hypertension responds well to β-βadrenoceptors blockers, which lower
plasma renin activity, and to angiotensin inhibitors—supporting a role for excess renin and angiotensin in this
population.
Mechanism & Sites of Action
Renin release from the kidney cortex is stimulated by reduced renal arterial pressure, sympathetic neural stimulation,
and reduced sodium delivery or increased sodium concentration at the distal renal tubule. Renin acts upon
angiotensinogen to split off the inactive precursor decapeptide angiotensin I. Angiotensin I is then converted,
primarily by endothelial ACE, to the arterial vasoconstrictor octapeptide angiotensin II, which is in turn converted
in the adrenal gland to angiotensin III. Angiotensin II has vasoconstrictor and sodium-retaining activity. Angiotensin
II and III both stimulate aldosterone release.
ACE is an enzyme with many substrates, and inhibition of ACE may induce effects unrelated to reducing the levels
of angiotensin II. Since ACE inhibitors increase bradykinin (potent vasodilator via nitric oxide release) levels
and bradykinin stimulates prostaglandin biosynthesis, bradykinin and/or prostaglandins may contribute to the
pharmacological effects of ACE inhibitors. ACE inhibitors also diminish the rate of bradykinin inactivation.
Vasodilation occurs as a result of the combined effects of lower vasoconstriction caused by diminished levels of
angiotensin II and the potent vasodilating effect of increased
bradykinin.] ACE inhibitors are highly selective drugs. They do not interact directly with other components of the
renin-angiotensin system, and their principal pharmacological and clinical effects apparently arise from suppression
of synthesis of angiotensin II.
(1) Sulfhydryl-containing ACE inhibitors structurally related to captopril (dipeptide)
(2) Dicarboxyl-containing ACE inhibitors structurally related to enalapril (Tripeptide), lisinopril, benazepril,
quinapril, ramipril
(3) Phosphorus-containing ACE inhibitors structurally related to fosinopril. Many ACE inhibitors are estercontaining prodrugs that are 100 to 1000 times less potent but have a much better oral bioavailability than the active
molecules.
(Captopril is not a prodrug remaining drugs are prodrugs)
Adverse effects of ACE inhibitors
i.
Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic
due to diuretics, salt restriction, or gastrointestinal fluid loss.
ii.
Hyperkalemia, loss of taste (dysgusia)
152
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
iii.
CONTACT;sahadevparmar_22@yahoo.com
Dry cough sometimes accompanied by wheezing, and angioedema. Bradykinin and substance P seem to
be responsible for the cough and angioedema seen with ACE inhibition.
iv.
Recent evidence also implicates first trimester exposure to ACE inhibitors in increased teratogenic risk.
Captopril, particularly when given in high doses to patients with renal insufficiency, may cause neutropenia
or proteinuria.
Important drug interactions
i.
Patients with potassium supplements or potassium-sparing diuretics (spirolonolactone), which can
result in hyperkalemia.
ii.
Nonsteroidal anti-inflammatory drugs may impair the hypotensive effects of ACE inhibitors by blocking
bradykinin-mediated vasodilatation, which is at least in part, prostaglandin mediated.
Angiotensin II receptor (Type AT1) antagonist
Losartan and valsartan were the first marketed blockers of the angiotensin II type 1 (AT1) receptor. More recently,
candesatan, eprosartan, irbesartan, and telmisartan have been released. They have no effect on bradykinin
metabolism and are therefore more selective blockers of angiotensin effects than ACE inhibitors. They also
have the potential for more complete inhibition of angiotensin action compared with ACE inhibitors because there
are enzymes other than ACE that are capable of generating angiotensin II. Angiotensin receptor blockers provide
benefits similar to those of ACE inhibitors in patients with heart failure and chronic kidney disease. The adverse
effects are similar to those described for ACE inhibitors, including the hazard of use during pregnancy. Cough and
angioedema are very less with angiotensin receptor blockers than with ACE inhibitors.
Calcium Channel Blockers
An increased concentration of cytosolic Ca2+ causes increased contraction in cardiac and vascular smooth muscle
cells. These drugs also may produce negative inotropic and chronotropic effects in the heart. In addition to their
antianginal and antiarrhythmic effects, calcium channel blockers also reduce peripheral resistance and blood
pressure. The mechanism of action in hypertension is inhibition of calcium influx into arterial smooth muscle cells.
Since contraction of vascular smooth muscle is dependent on the free intracellular concentration of Ca2+, inhibition
of transmembrane movement of Ca2+ through voltage-sensitive (L-Type) Ca2+ channels can decrease the total
amount of Ca2+ that reaches intracellular sites.
Phenyl alkylamines: verapamil (congener of papaverine), Benzodiazepine: Diltiazem, Dihydropyridines:
nifedipine, felodipine, amlodipine, felodipine, isradipine, nicardipine, nifedipine, and nisoldipine) are all equally
effective in lowering blood pressure. Hemodynamic differences among calcium channel blockers may influence the
choice of a particular agent. Nifedipine and the other dihydropyridine agents are more selective as vasodilators
153
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
and have less cardiac depressant effect than verapamil and diltiazam (block Ca2+ channels in cardiac cells).
Verapamil has the greatest depressant effect on the heart and may decrease heart rate and cardiac output.
L-Verapamil is a more potent calcium channel blocker than is D-verapamil. Nifedipine preferentially block
Ca2+ channels in vascular smooth muscle; their cardiac electrophysiological effects, such as heart rate
acceleration, result principally from reflex sympathetic activation secondary to peripheral vasodilation. Another
difference in calcium channel blocker is that Sodium channel block is modest with verapamil and still less marked
with diltiazem. It is negligible with nifedipine and other dihydropyridines.
All of the Ca2+ channels blockers lower blood pressure by relaxing arteriolar smooth muscle and decreasing
peripheral vascular resistance. As a consequence of a decrease in peripheral vascular resistance, the Ca2+ channel
blockers evoke a baroreceptor-mediated sympathetic discharge and response is more in case of dihydropyridines.
Short-acting nifedipine for hypertension or Dihydropyridines may cause the increased risk of myocardial
infarction or mortality due to tachycardia may occur from the adrenergic stimulation of the sinoatrial node; this
response is generally quite modest except when the drug is administered rapidly. Tachycardia is typically minimal to
absent with verapamil and Diltiazem because of the direct negative chronotropic effect of these two drugs. Indeed,
the concurrent use of β receptor antagonist drug may magnify negative chronotropic effects of nifedipine but
the concurrent use of β receptor antagonists with either verapamil or diltiazam may be problematic because
they itself have cardiac depressant effect on heart. Sustained-release calcium blockers or calcium blockers with
long half-lives provide smoother blood pressure control and are more appropriate for treatment of chronic
hypertension. Intravenous nicardipine is available for the treatment of hypertension when oral therapy is not
feasible, although parenteral verapamil and Diltiazem could be used for the same indication. Nicardipine is typically
infused at rates of 2–15 mg/h. Oral short-acting nifedipine has been used in emergency management of severe
hypertension.
Felodipine may have even greater vascular specificity than does nifedipine or amlodipine. At concentrations
producing vasodilation, there is no negative inotropic effect.
A major metabolite of diltiazam is desacetyldiltiazem, which has about one-half of diltiazem potency as a
vasodilator. N-Demethylation of verapamil results in production of norverapamil, which is biologically active but
much less potent than the parent compound. The half-life of norverapamil is about 10 hours. The metabolites of the
dihydropyridines are inactive or weakly active.
Toxicity and Untoward Responses.
Excessive inhibition of calcium influx can cause serious cardiac depression, including cardiac arrest, bradycardia,
atrioventricular block, and heart failure. The most common side effects caused by the Ca2+ channel antagonists,
particularly the dihydropyridines, are due to excessive vasodilation which results in increased adnergic stimulation
and tacchy cardia. Nimodipine may produce muscle cramps when given in the large doses required for a beneficial
effect in patients with subarachnoid hemorrhage. Worsened myocardial ischemia has been observed in two studies
with the dihydropyridine nifedipine. Some Ca2+ channel antagonists can cause an increase in the concentration
154
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
of digoxin in plasma, although toxicity from the cardiac glycoside rarely develops. The use of verapamil to treat
digitalis toxicity thus is contraindicated.
Β-Adrenoceptor antagonists
Mostly all β-βadrenoceptors-blocking agents are very useful for lowering blood pressure in mild to moderate
hypertension.
1.
In severe hypertension, β blockers are especially useful in preventing the reflex tachycardia that often
results from treatment with direct vasodilators (nifedipine).
2.
Propranolol inhibits the stimulation of renin production by catecholamines (mediated by β1 receptors).
It is likely that propranolol's effect is due in part to depression of the renin-angiotensin-aldosterone
system.
Propranolol decreases blood pressure primarily as a result of a decrease in cardiac output. Other β blockers may
decrease cardiac output or decrease peripheral vascular resistance to various degrees, depending on cardioselectivity
and partial agonist activities. Beta blockade in brain, kidney, and peripheral adrenergic neurons has been proposed
as contributing to the antihypertensive effect observed with β-receptor blockers. It is believed that the brain appears
unlikely to be the primary site of the hypotensive action of these drugs, because some β blockers that do not
readily cross the blood-brain barrier because of hydrophilic (eg, nadolol) are nonetheless effective
antihypertensive agents.
Although Propranolol most effective in patients with high plasma renin activity, propranolol also reduces blood
pressure in hypertensive patients with normal or even low renin activity. Beta blockers might also act on peripheral
presynaptic β adrenoceptors to reduce sympathetic vasoconstrictor nerve activity,
Toxicity
The principal toxicities of propranolol result from blockade of cardiac, vascular, or bronchial β receptors. The most
important of these predictable extensions of the β-blocking action occur in patients with bradycardia or cardiac
conduction disease, asthma, peripheral vascular insufficiency, and diabetes.
d.
Bronchoconstriction: Propranolol has a serious and potentially lethal side effect when administered to an
asthmatic. An immediate contraction of the bronchiolar smooth muscle prevents air from entering the
lungs. Deaths by asphyxiation have been reported for asthmatics who were inadvertently administered the
drug. Therefore, propranolol must never be used in treating any individual with obstructive pulmonary
disease.
e.
Arrhythmias: Treatment with the β-blockers must never be stopped quickly because of the risk of
precipitating cardiac arrhythmias, which may be severe. The β-blockers must be tapered off gradually for 1
week. Long-term treatment with a antagonist leads to up-regulation of the β-receptor. On suspension of
therapy, the increased receptors can worsen angina or hypertension.
155
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
f.
CONTACT;sahadevparmar_22@yahoo.com
Disturbances in metabolism: The β-blockers may disturb lipid metabolism, decreasing high-density
lipoproteins (HDL) and increasing plasma triacylglycerol. β-Blockade leads to decreased glycogenolysis
and decreased glucagon secretion. Fasting hypoglycemia may occur. So, Cardioselective β-blockers are
preferred in treating insulin-dependent asthmatics.
Receptor Antagonists with Additional Cardiovascular Effects ("third Generation “beta Blockers)
In addition to the classical non-subtype selective and b1-selective adrenergic receptor antagonists, there also are a
series of drugs that possess vasodilatory actions. These effects are produced through a variety of mechanisms
including
9
a1 adrenergic receptor blockade : labetalol, carvedilol
9
Increased production of NO: Nebivolol
9
Opening of K+ channels : Tilisolol
9
Antioxidant action : carvedilol
9
b2-agonist properties (celiprolol, carteolol, and bopindolol),
9
Ca2+ entry blockade: carvedilol, betaxolol, and bevantolol
Labetalol
The R, R isomer is about four times more potent as a beta receptor antagonist than is racemic labetalol. The
R, S isomer is almost devoid of both alpha and beta blocking effects. The S, R isomer has almost no b blocking
activity. The S,S isomer is devoid of b blocking activity and has a potency similar to that of racemic labetalol as an
a1 receptor antagonist. The R ,R isomer has some intrinsic sympathomimetic activity at b2 adrenergic receptors; this
may contribute to vasodilation. Labetalol also may have some direct vasodilating capacity.
Diuretics
Diuretics decrease plasma volume and subsequently decrease venous return to the heart (preload). This decreases the
cardiac workload and oxygen demand. Thiazides diuretics, such as hydrochlorothiazide, lower blood pressure,
initially by increasing sodium and water excretion. This causes a decrease in extracellular volume, resulting in a
decrease in cardiac output and renal blood flow. With long-term treatment, plasma volume approaches a normal
value, but peripheral resistance decreases. Spironolactone, a potassium- sparing diuretic, is often used with
Thiazides to balance the K+ loss. These agents counteract the sodium and water retention observed with other
agents used in the treatment of hypertension like hydralazine (vasodilator). Thiazides are therefore useful in
combination therapy with a variety of other antihypertensive agents including β-blockers and ACE inhibitors.
Thiazides diuretics are particularly useful in the treatment of black or elderly patients, and in those with chronic
renal disease. Thiazides diuretics are not effective in patients with inadequate kidney function (Creatinine clearance
less than 50 ml/min).
156
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Adverse effects: Thiazides diuretics induce (HHH) Hypokalemia and Hyperuricemia in 70% of patients, and
Hyperglycemia in 10% of patients. Serum potassium levels should be monitored closely in patients who are
predisposed to cardiac arrhythmias (particularly individuals with left ventricular hypertrophy, ischemic heart
disease, or chronic congestive heart failure) and who are concurrently being treated with both thiazide diuretics
and digitalis glycosides as potency of digitalis glycosides is increased due to K+ loss caused by Thiazides.
Diuretics should be avoided in the treatment of hypertensive diabetics or patients with hyperlipidemia.
It has been found that loop diuretics are useful in treatment of CHF while Thiazides are found to be more
useful as antihypertensive.
Adnergic blockers
Prazosin, oxazosin and terazosin produce a competitive block of α1 adrenoceptors. They decrease peripheral
vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth
muscle. These drugs cause only minimal changes in cardiac output, renal blood flow, and glomerular filtration rate.
Therefore, long-term tachycardia and increased renin release do not occur. Postural hypotension may occur in some
individuals. Prazosin is used to treat mild to moderate hypertension and is prescribed in combination with
propranolol or a diuretic for additive effects. Reflex tachycardia and first dose syncope are almost universal adverse
effects. Concomitant use of a β-blocker may be necessary to blunt the short-term effect of reflex tachycardia.
Centrally acting cholinergic drugs
Clonidine
is partial α2-agonist diminishes central adrenergic outflow. Clonidine is used primarily for the treatment of mild
to moderate hypertension that has not responded adequately to treatment with diuretics alone. Clonidine does not
decrease renal blood flow or glomerular filtration and therefore is useful in the treatment of hypertension
complicated by renal disease. Clonidine is absorbed well after oral administration and is excreted by the kidney.
Because it causes sodium and water retention, clonidine is usually administered in combination with a diuretic.
Adverse effects are generally mild, but the drug can produce sedation and drying of nasal mucosa. Rebound
hypertension occurs following abrupt withdrawal of clonidine. The drug should therefore be withdrawn slowly if
the clinician wishes to change agents. It is also used in withdrawal symptoms of opiates.
Methyldopa
This α2--agonist is converted to methylnorepinephrine centrally to diminish the adrenergic outflow from the
CNS, leading to reduced total peripheral resistance and a decreased blood pressure. Cardiac output is not decreased
and blood flow to vital organs is not diminished. Because blood flow to the kidney is not diminished by its use, α-
157
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
methyldopa is especially valuable in treating hypertensive patients with renal insufficiency. The most common
side effects of α-methyldopa are sedation and drowsiness.
Vasodilators
Hydralazine
Causes direct vasodilation, acting primarily on arteries and arterioles. This results in a decreased peripheral
resistance, which in turn prompts a reflex elevation in heart rate and cardiac output. Adverse effects of hydralazine
therapy include headache, nausea, sweating, arrhythmia, and precipitation of angina. A lupus-like syndrome can
occur with high dosage, but it is reversible on discontinuation of the drug.
Minoxidil
It is a prodrug and converted in to the metabolite which acts as a K+ channel opener. This drug causes dilation
of resistance vessels (arterioles). Minoxidil causes serious sodium and water retention, leading to volume
overload, edema, and congestive heart failure. Minoxidil treatment also causes hypertrichosis (the growth of
body hair). This drug is now used topically to treat male pattern baldness.
Diazoxide
Is thiazide like diuretic but it has opposite renal action.
1.
It can cause sodium and water retention
2.
Inhibits insulin secretion from β cells of pancreas resulting in hyperglycemia or precipitation of
diabetes
3.
Can cause hyperuricemia by inhibiting uric acid excretion and gout can occur
Sodium nitroprusside (reduce both preload and after load)
Nitroprusside is administered intravenously, and causes prompt vasodilation, with reflex tachycardia. It is capable
of reducing blood pressure in all patients, regardless of the cause of hypertension. The drug has little effect outside
the vascular system, acting equally on arterial and venous smooth muscle. Because nitroprusside also acts on the
veins, it can reduce cardiac preload. Nitroprusside is metabolized rapidly and requires continuous infusion to
maintain its hypotensive action. Nitroprusside metabolism results in cyanide ion production, although cyanide
toxicity is rare and can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is
less toxic and is eliminated by the kidneys. Nitroprusside is poisonous if given orally because of its hydrolysis to
cyanide.
Antihypertensive drugs for emergency
Diazoxide, sodium nitroprusside, esmolol, phenetolamine, hydralazine
Antihypertensive drugs for pregnancy
158
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Cardioselective beta blockers, prazosin, clonidine, hydralazine, methyl dopa
Antihypertensive drugs avoided in pregnancy
Diuretics, ACE inhibitors, AT1 antagonist, nonselective β blockers, reserpine
159
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ANGINA
Angina, which is sometimes called angina pectoris, is chest pain that is caused by inadequate coronary blood flow to
the myocardium. When coronary blood flow cannot deliver sufficient oxygen to support cardiac oxidative
metabolism (reduced oxygen supply/demand ratio), the myocardium becomes hypoxic. This triggers pain receptors
within the heart, which lead to the classical presentation of chest pain and the sensation of substernal heaviness or
pressure. Coronary blood flow can be decreased by
1) Transient constriction of the coronary arteries (i.e., vasospasm),
2) Chronic narrowing of a coronary artery (i.e., fixed stenosis) caused by atherosclerosis, or
3) The formation of a blood clot within the vessel lumen (i.e., coronary thrombosis).
Prinzmetal's angina, also known as variant angina or angina inversa, is
caused by vasospasm, a
narrowing of the coronary arteries caused by contraction of the smooth muscle tissue in the vessel
walls rather than directly by atherosclerosis (buildup of fatty plaque and hardening of the arteries). Prinzmetal
angina typically responds to nitrates and dihydropyridine calcium channel blockers.
Stable angina refers to the more common understanding of angina related to myocardial ischemia. Typical
presentations of stable angina is that of chest discomfort and associated symptoms precipitated by some activity
(running, walking, etc) with minimal or non-existent symptoms at rest. Chronic stable angina is caused by a
chronic narrowing of coronary arteries due to atherosclerosis. This form of angina is most
commonly treated with drugs that reduce oxygen demand. These drugs include beta-blockers, calcium-channel
blockers, and nitrodilators. They act by decreasing heart rate, contractility, afterload and preload. Prophylaxis
against thrombosis with an antiplatelet drug, usually aspirin.
