Ministry of Education and Science of Ukraine
Ministry of Public Health of Ukraine
Sumy State University
Medical Institute
3924 METHODICAL INSTRUCTIONS
for practical work
on the topic “Clinical Pharmacology of Drugs Used
in the Treatment of Internal Diseases”
(аccording to the Bologna Process)
for the students of speciality 7.110101 “Medical Care”
of the full-time course of study
Sumy
Sumy State University
2015
Methodical instructions for practical work on the topic
“Clinical Pharmacology of Drugs Used in the Treatment of Internal
Diseases” / compiler A. A. Roschupkin. – Sumy : Sumy State
University, 2015. – 134 p.
The Department of Biophysics, Biochemistry, Pharmacology, and
Biomolecular Engineering
1.
GENERAL
PRINCIPLES
PHARMACOLOGY
OF
CLINICAL
1.1.
PRINCIPLES
OF
PHARMACOKINETICS
PHARMACODYNAMICS
AND
Any substance that produces a change in biological function
through its chemical actions and has been registred as a drug in
specific drug's form by Ukrainian Pharmocology Committee may be
used as a DRUG. Drugs may be synthetic in origin, chemicals
obtained from plants or animals, or products of genetic engineering.
A MEDICINE is a chemical preparation, which usually but not
necessarily contains one or more drugs, administered with the
intention of producing a therapeutic effect. Medicines usually contain
other substances (excipients, stabilisers, solvents, etc.) besides the
active drug to make them more convenient to use. To be a drug, the
substance must be administered in the body rather than being
released by physiological mechanism. In majority of cases the drug
molecule interacts with specific molecules in the biological system
that plays a regulatory role (receptor). The receptors are different
components of a cell or an organism that interact with drugs and
initiate a chain of biochemical events leading to the drug's intended
effects.
In most cases, drugs known as chemical antagonists may interact
directly with other drugs, while a few other drugs (e.g., osmotic
agents) interact almost exclusively with water molecules. Drugs may
be synthesized within the body (e.g., hormones) or may be chemicals
not synthesized in the body (xenobiotics). Poisons may be used as
drugs too. The effects (positive or toxical) depend on the doses.
Toxins are usually defined as poisons of biologic origin, i.e.,
synthesized by plants or animals, in contrast to inorganic poisons
such as lead and arsenic.
Receptors have become the central focus of investigation of drug
effects and their mechanisms of action (Pharmocodynamics). Many
drug receptors have been isolated and characterized in detail, thus
3
opening the way to precise understanding of the molecular basis of
drug action.
The actions and clinical uses of drugs may be categorised as
follows:
Receptors largely determine the quantitative relations between
dose or concentration of drug and pharmacologic effects. The
receptor's affinity for binding a drug determines the concentration of
the drug required forming a significant number of drug-receptor
complexes, and the total number of receptors may limit the maximal
effect of a drug.
Receptors are responsible for selectivity of drug action. The
molecular size, shape, and electrical charge of a drug determine
whether and with what affinity it will bind to a particular receptor
among the vast array of chemically different binding sites available
in a cell, tissue, or a patient. Accordingly, changes in the chemical
structure of a drug can dramatically increase or decrease a new drug
affinity for different classes of receptors, with resulting alterations in
therapeutic and toxic effects.
Receptors mediate the actions of both pharmacologic agonists and
antagonists. Some drugs and many natural ligands, such as hormones
and neurotransmitters, regulate the function of receptor
macromolecules as agonists, i.e., they activate the receptor to signal
as a direct result of binding to it. Other drugs function as
pharmacologic antagonists, i.e., they bind to receptors but do not
activate generation of a signal. Consequently, they interfere with the
ability of an agonist to activate the receptor. Thus, the effect of a socalled "pure" antagonist on a cell or in a patient depends entirely on
its preventing the binding of agonist molecules and blocking their
biological actions. Some of the most useful drugs in clinical
medicine are pharmacological antagonists.
In regular clinical practice, a drug is intended to reach its site of
action after administration by a convenient route. In some cases, the
drug is either readily absorbed or distributed, or it is administered
and then converted into active drugs by biological processes in the
body. This process is known as Pharmacokinetics. In only a few
cases, it is possible to directly apply a drug to its target site, e.g.,
4
topical application of anti-inflammatory agent to inflamed skin or
mucous membrane. Most often, a drug is administered into one body
compartment, e.g., the gut, and must move to its site of action in
another compartment, eg, the brain. This requires that the drug
should be absorbed into the blood from its site of administration and
distributed to its site of action, permeating through the various
histological barriers that separate these compartments. For a drug
given orally to produce an effect in the central nervous system, these
barriers include the tissues that comprise the wall of the intestine, the
capillaries that perfuse the gut, and the "blood-brain barrier," the
walls of the capillaries that perfuse the brain. Finally, after bringing
about its effect, a drug should be eliminated at a reasonable rate by
metabolic inactivation, by excretion from the body, or by a
combination of these processes.
1.2.
ROUTES OF ADMINISTRATION
Common routes of administration and some of their features
include the following:
1. Oral (swallowed): The oral route offers maximum convenience,
but absorption may be slower and less complete than when parenteral
routes are used. Ingested drugs are subject to the first-pass effect, in
which a significant amount of the agent is metabolized in the gut
wall and the liver before it reaches the systemic circulation. Thus,
some drugs have low bioavailability when given orally.
2. Intravenous: The intravenous route offers instantaneous and
complete absorption (by definition, bioavailability is 100%). This
route is potentially more dangerous, however, because of the high
blood levels that am produced if administration is too rapid.
3. Intramuscular: Absorption from an intramuscular injection site
is often (not always) faster and more complete (higher
bioavailability) than with oral administration. Large volumes
(e.g., > 5 mL into each buttock) may be given. First-pass metabolism
is avoided.
5
4. Subcutaneous: The subcutaneous route offers slower absorption
than the intramuscular route. Large volume bolus doses are less
feasible. First-pass metabolism is avoided.
5. Buccal and sublingual: The buccal route (in the pouch between
gums and cheek) permits direct absorption into the systemic venous
circulation, bypassing the hepatic portal circuit and first-pass
metabolism. This process may be fast or slow depending on the
physical formulation of the product. The sublingual route (under the
tongue) offers the same features as the buccal route.