Unstable angina is caused by transient formation and dissolution of a blood clot (thrombosis) within a
coronary artery. The clot may also form because diseased coronary artery endothelium (endothelial dysfunction) is
unable to produce nitric oxide and prostacyclin that inhibit platelet aggregation and clot formation. When the clot
forms, coronary flow is reduced, leading to a reduction in the oxygen supply/demand ratio ("supply ischemia"). If
the clot completely occludes the coronary artery for a sufficient period of time, the myocardium supplied by the
vessel may become infracted (acute myocardial infarction) and become irreversibly damaged. This form of angina
is treated with drugs that reduce oxygen demand (i.e., beta-blockers, calcium-channel blockers, nitrodilators), but
more importantly, this form of angina is treated with drugs that inhibit thrombus
formation (e.g., anti-platelet drugs and aspirin). Heparin and platelet glycoprotein receptor
antagonists add to this benefit.
160
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Anti anginal drugs
Some of these drugs reduce oxygen demand by decreasing heart rate (decreased chronotropy) and contractility
(decreased inotropy), while other drugs reduce afterload and or preload on the heart. Afterload and preload reducing
drugs act by dilating peripheral arteries and veins. Direct vasodilation of the coronary arteries is ineffective as a
therapeutic approach and may actually worsen the ischemia by producing coronary vascular steal.
Increase Oxygen Delivery: Coronary vasodilators &Anti-thrombotic drugs
Decrease Oxygen Demand: Vasodilators (reduce afterload and preload) & Cardiac depressants (reduce heart rate
and contractility)
A. Vasodilators (dilate arteries and veins)
- Calcium-channel blockers
- Nitrodilators: Short acting (Glyceryl trinitrate, Nitroglycerine, Isosorbide dinitrate), Long
acting (Isosorbide mononitrate, Erythrityl tetranitrate)
B. Cardio inhibitory drugs (reduce heart rate and contractility)
- Beta-blockers: Propranolol, Metoprolol, Atenolol
- Calcium-channel blockers
ƒ
Verapamil (Phenylalkylamine derivative),
ƒ
Diltiazam (Benzothiazepine analogue) and
ƒ
Nifedipine (Dihydropyridines)
C. Anti-thrombotic drugs (prevent thrombus formation)
- Anticoagulants
- Anti-platelet drugs
Trimetazidine are known as pFOX inhibitors because they partially inhibit the fatty acid oxidation pathway in
myocardium. Because metabolism shifts to oxidation of fatty acids in ischemic myocardium, the oxygen
requirement per unit of ATP produced increases. Partial inhibition of the enzyme required for fatty acid oxidation
(long chain 3-ketoacyl thiolase, LC-3KAT) appears to improve the metabolic status of ischemic tissue. However,
blockade of late sodium current that facilitates calcium entry may play a larger role in the action of
ranolazine.
Nicorandil is a nicotinamide nitrate ester combines activation of the potassium KATP channel with
nitrovasodilator (nitric oxide donor) actions. It is both an arterial and a venous dilator, and causes the expected
unwanted effects of headache, flushing and dizziness. It is used for patients who remain symptomatic despite
optimal management with other drugs, often while they await surgery or angioplasty.
161
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Dipyridamole is a powerful coronary dilator which increases the total coronary flow by preventing uptake and
degradation of adenosine which is a local mediator involved in auto regulation of coronary flow in response to
ischaemia. Dipyridamole also inhibits platelet aggregation by potentiating PGI2 and increasing cAMP in
platelets which have antiplatelet aggregation effect.
Oxyphedrine improve myocardial metabolism so that heart can sustain hypoxia better. It has an adnergic effect
on heart contractility and A-V conduction
β-Adrenoceptor antagonists are important in prophylaxis of angina, and in treating patients with unstable angina.
They work for these indications by reducing cardiac oxygen consumption. In addition, they reduce the risk of death
following myocardial infarction, probably via their antidysrhythmic action. Their effects on coronary vessels are of
minor importance, although these drugs are avoided in variant angina because of the theoretical risk that they will
increase coronary spasm.
Calcium channel blockers block Ca2+ entry by preventing opening of voltage-gated L-type calcium channels.
There are three main L-type antagonists, typified by
Verapamil (Phenylalkylamine derivative or analogs of Paperverine),
Diltiazam (Benzothiazepine analogue) and
Nifedipine (Dihydropyridines)
162
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Mainly affect heart and smooth muscle, inhibiting the Ca2+ entry caused by depolarisation in these tissues.
Selectivity between heart and smooth muscle varies: verapamil is relatively Cardioselective, nifedipine
relatively smooth muscle-selective, and diltiazam is intermediate. Nimodipine
is
has some selectivity for
cerebral vasculature and is sometimes used in the hope of reducing cerebral vasospasm following
subarachnoid haemorrhage. Vasodilator effect (mainly dihydropyridines) is mainly on resistance vessels, reducing
afterload. Calcium antagonists dilate coronary vessels, which is important in variant angina. Effects on heart
(verapamil, diltiazem): antidysrhythmic action (mainly atrial tachycardias), because of impaired atrioventricular
conduction; reduced contractility. Nifedipine typically causes reflex tachycardia; diltiazem causes little or no
change in heart rate and verapamil slows the heart rate. Calcium antagonists also have a negative inotropic effect,
which results from the inhibition of the slow inward current during the action potential plateau. Unwanted effects
include headache, constipation (verapamil) and ankle oedema (dihydropyridines). There is a risk of causing cardiac
failure or heart block, especially with verapamil.
Clinical uses of calcium channel blockers:
1.
Antidysrhythmic (mainly verapamil)
2.
Angina (e.g. diltiazam)
3.
Hypertension (mainly dihydropyridines).
Control of smooth muscle contraction and site of action of calcium channel-blocking drugs. Contraction is triggered
by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels.
The calcium combines with calmodulin to form a complex that converts the enzyme myosin light chain kinase to its
active form (MLCK*). The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin
163
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
with actin. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle by
accelerating the inactivation of MLCK (heavy arrows) and by facilitating the expulsion of calcium from the cell.
Nitrates
The organic nitrates, such as nitroglycerin are thought to relax vascular smooth muscle by their intracellular
conversion to nitrite ions and then to nitric oxide (NO), which in turn activates guanylate cyclase and increases
the cells' cyclic GMP. Elevated cGMP ultimately leads to dephosphorylation of the myosin light chain, resulting in
vascular smooth muscle relaxation. Nitroglycerin is denitrated by glutathione S-transferase. Free nitrite ion is
released, which is then converted to nitric oxide. While tolerance may because in part by a decrease in tissue
sulfhydryl groups, it can be only partially prevented or reversed with a sulfhydryl-regenerating agent.
At therapeutic doses, nitroglycerin has two major effects. First, it causes dilation of the large veins, resulting in
pooling of blood in the veins. This diminishes preload (venous return to the heart), and reduces the work of the
heart. Second, nitroglycerin dilates the coronary vasculature, providing increased blood supply to the heart muscle.
Nitroglycerin causes a decrease in myocardial oxygen consumption because of decreased cardiac work.
The time to onset of action varies from one minute for nitroglycerin to more than one hour for isosorbide
mononitrate. The liver contains a high-capacity organic nitrate reductase that removes nitrate groups in a stepwise
fashion from the parent molecule and ultimately inactivates the drug. Therefore, oral bioavailability of the traditional
organic nitrates (eg, nitroglycerin and isosorbide dinitrate) is very low (typically < 10–20%). For this reason, the
sublingual route, which avoids the first-pass effect, is preferred for achieving a therapeutic blood level rapidly. The
164
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation: orthostatic hypotension,
tachycardia, and throbbing headache.
Nitrite ion reacts with hemoglobin (which contains ferrous iron) to produce methemoglobin (which contains
ferric iron). Because methemoglobin has a very low affinity for oxygen, large doses of nitrites can result in
pseudocyanosis, tissue hypoxia, and death. Fortunately, the plasma level of nitrite resulting from even large doses of
organic and inorganic nitrates is too low to cause significant methemoglobinemia in adults.
The adverse effect methemoglobinemia is useful in cyanide poisoning.
Cyanide poisoning results from
complexing of cytochrome iron by the CN– ion. Methemoglobin iron has a very high affinity for CN–; thus,
administration of sodium nitrite (NaNO2) soon after cyanide exposure will regenerate active cytochrome. The
cyanmethemoglobin produced can be further detoxified by the intravenous administration of sodium thiosulfate
(Na2S2O3); this results in formation of thiocyanate ion (SCN–), a less toxic ion that is readily excreted.
Methemoglobinemia, if excessive, can be treated by giving methylene blue intravenously.
Amyl nitrite and related nitrites are highly volatile liquids. Amyl nitrite is available in fragile glass ampules
packaged in a protective cloth covering. The ampule can be crushed with the fingers, resulting in rapid release of
inhalable vapors through the cloth covering.
Isosorbide dinitrate is an orally active nitrate. The drug is not readily metabolized by the liver or smooth muscle
and has a lower potency than nitroglycerin in relaxing vascular smooth muscle.
Sildenafil (Viagra) acts to increase cGMP by inhibiting its breakdown by phosphodiesterase isoform 5 (PDE 5).
Drug that increases cGMP might be of value in erectile dysfunction. Sildenafil also has effects on color vision,
causing difficulty in blue-green discrimination. Two similar PDE-5 inhibitors, tadalafil and vardenafil, are available.
The organic nitrates are avoided with sildenafile to prevent sever hypotensive shock and death.
Erythrityl tetranitrate are longer acting and hence only used for chronic prophylaxis.
165
Myocardial infarction
Myocardial infarction occurs when a coronary artery has been blocked by thrombus. This may be fatal and is a
common cause of death, usually as a result of mechanical failure of the ventricle or from dysrhythmia. Cardiac
myocytes rely on aerobic metabolism. If the supply of oxygen remains below a critical value, a sequence of events
leading to cell death (by necrosis or apoptosis). Prevention of irreversible ischaemic damage following an episode of
coronary thrombosis is an important therapeutic aim.
The main possibilities among existing therapeutic drugs are:
A. Thrombolytic and antiplatelet drugs (aspirin and clopidogrel) to open the blocked artery and prevent
their reocclusion
B. Oxygen
C.
Opioids to prevent pain and reduce excessive sympathetic activity
D. β-adrenoceptor antagonists
E.
Angiotensin-converting enzyme (ACE) inhibitors
The latter two classes of drug reduce cardiac work and thereby the metabolic needs of the heart. The β-adrenoceptor
antagonists have an important benefit during chronic treatment in reducing dysrhythmic deaths, and are widely used
in patients with unstable angina.
166
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
DR
RUGS USED IN PE
EPTIC ACIID- DISEA
ASES
Over 99% of peptic ulcerrs are caused by infection witth the gram neggative rod shapped bacterium Helicobacter pylori
oidal anti-inflaammatory drrugs (NSAIDss). Drugs usedd in the treatm
ment of acid--peptic
or by usee of nonstero
disorders may
m be divided
d into two classses: agents thatt
9
reeduce intragasttric acidity andd
9
A
Agents
that prom
mote mucosal defense
9
E
Eradicate
the Helicobacter
H
pylori infection
Physiolo
ogy of acid secretion
The pariettal cell contains receptors for
f gastrin, histamine
h
(H2),
) and acetylccholine (musccarinic, M3). When
acetylcholiine or gastrin bind
b
to the parietal cell recepptors, they causse an increase in cytosolic caalcium, which in
i turn
stimulates protein kinasees that stimulate acid secretionn from a H+/K
K+ ATPase (thee proton pump) on the canalicular
surface. Histamine
H
bindss to the H2 recceptor on the parietal
p
cell, reesulting in actiivation of adennylyl cyclase, which
increases intracellular
i
cy
yclic adenosinee monophosphaate (cAMP). cA
AMP activates protein kinasees that stimulatte acid
secretion by
b the H+/K+ ATPase.
A
In huumans, it is beelieved that thhe major effectt of gastrin uppon acid secrettion is
mediated indirectly
i
through the releasse of histaminee from ECL cells
c
(enterochrromaffin-like) rather than thhrough
direct parieetal cell stimullation.
167
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Secretion of gastric acid, mucus and bicarbonate
•
The control of the gastrointestinal tract is through nervous and humoral mechanisms.
o
Acid is secreted from gastric parietal cells by a proton pump (K+/H+ ATPase).
o
The three endogenous secretagogues for acid are histamine, acetylcholine and gastrin.
o
Prostaglandins E2 and I2 inhibit acid, stimulate mucus and bicarbonate secretion, and dilate
mucosal blood vessels.
•
The genesis of peptic ulcers involves:
o
infection of the gastric mucosa with Helicobacter pylori.
o
an imbalance between the mucosal-damaging (acid, pepsin) and the mucosal-protecting
agents (mucus, bicarbonate, prostaglandins E2 and I2, and nitric oxide ).
168
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Classification of anti peptic ulcer
F. Reduction in gastric acid secretion
V.
VI.
VII.
VIII.
H2 blockers : Cimetidine, Ranitidine, Roxatidine, Famotidine, Loxatidine
Proton pump inhibitors : Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole
Anticholinergics : Pirenzepine, Propantheline, Oxyphenonium
Prostaglandin analogue : Misoprostol, Enaprostil
G. Ulcer protective : Sucralfate, Colloidal bismuth sub citrate
H. Ulcer healing : Carbenoxlone sodium
I.
Antimicrobial : Clarithromycin, Metronidazole, Tetracycline, Amoxicillin, Colloidal bismuth sub citrate
J.
Neutralization of gastric acid
III.
systemic : sodium bicarbonate, sodium citrate
IV.
Nonsystemic : Magnesium hydroxide, aluminum hydroxide gel
H2 antagonists
are especially effective at inhibiting nocturnal acid secretion (which depends largely on histamine) but have a
modest impact on meal-stimulated acid secretion (which is stimulated by gastrin and acetylcholine as well as
histamine). Cimetidine, ranitidine, Famotidine, and nizatidine. All four agents are rapidly absorbed from the
intestine. Cimetidine, ranitidine, and Famotidine undergo first-pass hepatic metabolism resulting in a bioavailability
of approximately 50%. Nizatidine has little first-pass metabolism and a bioavailability of almost 100% .
Only Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of
estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia
or impotence in men and galactorrhea in women.
Drug Interactions
Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those
catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4. Hence, the half-lives of drugs metabolized by this
pathway. Negligible interaction occurs with nizatidine and Famotidine, Ranitidine.
H2 antagonists compete with certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except
Famotidine inhibit gastric first-pass metabolism of ethanol, especially in women. Increased bioavailability of
ethanol could lead to increased blood ethanol levels.
169
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
n pump in
nhibitors
Proton
omeprazole, lansoprazo
ole, rabeprazoole, pantoprazzole, and esom
meprazole. Alll are substitutted benzimidaazoles.
Omeprazole is a racemiic mixture of R- and S-isom
mers. Esomeprazole is the S-isomer of omeprazole.
o
A are
All
available inn oral formulations. Esomep
prazole, lansop
prazole, and pantoprazole
p
are also available in intravvenous
formulatioons.
Proton pum
mp inhibitors are administeered as inactivve prodrugs. To protect thhe acid-labile prodrug from rapid
destructionn within the gastric
g
lumen, oral products are formulateed for delayedd release as accid-resistant, enntericcoated cappsule or tablet formulations. After passingg through the stomach into the alkaline intestinal
i
lumeen, the
enteric coaatings dissolvee and the proodrug is absorrbed. Within the
t acidified compartment
c
the prodrug rapidly
r
becomes protonated
p
and
d is concentratted more than 1000-fold witthin the pariettal cell canalicculus by HenddersonHasselbalcch trapping. Th
he rate of connversion is invversely proporrtional to the pKa of the drrug. .Conversiion of
omeprazole to a sulfen
namide in thee acidic secrettory canaliculii of the pariettal cell. The suulfenamide intteracts
t proton pum
mp, thereby irrreversibly inhibbiting its activvity. The otherr three
covalently with sulfhydrryl groups in the
proton pum
mp inhibitors undergo
u
analoggous conversioons. Lansopraazole is also available
a
as a tablet formu
ulation
that disinttegrates in thee mouth or maay be mixed with
w water and administered
a
v oral syringee or enteral tube. The
via
170
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
patients thhose requiring
g immediate acid
a
suppressioon now can be treated paarenterally witth pantoprazoole or
lansoprazoole, both of wh
hich are approvved for intravennous administrration in the Unnited States.
Rabeprazoole (due to its higher pKa) orr immediate-rellease omeprazzole (due to itss rapid release and absorptionn) may
have a sligghtly faster onset of acid inhibbition than otheer oral formulaations.
Drug Interactions
y may alter absorption of druggs for which inntragastric aciddity affects druug bioavailabiliity, eg,
Decreased gastric acidity
Ketoconazzol and digox
xin. All protonn pump inhibittors are metabbolized by heppatic P450 cytoochromes, including
CYP2C19 and CYP3A4. Omeprazolee may inhibit the metabolissm of diazepaam and phenyytoin. Esomepprazole
also may decrease
d
metab
bolism of diazeepam. Lansoprazole may enhhance clearancee of theophylliine. Rabeprazoole and
pantoprazoole have no sig
gnificant drug innteractions
Zollinger--Ellison Syndrrome is mainlyy treated by proton pump in
nhibitors
sal Prote
ective Ag
gents
Mucos
Sucralfate is a salt of octtasulfated succrose complexxed to aluminu
um hydroxidee. In an acid ennvironment (pH
H <4),
u
exteensive cross-linnking to produuce a viscous, sticky
s
polymerr that adheres too epithelial cellls and
sucralfate undergoes
ulcer craterrs for up to 6 hours
h
after a siingle dose. In addition
a
to inhhibiting hydrolyysis of mucosaal proteins by pepsin,
p
sucralfate may have add
ditional cytoprootective effectts, including sttimulation of local
l
productioon of prostaglaandins
171
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
and epidermal growth factor. It is believed that the negatively charged sucrose sulfate binds to positively charged
proteins in the base of ulcers or erosion, forming a physical barrier that restricts further caustic damage and
stimulates mucosal prostaglandin and bicarbonate secretion. Because it is not absorbed, Sucralfate is virtually
devoid of systemic adverse effects but Sucralfate may bind to other medications, impairing their absorption. The
most common side effect of sucralfate is constipation (about 2%) as some aluminum can be absorbed.
Sucralfate forms a viscous layer in the stomach that may inhibit absorption of other drugs, including phenytoin,
digoxin, cimetidine, ketoconazole, and fluoroquinolone antibiotics.
Colloidal Bismuth Compounds
Bismuth subsalicylate undergoes rapid dissociation within the stomach, allowing absorption of salicylate. Like
sucralfate, bismuth probably coats ulcers and erosions, creating a protective layer against acid and pepsin. It may
also stimulate prostaglandin, mucus, and bicarbonate secretion. Bismuth subsalicylate reduces stool frequency and
liquidity in acute infectious diarrhea, due to salicylate inhibition of intestinal prostaglandin and chloride secretion.
Bismuth has direct antimicrobial effects and binds enterotoxins, accounting for its benefit in preventing and treating
traveler's diarrhea. Bismuth compounds have direct antimicrobial activity against H pylori. Triple therapy
“consisting of bismuth subsalicylate, tetracycline and metronidazole for the eradication up to 90%of H pylori
infection. Second-line regimens include combinations of two antimicrobial agents (metronidazole, amoxicillin or
clarithromycin) with an antisecretory agent (preferably omeprazole). Bismuth causes blackening of the stool,
which may be confused with gastrointestinal bleeding. Liquid formulations may cause harmless darkening of the
tongue. Prolonged usage of some bismuth compounds may rarely lead to bismuth toxicity, resulting in
encephalopathy (ataxia, headaches, confusion, and seizures).
Prostaglandin Analogs
The human gastrointestinal mucosa synthesizes a number of prostaglandins, the primary ones are prostaglandins E
and F. Misoprostol, a methyl analog of PGE1, has both acid inhibitory and mucosal protective properties.