6. Rectal (suppository): The rectal route offers partial avoidance
from the first-pass effect (though not as complete as the sublingual
route). Larger amounts of drugs and drugs with unpleasant taste are
better administered rectally than by the buccal or sublingual routes.
Some drugs administered rectally may cause significant irritation.
7. Inhalation: In case of respiratory diseases, the inhalation route
offers delivery closest to the target tissue. This route often provides
rapid absorption because of the large alveolar surface area available.
8. Topical: The topical route includes application to the skin or to
the mucous membrane of the eye, nose, throat, airway, or vagina for
local effect. The rate of absorption varies with the area of application
and the drug formulation but is usually slower than any of the routes
listed above.
9. Transdermal: The transdermal route involves application to the
skin for systemic effect. Absorption usually occurs very slowly, but
the first-pass effect is avoided.
1.3.
DRUG INTERECTIONS
The practical doctors prescribe more than one drug usually. But, if
the doctor wants to prescribe a few different drugs by chemical
structure and pharmacological action, he must remember about
interactions’ between the drugs.
There are several types of drug-drug interections - Addition,
Synergism, Potentation, Antagonism (Table 1).
6
Table 1- Type of drug-drug interactions
Type of interaction
ADDITION – the response elicited by
combined drugs is EQUAL TO the combined
responses of individual drugs
SYNERGISM – the response elicited by
combined drugs is MORE THAN the
combined responses of individual drugs
POTENTATION – a drug which has no
effects or has small effect enhances the effect
of a another drug
ANTAGONISM – a drug inhibits the
effect of another drug. Usually the
antagonism has no inherent activity
Mathematical
example
1+1=2
1+1>2
0+1>1
1+1=0
Drug ANTAGONISM occurs by various mechanisms:
– Chemical antagonism (interaction in solution)
– Pharmacokinetic antagonism (one drug affects the absorption,
metabolism or excretion of another)
– Competitive antagonism (both drugs bind to the same site of
the receptors); the antagonism may be reversible or irreversible
– Non-competitive antagonism (the antagonist interrupts
receptor-effector linkage)
– Physiological antagonism (two agents produce opposing
physiological effects)
The goal of therapy is to achieve a positive outcome with least
side effects. When a medicine is selected for a particular patient, the
doctor must determine the lowest possible dose to achieve the
desirable goal. This aim is achieved by creating the therapeutic
concentration of the drug in the tissue close to the target receptor.
This “safe dosing” is achieved by testing on healthy volunteers and
patients with average physical ability to absorb, distribute, and
eliminate this drug; although it has to be kept in mind that this drug
7
may not be suitable for all patients. Several physiological factors and
parameters require the reorganization of dose levels and calibration
of the aimed concentration. These factors may be physiological
(organ maturation in infants) or pathological (heart failure, renal
failure etc). In most clinical setups, medications are administered in a
way so as to maintain a constant presence of the active biological
form of the drug in the body, i.e., just the required amount of
medication is administered so as to replenish the volume of drug lost
from the body by process of elimination. Therefore, calculation of
the appropriate maintenance dose is, also, of vital importance. In the
next step, the clinician should consider the time of action of the drug
administered. This decision is based upon the approach to treatment
and the severity of the disease. The frequency of administration per
day depends upon various pharmacological parameters like volume
of distribution, availability, elimination rate, half-life of the drug,
bioavailability, etc. The most frequent areas of concern which can
cause dangerous consequences are creation of very low or very high
target concentration for a very long period of time and incidences of
drug accumulation which may cause toxicity.
Whenever drug doses are repeated, the drug will accumulate in the
body until dosing stops. This is because it takes an infinite time (in
theory) to eliminate all of a given dose. In practical terms, this means
that if the dosing interval is shorter than four half-lives, accumulation
will be detectable. Accumulation is inversely proportional to the
fraction of the dose lost in each dosing interval. The fraction lost is 1
minus the fraction remaining just before the next dose. The fraction
remaining can be predicted from the dosing interval and the half-life.
THERAPEUTIC RANGE is the ratio between the dose that
produces toxicity and the therapeutic dose of the drug, used as a
measure of the relative safety of the drug for particular treatment.
THERAPEUTIC INDEX = Toxic Dose/Effective Dose
The drug is administered once every half-life (i.e., every 8 hours).
Drug continues to accumulate (i.e., concentrations rise) until steady
state (rate in = rate out) is reached at approximately 5 half-lives
(about 40 hours). It is very important in practical work to remember
8
about the therapeutic index and therapeutic range of a drug. (by
Charles R. Craig et al.)
Thus therapeutic
index is a measure of
the drug's safety,
since a large value
indicates that there is
a
wide
margin
between doses that
are effective and
doses that are toxic.
The
therapeutic
index
is
used
assessing safety of
drugs. It is the
difference
between
the mimimum and
Picture 1 - Concentration / time profile for a maximum therapeutic
hypothetical drug administered orally in
toxic concentrations
multiple doses
of a drug. A narrow
therapeutic index is a
very small range of doses at which a medication provides benefits
without causing severe or fatal complications.
2.
ANTIHYPERTENSIVE AGENTS
2.1.
GENERAL
PRINCIPLES
TREATMENT
OF
HYPERTENSION
Hypertension is diagnosed when through regular check-ups of
high blood pressure in a patient. The diagnosis is primarily a
prediction to consequences for the patient rather than citing the cause
of the pathology.
Epidemiological studies indicate that high blood pressure
poses a direct risk to organs such as heart, kidney and brain and may
9
cause damage to them. Even incidences of mild hypertension
(BP 140/90 mmHg) increase the overall risk of organ damage.
Hypertension is caused by an increase in peripheral vascular
smooth muscle tone, which leads to increased arteriolar resistance
and thereby reduced capacitance of the venous system. In most cases,
the cause of the increased vascular tone is unknown. Hypertension is
an extremely common disorder, and it has been estimated that 20
percent of the population is suffering from this chronic disorder. It
has also been noted that most of these individuals are mostly
asymptomatic, but chronic hypertension may be systolic or diastolic
and can lead to increased risk of cardiovascular problems which may
be strokes, acute myocardial infarction, and congestive heart failure
or renal damage.