Misoprostol reduces the incidence of NSAID-induced ulcers. It is believed to stimulate mucus and bicarbonate
secretion and enhance mucosal blood flow. In addition, it binds to a prostaglandin receptor on parietal cells,
reducing histamine-stimulated cAMP production and causing modest acid inhibition. Prostaglandins have a variety
of other actions, including stimulation of intestinal electrolyte and fluid secretion, intestinal motility, and uterine
contractions. Because misoprostol stimulates uterine contractions, it should not be used during pregnancy.
M1 muscarinic receptor antagonists
Pirenzepine and telenzepine can reduce basal acid production by 40% to 50%.
172
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Antacids
Are weak bases that react with gastric hydrochloric acid to form a salt and water. They directly neutralise acid, thus
raising the gastric pH; this also has the effect of inhibiting the activity of peptic enzymes, which practically ceases at
pH 5. Most antacids in common use are salts of magnesium and aluminium. Magnesium salts cause diarrhoea and
aluminium salts constipation, so mixtures of these two can, happily, be used to preserve normal bowel function.
Sodium bicarbonate acts rapidly and is said to raise the pH of gastric juice to about 7.4. Carbon dioxide is
liberated, and this causes eructation (belching). The carbon dioxide stimulates gastrin secretion and can result in a
secondary rise in acid secretion. Because some sodium bicarbonate is absorbed in the intestine, large doses or
frequent administration of this antacid can cause alkalosis, the onset of which can be insidious. To avoid this
possibility, sodium bicarbonate should not be prescribed for long-term treatment, nor should it be given to
patients who are on a sodium-restricted diet i.e. for hypertensive patients.
Magnesium hydroxide is an insoluble powder that forms magnesium chloride in the stomach. It does not produce
systemic alkalosis, because Mg2+ is poorly absorbed from the gut. Another salt, magnesium trisilicate, is an
insoluble powder that reacts slowly with the gastric juice, forming magnesium chloride and colloidal silica. This
agent has a prolonged antacid effect, and it also adsorbs pepsin.
Aluminium hydroxide gel forms aluminium chloride in the stomach; when this reaches the intestine, the chloride is
released and is reabsorbed. Aluminium hydroxide raises the pH of the gastric juice to about 4, and also adsorbs
pepsin.
Alginates or simeticone are sometimes combined with antacids. The former are believed to increase the viscosity
and adherence of mucus to the oesophageal mucosa, forming a protective barrier, whereas the latter is a surface
active compound that, by preventing 'foaming', can relieve bloating and flatulence.
All antacids may affect the absorption of other medications by binding the drug (reducing its absorption) or by
increasing intragastric pH so that the drug's dissolution or solubility (especially weakly basic or acidic drugs) is
altered. Therefore, antacids should not be given within 2 hours of doses of tetracyclines, fluoroquinolones,
itraconazole, and iron.
173
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
AN
NTIEMET
TIC DRU
UGS
174
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Emetics: Apomorphine and Ipecac
Apomorphine: is a Semisynthetic derivative of morphine and acts via D2 agonist on CTZ.
Ipecac: should be available in household for emergency emesis, its main principal is emetine.
Classification of antiemetics drugs:
G. Anticholinergics: Hyoscine, Dicyclomine
H. H1 antihistaminics: Promethazine, Diphenhydramine, Cyclizine, Meclozine, Cinnarizine
I.
Neuroleptics or antipsychotic drugs: Chlorpromazine, Prochlorperazine, Haloperidol
J.
Prokinetics: Metoclopramide, Domperidone, Cisapride, Mosapride
K. 5-HT3 antagonists: ondansetron, Granisetron
L. Adjuvant antiemetics: Benzodiazepines, Dexamethasone, Cannabinoids
The reflex mechanism of vomiting
•
Emetic stimuli include:
o
chemicals or drugs in blood or intestine
o
Neuronal input from gastrointestinal tract, labyrinth and central nervous
system (CNS).
•
Pathways and mediators include:
o
impulses from chemoreceptor trigger zone and various other CNS centres
relayed to the vomiting centre
o
Chemical transmitters such as histamine, acetylcholine, dopamine and 5hydroxytryptamine, acting on H1, muscarinic, D2 and 5-HT3 receptors,
respectively.
•
•
Antiemetic drugs include:
o
H1 receptor antagonists (e.g. cyclizine)
o
muscarinic antagonists (e.g. hyoscine)
o
5-HT3 receptor antagonists (e.g. ondansetron)
o
D2 receptor antagonists (e.g. metoclopramide)
o
cannabinoids (e.g. nabilone )
o
Neurokinin-1 antagonists (e.g. aprepitant ).
Main side effects of principal antiemetics include:
o
drowsiness and antiparasympathetic effects (hyoscine, nabilone
>
cinnarizine)
o
dystonic reactions (thiethylperazine > metoclopramide)
175
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
o
general CNS disturbances (nabilone )
o
Headache, gastrointestinal tract upsets (ondansetron).
CONTACT;sahadevparmar_22@yahoo.com
Clinical use of antiemetic drugs
•
•
Histamine H1 receptor antagonists
o
cyclizine: motion sickness
o
cinnarizine: motion sickness, vestibular disorders (e.g. Ménière's disease)
o
Promethazine: severe morning sickness of pregnancy.
Muscarinic receptor antagonists:
o
•
Hyoscine: motion sickness.
Dopamine D2 receptor antagonists:
o
phenothiazines (e.g. prochlorperazine ): vomiting caused by uraemia, radiation, viral
gastroenteritis, severe morning sickness of pregnancy
o
Metoclopramide: vomiting caused by uraemia, radiation, gastrointestinal disorders,
cytotoxic drugs.
•
5-Hydroxytryptamine 5-HT3 receptor antagonists (e.g. ondansetron): cytotoxic drugs or radiation,
postoperative vomiting.
•
Cannabinoids (e.g. nabilone ): cytotoxic drugs
H1 antagonists, cinnarizine, cyclizine, meclizine and promethazine are the most commonly employed; they
are effective against nausea and vomiting arising from many causes, including motion sickness and the presence of
irritants in the stomach. None are very effective against substances that act directly on the CTZ. Promethazine has
proven of particular benefit for morning sickness of pregnancy, and has been used by NASA to treat space
motion sickness. Drowsiness and sedation, while possibly contributing to their clinical efficacy, are the chief
unwanted effects.
Muscarinic antagonists are also good general purpose antiemetics. Hyoscine (scopolamine ) is the most
widely used example. It is employed principally for prophylaxis and treatment of motion sickness, and may be
administered orally or as a transdermal patch. Dry mouth and blurred vision are the most common unwanted
effects. Drowsiness also occurs, but the drug has less sedative action than the antihistamines.
Selective 5-HT3 receptor antagonists, including ondansetron, granisetron, tropisetron and
dolasetron, are of particular value in preventing and treating postoperative nausea and vomiting, or that caused by
176
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
radiation therapy or administration of cytotoxic drugs such as cisplatin . The primary site of action of these drugs is
the CTZ. They may be given orally or by injection (sometimes helpful if nausea is already present).
Unwanted effects such as headache and gastrointestinal upsets are relatively uncommon.
Antipsychotic phenothiazines, such as chlorpromazine, perphenazine
, prochlorperazine
and
trifluoperazine, are effective antiemetics commonly used for treating the more severe manifestations of these
disorders, particularly the nausea and vomiting associated with cancer, radiation therapy, cytotoxics, opioids,
anaesthetics and other drugs. They can be administered orally, intravenously or by suppository. They act mainly as
antagonists of the dopamine D2 receptors in the CTZ but may also block histamine and muscarinic receptors.
Unwanted effects are relatively frequent and include sedation (especially chlorpromazine), hypotension, and
extrapyramidal symptoms including dystonias and tardive dyskinesia.
Other antipsychotics, such as haloperidol and levomepromazine also act as D2 antagonists in the CTZ and can be
used for acute chemotherapy-induced emesis.
Metoclopramide and domperidone
Metoclopramide is a D2 receptor antagonist closely related to the phenothiazine group, that acts centrally on the
CTZ and also has a peripheral action on the gastrointestinal tract itself, increasing the motility of the oesophagus,
stomach and intestine. This not only adds to the antiemetic effect but explains its use in the treatment of gastrooesophageal reflux and hepatic and biliary disorders. As metoclopramide also blocks dopamine receptors
elsewhere in the central nervous system (CNS), it produces a number of unwanted effects including
parkinsonian’s like symptoms i.e. disorders of movement (more common in children and young adults), fatigue,
motor restlessness, spasmodic torticollis (involuntary twisting of the neck) and occulogyric crises (involuntary
upward eye movements). It stimulates prolactin release, causing galactorrhoea and disorders of menstruation.
Domperidone is a similar drug often used to treat vomiting due to cytotoxic therapy as well as gastrointestinal
symptoms. Unlike metoclopramide, it does not readily penetrate the blood-brain barrier and is consequently
less prone to produce central side effects. Both drugs are given orally, have plasma half-lives of 4-5 hours and are
excreted in the urine.
Cannabinoids
Anecdotal evidence originally suggested the possibility of using cannabinoids as antiemetics. Since that time,
synthetic cannabinol derivatives such as nabilone have been found to decrease vomiting caused by agents that
stimulate the CTZ, and are sometimes effective where other drugs have failed. The antiemetic effect is
antagonised by naloxone, which implies that opioid receptors may be important in the mechanism of action.
Steroids and neurokinin antagonists
177
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
High-dose glucocorticoids (particularly dexamethasone) can also control emesis, especially when this is caused by
cytotoxics such as cisplatin. The mechanism of action is not clear. Dexamethasone can be used alone but is frequently
deployed in combination with a phenothiazine, ondansetron or the neurokinin-1 antagonist aprepitant. Substance P
causes vomiting when injected intravenously and is also found both in gastrointestinal vagal afferent nerves and
in the vomiting centre itself, neurokinin-1 antagonists could be effective antiemetics.
178
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
DRUGS EFFECTING ON GIT MOTILITY
GI tract, organized into two connected networks of neurons: the myenteric (Auerbach's) plexus, found between the
circular and longitudinal muscle layers and is responsible for motor control, while other is e submucosal
(Meissner's) plexus, found below the epithelium which regulates secretion, fluid transport, and vascular flow. ACh
released from primary motor neurons in the myenteric plexus, is the principal immediate mediator of muscle
contractility.
A. Choline Derivatives
M3 receptor is more important (while M1was involved in acid secretion). Its activation increases intracellular Ca2+,
an effect mediated by the Gq-PLC-IP3 pathway. ACh itself is not used pharmacologically because it affects all
classes of cholinergic receptors (nicotinic and muscarinic) and is degraded rapidly by acetylcholinesterase.
Modification of the structure of ACh has yielded drugs such as bethanechol that have increased receptor selectivity
and that resist enzymatic hydrolysis. The side effects include bradycardia, flushing, diarrhea and cramps,
salivation, and blurred vision.
B. Dopamine-Receptor Antagonists
Dopamine has several inhibitory effects on motility, including reduction of lower esophageal sphincter and
intragastric pressures. By antagonizing the inhibitory effect of dopamine on myenteric motor neurons, dopamine
receptor antagonists are effective as prokinetic agents; they have the additional advantage of relieving nausea and
vomiting by antagonism of dopamine receptors in the chemoreceptor trigger zone. Examples of such agents are
metoclopramide and domperidone.
Prokinetic agents are medications that enhance coordinated GI motility and transit of material in the GI tract.
The mechanisms of action of metoclopramide are complex and involve
I.
II.
5-HT4-receptor agonism
5-HT3-antagonism
III.
Possible sensitization of muscarinic receptors on smooth muscle
IV.
Dopamine receptor antagonism
The major side effects of metoclopramide include extrapyramidal effects, such as those seen with the
Phenothiazines. after intravenous administration, and parkinsonian-like symptoms that may occur several weeks
after initiation of therapy generally respond to treatment with anticholinergic or antihistaminic drugs and are
reversible upon discontinuation of metoclopramide and Tardive dyskinesia can also occur. Like other dopamine
antagonists, metoclopramide also can cause galactorrhea by blocking the inhibitory effect of dopamine on
prolactin release. Methemoglobinemia has been reported occasionally in premature and full-term neonates
receiving metoclopramide.
179
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
In contrast to metoclopramide, domperidone predominantly antagonizes the dopamine D2 receptor without
major involvement of other receptors and has modest prokinetic activity. Although it does not readily cross the
blood-brain barrier to cause extrapyramidal side effects, domperidone exerts effects in the parts of the CNS that lack
this barrier, such as those regulating emesis, temperature, and prolactin release. As is the case with metoclopramide,
domperidone does not appear to have any significant effects on lower gastrointestinal motility. Other D2-receptor
antagonists being explored as prokinetic agents include levosulpiride, the levoenantiomer of sulpiride.
C. Serotonin (5-HT4) agonists
Plays an important role in the normal motor and secretory function of the gut. The enterochromaffin cell, a
specialized cell lining the mucosa of the gut, produces most of this 5-HT and rapidly releases 5-HT in response to
chemical and mechanical stimulation (e.g., food boluses; noxious agents such as cisplatinum; certain microbial
toxins; adrenergic, cholinergic). 5-HT triggers the peristaltic reflex by stimulating intrinsic sensory neurons in the
myenteric plexus (via variant 5-HT receptors, 5-HT1p, and via 5-HT4 receptors), as well as extrinsic vagal and spinal
sensory neurons (via 5-HT3 receptors). 5-HT4 stimulation of excitatory motor neurons enhances ACh release at the
neuromuscular junction, and both 5-HT3 and 5-HT4 receptors facilitate interneuronal signaling.
Cisapride (5-HT4 agonism) is a substituted piperidinyl benzamide used as prokinetic agent that appears to
stimulate 5-HT4 receptors and increase adenylyl cyclase activity within neurons. It also has weak 5-HT3
antagonistic properties and may directly stimulate smooth muscle. it was a commonly, particularly for
gastroesophageal reflux disease and gastroparesis. its potential to induce serious and occasionally fatal cardiac
arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. These
arrhythmias result from a prolonged QT interval (interaction with K+ channels). Cisapride-induced ventricular
arrhythmias occur most often when the drug is combined with other drugs that inhibit CYP3A4; such combinations
inhibit the metabolism of cisapride and lead to high plasma concentrations of the drug.
D. Motilin Agonists: Macrolides and Erythromycin
Motilin is a 22-amino acid peptide hormone found in the gastrointestinal M cells, as well as in some
enterochromaffin cells of the upper small bowel. The effects of motilin can be mimicked by erythromycin and other
macrolide antibiotics, including oleandomycin, azithromycin, and clarithromycin.
180
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Drugs used for constipation and diarrhea
Cathartic > Purgative > Laxative
Classification
1.
Bulk forming: Dietary fibers i.e. Bran, Ispaghula, Methylcellulose, Psyllium
2.
Stool softener: DOSS, Liquid paraffin
3.
Stimulant purgatives:
4.
•
Fixed oil: Castor oil
•
Diphenylmethanes: Phenolphthalein, Bisacodyl
•
Anthraquinones (Emodins): Senna, Cascara, Sagrada
Osmotic purgatives: Lactulose (Semisynthetic disaccharide of fructose and galactose), Magnesium salts
(sulfate and hydroxide) Sodium salts (sulfate and phosphate)
Mechanism of action:
a)
Inhibiting Na+K+ATPase pump in villous cells and thus impairing electrolyte and water
absorption. Rotavirus causes diarrhea by blocking this pump.
b) Stimulating adenylcyclase in crypt cells and thus increasing water and electrolyte secretion.
Cholera toxin and other toxin activate adenylyl cyclase and cause diarrhea.
c)
Enhancing PGs synthesis in mucosa which increases secretion.
d) Structural injury to the absorbing intestinal mucosal cells.
Bran, (Ispaghula, Psyllium forms a natural colloidal mucilage), methylcellulose and carboxymethylcellulose
absorbs water in the intestine, swells, increases water content of faeces.
Certain dietary fibers like gums, lignins and pectins bind to bile acids and promote their excretion resulting in
decreased bile which is synthesized from cholesterol. So for the synthesis of bile acid, cholesterol is degraded in
liver which results in plasma LDL lowered.
DOSS (Dioctyl sodium sulphosuccinate): is an anionic surfactant softens the stool by net water accumulation. It
emulsifies the colonic contents and increases penetration of water to faeces. By detergent action it can disrupt
mucosal barrier and hence the absorption of many non absorbable drugs like liquid paraffin.
Liquid paraffin impairs the absorption of Fat soluble vitamins.
Castor oil: contains TGs of ricin-oleic acid which is apolar long chain fatty acid. This is hydrolyzed in ileum lipase
to ricin-oleic acid and glycerol. Ricin-oleic being polar is poorly absorbed which irritate the mucosa and
stimulate intestinal contractions. So it causes the structural damage to villous cells.
181
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Lactulose: Semisynthetic disaccharide of fructose and galactose. It also causes reduction of blood NH3
concentration so also used in hepatic coma. Other drugs which reduce the blood NH3 are sodium benzoate,
sodium phenyl acetate. They combine ammonia in the blood to form hippuric acid or phenyl acetic glutamine
which rapidly excreted in urine.
Treatment of diarrhoea
During an episode of diarrhoea, there is an increase in the motility of the gastrointestinal tract, accompanied by an
increased secretion coupled with a decreased absorption of fluid, which leads to a loss of electrolytes (particularly
Na+) and water. Cholera toxins and some other bacterial toxins produce a profound increase in electrolyte and
fluid secretion by irreversibly activating the guanine nucleotide regulatory proteins that couple the surface receptors
of the mucosal cells to adenylate cyclase.
There are three approaches to the treatment of severe acute diarrhoea:
1) maintenance of fluid and electrolyte balance
2) use of anti-infective agents
3) Use of spasmolytic or other antidiarrhoeal agents.
In the ileum there is cotransport of Na+ and glucose across the epithelial cell. The presence of glucose (and
some amino acids ) therefore enhances Na+ absorption and thus water uptake. Preparations of sodium chloride
and glucose for oral rehydration are available in powder form, ready to be dissolved in water before use.
Campylobacter sp. is the commonest strain of bacterial organism causing gastroenteritis in the UK, and severe
infections may require erythromycin or ciprofloxacin and cotrimoxazole. The most common bacterial organisms
encountered by travellers include Escherichia coli, Salmonella and Shigella, as well as protozoa such as Giardia
and Cryptosporidium spp. Chemotherapy may be necessary in treating these and other more serious infections.
Antimotility and spasmolytic agents
The main pharmacological agents that decrease motility are opiates and muscarinic receptor antagonists.
The main opiates used for the symptomatic relief of diarrhoea are codeine (a morphine congener), diphenoxylate
and loperamide (both pethidine congeners that do not readily penetrate the blood-brain barrier and are used only
for their actions in the gut). All may have unwanted effects including constipation, abdominal cramps, drowsiness
and dizziness. Paralytic ileus can also occur. They should not be used in young (< 4 years of age) children.
Loperamide is the drug of first choice for traveller's diarrhoea and is a component of several proprietary
antidiarrhoeal medicines. It has a relatively selective action on the gastrointestinal tract and undergoes significant
182
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
enterohepatic cycling. It reduces the frequency of abdominal cramps, decreases the passage of faeces and shortens
the duration of the illness.
Diphenoxylate also lacks morphine-like activity in the CNS. Preparations of diphenoxylate usually contain atropine
as well. Codeine and loperamide have antisecretory actions in addition to their effects on intestinal motility.
Cannabinoid receptor agonists also reduce gut motility in animals, most probably by decreasing acetylcholine
release from enteric nerves.
Muscarinic receptor antagonists decrease spasm by inhibiting parasympathetic activity. Agents available include
atropine, hyoscine, propantheline and dicycloverine. The last named is thought to have some additional direct
relaxant action on smooth muscle. Mebeverine, a derivative of reserpine , has a direct relaxant action on
gastrointestinal smooth muscle.
Adsorbents
The main preparations used contain kaolin, pectin, chalk, charcoal, methyl cellulose and activated attapulgite
(magnesium aluminium silicate). These agents may act by adsorbing micro-organisms or toxins, by altering
the intestinal flora or by coating and protecting the intestinal mucosa.
183
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
DRUGS FOR CHRONIC BOWEL DISEASE
This category comprises irritable bowel syndrome, ulcerative colitis and Crohn's disease. Ulcerative colitis and
Crohn's disease are inflammatory disorders. Crohn's disease is a granulomatous condition especially affecting the
terminal ileum and the colon.
1. Glucocorticoids
Glucocorticoids are potent anti-inflammatory agents . The drugs of choice are prednisolone or budesonide , given
orally or locally into the bowel by suppository or enema.
2. Aminosalicylates
While glucocorticoids are useful for the acute attacks of inflammatory bowel diseases, they are not the ideal for
the long-term treatment (because of their side effects). Maintenance of remission in both ulcerative colitis and
Crohn's is generally achieved using the aminosalicylates, although they are less useful in the latter condition.
Sulfasalazine is a combination of the sulfonamide sulfapyridine with 5-aminosalicylic acid. The latter forms the
active moiety when it is released in the colon. It may reduce inflammation by scavenging free radicals, by inhibiting
prostaglandin and leukotriene production, and/or by decreasing neutrophil chemotaxis and superoxide generation. Its
unwanted effects are diarrhoea, salicylate sensitivity and interstitial nephritis. 5-aminosalicylic acid is not absorbed
but the sulfapyridine moiety, which seems to be therapeutically inert in this instance, is absorbed, and its unwanted
effects are those associated with the sulfonamides. Newer compounds in this class, which presumably share a
similar mechanism of action, include mesalazine (5-aminosalicylic acid itself), olsalazine (two molecules of 5aminosalicylic acid linked by a diazo bond, which is hydrolysed by colonic bacteria) and balsalazide (4aminosalicylic acid).
3. Other drugs
The immunosuppressants azathioprine and 6-mercaptopurine are also sometimes used in patients with severe
disease. Recently, the cytokine inhibitor infliximab has been used with success for the treatment of inflammatory
bowel diseases. The drug is expensive, and in the UK its use is restricted to severe Crohn's disease that is
unresponsive to glucocorticoids or immunomodulators. The antiallergy drug sodium cromoglicate is sometimes
used for treating gastrointestinal symptoms associated with food allergies.
184
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Drugs used to treat cholesterol cholelithiasis
The commonest pathological condition of the biliary tract is cholesterol cholelithiasis, i.e. the formation of
gallstones with high cholesterol content. Surgery is generally the preferred option, but there are orally active drugs
that dissolve non-calcified 'radiolucent' cholesterol gallstones. The principal agent is ursodeoxycholic acid, a minor
constituent of human bile. Diarrhoea is the main unwanted effect.
Drugs affecting biliary spasm
Biliary colic, the pain produced by the passage of gallstones through the bile duct, can be very intense, and
immediate relief may be required. Buprenorphine relieves the pain effectively. Atropine is commonly employed to
relieve biliary spasm because it has antispasmodic action and may be used in conjunction with morphine. The
nitrates can produce a marked fall of intrabiliary pressure and may be used to relieve biliary spasm.
185
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
5-HYDROXYTRYPTAMINE RECEPTORS
•
There are seven types (5-HT1-7), with further subtypes of 5-HT1 (A-F) and 5-HT2 (A-C). All are G-protein-coupled receptors,
except 5-HT3, which is a ligand-gated cation channel.
•
5-HT1 receptors occur mainly in central nervous system (CNS) (all subtypes) and some blood vessels (5-HT1D subtype).
Effects, mediated through inhibition of adenylate cyclase, are neural inhibition and vasoconstriction. Specific agonists
include sumatriptan (used in migraine therapy) and buspirone (used in anxiety). Ergotamine is a partial agonist. Specific
antagonists include spiperone and methiothepin.
•
5-HT2 receptors occur in CNS and many peripheral sites (especially blood vessels, platelets, autonomic neurons). Neuronal
and smooth muscle effects are excitatory. Some blood vessels dilated as a result of nitric oxide release from endothelial
cells. 5-HT2 receptors act through the phospholipase C/inositol trisphosphate pathway. Specific ligands include lysergic acid
diethylamide (LSD; agonist in CNS, antagonist in periphery). Specific antagonists are Ketanserin, methysergide and
cyproheptadine.
•
5-HT3 receptors occur in peripheral nervous system, especially nociceptive afferent neurons and enteric neurons, and in CNS.
Effects are excitatory, mediated through direct receptor-coupled ion channels. Specific agonist is 2-methyl-5-HT. Specific
antagonists include ondansetron and tropisetron. These are mostly used to treat anti-cancer drug induced emesis like
cisplatin. Antagonists are used mainly as antiemetic drugs but may also be anxiolytic.
•
5-HT4 receptors occur mainly in the enteric nervous system (also in CNS). Effects are excitatory, through stimulation of
adenylate cyclase, causing increased gastrointestinal motility. Specific agonists include metoclopramide, cisapride (used to
stimulate gastric emptying).
•
Little is known so far about the function and pharmacology of 5-HT5-7 receptors.
186
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Receptor
1A
Location
CNS
Main effects
Neuronal inhibition
Behavioural effects: sleep,
feeding, thermoregulation,
anxiety
Second messenger
↓cAMP
Agonists
Buspirone, 5carboxamidotryptamine
Antagonists
Spiperone
Methiothepin
Ergotamine
1B
CNS
Vascular
smooth
muscle
Presynaptic inhibition
Behavioural effects
Pulmonary vasoconstriction
↓cAMP
Ergotamine, 5carboxamidotryptamine
Methiothepin
1D
CNS
Blood
vessels
Cerebral vasoconstriction
Behavioural effects:
locomotion
↓cAMP
5carboxamidotryptamine,
Sumatriptan
Methiothepin
Ergotamine
2A
Smooth
muscle
Platelets
Smooth muscle contraction
(gut, bronchi, etc.)
Platelet aggregation
Vasoconstriction/vasodilatation
↑IP3/DAG
α-Me-5-HT LSD (CNS)
LSD (periphery)
Ketanserin
Cyproheptadine
Pizotifen (nonselective)
Methysergide
3
PNS
Emesis
Behavioural effects: anxiety
None-ligand-gated
cation channel
4
PNS (GI
tract)
CNS
Increases GI motility
↑cAMP
Cisapride, 5-Methoxytryptamine,
Metoclopramide
7
CNS
GI tract
Blood
vessels
↑cAMP
LSD or lysergic acid
diethylamide
Ondansetron
Tropisetron
Granisetron
187
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Important drugs that act on 5-HT receptors in the periphery include the following.
•
Selective 5-HT1A agonists, such as 8-hydroxy-2-(di-n-propylamino) tetralin are potent hypotensive agents,
acting by a central mechanism, but are not used clinically.
•
5-HT1D receptor agonists (e.g. sumatriptan) used for treating migraine.
•
5-HT2 receptor antagonists (e.g. dihydroergotamine, methysergide, cyproheptadine, ketanserin, ketotifen,
pizotifen) act mainly on 5-HT2 receptors but also block other 5-HT receptors, as well as α adrenoceptors
and histamine receptor. Dihydroergotamine and methysergide belong to the ergot family (see below)
and are used mainly for migraine prophylaxis. Other 5-HT2 antagonists are used to control the
symptoms of carcinoid tumours.
•
5-HT3 receptor antagonists (e.g. ondansetron, granisetron, tropisetron) are used as antiemetic drugs
particularly for controlling the severe nausea and vomiting that occurs with many forms of cancer
chemotherapy.
•
5-HT4 receptor agonists, which stimulate coordinated peristaltic activity (known as a 'prokinetic action'),
are used for treating gastrointestinal disorders. Metoclopramide acts in this way, although it also affects
dopamine receptors. The new drug tegaserod is more selective and is used to treat irritable bowel
syndrome.
5-HT is also important as a neurotransmitter in the CNS, and several important antipsychotic and antidepressant drugs
owe their actions to effects on these pathways. LSD is a relatively non-selective 5-HT receptor agonist or partial
agonist, which acts centrally as a potent hallucinogen.
Ergot alkaloids
•
These active substances are produced by a fungus that infects cereal crops; it is responsible for occasional
poisoning incidents. The most important compounds are:
•
o
Ergotamine, Dihydroergotamine, used in migraine
o
Ergometrine, used in obstetrics to prevent postpartum haemorrhage
o
Methysergide, used to treat carcinoid syndrome, and occasionally for migraine prophylaxis
o
Bromocriptine, used in Parkinsonism and endocrine disorders.
Main sites of action are 5-HT receptors, dopamine receptors and adrenoceptors (mixed agonist, antagonist
and partial agonist effects).
•
Unwanted effects include nausea and vomiting, vasoconstriction (ergot alkaloids are contraindicated in
patients with peripheral vascular disease).
188
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
A. Drugs for acute migraine attack
Sumatriptan: 5-HT1Dreceptor agonist Constricts large arteries, inhibits trigeminal nerve transmission. Others
includes Almotriptan, Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Zolmitriptan.
Ergotamine: 5-HT1 receptor partial agonist; also affects α-adrenoceptors Vasoconstrictor Blocks trigeminal nerve
transmission. Coffee increases effectiveness of ergot alkaloids.
B. Drugs for prophylaxis of migraine
Propranolol and similar drugs (e.g. metoprolol): these drugs are most widely used for prophylaxis of migraine.
β-adrenoceptor antagonists Mechanism of antimigraine effect not clear, but it can cause Fatigue
Bronchoconstriction
Methysergide: 5-HT2 receptor antagonist/partial agonist
Pizotifen:
5-HT2
receptor
antagonist,
also
muscarinic
acetylcholine
antagonist,
Weight
gain
Antimuscarinic side effects
Cyproheptadine: 5-HT2 receptor antagonist, also blocks histamine receptors and calcium channels, also cause
weight gain
189
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Carcinoid syndrome is a rare disorder associated with malignant tumours of enterochromaffin cells, which usually
arise in the small intestine and metastasise to the liver. These tumours secrete a variety of chemical mediators: 5-HT
is the most important, but neuropeptides, such as substance P , and other agents, such as prostaglandins and
bradykinin, are also produced. The release of these substances into the bloodstream results in several unpleasant
symptoms, including flushing, diarrhoea, bronchoconstriction and hypotension, which may cause dizziness or
fainting. Stenosis of heart valves, which can result in cardiac failure, also occurs.
Adenosine receptors
Adenosine which is a purine formed from AMP by the action of enzyme adenosine kinase .
The main effects of adenosine and the receptors involved are as follow.
•
Vasodilatation, including coronary vessels (A2), except in the kidney, where A1 receptors produce
vasoconstriction. Adenosine infusion causes a fall in blood pressure.
•
Inhibition of platelet aggregation (A2).
•
Block of cardiac atrioventricular conduction (A1) and reduction of force of contraction.
•
Bronchoconstriction,
especially
in
asthmatic
subjects
(A1);
the
antiasthmatic
effect
of
methylxanthines may partly reflect A1 receptor antagonism.
•
Release of mediators from mast cells (A3): this contributes to bronchoconstriction.
•
Stimulation of nociceptive afferent neurons, especially in the heart (A2): adenosine release in response to
ischaemia has been suggested as a mechanism of anginal pain.
•
Inhibition of transmitter release at many peripheral and central synapses (A1). In the CNS, adenosine
generally exerts a pre- and postsynaptic depressant action, reducing motor activity, depressing respiration,
inducing sleep and reducing anxiety, all of which effects are the opposite of those produced by
methylxanthines.
•
Neuroprotection, in cerebral ischaemia, probably through inhibition of glutamate release through A1
receptors.
Because of its inhibitory effect on cardiac conduction, adenosine may be used as an intravenous bolus injection to
terminate supraventricular tachycardia. It is safer than alternative drugs such as β-adrenoceptor antagonists or
verapamil, because of its short duration of action. Otherwise, adenosine is not used therapeutically, although
longer-lasting A1 receptor agonists might prove useful in various conditions (e.g. hypertension, ischaemic heart
disease and stroke). Selective adenosine receptor antagonists could also have advantages over theophylline in the
treatment of asthma . Adenosine uptake is blocked by dipyridamole, a vasodilator and antiplatelet drug.
190
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
HISTAMINE
(b-aminoethylimidazole) is formed from decarboxylation of Imidazole ring containing amino acid histidine. Histamine is a
basic amine, stored in mast cell and basophil granules, and secreted when C3a and C5a interact with specific membrane
receptors or when antigen interacts with cell-fixed immunoglobulin E. Histamine plays a central role in immediate
hypersensitivity (Type 1) and allergic responses. The actions of histamine on bronchial smooth muscle and blood vessels
account for many of the symptoms of the allergic response. In addition, certain clinically useful drugs can act directly on
mast cells to release histamine, thereby explaining some of their untoward effects. Histamine has a major role in the
regulation of gastric acid secretion and also modulates neurotransmitter release. Stimulation of IgE receptors also
activates phospholipase A2 (PLA2), leading to the production of a host of mediators, including platelet-activating factor
(PAF) and metabolites of arachidonic acid. Leukotriene D4, which is generated in this way, is a potent contractor of the
smooth muscle of the bronchial tree. Kinins also are generated during some allergic responses. Thus the mast cell secretes a
variety of inflammatory mediators in addition to histamine, each contributing to the major symptoms of the allergic
response. Epinephrine and related drugs that act through b2 adrenergic receptors increase cellular cyclic AMP and
thereby inhibit the secretory activities of mast cells. So are given in anaphylactic shock treatment. However, the
beneficial effects of b adrenergic agonists in allergic states such as asthma are due mainly to their relaxant effect on
bronchial smooth muscle. Cromolyn or Cromoglicate sodium is used clinically because it inhibits the release of
mediators from mast and other cells in the lung.
Drug which release histamine: Tubocurarine, succinylcholine, morphine, Polymyxin B, bacitracin,
Vancomycin-induced "red-man syndrome" involving upper body and facial flushing and hypotension may be mediated
through histamine release. Bradykinin is a poor histamine releaser, whereas kallidin (Lys-bradykinin) and substance P, with
more positively charged amino acids, are more active.
191
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
•
Histamine produces effects by acting on H1, H2 or H3 (and possibly H4) receptors on target cells.
•
The main actions in humans are:
•
o
Stimulation of gastric secretion (H2)
o
Contraction of most smooth muscle, except blood vessels (H1)
o
Cardiac stimulation (H2)
o
Vasodilatation (H1)
o
Increased vascular permeability (H1).
Injected intradermally, histamine causes the 'triple response': reddening (local vasodilatation), weal
(direct action on blood vessels) and flare (from an 'axon' reflex in sensory nerves releasing a peptide
mediator).
•
The main pathophysiological roles of histamine are:
o
as a stimulant of gastric acid secretion (treated with H2-receptor antagonists)
o
as a mediator of type I hypersensitivity reactions such as urticaria and hay fever (treated with H1receptor antagonists).
•
H3 receptors occur at presynaptic sites and inhibit the release of a variety of neurotransmitters.
H1 antagonists
A. Sedating H1 antagonists (1st generation antihistaminics)
1.
Chlorpheniramine , Clemastine
2.
Diphenhydramine- Mainly used as a mild hypnotic, also show significant antimuscarinic effects
3.
Cyproheptadine - Used also for migraine due to additional 5-hydroxytryptamine antagonist activity
4.
Promethazine- Also used for motion sickness, Used for anaesthetic premedication to prevent postoperative vomiting, , weak blockade at α1 adrenoceptors
5.
Hydroxyzine – used also to treat anxiety
6.
Alimemazine- Used for premedication
7.
Doxylamine, Triprolidine - Mainly used as an ingredient of proprietary decongestant and other medicines
192
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
B. Non-sedating H1 antagonists (2nd generation antihistaminics, Do not penetrate the blood-brain
barrier)
1.
Desloratidine: Metabolite of loratidine
2.
Fexofenadine: Metabolite of Terfenadine
3.
Levocetrizine: Isomer of cetrizine
4.
Terfenadine: Grapefruit juice inhibits metabolism; rare fatal arrhythmias or QT
interval prolongation as it blocks the K+ conduction in heart leading to ventricular
tachycardia. The arrhythmiac potential increases when given with erythromycin,
ketoconazole etc.
5.
Mizolastine: May cause QT interval prolongation
6.
Azelastine: in addition to inhibit histamine release, it also inhibits inflammation triggered
by leukotrienes and given as nasal spray for rhinitis.
7.
Acrivastine
8.
Loratidine
Some important drugs
I.
Antihistaminic which increases the appetite and weight gain: Buclizine (used for underweight
children), Cyproheptadine, Astimazol
While the adnergic drugs called anorectics like Fenfluramine and Desfluramine is appetite suppressant.
II.
Mepyramine : also have local anaesthetic property also or membrane stabilizing activity (antiarrythimic
III.
Cinnarizine: is drug choice for vertigo, it is antihistaminic, anticholinergic, anti-5-HT and
vasodilator also. It inhibits vestibular sensory nuclei, post-rotatary labyrinthine refluxes by reducing the
calcium influx from endolympth into vestibular sensory cells.
IV.
Diphenhydramine is generally combined with Thecolic acid to reduce the sedative effect of
193
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
diphenhydramine.
H2 blockers: are used to treat ulcers and includes the drug like cimetidine, ranitidine etc.
194
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
EICOSANOIDS
The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release lysosomal
enzymes; arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized.
The cyclooxygenase (COX) pathway of arachidonate metabolism produces prostaglandins, which have a variety of
effects on blood vessels, on nerve endings, and on cells involved in inflammation. The discovery of cyclooxygenase
isoforms (COX-1 and COX-2) led to the concepts that the constitutive COX-1 isoform tends to be homeostatic in
function, while COX-2 is induced during inflammation and tends to facilitate the inflammatory response. On
this basis, highly selective COX-2 inhibitors have been developed and marketed on the assumption that such
selective inhibitors would be safer than nonselective COX-1 inhibitors but without loss of efficacy. The
lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic
effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in
vascular permeability.
Kinins, neuropeptides, and histamine are also released at the site of tissue injury, as are complement
components, cytokines, and other products of leukocytes and platelets. Stimulation of the neutrophil membranes
produces oxygen-derived free radicals. Superoxide anion is formed by the reduction of molecular oxygen, which
may stimulate the production of other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The
interaction of these substances with arachidonic acid results in the generation of chemotactic substances, thus
perpetuating the inflammatory process.
In mammals, the main eicosanoid precursor is arachidonic acid (5, 8, 11, 14-eicosatetraenoic acid), a 20-carbon
unsaturated fatty acid containing four double bonds (hence eicosa, referring to the 20 carbon atoms, and tetraenoic,
referring to the four double bonds). In most cell types, arachidonic acid is esterified in the phospholipid pool, and
the concentration of the free acid is low. The principal eicosanoids are the prostaglandins, the thromboxanes
and the leukotrienes, although other derivatives of arachidonate, for example the lipoxins, are also produced.