Tablе 2 - Classification of hipertension for adults
Pressure Category
Blood Pressure (mm Hg)
Systolic
Diastolic
Normal
< 120
< 80
Pre-hypertension
120–139
80–89
Hypertension, stage 1
140–159
90–99
Hypertension, stage 2
< 160
< 100
A specific cause of hypertension can be established in only 1015% of patients. It is important to consider specific causes in each
case, however, because some of them are amenable to definite
surgical treatment: renal artery constriction, coarctation of the aorta,
pheochromocytoma, Cushing's disease, and primary aldosteronism.
Patients in whom no specific cause of hypertension can be found
are said to have essential hypertension.
High blood pressure is usually caused by a combination of several
(multifactorial) disorders. Epidemiologic evidence points to genetic
inheritance, psychological stress, and environmental and dietary
10
factors (high salt and low potassium or calcium intakes) that perhaps
contribute to the development of hypertension. Blood pressure
increase with age does not occur in populations with low daily
sodium intake.
Ther are many factors influencing blood pressure. More often, we
have the combination of three factors:
Arterial blood pressure = CARDIAC OUTPUT × PERIPHERAL
RESISTANCE x BLOOD VOLUME
Picture 2 - Main pharmacological groups that are clinicaly used in
the treatment of hypertension
Mild hypertension can often be controlled with a single drug.
More severe hypertension may require treatment with several drugs
that are selected to minimize adverse effects of the combined
regimen.
11
Table 3 - Exampels of target action
Reduce
overload
fluid Diuretics and captopril decrease blood
volume by increasing the volume of water
in the excreted urine
Reduce sympathetic Clonidine is an agonist at α2 receptors.
outflow from the Postsynaptic
α2
receptors
inhibit
brain
sympathetic outflow, and presynaptic α2
receptors inhibit further release of the
sympathetic agonist, norepinephrine
Block adrenergic Atenolol is a β1 adrenergic receptor
receptors in the antagonist that reduces heart rate and
heart
myocardial work
Dilate blood vessels Prasosin blocks α1 adrenergic receptors,
causing vasodilation.
Nifedipine blocks calcium entry into smooth
muscle cells of arterial walls, preventing
contraction.
Hydralazine relaxes arterioles
2.2.
CLINICAL USES OF ANTIHYPERTENSIVE DRUGS
Ther are some more important aspects that doctors must
remember:
Pharmacotherapy: Treatment for hypertension is complex
because the disease is often asymptomatic and is diagnosed by
chance. Also, the fact is that the drugs are expensive and may cause
adverse compensatory effects which may precipitate into a crisis long
with significant drug related toxicity. Howewer, the overall toxic
effect of the drugs can be reduced, and the effect over compensation
can be minimized by use of combination of drugs prescribed at a
lower dose. This therapeutic approach is generally accepted in
patients with severe or resistant hypertension. In normal practice,
these drugs are added in a stepwise fashion and each additional drug
12
is chosen from a different subgroup until target blood pressure has
been achieved.
The regulatory steps include lifestyle modification like restriction
of amount of salt in diet, weight management, physical exercises and
medications. Treatment is generally initiated with any of the 5 firstline choice drugs, depending upon the patient:
1. Diuretics.
2. Sympathoblockers.
3. Ca+ channel blockers.
4. ACE inhibitors.
5. Angiotensin II receptor blockers.
If blood pressure is inadequately controlled, a second drug is
added. A β-blocker is usually added if the initial drug was a diuretic,
or a diuretic is added if the first drug was a β-blocker. A vasodilator
can be added as a third step for those patients who still fail to
respond.
2.3.
CLASSIFICATION OF ANTIHYPERTENSIVE DRUGS
I First-line therapy:
- Diuretics:
1.
Thiazides and related agents (hydrochlorothiazide,
chlorthalidone, etc.)
2.
Loop diuretics (furosemide, bumetanide, torsemide,
ethacrynic acid)
3.
Potassium sparing diuretics (spironolacton, triamteren)
- Adrenoreceptor-blocking agents:
1.
β-Adrenergic
antagonists
(metoprolol,
atenolol,
bisoprolol etc.)
2.
Mixed adrenergic antagonists (labetalol, carvedilol)
- Blockers of slow Ca2+channels (verapamil, diltiazem,
nimodipine, felodipine, nicardipine, isradipine, amlodipine)
13
- Angiotensin-converting enzyme inhibitors (captopril,
enalapril, lisinopril, quinapril, ramipril, benazepril, fosinopril,
moexipril, perindopril, trandolapril)
– Angiotensin II receptor antagonists (or blockers) (losartan,
candesartan, irbesartan, valsartan, telmisartan, eprosartan)
II Second-line therapy:
- Vasodilators:
1.
Arterial (hydralazine, minoxidil, diazoxide, fenoldopam)
2.
Myotropical (dibazol, papaverin)
- Sympatholytic drugs:
1.
Alpha-adrenergic antagonists (prazosin, terazosin,
doxazosin, phenoxybenzamine, phentolamine)
2.
Centrally acting antyhypertensive agents (methyldopa,
clonidine, guanabenz, guanfacine)
3.
Adrenergic neuron blocking agents (guanadrel,
reserpine)
- Potassium channel activators (monoxidil, diazoxidum)
- Nitric oxide donors (sodium nitroprusside)
– Gangloiblockers (pentaminum, hygronium, benzohexonium)
The ability of drugs to control the compensatory responses
induced by other drugs in steps 2 and 3 should be noted (e.g.,
propranoloi reduces the tachycardia induced by hydralazine). Thus,
rational polypharmacy minimizes toxicities while producing additive
or supra-additive therapeutic effects.
1. Monotherapy: It has been found in large clinical studies that
many patients do well on a single drug (e.g., an ACE inhibitor,
calcium channel blocker, or α-blocker). This approach to the
treatment of mild and moderate hypertension has become more
popular than stepped care because of its simplicity, better patient
compliance, and with modern drugs, a relatively low incidence of
toxicity.
2. Age and Ethnicity: Older patients of most races respond better
to diuretics and beta-blockers than to ACE inhibitors. Blacks of all
ages respond better to diuretics and calcium channel blockers, less
well to ACE inhibitors.
14
3. Malignant Hypertension: Malignant hypertension is an
accelerated phase of severe hypertension associated with rising blood
pressure and rapidly progressing damage to vessels and end organs.
This condition may be signaled by deterioration of renal function,
encephalopathy, and retinal hemorrhages or by angina, stroke, or
myocardial infarction. Management of malignant hypertension must
be carried out on an emergency basis in the hospital. Powerful
vasodilators (nitroprusside or diazoxide) are combined with
diuretics (furosemide) and β-blockers to lower blood pressure to the
140–160/90–110 mm Hg range promptly (within a few hours).
Further reduction is then pursued more slowly.
2.3.1. DIURETICS
These agents are inhibitors of renal ion transporters that decrease
the reabsorption of Na+ at different sites in nephron. As a result, Na+
and other ions, such as Cl-, enter the urine in greater than normal
amounts along with water, which is carried passively to maintain
osmotic equilibrium. Diuretics thus increase the volume of urine and
often change its pH as well as the ionic composition of the urine and
blood. The efficacy of the different classes of diuretics varies
considerably: with the increase in Na+ secretion varying from less
than two percent for the weak, potassium-sparing diuretics to over
20% for the most potent loop diuretics. In addition to these iontransport inhibitors, there are osmotic diuretics that prevent water
reabsorption as well as aldosterone antagonists and a carbonic
anhydrase inhibitor. The major clinical uses of diuretics are in
managing disorders involving abnormal fluid retention (edema) or
treating hypertension in which their diuretic action causes a
decreased blood volume, leading to reduced blood pressure.
Initial decrease of blood pressure owing to diuretics use is the
result of increased sodium and water excretion and reduced volume
of circulating blood. In 6–8 weeks after initiation of treatment with
diuretics, diuretic effect is gradually reduced and cardiac output is
normalized. It is the result of renin activity increase owing to
reduction of plasma volume and blood pressure. Under these
15
conditions, hypotensive effect of diuretics develops owing to
decrease of peripheral vessels resistance. Reduction of blood-vessel
tone is the result of gradual decrease of intracellular sodium and
increase of intracellular potassium in cells of vessel walls.
Drug
Mechanism
of Action
Indication
Adverse
Effect
1
2
3
4
5
Chlorothiazide
Chlorthalidone
Hydrochlorothiazide
Indapamide
Metolazone
Inhibits sodium
and
chloride
reabsorpion
in
thick ascending
loop of Henle
and early distal
tubule. Loss of
K+, Na+, and CIcauses
3
×
increases in urine
output. Sodium
loss results in
GFR
Ideal
starting
agent
for
hypertension,
chronic edema,
idiopathic
hypercalcuria.
Used
to
DECREASE
urine output in
diabetes
insipidus
(low
GFR
causes
increased
reabsorption in
proximal
nephron, works
only with saltrestricted diet)
Hypokalemia,
hyponatremia,
hyperglycemia,
hyperuricemia,
hypercalcemia,
oliguria, anuria,
weakness,
decreased
placental flow,
sulfonamide
allergy,
GI
distress
Thiazide diuretics
Group
Table 4 - Summaries of diuretic drugs
16
Table 4 continuation
Potassium- sparing diuretics
Loop acting diuretics
1
2
3
4
Furosemide
Torasemide
Bumetanide
Etnacrynic
acid
Inhibits chloride
reabsorption in
the
thick
ascending limb
of the loop of
Henle. High loss
of K+ in urine
Preferred diuretic
in patients with
low GFR and in
hypertensive
emergencies,
edema,
pulmonary
edema,
to
mobilize
large
volumes of fluid,
and reduce serum
potassium levels
Hyponatremia,
hypokalemia,
dehydration,
hypotension,
hyperglycemia,
hyperuricemia,
hypocalcemia,
ototoxicity,
sulfonamide
allergy,
hypomagnesemia,
hypochloremic
alkalosis,
hypovolemia
Amiloride
Spironolactone
(Aldactone)
Triamteren
Antagonist
of
aldosterone
(aldosterone
causes
Na+
retention).
Directly
increases
Na+
excretion
and
decreases
K+
secretion
in
distal convoluted
tubule
Used with other
diuretics because
K+-sparing
effects
lessen
hypokalemic
effects.
May
correct metabolic
alkaosis.
Also
used to treat or
diagnose
hyperaldosteronism.
(NOT triamteren)
Hyperkalemia,
sodium or water
depletion. Patients
with
diabetes
mellitus
may
develop glucose
intolerance.
Spironolactone
causes endocrine
imbalances (acne,
oily
skin,
hirsutism,
gynecomastia)
17
5
Table 4 continuation
2
3
4
5
Acetazolamide
Carbonic
anhydrase
inhibitors
potently inhibit
carbonic
anhydrase,
resulting
in
nearly complete
abolition
of
NaHCO3
reabsorption in
the
proximal
tubule
Although
acetazolamide is
used
for
treatment
of
edema.
The
major indication
for
carbonic
anhydrase
inhibitors
is
open-angle
glaucoma
May
cause
bone marrow
depression,
skin toxicity,
sulfonamidelike
renal
lesions,
and
allergic
reactions
in
patients
hypersensitive
to sulfonamides
Mannitol
Urea
Osmotically
inhibits sodium
and
water
reabsorption.
Initially increases
plasma volume
and
blood
pressure
Acute
renal
failure,
acute
closed
angle
glaucoma, brain
edema, to remove
overdoses
of
some drugs
Headache,
nausea,
vomiting,
chills,
dizziness,
polydipsia,
lethargy,
confusion, and
chest pain
Osmotic diuretics
Carbonicanhydrase inhibitors
1
2.3.2. INHIBITORS OF THE RENIN-ANGIOTENSIN SYSTEM
A major role in controlling blood pressure for both short and long
time periods is played by the renin-angiotensin system (RAS). Apart
from that it also plays a significant role in the pathogenesis of
hypertension, acute myocardial infarction, diabetic retinopathy and
congestive heart failure. This has lead to significant increase of
research and exploration of the RAS and methods of its inactivation
and reduction of action. In some individuals, renin, angiotensin and
aldosterone play a significant role when it comes to development of
18
essential hypertension in these individuals. Almost 20% of such
patients have either pathologically high or low plasma renin activity.