In most instances, the initial and rate-limiting step in eicosanoid synthesis is the liberation of arachidonate, either in
a one-step process or a two-step process, from phospholipids by the enzyme phospholipase A2 (PLA2). Several
species exist, but the most important is probably the highly regulated cytosolic PLA2. This enzyme generates not
only arachidonic acid (and thus eicosanoids) but also lysoglyceryl-phosphorylcholine (lyso-PAF), the precursor
of platelet activating factor, another inflammatory mediator.
The free arachidonic acid is metabolised by several pathways, including the following.
•
Fatty acid cyclo-oxygenase (COX). Two main isoform forms, COX-1 and COX-2, transform arachidonic
acid to prostaglandins and thromboxanes.
•
Lipoxygenases. Several subtypes synthesize leukotrienes, lipoxins or other compounds
195
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
196
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
The term prostanoids encompasses the prostaglandins and the thromboxanes.
•
PGI2 (prostacyclin), predominantly from vascular endothelium, acts on IP receptors, producing
vasodilatation and inhibition of platelet aggregation.
•
Thromboxane (TX) A2, predominantly from platelets, acts on TP receptors, causing platelet aggregation
and vasoconstriction.
•
PGE2 is prominent in inflammatory responses and is a mediator of fever. Main effects are:
o
EP1 receptors: contraction of bronchial and gastrointestinal tract (GIT) smooth muscle
o
EP2 receptors: relaxation of bronchial, vascular and GIT smooth muscle
o
EP3 receptors: inhibition of gastric acid secretion, increased gastric mucus secretion, contraction
of pregnant uterus and of GIT smooth muscle, inhibition of lipolysis and of autonomic
neurotransmitter release.
•
PGF2α acts on FP receptors, found in uterine (and other) smooth muscle, and corpus luteum, producing
contraction of the uterus and luteolysis (in some species).
197
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
•
CONTACT;sahadevparmar_22@yahoo.com
PGD2 is derived particularly from mast cells and acts on DP receptors, causing vasodilatation and
inhibition of platelet aggregation.
Prostaglandins of the E series are also pyrogenic (i.e. they induce fever). High concentrations are found in
cerebrospinal fluid during infection, and there is evidence that the increase in temperature (attributed to cytokines) is
actually finally mediated by the release of PGE2. NSAIDs exert antipyretic actions by inhibiting PGE2 synthesis in
the hypothalamus.
Clinical uses of prostanoids
•
Gynecological and obstetric
o
termination of pregnancy: Gemeprost or misoprostol (a metabolically stable prostaglandin (PG)
E analogue)
•
o
induction of labour: Dinoprostone (PGE2 analogue)
o
Postpartum haemorrhage: Carboprost ( 15-α methyl PGF2α analogue)
Gastrointestinal
o
•
or misoprostol
to prevent ulcers associated with non-steroidal anti-inflammatory drug use: misoprostol
Cardiovascular
o
to maintain the patency of the ductus arteriosus until surgical correction of the defect in babies
with certain congenital heart malformations: Alprostadil (PGE1)
o
to inhibit platelet aggregation (e.g. during haemodialysis): Epoprostenol or Cicaprost (PGI2
analogue ), especially if heparin is contraindicated
o
•
Primary pulmonary hypertension: Epoprostenol.
Ophthalmic
o
Open-angle glaucoma: latanoprost (PGF2α analogue)
eye drops.
Dinoprostone (PGE2 analogue)
Carboprost ( 15-α methyl PGF2α analogue)
latanoprost (PGF2α analogue)
Misoprostol (PGE1 analogue)
Misoprostol is approved for use in the prevention of NSAID-induced gastric ulcers. It acts upon gastric parietal
cells, inhibiting the secretion of gastric acid via G-protein coupled receptor-mediated inhibition of adenylate cyclase,
which leads to decreased intracellular cyclic AMP levels and decreased proton pump activity at the apical surface of
the parietal cell. Because other classes of drugs, especially H2-receptor antagonists and proton pump inhibitors, are
more effective for the treatment of acute peptic ulcers, Misoprostol is only indicated for use by people who are both
198
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
taking NSAIDs and are at high risk for NSAID-induced ulcers, including the elderly and people with ulcer
complications. Misoprostol is sometimes co-prescribed with NSAIDs to prevent their common adverse effect of
gastric ulceration (e.g. with Diclofenac in Arthrotec). Misoprostol may stimulate increased secretion of the
protective mucus that lines the gastrointestinal tract and increase mucosal blood flow, thereby increasing mucosal
integrity—however, these effects are not pronounced enough to warrant prescription of misoprostol at doses lower
than those needed to achieve gastric acid suppression
199
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
BRADYKININ
BK is a nonapeptide 'clipped' from a plasma α-globulin, kininogen, by kallikrein.
•
It is converted by kininase I to an octapeptide, BK1-8 (des-Arg9-BK), and inactivated by kininase II
(angiotensin-converting enzyme) in the lung.
•
•
Pharmacological actions:
o
vasodilatation (largely dependent on endothelial cell nitric oxide and prostaglandin I2)
o
increased vascular permeability
o
stimulation of pain nerve endings
o
stimulation of epithelial ion transport and fluid secretion in airways and gastrointestinal tract
o
Contraction of intestinal and uterine smooth muscle.
There are two main subtypes of BK receptors: B2, which is constitutively present, and B1, which is induced
in inflammation.
Leukotrienes
•
5-Lipoxygenase oxidises arachidonate to give 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is
converted to leukotriene (LT) A4. This, in turn, can be converted to either LTB4 or to a series of glutathione
adducts, the cysteinyl-leukotrienes LTC4, LTD4 and LTE4.
•
LTB4 mainly involves in inflammatory cells, acting on specific receptors, causes adherence, chemotaxis and
activation of polymorphs and monocytes, and stimulates proliferation and cytokine production from macrophages
and lymphocytes.
•
The cysteinyl-leukotrienes cause:
o
Contraction of bronchial muscle mainly LTC4, LTD4
o
Vasodilatation in most vessels, but coronary vasoconstriction.
o
LTB4 is an important mediator in all types of inflammation; the cysteinyl-leukotrienes are of particular
importance in asthma.
200
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
o
CONTACT;sahadevparmar_22@yahoo.com
The CysLT-receptor or leukotriene antagonist zafirlukast and montelukast are now in use in the
treatment of asthma. Cysteinyl-leukotrienes may mediate the cardiovascular changes of acute
anaphylaxis.
201
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ASTHMA
Asthma is defined as recurrent reversible airway obstruction, with attacks of wheeze, shortness of breath and often
nocturnal cough. Severe attacks cause hypoxaemia and are life-threatening. Essential features include: airways
inflammation, which causes bronchial hyper-responsiveness, which in turn results in recurrent reversible airway
obstruction. Pathogenesis involves exposure of genetically disposed individuals to allergens; activation of Th2
lymphocytes and cytokine generation promote:
o
Differentiation and activation of eosinophils
o
IgE production and release
o
Expression of IgE receptors on mast cells and eosinophils.
o
Important mediators include leukotriene B4 and cysteinyl leukotrienes (C4 and D4); interleukins IL4, IL-5, IL-13; and tissue-damaging eosinophil proteins.
DRUGS USED TO TREAT ASTHMA
There are two categories of antiasthma drugs: bronchodilators and anti-inflammatory agents. Bronchodilators reverse
the bronchospasm of the immediate phase; anti-inflammatory agents inhibit or prevent the inflammatory components
of both phases.
Theophylline and leukotriene antagonists, such as montelukast, also exert a corticosteroid-sparing effect
Cromoglicate (see below) has only a weak effect and is now seldom used.
BRONCHODILATORS
The main drugs used as bronchodilators are β2-adrenoceptor agonists; others include xanthines, cysteinyl leukotriene
receptor antagonists and muscarinic receptor antagonists.
β-Adrenoceptor agonists
Two categories of β2-adrenoceptor agonists are used in asthma.
•
Short-acting agents: Salbutamol and Terbutaline, duration of action is 3-5 hours.
•
Longer-acting agents: e.g. Salmeterol and Formoterol, the duration of action is 8-12 hours.
•
Others are Adrenaline, Ephedrine, Isoprenaline
Xanthine drugs
There are three pharmacologically active, naturally occurring methylxanthines: theophylline , theobromine and
caffeine . Theophylline
(1,3-dimethylxanthine), which is also used as theophylline
ethylenediamine (known as
aminophylline ), is the main therapeutic drug of this class.
202
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Actions
Antiasthmatic. Methylxanthines have long been used as bronchodilators.
Central nervous system. Methylxanthines stimulate the CNS, increasing alertness. They can cause tremor and
nervousness, and can interfere with sleep and have a stimulant action on respiration. This may be useful in patients
with COPD and reduced respiration evidenced by a tendency to retain CO2 (see below).
Cardiovascular. Methylxanthines stimulate the heart having positive chronotropic and inotropic actions, while
relaxing vascular smooth muscle. They cause generalised vasodilatation but constrict cerebral blood vessels.
Kidney. Methylxanthines are weak diuretics, although this effect is not therapeutically useful.
Mechanisms of action
The relaxant effect on smooth muscle has been attributed to inhibition of the phosphodiesterase (PDE) isoenzymes,
with resultant increase in cAMP and/or cGMP . However, the concentrations necessary to inhibit the isolated enzymes
exceed the therapeutic range of plasma concentrations.
Competitive antagonism of adenosine at adenosine A1 and A2 receptors may contribute, but the PDE inhibitor
enprofylline, which is a potent bronchodilator, is not an adenosine antagonist.
Type IV PDE is implicated in inflammatory cells and non-specific methylxanthines may have some anti- inflammatory
effect. (Roflumilast, a type IV PDE inhibitor.
Clinical use of theophylline
•
As a second-line drug, in addition to steroids, in patients whose asthma does not
respond adequately to β2-adrenoceptor agonists.
•
Intravenously (as aminophylline
, a combination of theophylline
with
ethylenediamine to increase its solubility in water) in acute severe asthma.
Muscarinic receptor antagonists
The main compound used as a bronchodilator is ipratropium, is a quaternary derivative of N-isopropylatropine.
Cysteinyl leukotriene receptor antagonists
All the cysteinyl leukotrienes (LTC4, LTD4 and LTE4) act on the same high-affinity cysteinyl leukotriene receptor
termed CysLT1. Two receptors have been cloned, CysLT1 and CysLT2, and both are expressed in respiratory mucosa
and infiltrating inflammatory cells, but the functional significance of each is unclear. The 'lukast' drugs (montelukast
and zafirlukast ) antagonise only CysLT1.
203
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Used for some patients with chronic obstructive pulmonary disease, especially long-acting drugs (e.g. tiotropium).
ANTI-INFLAMMATORY AGENTS
The main drugs used for their anti-inflammatory action in asthma are the glucocorticoids.
Glucocorticoids
Systemic : Prednisolone, Hydrocortisone
Inhalational: Triamcinolone, Beclomethasone
They are not bronchodilators but prevent the progression of chronic asthma and are effective in acute severe asthma.
Actions and mechanism
The basis of the anti-inflammatory action of glucocorticoids . An important action, of relevance for asthma, is that they
decrease formation of cytokines), in particular the Th2 cytokines that recruit and activate eosinophils and are
responsible for promoting the production of IgE and the expression of IgE receptors . Glucocorticoids also inhibit the
generation of the vasodilators PGE2 and PGI2, by inhibiting phospholipase A2. By inducing annexin 1, they could
inhibit production of leukotrienes and platelet- activating factor, although there is currently no direct evidence that
the release of this protein is involved in the antiasthma effects of glucocorticoids. The main compounds used are
beclometasone, budesonide , fluticasone, mometasone and ciclesonide.
Cromoglicate and nedocromil ('mast cell stabiliser')
These drugs are now hardly used for the treatment of asthma. Cromoglicate is a 'mast cell stabiliser', preventing hista
release from mast cells.
Anti-IgE treatment
Omalizumab is a humanised monoclonal anti-IgE antibody. It is effective in patients with allergic asthma as well
204
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
allergic rhinitis.
COUGH
Cough is a protective reflex that removes foreign material and secretions from the bronchi and bronchioles. It
is a very common adverse effect of angiotensin-converting enzyme inhibitors.
Drugs for cough
Codeine (methylmorphine) is a weak opioid. Dextromethorphan and pholcodine are believed to have fewer
adverse effects.
205
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
NSAIDS
They provide symptomatic relief from pain and swelling in chronic joint disease such as occurs in osteo- and
rheumatoid arthritis, and in more acute inflammatory conditions such as sports injuries, fractures, sprains and other
soft tissue injuries. They also provide relief from postoperative, dental and menstrual pain, and from the pain of
headaches and migraine.
COX-1 is a constitutive enzyme expressed in most tissues, including blood platelets. It has a 'housekeeping' role in
the body, being involved in tissue homeostasis, and is responsible for the production of prostaglandins involved in,
for example, gastric cytoprotection platelet aggregation renal blood flow auto regulation and the initiation of
parturition.
In contrast, COX-2 is induced in inflammatory cells when they are activated, and the primary inflammatory
cytokines-interleukin (IL)-1 and tumour necrosis factor (TNF)-α are important in this regard. Thus the COX-2
isoform is responsible for the production of the prostanoid mediators of inflammation although there are some
significant exceptions. For example, there is a considerable pool of 'constitutive' COX-2 present in the central
nervous system (CNS) and some other tissues, although its function is not yet completely clear.
Most 'traditional' NSAIDs are inhibitors of both isoenzymes of COX by inhibiting dioxygenation step. although
they vary in the degree to which they inhibit each isoform. It is believed that the anti-inflammatory action (and
probably most analgesic actions) of the NSAIDs is related to their inhibition of COX-2, while their unwanted
effects-particularly those affecting the gastrointestinal tract-are largely a result of their inhibition of COX-1.
Compounds with a selective inhibitory action on COX-2 are now in clinical use, but expectations that these
inhibitors would transform the treatment of inflammatory conditions have received a setback because of an
increase in cardiovascular risk (Rolecoxib)
Normal body temperature is regulated by a centre in the hypothalamus that controls the balance between heat loss
and heat production. Fever occurs when there is a disturbance of this hypothalamic 'thermostat', which leads to the
set point of body temperature being raised. NSAIDs 'reset' this thermostat. The NSAIDs exert their antipyretic
action largely through inhibition of prostaglandin production in the hypothalamus. During an inflammatory
reaction, bacterial endotoxins cause the release from macrophages of a pyrogen-IL-1 which stimulates the
generation, in the hypothalamus, of E-type prostaglandins that elevate the temperature set point. COX-2 may
have a role here, because it is induced by IL-1 in vascular endothelium in the hypothalamus.
So NASIDS have following actions:
•
Anti-inflammatory action: the decrease in prostaglandin E2 and prostacyclin reduces vasodilatation
and, indirectly, oedema. Accumulation of inflammatory cells is not reduced.
206
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
•
CONTACT;sahadevparmar_22@yahoo.com
An analgesic effect: decreased prostaglandin generation means less sensitisation of nociceptive nerve
endings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine. Relief of headache is
probably a result of decreased prostaglandin-mediated vasodilatation.
•
An antipyretic effect: interleukin-1 releases prostaglandins in the central nervous system, where they
elevate the hypothalamic set point for temperature control, thus causing fever. NSAIDs prevent this.
Classification
A. Nonselective COX inhibitors
1.
Salicylates: Aspirin, Diflunisal
2.
Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone
3.
Anthranilic acid derivatives: Mephenamic acid
4.
Aryl acetic acid derivatives: Diclofenac
5.
Indole derivatives: Indomethacin, Sulindac
6.
Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flubiprofen
7.
Oxicam derivatives: Piroxicam, Tenoxicam
8.
Pyrrolo-pyrrole derivatives: Ketorolac
B. Preferential COX-2 inhibitors: Nimesulide, Meloxicam, Nabumetone
C. Selective COX-2 inhibitors: Celecoxib, Rofecoxib, Valdecoxib, Parecoxib (Prodrug of valdecoxib)
D. Analgesic-antipyretic with poor anti-inflammatory: Paracetamol
1.
Pyrozolone derivatives: Metamizole (Dipyrone), Propiphenazone
2.
Benzoxazocine derivatives: Nefopam
207
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Some important points:
1.
NSAIDS which are prodrugs: Sulindac, Fenoprofen, Nabumetone
2.
NSAIDS which reduce chemotaxis of leukocytes and useful in acute gout: Indomethacin, Naproxen,
Piroxicam
3.
Drugs for post-operative pain: Ketorolac, Nefopam, Etodolac
4.
Gastric intolerance to conventional NASIDS uses Rofecoxib or selective COX-2 inhibitors.
5.
Patients with history of asthma or anaphylaxis: Nimesulide
Some adverse effects of NASIDS:
•
Aspirin cause local damage to the gastric mucosa directly or some gastric bleeding. Oral
administration of prostaglandin analogues such as misoprostol (PGE1 analogue) can diminish the gastric
damage produced by these agents.
•
Severe rashes or idiosyncratic reaction are common with Mefenamic acid and Sulindac.
•
Analgesic nephropathy characterised by chronic nephritis and renal papillary necrosis is caused by
chronic NSAID consumption i.e. Phenacetin (Prodrug of Paracetamol) one of its metabolite but
paracetamol is safe.
•
Paracetamol over dose can cause liver toxicity. This occurs when the liver enzymes catalysing the
normal conjugation reactions are saturated, causing the drug to be metabolised instead by mixed function
oxidases. The resulting toxic metabolite, N-acetyl-p-benzoquinone imine, is inactivated by conjugation
with glutathione, but when glutathione is depleted the toxic intermediate accumulates and reacts with
nucleophilic constituents in the cell. This causes necrosis in the liver and also in the kidney tubules. The
liver damage can be prevented by giving agents that increase glutathione formation in the liver
(N-acetylcysteine intravenously, or methionine orally).
•
Rolecoxib severe cardiovascular toxicity and hence banned.
•
Phenylbutazone severe agranulocytosis and fluid retention.
Aspirin
Aspirin is rapidly hydrolysed by esterases in the plasma and the tissues-particularly the liver-yielding salicylate.
Salicylate is oxidized, some is conjugated to give the glucuronide or sulfate before excretion. Aspirin cause
Salicylism and Reye's syndrome (a rare disorder of children that is characterised by hepatic encephalopathy
following an acute viral illness).
Salicylate poisoning is a result of disturbances of the acid-base and the electrolyte balance that may be seen in
patients treated with high doses of salicylate-containing drugs and in attempted suicides. These drugs can uncouple
oxidative phosphorylation (mainly in skeletal muscle), leading to increased oxygen consumption and thus
increased production of carbon dioxide. This stimulates respiration, which is also stimulated by a direct action of the
208
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
drugs on the respiratory centre. The resulting hyperventilation causes a respiratory alkalosis that is normally
compensated by renal mechanisms involving increased bicarbonate excretion. Larger doses can cause a depression
of the respiratory centre, which leads eventually to retention of carbon dioxide and thus an increase in plasma carbon
dioxide. Because this is superimposed on a reduction in plasma bicarbonate, an uncompensated respiratory acidosis
will occur. This may be complicated by a metabolic acidosis, which results from the accumulation of metabolites of
pyruvic, lactic and acetoacetic acids (an indirect consequence of interference with carbohydrate metabolism)
•
Aspirin causes a potentially hazardous increase in the effect of warfarin, partly by displacing it from
plasma proteins so increase the risk of bleeding.
•
Aspirin being a weak acid also interferes with the effect of uricosuric agents such as probenecid and
sulfinpyrazone , and because low doses of aspirin may, on their own, reduce urate excretion, so aspirin
should not be used in gout.