Blood pressures of patients having high level of renin responds well
to drugs like β-adrenoceptor blockers whereas angiotensin inhibitors
work well for both excess renin and angiotensin levels in the body.
Kidney cortex releases renin under stimulation of reduced renal
arterial pressure, sympathetic neural stimulation and reduced sodium
delivery or increased sodium concentration at the distal renal tubule.
Angiotensinogen is acted upon by renin by splitting off the inactive
precursor of angiotensin I. Angiotensin I is then converted into
angiotensin II, which is an arterial vasoconstrictor primarily, by the
endothelial ACE; finally it is converted into Angiotensin III, in the
adrenal glands. Angiotensin II has vasoconstrictor and sodiumretention activity.
Angiotensin II inhibitors block the formation of angiotensin II and
inhibit its action, lower blood pressure principally by decreasing
peripheral vascular resistance, improving tissue perfusion, and
reducing cardiac afterload. Cardiac output and heart rate are not
significantly changed. Unlike direct vasodilators, these agents do not
result in reflex sympathetic activation and can be used safely in
persons with ischemic heart disease. The absence of reflex
tachycardia may be due to downward resetting of the baroreceptors
or to enhanced parasympathetic activity. They also cause natriuresis
by inhibiting secretion of aldosterone and by reducing the direct
stimulatory effect of angiotensin II on reabsorption of Na+ and
HCO3- in the early part of the proximal convoluted tubule.
These drugs can be classified into three broad groups based on
chemical structure:
1) Sulfhydryl-containing ACE inhibitors structurally related to
captopril (e.g., fentiapril, pivalopril, zofenopril, and alacepril);
2) Dicarboxyl-containing ACE inhibitors structurally related to
enalapril (e.g., lisinopril, benazepril, quinapril, moexipril, ramipril,
trandolapril, spirapril, perindopril, pentopril, and cilazapril);
3) phosphorus-containing ACE inhibitors structurally related to
fosinopril.
19
Many ACE inhibitors are ester-containing prodrugs that are 100 to
1000 times less potent but have a much better oral bioavailability
than the active molecules.
In general, ACE inhibitors differ with regard to three properties:
potency, whether ACE inhibition is primarily a direct effect of the
drug itself or the effect of an active metabolite, and pharmacokinetics
(i.e., extent of absorption, effect of food on absorption, plasma halflife, and tissue captopril).
Drugs
Captopril, the first ACE inhibitor to be marketed, is a potent ACE
inhibitor. Given orally, captopril is absorbed rapidly and has a
bioavailability of about 75%. Peak concentrations in plasma occur
within an hour, and the drug is cleared rapidly with a half-life of
approximately 2 hours. Most of the drug is eliminated in urine:
40–50% as captopril, and the rest as dimer captopril disulfide and
captopril-cysteine disulfide. The oral dose of captopril ranges from
6.25–150 mg two to three times daily, with 6.25 mg three times daily
or 25 mg twice daily being appropriate for the initiation of therapy
for heart failure or hypertension, respectively. Most patients should
not receive daily doses in excess of 150 mg. Since food reduces the
oral bioavailability of captopril by 25–30%, the drug should be given
1 hour before meals.
Enalapril maleate is a prodrug that is hydrolyzed by esterases in
the liver to produce the active dicarboxylic acid, enalaprilat – a
highly potent inhibitor of ACE. Enalapril is absorbed rapidly when
given orally and has an oral bioavailability of about 60% (not
reduced by food). Although peak concentrations of enalapril in
plasma occur within an hour, enalaprilat concentrations peak only
after 3–4 hours. Enalapril has a half-life of only 1.3 hours, but
enalaprilat, because of tight binding to ACE, has a plasma half-life of
about 11 hours. Nearly all the drug is eliminated by the kidneys as
either intact enalapril or enalaprilat. The oral dosage of enalapril
ranges from 2.5–40 mg daily (single or divided dosage), with 2.5 and
5 mg daily being appropriate for the initiation of therapy for heart
failure and hypertension, respectively. The initial dose for
20
hypertensive patients who are taking diuretics, are water- or Na+depleted, or have heart failure is 2.5 mg daily.
Enalaprilat is not absorbed orally but is available for intravenous
administration when oral therapy is not appropriate. For hypertensive
patients, the dosage is 0.625–1.25 mg given intravenously over 5
minutes. This dosage may be repeated every 6 hours.
Lisinopril is the lysine analogue of enalaprilat; unlike enalapril,
lisinopril itself is active. In vitro, lisinopril is a slightly more potent
ACE inhibitor than enalaprilat is. Lisinopril is absorbed slowly,
variably, and incompletely (about 30%) after oral administration (not
reduced by food); peak concentrations in plasma are achieved in
about 7 hours. It is cleared as the intact compound by the kidney, and
its half-life in plasma is about 12 hours. Lisinopril does not
accumulate in tissues. The oral dosage of lisinopril ranges from 5 to
40 mg daily (single or divided dosage), with 5 and 10 mg daily being
appropriate for the initiation of therapy for heart failure and
hypertension, respectively. A daily dose of 2.5 mg is recommended
for patients with heart failure who are hyponatremic or have renal
impairment.
Fosinopril contains a phosphinate group that binds to the active
site of ACE. Cleavage of the ester moiety by hepatic esterases
transforms fosinopril, a prodrug, into fosinoprilat, an ACE inhibitor
that in vitro is more potent than captopril yet less potent than
enalaprilat. Fosinopril is absorbed slowly and incompletely (36%)
after oral administration (rate, but not extent, is reduced by food).
Fosinopril is largely metabolized to fosinoprilat (75%) and to the
glucuronide conjugate of fosinoprilat. These are excreted both in the
urine and bile; peak concentrations of fosinoprilat in plasma are
achieved in about 3 hours. Fosinoprilat has an effective half-life in
plasma of about 11.5 hours, and its clearance is not significantly
altered by renal impairment. The oral dosage of fosinopril ranges
from 10 to 80 mg daily (single or divided dosage). The dose is
reduced to 5 mg daily in patients with Na+ or water depletion or
renal failure.