•
Aspirin potentiates the hypoglycemic effect of oral hypoglycemic drugs like Tolbutamide, Glibenclamide
209
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Meloxicam: The drug is popular in Europe and many other countries for most rheumatic diseases and has recently
been approved for treatment of osteoarthritis in the USA. Meloxicam is known to inhibit synthesis of
thromboxane A2; it appears that even at supratherapeutic doses its blockade of thromboxane A2 does not reach
levels that result in decreased in vivo platelet function.
Valdecoxib has no effect on platelet aggregation or bleeding time. Valdecoxib was withdrawn from the market in
the USA in early 2005 in response to FDA concerns about cardiovascular risks and Stevens-Johnson syndrome,
but the drug is still available in other countries.
Diflunisal is derived from salicylic acid, it is not metabolized to salicylic acid or salicylate. It undergoes an
enterohepatic cycle with reabsorption of its glucuronide metabolite followed by cleavage of the glucuronide to again
release the active moiety.
Etodolac provides good postoperative pain relief after coronary artery bypass operations, although transient
impairment of renal function has been reported.
Ketorolac drug is an effective analgesic and has been used successfully to replace morphine in some situations
involving mild to moderate postsurgical pain. It is most often given intramuscularly or intravenously.
Nefopam is a nonopioid analgesic which does not inhibit PG synthesis. It also has anticholinergic activity. It
provides good postoperative pain relief
Indomethacin is an indole derivative. It is a potent nonselective COX inhibitor and may also inhibit
phospholipase A and C, reduce neutrophil migration, and decrease T cell and B cell proliferation.
Indomethacin is more effective in relieving inflammation than is aspirin or any of the other NSAIDs.
Indomethacin is indicated for use in rheumatic conditions and is particularly popular for gout and ankylosing
spondylitis. In addition, it has been used to treat patent ductus arteriosus. Indomethacin can cause CNS effects are
dizziness, vertigo, light-headedness, and mental confusion and hence avoided during the driving of vehicles.
Piroxicam an oxicam is a nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear
leukocyte migration or chemotaxis of leukocytes, decreases oxygen radical production, and inhibits lymphocyte
function. Its long half-life permits once-daily dosing.
Naproxen is potent particularly inhibiting leukocyte migration and hence suitable for acute gout.
Ketoprofen is a propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase.
210
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Nabumetone is prodrug and the only nonacid NSAID in current use; it is converted to the active acetic acid
derivative in the body. It is given as a ketone prodrug that resembles naproxen in structure.
Sulindac is a sulfoxide prodrug. It is reversibly metabolized to the active sulfide metabolite, which is excreted in
bile and then reabsorbed from the intestine. The enterohepatic cycling prolongs the duration of action. In addition to
its rheumatic disease indications, sulindac suppresses familial intestinal polyposis; it may inhibit the development of
colon, breast, and prostate cancer in humans.
Phenylbutazone has powerful anti-inflammatory effects but weak analgesic and antipyretic activities.
Phenylbutazone is prescribed chiefly in short term therapy of acute gout and in acute rheumatoid arthritis when
other NSAID agents have failed. Phenylbutazone is extensively bound to plasma proteins. This property causes
displacement of warfarin, oral hypoglycemics and sulfonamides from binding sites on plasma proteins, causing
transient elevations in the free fraction of these drugs. The most serious adverse effects are agranulocytosis and
aplastic anemia. Other side effects include fluid and electrolyte (sodium and chloride) retention, with resulting
edema and decreased urine volume. Phenylbutazone reduces the uptake of iodine by the thyroid gland,
sometimes resulting in goiter and myxedema.
Diclofenac is approved for long-term use in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing
spondylitis. It is more potent than indomethacin or naproxen. Diclofenac accumulates in synovial fluid.
Acetaminophen or Paracetamol and Phenacetin act by inhibiting prostaglandin synthesis in the CNS. This
explains their antipyretic and analgesic properties. They have less effect on cyclooxygenase in peripheral tissues,
which accounts for their weak anti-inflammatory activity. Acetaminophen and phenacetin do not affect platelet
function or increase blood clotting time, and they lack many of the side-effects of aspirin. Phenacetin can no
longer be prescribed in the United States because of its potential for renal toxicity. Acetaminophen is the
analgesic-antipyretic of choice for children with viral infections or chicken pox (aspirin increases the risk of Reye's
syndrome). Acetaminophen does not antagonize the uricosuric agent probenecid and therefore may be used in
patients with gout taking that drug. Acetaminophen is a suitable substitute for the analgesic and antipyretic effects of
aspirin in those patients with gastric complaints and in those for whom prolongation of bleeding time would be a
disadvantage or who do not require the anti- inflammatory action of aspirin.
Under normal circumstances, acetaminophen is conjugated in the liver to form inactive glucuronidated or sulfated
metabolites. A portion of acetaminophen is hydroxylated to form N-acetyl-benzoquinoneimine--a highly reactive
and potentially dangerous metabolite that reacts with sulfhydryl groups. At normal doses of acetaminophen, the Nacetyl-benzoquinoneimine reacts with the sulfhydryl group of glutathione, forming a nontoxic substance.
Acetaminophen and its metabolites are excreted in the urine. With large doses of acetaminophen, the available
glutathione in the liver becomes depleted and N-acetyl-benzoquinoneimine reacts with the sulfhydryl groups of
hepatic proteins, forming covalent bonds. Hepatic necrosis, a very serious and potentially life-threatening
211
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
condition, can result. Administration of N-acetylcysteine, which contains sulfhydryl groups to which the toxic
metabolite can bind, can be life-saving if administered within 10 hours of the overdose.
Ibuprofen is safest NASIDS among the conventional NASIDS. Flurbiprofen is mostly used as ocular antiinflammatory.
212
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ANTI-GOUT DRUGS
Gout is a metabolic disease in which plasma urate concentration is raised because of overproduction (sometimes
linked to indulgence in alcoholic beverages, especially beer, or purine-rich foods such as offal, or increased cell
turnover as in haematological malignancies, particularly when treated with cytotoxic drugs) or impaired excretion of
uric acid. It is characterised by very painful intermittent attacks of acute arthritis produced by the deposition of
crystals of sodium urate (a product of purine metabolism) in the synovial tissue of joints and elsewhere. When
an inflammatory response is evoked, involving activation of the kinin, complement and plasmin systems, generation
of lipoxygenase products such as leukotriene B4 and local accumulation of neutrophil granulocytes. These
engulf the crystals by phagocytosis, releasing tissue-damaging toxic oxygen metabolites and subsequently
causing lysis of the cells with release of proteolytic enzymes. Urate crystals also induce the production of IL-1
and possibly other cytokines too.
Drugs used to treat gout may act in the following ways:
•
By inhibiting uric acid synthesis: Allopurinol (Main prophylactic drug)
•
By increasing uric acid excretion (uricosuric agents: Probenecid , Sulfinpyrazone both are also used as
prophylactic drug)
•
By inhibiting leucocyte migration into the joint (Colchicine for acute attack)
•
By a general anti-inflammatory and analgesic effect (NSAIDs).
Allopurinol
Allopurinol is an analogue of hypoxanthine and reduces the synthesis of uric acid by competitive inhibition of
xanthine oxidase. Some inhibition of de novo purine synthesis also occurs. Allopurinol
is converted to
alloxanthine by xanthine oxidase, and this metabolite, which remains in the tissue for a considerable time, is an
effective non-competitive inhibitor of the enzyme. The pharmacological action of allopurinol is largely due to
alloxanthine. Allopurinol reduces the concentration of the relatively insoluble urates and uric acid in tissues, plasma
and urine, while increasing the concentration of their more soluble precursors, the xanthines and hypoxanthines. The
deposition of urate crystals in tissues (tophi) is reversed, and the formation of renal stones is inhibited. Allopurinol
is the drug of choice in the long-term treatment of gout, but it is ineffective in the treatment of an acute attack and
may even exacerbate the inflammation.
213
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Allopurinol can cause potentially fatal skin diseases (Stevens-Johnson syndrome and toxic epidermal
necrolysis-a horrible disorder where skin peels away in sheets as if scalded) are rare but devastating.
•
Allopurinol increases the effect of mercaptopurine , an antimetabolite used in cancer chemotherapy and
also that of azathioprine (an immunosuppressant used to prevent transplant rejection which is metabolised
to mercaptopurine) . Allopurinol also enhances the effect of another anticancer drug, cyclophosphamide
.
Colchicine
Colchicine is drug choice for acute attack. Colchicine an alkaloid extracted from the autumn crocus. It has a
specific effect in gouty arthritis and can be used both to prevent and to relieve acute attacks. It prevents migration
of neutrophils into the joint, apparently by binding to tubulin, resulting in the depolymerisation of the
microtubules and reduced cell motility. Colchicine-treated neutrophils develop a 'drunken walk'. Colchicine may
also prevent the production of a putative inflammatory glycoprotein by neutrophils that have phagocytosed
urate crystals, and other mechanisms may also be important in bringing about its effects.
214
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Drugs acting on blood
Haemostasis is the arrest of blood loss from damaged blood vessels and is essential to life. A wound causes
vasoconstriction, accompanied by:
•
Adhesion and activation of platelets
•
Fibrin formation.
Platelet activation leads to the formation of a haemostatic plug, which stops the bleeding and is subsequently
reinforced by fibrin.
Thrombosis is the pathological formation of a 'haemostatic' plug within the vasculature in the absence of bleeding.
An arterial thrombus is composed of so-called white thrombus consisting mainly of platelets and leucocytes in a
fibrin mesh. It is usually associated with atherosclerosis. It interrupts blood flow, causing ischaemia or death
(infarction) of the tissue beyond. Venous thrombus is composed of 'red thrombus' and consists of a small white head
and a large jelly-like red tail, similar in composition to a blood clot, which streams away in the flow. Thrombus can
break away, forming an embolus; this may lodge in the lungs or, if it comes from the left heart or a carotid artery, in
the brain or other organs, causing death or other disaster.
Drugs affect haemostasis and thrombosis in three distinct ways, by affecting:
•
Blood coagulation (fibrin formation)
•
Platelet function
•
Fibrin removal (fibrinolysis).
215
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Blood coagulation
•
Inactive precursors are activated in series, each giving rise to more of the next.
•
The last enzyme, Thrombin (factor IIa) , derived from prothrombin (II), converts soluble fibrinogen (I) to
an insoluble meshwork of fibrin in which blood cells are trapped, forming the clot.
•
There are two pathways in the cascade:
o
The extrinsic pathway, which operates in vivo
o
The intrinsic or contact pathway, which operates in vitro.
•
Both pathways result in activation of factor X, which then converts prothrombin to thrombin .
•
Calcium ions and a negatively charged phospholipid (PL) are essential for three steps, namely the actions of:
o
Factor IXa on X
o
Factor VIIa on X
o
Factor Xa on II.
•
PL is provided by activated platelets adhering to the damaged vessel.
•
Some factors promote coagulation by binding to PL and a serine protease factor; for example, factor Va in the
activation of II by Xa, or VIIIa in the activation of X by IXa.
The role of thrombin
216
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Thrombin (factor IIa) cleaves fibrinogen, producing fragments that polymerise to form fibrin. It also activates factor
XIII, a fibrinoligase, which strengthens fibrin-to-fibrin links, thereby stabilizing the coagulum. In addition to
coagulation, thrombin also causes platelet aggregation, stimulates cell proliferation and modulates smooth muscle
contraction.
Drugs that act on the coagulation cascade
Classic haemophilia A, caused by lack of factor VIII, and an even rarer form of haemophilia (haemophilia B or
Christmas disease) caused by lack of factor IX (also called Christmas factor).
Vitamin K is a fat-soluble vitamin occurring naturally in plants. It is essential for the formation of clotting factors
II, VII, IX and X. These are all glycoproteins with several γ-carboxyglutamic acid (Gla) residues. γ-Carboxylation
occurs after the synthesis of the chain, and the carboxylase enzyme requires vitamin K as a cofactor. The
reduced vitamin K (the hydroquinone ) acts as a cofactor in the conversion of glutamic acid (Glu) to γcarboxyglutamic acid (Gla). During this reaction, the reduced form of vitamin K is converted to the epoxide,
which in turn is reduced to the quinone and then the hydroquinone.
Natural vitamin K (phytomenadione) may be given orally or by injection. If given by mouth, it requires bile salts
for absorption, and this occurs by a saturable energy-requiring process in the proximal small intestine. A synthetic
preparation, menadiol sodium phosphate, is also available. It is water-soluble and does not require bile salts for its
absorption. This synthetic compound takes longer to act than phytomenadione. There is very little storage of vitamin
K in the body. It is metabolised to more polar substances that are excreted in the urine and the bile. Vitamin K is
used for prevention of bleeding from excessive oral anticoagulation (e.g. by warfarin) and in babies: to
prevent haemorrhagic disease of the newborn.
Anticoagulants
217
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Heparin is not a single substance but a family of sulfated glycosaminoglycans (mucopolysaccharides) DGlucosamine + L-Iduronic acid + D-Glucuronic acid. It is present together with histamine in the granules of mast
cells. Heparin inhibits coagulation, both in vivo and in vitro, by activating antithrombin III.
Antithrombin III inhibits thrombin
and other serine proteases by binding to the
active serine site. The main hazard of heparin is haemorrhage, which is treated by stopping therapy and, if
necessary, giving protamine sulfate (heparin antagonist). This heparin antagonist is a strongly basic
protein that forms an inactive complex with heparin.
Heparin fragments (e.g. enoxaparin, dalteparin) or a synthetic pentasaccharide (fondaparinux), referred to as lowmolecular-weight heparins (LMWHs), are used increasingly in place of unfractionated heparin.
Heparin is not absorbed from the gut because of its charge and large size, and it is therefore given intravenously or
subcutaneously.
Antithrombin III-independent anticoagulants
Hirudins are direct thrombin inhibitors derived from the anticoagulant present in saliva from the medicinal
leech. Lepirudin is a related polypeptide that binds irreversibly both to the fibrin-binding and catalytic sites
on thrombin.
VITAMIN K ANTAGONISTS: WARFARIN
Warfarin is the most important oral anticoagulant. S-isomer is more potent then R-isomer. Vitamin K antagonists
act by interfering with the post-translational γ-carboxylation of glutamic acid residues in clotting factors II,
VII, IX and X. They do this by inhibiting enzymic reduction of vitamin K to its active hydroquinone form.
Their effect takes several days to develop because of the time taken for degradation of preformed carboxylated
clotting factors. Their onset of action thus depends on the elimination half-lives of the relevant factors. Factor
VII, with a half-life of 6 hours, is affected first, then IX, X and II, with half-lives of 24, 40 and 60
hours, respectively.
Dicumarole: can cause bleeding at normal dose.
218
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
A. Factors that potentiate oral anticoagulants :
Various diseases and drugs potentiate warfarin, increasing the risk of haemorrhage.
1. Disease
Liver disease interferes with the synthesis of clotting factors; conditions in which there is a high metabolic rate, such as
fever and thyrotoxicosis, increase the effect of anticoagulants by increasing degradation of clotting factors.
2. Agents that inhibit hepatic drug metabolism
Examples include cimetidine , imipramine, co-trimoxazole, chloramphenicol , ciprofloxacin, metronidazole ,
amiodarone and many antifungal azoles. Stereoselective effects (warfarin is a racemate, and its isomers are metabolised
differently from one another)
3. Drugs that inhibit platelet function. Aspirin increases the risk of bleeding if given during warfarin therapy,
although this combination can be used safely with careful monitoring. Other non-steroidal anti-inflammatory drugs
(NSAIDs) also increase the risk of bleeding, partly by their effect on platelet thromboxane synthesis and, in the case of
some NSAIDs, also by inhibiting warfarin metabolism as above. Some antibiotics, including moxalactam and
carbenicillin, inhibit platelet function.
4. Drugs that displace warfarin from binding sites on plasma albumin. Some of the NSAIDs and chloral hydrate ,
for example, result in a transient increase in the concentration of free warfarin in plasma. This mechanism seldom
causes clinically important effects, unless accompanied in addition by inhibition of warfarin metabolism, as with
phenylbutazone.
5. Drugs that inhibit reduction of vitamin K. Such drugs include the cephalosporins like cefamendole and
cefoperazone.
6. Drugs that decrease the availability of vitamin K. Broad-spectrum antibiotics and some sulfonamides depress the
intestinal flora that normally synthesize vitamin K2 (a form of vitamin K made by gut bacteria); this has little effect
unless there is concurrent dietary deficiency.
7. Liquid paraffin reduce the absorption of vitamin K.
B. Factors that lessen the effect of oral anticoagulants
1. Physiological state/disease
There is a decreased response to warfarin in conditions (e.g. pregnancy) where there is increased coagulation factor
synthesis. Similarly, the effect of oral anticoagulants is lessened in hypothyroidism, which is associated with
reduced degradation of coagulation factors.
2. Vitamin K. This vitamin is a component of some parenteral feeds and vitamin preparations.
3. Oral contraceptives increase the blood levels of blood clotting factors.
219
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
4. Drugs that induce hepatic P450 enzymes. Enzyme induction (e.g. by rifampicin, carbamazepine
,
barbiturates, griseofulvin ) increases the rate of degradation of warfarin. Induction may wane only slowly after the
inducing drug is discontinued, making it difficult to adjust the dose appropriately.
6.
Drugs that reduce absorption. Drugs that bind warfarin in the gut, for example colestyramine, reduce its
absorption
ANTIPLATELET DRUGS OR ANTITHROMBOTIC DRUGS
Healthy vascular endothelium prevents platelet adhesion. Platelets adhere to diseased or damaged areas and
become activated, i.e. they change shape, exposing negatively charged phospholipids and glycoprotein (GP)
IIb/IIIa receptors, and synthesise and/or release various mediators, for example thromboxane A2 and ADP,
which activate other platelets, causing aggregation. Aggregation entails fibrinogen binding to GPIIb/IIIa
receptors on adjacent platelets. Activated platelets constitute a focus for fibrin formation. Chemotactic factors and
growth factors necessary for repair, but also implicated in atherogenesis, are released during platelet activation.
220
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Antiplatelet drugs
•
Aspirin inhibits cyclo-oxygenase irreversibly. The balance between prostaglandin (PG) I2 (an inhibitor
of aggregation generated by vascular endothelium) and thromboxane (a stimulant of aggregation generated
by platelets) is thus altered, because the endothelium can synthesise more enzyme but platelets cannot.
Aspirin is very important clinically.
•
Clopidogrel is a prodrug. Given by mouth, it inhibits platelet responses to ADP. Its actions are additive
with aspirin .
•
Antagonists of GPIIb/IIIa receptors include a monoclonal antibody (abciximab
) and several
oligopeptides (e.g. tirofiban). They inhibit diverse agonists, for example ADP and thromboxane (TX) A2,
because different pathways of activation converge on GPIIb/IIIa receptors. They are used intravenously for
short-term treatment.
•
Dipyridamole is a phosphodiesterase inhibitor. It is used in addition to aspirin .
•
Epoprostenol (synthetic PGI2) is chemically unstable. Given as an intravenous infusion, it acts on I
Prostanoid (IP) phosphate receptors on vascular smooth muscle and platelets, stimulating adenylate
cyclase and thereby causing vasodilatation and inhibiting aggregation caused by any pathway (e.g. ADP
and TXA2).
•
Agents that inhibit TXA2 synthesis or block TXA2 receptors, or have both actions, are available but are not
used clinically.
Aspirin alters the balance between TXA2, which promotes aggregation, and PGI2, which inhibits it. Aspirin
inactivates cyclo-oxygenase (COX)-acting mainly on the constitutive form COX-1-by irreversibly acetylating a
serine residue in its active site. This reduces both TXA2 synthesis in platelets and PGI2 synthesis in endothelium.
Sulfinpyrazone being reversible rather than irreversible inhibitors of COX is also used.
Dipyridamole unlike aspirin , it caused no excess risk of bleeding. Dipyridamole is a vasodilator introduced to
treat angina pectoris.
Thienopyridine derivatives like Ticlopidine and Clopidogrel inhibits ADP-dependent aggregation. Its
action is slow in onset, taking 3-7 days to reach maximal effect.
221
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
222
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
FIBRINOLYSIS (THROMBOLYSIS)
Fibrinolytic (thrombolytic) drugs are used clinically, principally to reopen the occluded coronary artery in patients
with acute myocardial infarction, less commonly in patients with life-threatening venous thrombosis or pulmonary
embolism.
Streptokinase is a protein extracted from cultures of streptococci. It activates plasminogen. Infused
intravenously, it reduces mortality in acute myocardial infarction, and this beneficial effect is additive with aspirin .
Its action is blocked by anti bodies, which appear about 4 days or more after the initial dose. So streptokinase
is antigenic in nature. At least 1 year must elapse before it is used again.
223
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Alteplase and duteplase are, respectively, single- and double-chain recombinant tissue plasminogen
activators or tPA. They are more active on fibrin-bound plasminogen than on plasma plasminogen, and are
therefore said to be 'clot-selective'. Recombinant tPA is not antigenic, and can be used in patients likely to have
antibodies to streptokinase . Because of their short half-lives, they must be given as intravenous infusions.
Reteplase
is similar but has a longer elimination half-life, allowing for bolus administration and making for
simplicity of administration. It is available for clinical use in myocardial infarction.
The main hazard of all fibrinolytic agents is bleeding, including gastrointestinal haemorrhage and stroke. If
serious, this can be treated with tranexamic acid, fresh plasma or coagulation factors. Streptokinase can cause
allergic reactions and low-grade fever. Streptokinase causes a burst of plasmin formation, generating kinins and
can cause hypotension by this mechanism.
Antifibrinolytic and haemostatic drugs
Tranexamic acid inhibits plasminogen activation and thus prevents fibrinolysis. It can be given orally or
by intravenous injection. It is used to treat various conditions in which there is bleeding or risk of bleeding, such
as haemorrhage following prostatectomy or dental extraction, in menorrhagia (excessive menstrual blood loss) and
for life-threatening bleeding following thrombolytic drug administration.
Aprotinin inhibits proteolytic enzymes and is used for hyperplasminaemia caused by fibrinolytic drug overdose
and in patients at risk of major blood loss during cardiac surgery
224
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
DIURETICS
A "diuretic" is an agent that increases urine volume, while a "natriuretic" causes an increase in renal sodium
excretion. Because natriuretics almost always also increase water excretion, they are usually called diuretics.
PCT: In the extensively convoluted proximal tubule located in the cortex of the kidney, almost all of the glucose,
bicarbonate, amino acids and other metabolites are reabsorbed. Bicarbonate is normally completely reabsorbed in
the proximal tubule. This is achieved by combination with protons, yielding carbonic acid, which dissociates to form
carbon dioxide and water-a reaction catalysed by carbonic anhydrase present in the lumenal brush border of the
proximal tubule cells followed by passive reabsorption of the dissolved carbon dioxide. Carbonic anhydrase
inhibitors like Acetazolamide act in this site.
Ascending limb: Has very low permeability to water, i.e. the tight junctions really are 'tight'. Active reabsorption of
Na+, K+ and CI- is mediated by Na+/K+/2 Cl- symporter. Loop diuretics like furosemide, Ethacrynic acid block
this symporter.
Distal tubule: Na+/CI - transporter, which is sensitive to thiazide diuretics.
225
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Collecting tubules: The principal and intercalated cells of the collecting tubule are responsible for Na+- K+
exchange and for H+ secretion and K+ reabsorption, respectively. Stimulation of aldosterone receptors in the
principal cells results in Na+ reabsorption and K+ secretion. Aldosterone enhances Na+ reabsorption and promotes
K+ excretion. It promotes Na+ reabsorption by:
•
a rapid effect, stimulating Na+/H+ exchange by an action on membrane aldosterone receptors
•
a delayed effect, via nuclear receptors directing the synthesis of a specific protein mediator that activates
sodium channels in the apical membrane
Classification
A. High ceiling loop diuretics: (Inhibitors of Na+/K+/2 Cl- symporter)
1.
Sulphamoyl derivatives : Furosemide, Bumetanide
2.
Phenoxy acetic acid derivatives: Ethacrynic acid
B. Medium efficacy diuretics: (Inhibitors of Na+/Cl- symporter)
1.
Benzothiazides: Chlorothiazide, Hydrochloethiazide, Benzthiazide, Hydroflumethiazide
2.
Thiazides like (related heterocyclic’s): Chlorthalidone, Metolazone, Xipamide, Indapamide
C. Weak or adjuvant diuretic
a.
Carbonic anhydrase inhibitors: Acetazolamide
b.
Potassium sparing diuretics
i.
Aldosterone antagonist: Spironolactone
ii.
Inhibitors of renal epithelial Na+ channel : Triamterene, Amiloride
c.
Osmotic diuretics: Mannitol, Isosorbide, Glycerol
d.
Xanthines: Theophylline
Acetazolamide is a sulfonamide without antibacterial activity. Its main action is to inhibit the enzyme carbonic
anhydrase in the proximal tubular epithelial cells. Carbonic anhydrase catalyzes the reaction of CO2 and H2O
leading to H+ and HCO3-. The decreased ability to exchange Na+ for H+ in the presence of acetazolamide results in a
mild diuresis. Additionally, HCO3- is retained in the lumen with marked elevation in urinary pH. However,
carbonic anhydrase inhibitors are more often used for their other pharmacologic actions rather than for their
diuretic effect like glaucoma, epilepsy, mountain sickness because these agents are much less efficacious than
the thiazides or loop diuretics.
Loop diuretics are inhibitors of Na+/K+/2 Cl- symporter. The loop diuretics are the drugs of choice for reducing the
acute pulmonary edema of congestive heart failure. Because of their rapid onset of action, the drugs are useful in
emergency situations, such as acute pulmonary edema, which calls for a rapid, intense diuresis. Loop diuretics
226
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
(along with hydration) are also useful in treating hypercalcemia because they stimulate tubular Ca ++
secretion.
Adverse effect includes
1.
Ototoxicity: (particularly with Ethacrynic acid) and avoided with aminoglycosides.
2.
Hyperuricemia: Furosemide and ethacrynic acid compete with uric acid for the renal and biliary
secretory systems, thus blocking its secretion and thereby causing or exacerbating gouty attacks.
3.
Hypokalemia or Potassium depletion: The heavy load of Na+ presented to the collecting tubule results in
increased exchange of tubular Na+ for K+, with the possibility of inducing hypokalemia. The loss of K+
from cells in exchange for H+ leads to hypokalemic alkalosis. Hypokalemia can potentiate digoxin
toxicity. Potassium depletion can be averted by use of potassium-sparing diuretics or dietary
supplementation with K+.
4.
Hyperglycemia:
5.
Hypovolaemia and hypotension: Due to excessive Na+ loss and diuresis are
Some important points
•
Furosemide also has weak carbonic anhydrase activity.
•
Bumetanide is 40 times more potent than Furosemide.
•
Ethacrynic acid mainly causes hearing loss.
•
Chlorthalidone and Indapamide is long acting and particularly used as antihypertensive.
•
Shorter-acting drugs such as bendroflumethiazide while longer acting thiazide is Chlorthalidone.
•
Theophylline or methylxanthines block the renal adenosine A1 receptors.
•
Mannitol, Isosorbide and glycerol are orally active osmotic diuretics which are mainly used to reduce
intraocular tension or intra cranial tension.
Thiazides diuretics (Inhibitors of Na+/Cl- symporter) have an incompletely understood vasodilator action and can
cause hyperglycaemia. When used in the treatment of hypertension, the initial fall in blood pressure results from the
decreased blood volume caused by diuresis, but the later phase is also related to an action on vascular smooth
muscle. Note that diazoxide , a non-diuretic thiazide, has powerful vasodilator effects caused by activation of
KATP channels implicated in the control of membrane potential in vascular smooth muscle and in insulin secretion.
It markedly increases blood sugar, an effect opposite to that of chemically related sulfonylureas such as
glibenclamide that inhibit KATP channels and are used to treat diabetes. Indapamide
is said to lower blood
pressure with less metabolic disturbance than related drugs, possibly because it is marketed at a lower equivalent
dose.
227
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Clinical uses of thiazide diuretics (e.g. bendroflumethiazide )
•
Hypertension.
•
Mild heart failure (loop diuretics are usually preferred).
•
Severe resistant oedema (Metolazone, especially, is used, together with loop
diuretics).
•
To prevent recurrent stone formation in idiopathic hypercalciuria.
•
Nephrogenic diabetes insipidus.
Spironolactone is a aldosterone antagonist used to prevent hypokalaemia when combined with loop
diuretics or with thiazides. They compete with aldosterone for its intracellular receptors, thereby inhibiting distal
Na+ retention and K+ secretion. The spironolactone receptor complex is inactive, that is, it prevents translocation of
the receptor complex into the nucleus of the target cell, and thus does not bind to DNA. This results in a failure to
produce proteins that are normally synthesized in response to aldosterone. These mediator proteins normally
stimulate the Na+-K+ exchange sites of the collecting tubule. Thus, a lack of mediator proteins prevents Na +
reabsorption and therefore K + and H + secretion. Spironolactone active metabolite, canrenone, has a plasma
half-life of 16 hours Eplerenone differs from spironolactone by replacement of a 17-α-thioacetyl group with a
carbomethoxy group. Spironolactone can results in gynaecomastia, menstrual disorders and testicular atrophy.
Eplerenone has lower affinity for these receptors, and such oestrogen-like side effects are less common with
licensed doses of this drug.
Aldosterone antagonist spironolactone produces hyperkalaemia, which is potentially fatal. Potassium supplements
must not be co-prescribed, and close monitoring of plasma creatinine and electrolytes is needed if these drugs are
used for patients with impaired renal function, especially if other drugs that can increase plasma potassium,
such as ACE inhibitors, angiotensin receptor antagonists (sartans) or β-adrenoceptor antagonists are also
prescribed-as they often are for patients with heart failure.
Triamterene and Amiloride block Na + transport channels resulting in a decrease in Na+-K + exchange
directly i.e. they are not aldosterone antagonist. They have K+-sparing diuretic actions similar to that of
spironolactone. However, the ability of these drugs to block the K+-Na + exchange site in the collecting tubule does
not depend on the presence of aldosterone. Triamterene gives florescence to urine. Amiloride blocks the entry of
Li+ through Na+ channels in collecting ducts and prevent diabetes insipidus induced by lithium.
228
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Immunology & immunosuppressant drugs
1. Innate and
2. Adaptive immunity
Innate immunity: consist of cellular and biochemical defense that are present even before infections. Also
c/a natural or native immunity & provides first line of defense against infections. Non specific but recognizes
certain pattern like lipopolysaccharides (LPS) in gram-negative and teichoic acids in gram-positive bacteria,
dsRNA in replicating viruses, N-formylmethionine in bacterial proteins. It recognizes microbial products
that are often essential for microbial survival e.g. ds viral RNA, complex microbial lipids. Outset or eliminate
most infections within hours of encounter.
Components of the innate immune system
1.
Physical and chemical barriers (epithelia and antimicrobial substance produced at epithelial surface)
2.
Circulating effector cells: phagocytes (neutrophils, macrophages) and NK cells
3.
Circulating effector proteins (complements system, mediators of inflammation, etc)
4.
Cytokines (cell to cell communication proteins)
NK (Natural Killer) cells: are subsets of lymphocytes but are neither T or B lymphocytes. These are first line
of defense against viruses and some intracellular microbes. The mostly kill the tumor cells as they have very low
expression of MHC I which is generally high in case of normal cells.
Neutrophils also employ both oxygen-dependent and oxygen-independent pathways to generate
antimicrobial substances. Neutrophils are in fact much more likely than macrophages to kill ingested
microorganisms. Neutrophils exhibit a larger respiratory burst than macrophages and consequently are able to
generate more reactive oxygen intermediates and reactive nitrogen intermediates. In addition, neutrophils express
higher levels of defensins than macrophages do.
Adaptive immunity also k/a specific or acquired immunity. Immunity develops as a response to infection and
adapts to the infection. It increases in magnitude and capabilities with repeated exposure to microbes.
2
type of adaptive immune responses:
1) Humoral immunity mediated by antibodies in the blood and mucosal secretion. B-lymphocytes produce
antibodies. Antibodies are delivered as gamma globins which can be separated from albumins by
229
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
ceentrifugation Antibodies reccognize antigeens and target for eliminationn by various effectors
e
mechaanism.
prrincipal defensse against extraacellular microbbes and their tooxins
2) Ceell-mediated im
mmunity Med
diated by T lyymphocytes (T
TH and TC) prinncipal defense against intracellular
microbes (viruses
(
and some
s
bacteria)). Destroys miicrobial infected cell (TH) and
a tumor ceells (Tc). Tcelll only
recognize the antigen prresented by MHC
M
moleculees.
Antigen- substances that induces speciffic immune ressponses
mphocytes thaat have not encoountered a partticular antigen
Naïve – lym
230
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
a. Activation
A
off Tcell by An
ntigen presen
nting cell (A
APC
b.
I
Interaction
of
o MHC with
h Tcell
231
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
T cell activ
vation req
quires sign
nals from TCR
and costimula
atory mollecules
CD28
TCR
activated
a
d T cell
B7
MHC + peptide
Antig
gen prese
enting ce
ell
232
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Primary (central) lymphoid organs: provides microenvironment for development of
lymphocytes e.g. bone marrow and thymus
Secondary (peripheral) lymphoid organs: sites of interaction of antigen with mature lymphocytes e.g.
lymph nodes, spleen, mucosa-associated lymphoid tissue (MALT) and cutaneous-associated lymphoid tissue.
9
Active immunity-generated in the host by exposure to a foreign antigen.
9
Passive immunity-generated by transferring serum or sera, antitoxin, monoclonal antibodies and
lymphocytes from a specifically immunized individual to recipient. (ex maternal antibodies to fetus, antitetanus). It is the acquisition of immunity by receipt of preformed antibodies rather than by active
production of antibodies after exposure to antigen
Common agents of passive immunization
Antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain
animals, plants, and bacteria. Although they are most effective in neutralizing toxins, they can kill bacteria and other
microorganisms. Antitoxins are made within organisms, but can be injected into other organisms, including humans.
This procedure involves injecting an animal with a safe amount of a particular toxin. Then, the animal’s body makes
the antitoxin needed to neutralize the toxin. Later, the blood is withdrawn from the animal. When the antitoxin is
obtained from the blood, it is purified and injected into a human or other animal, inducing passive immunity. To
prevent serum sickness, it is often best to use antitoxin generated from the same species (i.e. use human antitoxin to
treat humans).
233
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Antiserum (antisera) is blood serum containing polyclonal antibodies. Antiserum is used to pass on passive
immunity to many diseases. Antibodies in the antiserum bind the infectious agent or antigen. The immune system
then recognizes foreign agents bound to antibodies and triggers a more robust immune response. The use of
antiserum is particularly effective against pathogens which are capable of evading the immune system in the
unstimulated state but which are not robust enough to evade the stimulated immune system.
Toxoid is a bacterial toxin (usually an exotoxin) whose toxicity has been weakened or suppressed either by
chemical (formalin) or heat treatment, while other properties, typically immunogenicity, are maintained.
Toxoids are used in vaccines as they induce an immune response to the original toxin or increase the response to
another antigen.
Important terms
9
Immunogenicity: ability to induce immune response. Immunogenicity is determined, in part, by four
properties of the immunogen: its foreignness, molecular size, chemical composition and complexity, and
ability to be processed and presented with an MHC molecule on the surface of an antigen-presenting cell or
altered self-cell.
9
Antigenicity: ability to bind with secreted antibodies and/or surface receptors all immunogen are antigen
but not vise versa. Many small molecules can binds to antibodies but cannot activates B cells on their own
(ex haptens)
9
Adjuvants are substances that, when mixed with an antigen and injected with it, enhance the
immunogenicity of that antigen. Adjuvants are often used to boost the immune response when an antigen
has low immunogenicity or when only small amounts of an antigen are available. For example, the
antibody response of mice to immunization with BSA can be increased fivefold or more if the BSA is
administered with an adjuvant. Aluminum potassium sulfate (alum) prolongs the persistence of antigen.
When an antigen is mixed with alum, the salt precipitates the antigen. Injection of this alum precipitate
results in a slower release of antigen from the injection site, so that the effective time of exposure to the
antigen increases from a few days without adjuvant to several weeks with the adjuvant. Water-in-oil
adjuvants also prolong the persistence of antigen. A preparation known as Freund’s incomplete adjuvant
contains antigen in aqueous solution, mineral oil, and an emulsifying agent such as mannide
monooleate, which disperses the oil into small droplets surrounding the antigen; the antigen is then
released very slowly from the site of injection. This preparation is based on Freund’s complete adjuvant,
the first containing heat-killed Mycobacterial as an additional ingredient. Muramyl dipeptide, a
component of the mycobacterial cell wall, activates macrophages, making Freund’s complete adjuvant far
more potent than the incomplete form.
234
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
9
CONTACT;sahadevparmar_22@yahoo.com
H
Haptens
are an
ntigenic but not immunogen
nic i.e Haptens are small moolecules that caan bind to antibbodies
buut cannot by themselves
t
indduce an immuune response. However, the conjugate forrmed by couppling a
haapten to a larg
ge carrier prottein is immunogenic and eliicits productioon of anti-haptten antibodies when
innjected into an animal. Such injections alsoo produce anti-carrier and anttihapten/ carrieer antibodies ass well.
In
n the body, th
he formation of hapten-carrrier conjugattes is the basis of allergic responses to drugs
su
uch as penicilllin. Penicilloyyl-protein behhaves as a haptten-carrier connjugate, with thhe penicilloyl group
accting as a hapttenic epitope. Streptomycin, aspirin, the soo-called “sulfaa-drugs” such as
a the sulfonam
mides,
soome anestheticcs (e.g., Succinnyl choline), annd some opiattes. All of thesse small moleccules first reacct with
prroteins to form
m drug-protein derivatives. When
W
this happeens, there is a possibility
p
thatt the immune system
s
w produce an anti-hapten reesponse to the drug, just as with
will
w penicillin. Drugs (and thheir metabolites) that
arre incapable off forming drug--protein conjuggates rarely eliccit allergic reacctions.
9
A
Avidity:
strength of multiple interactions is c/a avidity e. g. Ig M haas maximum avidity
a
becausse it is
peentameric so eaach arm can biind with two anntigen simultanneously.
Antibodies- are partt of Humoral immunity. They
T
are havinng molecular weight
w
1000000-900000. Theese are
protein made
m
up of 2 heavy and 2 light chains. B-lymphocytes produce antiibodies. Theyy are produced and
matured in
i bone marro
ow. Both H- & L- chains consist
c
of N-tterminal variaable (V) regioons and C-terrminal
constant (C)
( regions. V region partiicipate in antigen recognitiion and proviides diversity. H-chain C region
r
mediates effector functtions, also ancchor antibodyy molecules on
o B cells. Onn recognizing antigen,
a
dividees and
y B cells and anntibody secretiing plasma cellls
differentiatte into memory
Fab fraggments had antigen-bindinng activity (fraggment, antigenn binding).