Quinapril: Cleavage of the ester moiety by hepatic esterases
transforms quinapril, a prodrug, into quinaprilat, an ACE inhibitor
21
that is in vitro about as potent as benazeprilat. Quinapril is absorbed
rapidly (peak concentrations are achieved in 1 hour, but the peak
may be delayed after food), and the rate but not extent of oral
absorption (60%), may be reduced by food. Quinapril is metabolized
to quinaprilat and to other minor metabolites, and quinaprilat is
excreted in the urine (61%) and feces (37%). Peak concentrations of
quinaprilat in plasma are achieved in about 2 hours. Conversion of
quinapril to quinaprilat is reduced in patients with diminished liver
function. The initial half-life of quinaprilat is about 2 hours; a
prolonged terminal half-life of about 25 hours may be due to highaffinity binding of the drug to tissue ACE. The oral dosage of
quinapril ranges from 5 to 80 mg daily (single or divided dosage).
Ramipril: Cleavage of the ester moiety by hepatic esterases
transforms ramipril into ramiprilat; an ACE inhibitor that in vitro is
about as potent as benazeprilat and quinaprilat. Ramipril is absorbed
rapidly (peak concentrations of ramipril are achieved in 1 hour), and
the rate, but not extent of its oral absorption (50–60%) is reduced by
food. Ramipril is metabolized to ramiprilat and to inactive
metabolites (glucuronides of ramipril and ramiprilat and the
diketopiperazine ester and acid) that are excreted predominantly by
the kidneys. Peak concentrations of ramiprilat in plasma are achieved
in about 3 hours. Ramiprilat displays triphasic elimination kinetics
with half-lives of 2–4 hours, 9–18 hours, and greater than 50 hours.
This triphasic elimination is due to extensive distribution to all
tissues (initial half-life), clearance of free ramiprilat from plasma
(intermediate half-life), and dissociation of ramiprilat from tissue
ACE (terminal half-life). The oral dosage of ramipril ranges from
1.25 to 20 mg daily (single or divided dosage).
Moexipril is another prodrug whose antihypertensive activity is
almost entirely due to its de-esterified metabolite, moexiprilat.
Moexipril is absorbed incompletely, with bioavailability as
moexiprilat of about 13%. Bioavailability is markedly decreased by
food; therefore, the drug should be taken 1 hour before meals. The
time to peak plasma concentration of moexiprilat is almost 1.5 hours,
and the elimination half-life varies between 2 and 12 hours. The
recommended dosage range is 7.5 to 30 mg daily in one or two
22
divided doses. The dosage range is halved in patients who are taking
diuretics or who have renal impairment.
Perindopril is a prodrug, and 30–50% of systemically available
perindopril is transformed to perindoprilat by hepatic esterases.
Although the oral bioavailability of perindopril (75%) is not affected
by food, the bioavailability of perindoprilat is reduced by
approximately 35%. Perindopril is metabolized to perindoprilat and
to inactive metabolites (glucuronides of perindopril and
perindoprilat, dehydrated perindopril, and diastereomers of
dehydrated perindoprilat) that are excreted predominantly by the
kidneys. Peak concentrations of perindoprilat in plasma are achieved
in 3–7 hours. Perindoprilat displays biphasic elimination kinetics
with half-lives of 3 – 10 hours (the major component of elimination)
and 30–120 hours (owing to slow dissociation of perindoprilat from
tissue ACE). The oral dosage ranges from 2 to 16 mg daily (single or
divided dosage).
Table 5 - Comparison of currently available ACE-inhibitors
Agent
Captopril
Enalapril
Lisinopril
Ramipril
Quinilapril
Moexipril
Onset (min)
15–30
60
60
60–120
60
90
Duration (hr)
10-12
24
24
24
24
24
T 1\2 (hr)
2
11
12
13–17
2
2–9
Elimination
Renal
Renal
Renal
Renal
Renal
Renal+hepatic
Adverse Effects
In general ACE inhibitors are well tolerated and serious adverse
effects to their use are rare. Metabolic side effects are not generally
seen after prolonged therapy with ACE inhibitors. The drug does not
alter plasma concentration of uric acid or calcium, and have been
seen, to even prevent insulin sensitivity, in patients with resistance
towards insulin and effects like decrease of cholesterol and
lipoprotein levels in renal diseases pertaining to proteinuria.
23
Hypotension: A steep fall in blood pressure may occur following
the first dose of an ACE inhibitor in patients with elevated PRA. In
this regard, care should be exercised in patients who are saltdepleted, in patients being treated with multiple antihypertensive
drugs, and in patients who have congestive heart failure. In such
situations, treatment should be initiated with very small doses of
ACE inhibitors, or salt intake should be increased and diuretics
withdrawn before beginning therapy.
Cough: In 5% to 20% of patients, ACE inhibitors induce a
bothersome, dry cough; it usually is not dose-related, occurs more
frequently in women than in men, usually develops between 1 week
and 6 months after initiation of therapy, and sometimes requires
cessation of therapy. This adverse effect may be mediated by the
accumulation in the lungs of bradykinin, substance P, and/or
prostaglandins. Thromboxane antagonist - aspirin, and iron
supplementation reduce coughing induced by ACE inhibitors. Once
ACE inhibitors are stopped, the cough disappears usually within 4
days.
Hyperkalemia: Despite some reduction in the concentration of
aldosterone, significant K+ retention is rarely encountered in patients
with normal renal function who are not taking other drugs that cause
K+ retention. However, ACE inhibitors may cause hyperkalemia in
patients with renal insufficiency or in patients taking K+-sparing
diuretics, K+ supplements, adrenergic receptor blockers, or NSAIDs.
Acute Renal Failure: Angiotensin II, by constricting the efferent
arteriole, helps to maintain adequate glomerular filtration when renal
perfusion pressure is low. Consequently, inhibition of ACE can
induce acute renal insufficiency in patients with bilateral renal artery
stenosis, stenosis of the artery to a single remaining kidney, heart
failure, or volume depletion owing to diarrhea or diuretics. Older
patients with congestive heart failure are particularly susceptible to
ACE inhibitor–induced acute renal failure. However, in nearly all
patients who receive appropriate treatment, recovery of renal
function occurs without sequelae.
Fetopathic Potential:
Although ACE inhibitors are not
teratogenic during the early period of organogenesis (first trimester),
24
continued administration of ACE inhibitors during the second and
third trimesters can cause oligohydramnios, fetal calvarial
hypoplasia, fetal pulmonary hypoplasia, fetal growth retardation,
fetal death, neonatal anuria, and neonatal death. These fetopathic
effects may be due in part to fetal hypotension. While ACE inhibitors
are not contraindicated in women of reproductive age, once
pregnancy is diagnosed, it is imperative that ACE inhibitors should
be discontinued as soon as possible. If necessary, an alternative
antihypertensive regimen should be instituted. The fetus is not at risk
of ACE inhibitor-induced pathology if ACE inhibitors are
discontinued during the first trimester of pregnancy.
Skin rash: ACE inhibitors occasionally cause a maculopapular
rash that may or may not itch. The rash may resolve spontaneously or
may respond to a reduced dosage or a brief course of antihistamines.
Although initially attributed to the presence of the sulfhydryl group
in captopril, a rash also may occur with other ACE inhibitors, albeit
less frequently.
Proteinuria: ACE inhibitors have been associated with proteinuria
(more than 1 g/day); however, a causal relationship has been difficult
to establish. In general, proteinuria is not a contraindication for ACE
inhibitors because ACE inhibitors are renoprotective in certain renal
diseases associated with proteinuria, e.g., diabetic nephropathy.
Angioedema: In 0.1% to 0.5% of patients, ACE inhibitors induce
a rapid swelling in the nose, throat, mouth, glottis, larynx, lips,
and/or tongue. This untoward effect, called angioedema, apparently
is not dose-related, and if it occurs, it does so within the first week of
therapy, usually within the first few hours after the initial dose.
Airway obstruction and respiratory distress may lead to death. Most
cases of visceral angioedema occur in the absence of oropharyngeal
edema, and because the symptoms are nonspecific, diagnosis can be
elusive.
Dysgeusia: An alteration in or loss of taste can occur in patients
receiving ACE inhibitors. This adverse effect, which may occur more
frequently with captopril, is reversible.
Neutropenia is a rare but serious side effect of ACE inhibitors.
Although the frequency of neutropenia is low, it occurs
25
predominantly in hypertensive patients with collagen-vascular or
renal parenchymal disease.
Glycosuria: An exceedingly rare and reversible side effect of
ACE inhibitors is spillage of glucose into the urine in the absence of
hyperglycemia (Cressman et al., 1982). The mechanism is unknown.
Hepatotoxicity: Also exceedingly rare and reversible is
hepatotoxicity, usually of the cholestatic variety. The mechanism is
unknown.
Drug Interactions
Antacids may reduce the bioavailability of ACE inhibitors;
capsaicin may worsen ACE inhibitor-induced cough; NSAIDs,
including aspirin, may reduce the antihypertensive response to ACE
inhibitors; and K+-sparing diuretics and K+ supplements may
exacerbate ACE inhibitor–induced hyperkalemia. ACE inhibitors
may increase plasma levels of digoxin and lithium and may increase
hypersensitivity reactions to allopurinol.
2.3.3. ANGIOTENSIN II RECEPTOR ANTAGONISTS
As discussed earlier, angiotensin II has significant effect of
vasoconstriction, contraction of vascular tone of vessels rapid pressor
responses, slow pressor responses, thirst, vasopressin release,
aldosterone secretion, release of adrenal catecholamines,
enhancement of noradrenergic neurotransmission, increases in
sympathetic tone, changes in renal function, and cellular hypertrophy
and hyperplasia. ARBs selectively and potently inhibit most of the
above effects in vitro or in vivo of angiotensin II. Even though both
ACE inhibitors and ARBs block the RAS, these two classes of drugs
have important and significant differences which also change their
therapeutic value and use:
1. ARBs reduce activation of AT1 receptors more effectively than
do ACE inhibitors. ACE inhibitors reduce the biosynthesis of
angiotensin II produced by the action of ACE on angiotensin I but do
not inhibit alternative non-ACE angiotensin II – generating
pathways. Because ARBs block the AT1 receptor, the actions of
26
angiotensin II via the AT1 receptor are inhibited regardless of the
biochemical pathway leading to angiotensin II formation.
2. In contrast to ACE inhibitors, ARBs permit activation of AT2
receptors. ACE inhibitors increase renin release; however, because
ACE inhibitors block the conversion of angiotensin I to angiotensin
II, ACE inhibition is not associated with increased levels of
angiotensin II. ARBs also stimulate renin release; however, with
ARBs, this translates into a several-fold increase in circulating levels
of angiotensin II. Because AT2 receptors are not blocked by
clinically available ARBs, this increased level of angiotensin II is
available to activate AT2 receptors.
3. ACE inhibitors may increase angiotensin levels more than do
ARBs. ACE is involved in the clearance of angiotensin, so inhibition
of ACE may increase angiotensin levels more than do ARBs.
4. ACE inhibitors increase the levels of a number of ACE
substrates, including bradykinin.
Table 6 Comparisons of currently available receptor blockers
Agent
Losartan
Valsartan
Ibesartan
Candesartan
Telmisartan
Onset (min)
60–90
120
60–120
120-240
60–180
Duration (hr)
24
24
24
24
24
T 1\2 (hr)
2–9
6
11–15
9
24
Elimination
Hepatic+Renal
Hepatic
Hepatic
Hepatic+Renal
Hepatic
Oral bioavailability of ARBs is generally low (<50%, except for
irbesartan, with 70% available), and protein binding is high (>90%).
All ARBs are approved for the treatment of hypertension. In
addition, irbesartan and losartan are approved for diabetic
nephropathy, losartan is approved for stroke prophylaxis, and
valsartan is approved for patients with heart failure who are
intolerant of ACE inhibitors. The efficacy of ARBs in lowering
blood pressure is comparable with that of other established
antihypertensive drugs, with an adverse-effect profile similar to that
27
of placebo. ARBs also are available as fixed-dose combinations with
hydrochlorothiazide.