235
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Fc fragm
ment (fragment, crystallizabble). No antigeen binding acctivity at all. Because
B
it wass found to crysstallize
during coldd storage. Wheen antibody is digested
d
with different
d
enzym
me then followiing fragments are obtainedIggG + papain = Fab fragmen
nt + Fc fragmeent
IggG + pepsin = F(ab`)2 fragm
ment + degrad
ded peptides
IggG + mercapto
oethanol = 2H
H + 2L chains
IgG: MO
OST ABUNDA
ANT IN SER
RUM. It crossees the placentta and plays an
a important roole in protectinng the
developingg fetus. Having
g largest life sp
pan. (22 days))
IgM larrgest moleculaar weight (9000,000) antiboody. IgM is a monomer, but
b secreted IgM
I
in serum
m is a
pentamer.. Also contain
ns J (joining) chain
c
attachedd to μ-chain, needed
n
for polyymerization. First
F
Ig produ
uces in
primary response
r
to an
n antigen. Beccause of its higgh valency pentameric IgM iss more efficiennt than other isootypes
in binding antigens with many repeatinng epitopes succh as viral partticles and red blood cells (R
RBCs). For exaample,
when RBC
Cs are incuba
ated with speecific antibodyy, they clump
p together intto large aggreegates in a prrocess
called aggglutination. Ig
gM is the firrst isotype prroduced by the
t
neonate and
a
during a primary im
mmune
response. It activates th
he complemen
nt system (parrt of innate im
mmunity). It also
a
have maxximum tenden
ncy to
he complemen
nt system. Ig M has maximum avidity (strength of multiple
m
interacctions) becausse it is
activate th
pentamericc so each arm can
c bind with two
t antigens siimultaneously.
236
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
IgA: Predominant Ig inn external secreetion like exterrnal secretionss such as breaast milk, salivaa, tears, and mucus
m
n exist as a
of the bronnchial, genitourrinary, and diggestive tracts. Itt also has a seccretory compoonent. IgA can
monomer,, dimer, trimeer, or tetramerr. IgG, IgE, an
nd IgD alwayss exist as monoomers. Membrrane-bound IgM
M is a
monomer, but secreted Ig
gM in serum iss a pentamer.
IgE: involved in the innflammation and
a have shorrtest half life (2.5
(
days). IgE
E antibodies meediate the imm
mediate
ons that are reesponsible for the symptomss of hay feverr, asthma, hivees, and anaphyylactic
hypersenssitivity reactio
shock.
Ce
ell mediat
ated immu
unity
T lymph
hocytes: aree produce in bone marrow
w but maturee in thymus. While B cell are produced
d and
maturatioon in bone ma
arrow. They anntigen-bindingg receptor on thhe membrane is
i c/a T-cell reeceptor (TCR). They
recognize only peptide antigens
a
preseented by majoor histocompaatibility compllex (MHC) prrotein of otherr cells.
i
the small peptides
p
and presents the proocessed peptidees to T-cell recceptor.
MHC first processes the large protein into
MHC mollecules -polym
meric membranne glycoproteiins. MHC arre highly polyymorphic i.e. vary individdual to
individual.. MHC is the main
m
cause forr graft rejection.
•
2 types: class I MHC
M
(all nucleeated cells) andd class II MHC
C (only by antigen presentingg cells)
•
ubpopulationss: helper T cellls (TH) and cytotoxic T cells (TC)
su
•
TH cells bear CD4 while TC cells bears CD8 membrrane glycoprootein receptorr. TH recognizze the
peeptides presen
nted by MHC II while TC reecognize the peptides presen
nted by MHC I.
237
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Hypersensitivit
H
ty (Allergy): An
A abnormal response to antigens.
a
Four
F
Types of Hypersensitivvity Reactions:
n
Type I (Anaphylactic) Reactions
n
Type II
I (Cytotoxic) Reactions
n
Type III
I (Immune Complex)
C
Reaactions
n
Type IV
I (Cell-Mediiated) Reactions
Type I (Anap
phylactic) Reaactions
O
Occur
within minutes
m
of expo
osure to antigeen. Antigens coombine with IgE antibodies.. IgE binds to mast cells andd basophils,
caausing them to undergo degra
anulation and release
r
severall mediators:
1.. Histamine: Dilates
D
and inccreases permeaability of bloood vessels (sweelling and rednness), increasees mucus secreetion (runny
noose), smooth muscle
m
contracttion (bronchi).
2.. Prostaglandinns: Contraction
n of smooth muuscle of respiraatory system annd increased mucus
m
secretionn.
3.. Leukotrienes:: Bronchial sp
pasms.
A
Anaphylactic
shhock: Massive drop in blood pressure. Cann be fatal in minnutes.
238
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Type II (Cyttotoxic) Reacttions
I
Involve
activaation of compllement by IgG
G or IgM bind
ding to an anttigenic cell. Antigenic
A
cell iss lysed. E.g. Trransfusion
r
reactions:
ABO
O Blood grou
up system: Type
T
O is univversal donor. Incompatiblee donor cells are lysed as they
t
enter
b
bloodstream.
S
Similarly
in Rh
h Blood Groupp System: 85%
% of populationn is Rh positivve. Those whoo are Rh negatiive can be
s
sensitized
to destroy Rh posiitive blood cellls. Hemolytic disease of new
wborn: Fetal cells are destroyyed by maternnal anti-Rh
a
antibodies
that cross the placenta.
Type III (Im
mmune Compllex) Reactionss
I
Involve
reactioons against so
oluble antigenns circulating in serum. Usu
ually involve IgA antibod
dies. Antibodyy-Antigen
i
immune
com
mplexes are deposited in
n organs, acctivate compllement, and cause inflam
mmatory dam
mage. E.g.
G
Glomeruloneph
hritis: Inflamm
matory kidney damage.
Type IV (Ceell-Mediated) Reactions
R
Reactions aree delayed by one
o or more daays (delayed tyype hypersensiitivity). Delay is due to migrration of macroophages and T
cells to site of
o foreign antig
gens. Reactionns are frequentlly displayed onn the skin: itching, redness, swelling, painn. Tuberculosiss
skin test, Poiison ivy, Metalls.
239
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Hyperse
ensitivity re
eactions
240
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
VACCINES
Vaccines have the pathogen like characteristic but not true pathogen characteristic to activate the immune
system without causing life- threatening diseases.
Classification of vaccines
Vaccines
Live attenuated
Inactivated
1. Viral
2. Bacterial
Whole
Fractional
1. Virus
2. Bacteria
Protein based
1. Toxoids
2. Subunit
Polysaccrides
based
1. Pure
2. Conjugate
1.
241
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Classification of common vaccines used for human growth
242
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
¾
CONTACT;sahadevparmar_22@yahoo.com
Attenuated Viruses and Bacteria Cause Immunity without Disease
In some cases, microorganisms can be attenuated so that they lose their ability to cause significant disease
(pathogenicity) but retain their capacity for transient growth within an inoculated host. Attenuation often can be
achieved by growing a pathogenic bacterium or virus for prolonged periods under abnormal culture
conditions. This procedure selects mutants that are better suited to growth in the abnormal culture conditions
and are therefore less capable of growth in the natural host. For example, an attenuated strain of Mycobacterium
bovis called Bacillus Calmette-Guerin (BCG) was developed by growing M. bovis on a medium containing
increasing concentrations of bile. After 13 years, this strain had adapted to growth in strong bile and had become
sufficiently attenuated that it was suitable as a vaccine for tuberculosis. The Sabin polio vaccine and the measles
vaccine both consist of attenuated viral strains. The poliovirus used in the Sabin vaccine was attenuated by growth in
monkey kidney epithelial cells. The measles vaccine contains a strain of rubella virus that was grown in duck
embryo cells and later in human cell lines.
Attenuated vaccines have advantages and disadvantages. Because of their capacity for transient growth, such
vaccines provide prolonged immune-system exposure to the individual epitopes on the attenuated organisms,
resulting in increased immunogenicity and production of memory cells. As a consequence, these vaccines often
require only a single immunization, eliminating the need for repeated boosters.
A major disadvantage of attenuated vaccines is the possibility that they will revert to a virulent form.
¾
Pathogenic Organisms are Inactivated by Heat or Chemical Treatment
Another common approach in vaccine production is inactivation of the pathogen by heat or by chemical means so
that it is no longer capable of replication in the host. It is critically important to maintain the structure of epitopes on
surface antigens during inactivation. Heat inactivation is generally unsatisfactory because it causes extensive
denaturation of proteins; thus, any epitopes that depend on higher orders of protein structure are likely to be altered
significantly. Chemical inactivation with formaldehyde or various alkylating agents has been successful.
¾
Toxoids are Manufactured from Bacterial Toxins
Some bacterial pathogens, including those that cause diphtheria and tetanus, produce exotoxins. These exotoxins
243
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
produce many of the disease symptoms that result from infection. Diphtheria and tetanus vaccines, for example, can
be made by purifying the bacterial exotoxin and then inactivating the toxin with formaldehyde to form a
toxoid.
¾
Bacterial Polysaccharide Capsules Are Used as Vaccines
The virulence of some pathogenic bacteria depends primarily on the antiphagocytic properties of their hydrophilic
polysaccharide capsule. Coating of the capsule with antibodies and/ or complement greatly increases the ability of
macrophages and neutrophils to phagocytose such pathogens. The vaccine for Neisseria meningitidis, a common
cause of bacterial meningitis, also consists of purified capsular polysaccharides and Streptococcus pneumoniae.
i.
Inactivated whole virus vaccines
The outer virion coat should be left intact but the replicative function should be destroyed. To be effective, nonreplicating virus vaccines must contain much more antigen than live vaccines that are able to replicate in the host.
Preparation of killed vaccines may take the route of heat or chemicals. The chemicals used include formaldehyde
or beta- propiolactone. The traditional agent for inactivation of the virus is formalin. Excessive treatment can
destroy immunogenicity whereas insufficient treatment can leave infectious virus capable of causing disease.
ii.
Subunit Vaccines
It is now possible to produce non-replicating vaccines by identifying the peptide sites responsible for the major
antigenic sites of viral antigens, from which highly purified subunit vaccines can be produced. Increasing
purification may lead to loss of immunogenicity, and this may necessitate coupling to an immunogenic carrier
protein or adjuvant, such as an aluminum salt. Examples of purified subunit vaccines include the HA vaccines for
influenza A and B.
iii.
Recombinant Vector vaccines
Uses attenuated viruses or bacteria as vector to express major antigens of virulent pathogens like proteins of capsid.
Attenuated organism replicate within the host and expresses the gene product of the pathogen. Various organisms
have been used for vector vaccine: vaccinia virus, attenuated poliovirus, adenovirus, certain strain of streptococcus
etc. induces both humoral and cell-mediated immune response against target antigen.
iv.
Conjugate vaccines:
Virulence of some pathogenic bacteria depends on polysaccharide capsule. So purified capsular polysaccharides
can be used as vaccines. But these capsular polysaccharides antigens are coupled with to proteins carrier to
give conjugate vaccines which then stimulate T-cell as T-cell activation only needs proteins, generally small
peptides but the above component is polysaccrides.
244
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
v.
CONTACT;sahadevparmar_22@yahoo.com
DNA vaccines:
Plasmid DNA encoding antigenic protein injected directly into the muscle of the recipient. Encoded protein
antigen is expressed in muscle cells activating both humoral and cell-mediated response.
Advantages:
•
encoded protein is expressed in the host in its natural form
•
stimulates both humoral and cell mediated immunity
245
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Passive immunizing agents
Gas gangrene anti toxin, human normal immunoglobin, plague vaccine, rabies antiserum.
246
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
IMMUNOSUPPRESSANT DRUGS
Immunosuppressive drugs or immunosuppressive agents are drugs that inhibit or prevent activity of the immune
system. They are used in immunosuppressive therapy to:
•
Prevent the rejection of transplanted organs and tissues (e.g., bone marrow, heart, kidney, liver)
•
Treat autoimmune diseases or diseases that are most likely of autoimmune origin (e.g., rheumatoid arthritis,
multiple sclerosis, myasthenia gravis, systemic lupus erythematosus, Crohn's disease, pemphigus, and
ulcerative colitis).
•
Treat some other non-autoimmune inflammatory diseases (e.g., long term allergic asthma control).
These drugs are not without side-effects and risks. Because the majority of them act non-selectively, the immune
system is less able to resist infections and the spread of malignant cells. There are also other side-effects, such as
hypertension, dyslipidemia, hyperglycemia, peptic ulcers, liver, and kidney injury. The immunosuppressive drugs
also interact with other medicines and affect their metabolism and action.
1. Glucocorticoids
Glucocorticoids are used to suppress various allergic, inflammatory, and autoimmune disorders. They are also
administered as posttransplantory immunosuppressants to prevent the acute transplant rejection and graft-versushost disease. Glucocorticoids suppress the cell-mediated immunity. They act by inhibiting genes that code for
the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-γ, the most important of which is the IL-2.
Interleukin-2 is an important immune system regulator necessary for the clone expansion and survival of
activated lymphocytes T. Smaller cytokine production reduces the T cell proliferation. Glucocorticoids also
suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and IL-2 receptors. This
diminishes both B cell clone expansion and antibody synthesis. Glucocorticoids also inhibit MHC expression.
The anti-inflammatory effect on glucocorticoids is by inducing the lipocortin-1 (annexin-1) synthesis, which
then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate
arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2)
expression is also suppressed, potentiating the effect.
Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte
membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis,
phagocytosis, respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines,
tissue plasminogen activator, chemokines, etc.) from neutrophils, macrophages, and mastocytes.
247
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
2. Drugs acting on immunophilins
Ciclosporin / Cyclosporine
is a cyclic fungal peptide, composed of 11 amino acids. Ciclosporin is a calcineurin inhibitor (CNI). Calcineurin,
under normal circumstances induces the transcription of interleukin-2. Generally activation of T cell receptor
produces cascade of ca2+ ions which results in activation of protein kinase C. The ca2+ ions after binding to
calmodulin activates the membrane associated serine / threonine phosphatase called as calcineurin which
dephosphorylates the regulatory protein NFAT (Nuclear factor of activated T cell) which act as a
transcription factor for production of cytokine genes leading to production of IL-2 along with other interleukins,
interferon , TNF α.
Ciclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of immunocompetent
lymphocytes, especially T-lymphocytes. This complex of ciclosporin - cyclophilin inhibits calcineurin. The drug
also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.
Ciclosporin is one of the most nephrotoxic, impairs liver, gum hyperplasia, hirsuitism, tremors & seizures. It
should be avoided with other nephrotoxic toxic drugs like aminoglycosides, vancomycin, and amphotericin B.
Enzyme inducers like Phenytoin, phenobarbitone, rifampicin lower its blood levels.
While erythromycin, Ketoconazol, Cimetidine inhibits its metabolism and results in toxicity.
Tacrolimus
Tacrolimus is a macrolide lactone and acts by inhibiting calcineurin. The drug is used particularly in the liver and
kidney transplantations, although in some clinics it is used in heart, lung and heart/lung transplantations. It binds to
the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its
phosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell
cycle. Tacrolimus is more potent than ciclosporin and has less pronounced side-effects.
248
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
3. Cytostatics (Alkylating agents)
They inhibit cell division. In immunotherapy, they are used in smaller doses than in the treatment of malignant
diseases. They affect the proliferation of both T cells and B cells. Due to their highest effectiveness, purine
analogs are most frequently administered. The alkylating agents used in immunotherapy are nitrogen mustards
(cyclophosphamide), nitrosoureas, platinum compounds, and others. Cyclophosphamide is probably the most
potent immunosuppressive compound.
249
vPHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
Cyclophosphamide
is a nitrogen mustard alkylating agent adds an alkyl group (CnH2n+1) to DNA. It attaches the alkyl group to the
guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring. It is a "prodrug"; it is converted in
the liver to active forms that have chemotherapeutic activity. It predominantly effects the proliferation of B cells or
humoral immunity rather than cell mediated immunity or T cell immunity.
Cyclophosphamide is converted by mixed function oxidase enzymes in the liver to active metabolites. The main
active metabolite is 4-hydroxycyclophosphamide, which exists in equilibrium with its tautomer, aldophosphamide.
Most of the aldophosphamide is oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make
carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard and
acrolein. Acrolein is toxic to the bladder epithelium and can lead to hemorrhagic cystitis. This can be
prevented through the use of aggressive hydration and/or Mesna. Mesna (2‐
mercaptoethane sulfonate) is a sulfhydryl donor and binds acrolein.
Cyclophosphamide can also cause bone marrow depression, alopecia etc.
4.
Antimetabolites
Antimetabolites interfere with the synthesis of nucleic acids. These include:
I.
Folic acid analogues, such as methotrexate
II.
Purine analogues such as azathioprine and mercaptopurine
III.
Pyrimidines analogues
IV.
Protein synthesis inhibitors
Methotrexate is a folic acid analogue. It also has anti inflammatory property. It is first line of drug in the
treatment of autoimmune diseases (for example rheumatoid arthritis, myasthenia gravis) and in transplantations.
Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR), an enzyme that
participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about one thousand-fold
that of folate for DHFR. Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active
tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA
synthesis. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate,
therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.
Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of
the cell cycle. Logically, it therefore has a greater toxic effect on rapidly dividing cells (such as malignant and
250
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and
proliferation of these non-cancerous cells as well as causing the side effects listed.
Lower doses of methotrexate have been shown to be very effective for the management of rheumatoid arthritis,
Crohn's disease, and psoriasis. In these cases inhibition of dihydrofolate reductase (DHFR) is not thought to be the
main mechanism, but rather the inhibition of enzymes involved in purine metabolism, leading to accumulation of
adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T
cells. Methotrexate is a highly teratogenic drug.
Azathioprine and Mercaptopurine
Azathioprine is the main immunosuppressive cytotoxic substance. It is extensively used to control transplant
rejection reactions. Azathioprine is a purine synthesis inhibitor, inhibiting the proliferation of cells, especially
leukocytes. It is nonenzymatically cleaved to mercaptopurine that acts as a purine analogue and inhibits de
novo purine synthesis and damage to DNA. Because azathioprine suppresses the bone marrow, patients will be
more susceptible to infection. Caution should be exercised when it is used in conjunction with purine analogues such
as allopurinol. The enzyme thiopurine S-methyltransferase (TPMT) deactivates 6-mercaptopurine. Mercaptopurine
itself can also be administered directly.
By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both
the cell and the humoral immunity. It is also efficient in the treatment of autoimmune diseases and given in
treatment of rheumatoid arthritis.
Mycophenolate
Mycophenolic acid acts as a non-competitive, selective, and reversible inhibitor of Inosine-5′-monophosphate
dehydrogenase (IMPDH), which is a key enzyme in the de novo guanosine nucleotide synthesis. In contrast to
other human cell types, lymphocytes B and T are very dependent on this process.
5. Immunosuppressant antibodies
Muromonab CD3 is a monoclonal antibody against CD3 glycoprotein located near to the T cell receptor on
helper T cells.
Antithymocyte globulin binds to T cell and depletes them.
251
PHARMAGLIMPS- A GLIMPSE OF PHARMACY
CONTACT;sahadevparmar_22@yahoo.com
6. Cytotoxic antibiotics
Among these, dactinomycin is the most important. It is used in kidney transplantations. Other cytotoxic
antibiotics are anthracyclines, mitomycin C, bleomycin, mithramycin.
7. Opioids
Prolonged use of opioids may cause immunosuppression of both innate and adaptive immunity. Decrease in
proliferation as well as immune function has been observed in macrophages, as well as lymphocytes. It is thought
that these effects are mediated by opioid receptors expressed on the surface of these immune cells.
252