Losartan is well tolerated in patients with heart failure and is
comparable to enalapril with regard to improving exercise and is as
effective as captopril in improving symptoms and reduced mortality
more than has captopril.
In part via blood pressure-independent mechanisms, ARBs are
renoprotective in type 2 diabetes mellitus. Based on these results,
many experts now consider them the drugs of choice for
renoprotection in diabetic patients. Also, irebesartan appears to
maintain sinus rhythm in patients with persistent, long-standing atrial
fibrillation. Losartan is reported to be safe and highly effective in the
treatment of portal hypertension in patients with cirrhosis and portal
hypertension without compromising renal function.
Drugs
Candesartan cilexetil is an inactive ester prodrug that is
completely hydrolyzed to the active form, candesartan, during
absorption from the gastrointestinal tract. Peak plasma levels are
obtained 3 – 4 hours after oral administration, and the plasma halflife is about 9 hours. Plasma clearance of candesartan is due to renal
elimination (33%) and biliary excretion (67%). The plasma clearance
of candesartan is affected by renal insufficiency but not by mild to
moderate hepatic insufficiency. Candesartan cilexetil should be
administered orally once or twice daily for a total daily dosage of 4 –
32 mg.
Irbesartan: Peak plasma levels are obtained approximately
1.5–2 hours after oral administration, and the plasma half-life ranges
from 11 to 15 hours. Irbesartan is metabolized in part to the
glucuronide conjugate, and the parent compound and its glucuronide
conjugate are cleared by renal elimination (20%) and biliary
excretion (80%). The plasma clearance of irbesartan is unaffected by
either renal or mild to moderate hepatic insufficiency. The oral
dosage of irbesartan is 150–300 mg once daily.
Losartan: Approximately 14% of an oral dose of losartan is
converted to the 5-carboxylic acid metabolite EXP3174, which is
28
more potent than losartan as an AT1-receptor antagonist. The
metabolism of losartan to EXP3174 and to inactive metabolites is
mediated by CYP2C9 and CYP3A4. Peak plasma levels of losartan
and EXP3174 occur approximately 1–3 hours after oral
administration, respectively, and the plasma half-lives are 2.5 and
6–9 hours, respectively. Losartan should be administered orally once
or twice daily for a total daily dose of 25–100 mg. In addition to
being an ARB, losartan is a competitive antagonist of the
thromboxane A2-receptor and attenuates platelet aggregation.
Telmisartan: Peak plasma levels are obtained approximately
0.5–1 hour after oral administration, and the plasma half-life is about
24 hours. Telmisartan is cleared from the circulation mainly by
biliary secretion of intact drug. The plasma clearance of telmisartan
is affected by hepatic but not renal insufficiency. The recommended
oral dosage of telmisartan is 40 to 80 mg once daily.
Valsartan: Peak plasma levels occur approximately 2 – 4 hours
after oral administration, and the plasma half-life is about 9 hours.
Food markedly decreases absorption. Valsartan is cleared from the
circulation by the liver (about 70% of total clearance). The plasma
clearance of valsartan is affected by hepatic but not renal
insufficiency. The oral dosage of valsartan is 80–320 mg once daily.
Adverse Effects
The incidence of discontinuation of ARBs owing to adverse
reactions is comparable with that of placebo. Unlike ACE inhibitors,
ARBs do not cause cough, and the incidence of angioedema with
ARBs is much less than with ACE inhibitors. As with ACE
inhibitors, ARBs have teratogenic potential and should be
discontinued before the second trimester of pregnancy. ARBs should
be used cautiously in patients whose arterial blood pressure or renal
function is highly dependent on the renin–angiotensin system (e.g.,
renal artery stenosis). In such patients, ARBs can cause hypotension,
oliguria, progressive azotemia, or acute renal failure. ARBs may
cause hyperkalemia in patients with renal disease or in patients
taking K+ supplements or K+-sparing diuretics. ARBs enhance the
29
blood pressure–lowering effect of other antihypertensive drugs, a
desirable effect but one that may necessitate dosage adjustment.
2.3.4. ANTIADRENERGIC DRUGS
Adrenergic agonists increase blood pressure by stimulating the
heart (β1 receptors) and/or constricting peripheral blood vessels (α1
receptors). In hypertensive patients, adrenergic effects can be
suppressed by inhibiting release of adrenergic agonists or by
antagonizing adrenergic receptors.
Presynaptic adrenergic release inhibitors are divided into "central"
and "peripheral" antiadrenergics. Central antiadrenergics prevent
sympathetic (adrenergic) outflow from the brain by activating
inhibitory α2 receptors. By reducing sympathetic outflow, these
agents encourage "parasympathetic redominance"and prevent
norepinefrime release from peripheral nerve (e.g., those which
terminate on the heart). These agents deplete norepinephrine stores in
nerve terminals.
Alpha and beta blockers compete with endogenous agonists for
adrenergic receptors. Blockage of (α1-adrenergic receptors inhibits
vasoconstriction and occupation of β1 receptors prevents adrenergic
stimulation of the heart.
Selective α1 or β1 blockers replace nonspecific β blockers, because
they produce fewer undesirable effects.
Beta receptor antagonists are predominantly effective on the
cardiovascular system because of their therapeutic efficacy. These
antagonist preparations are widely used to treat hypertension, angina,
and acute coronary syndromes. Their potent use lies in the treatment
of congestive heart failure, supraventricular and ventricular
arrhythmias. Due to positive chronotropic and ionotropic effects of
catecholamines, β-receptor antagonists are capable of slowing down
heart rate and myocardial contractility. This effect is modest when
β receptors have a low tonic stimulation predisposed by stress,
anxiety, physical exercise or motion. But when the sympathetic
nervous system activity has been sufficiently activated, β-receptor
antagonists counteract the stimulatory effect and decrease the
30
anticipated rise in heart rate. Short term administration of β-receptor
antagonists, like propranolol, includes decrease in stroke volume and
cardiac output. Rise in peripheral resistance is seen as a
compensatory mechanism to normalize blood pressure due to
vascular response effect and receptor blockade. Evident rise in
sympathetic activity leads to activation of the vascular receptors. But
after prolonged use of β-receptor antagonists total peripheral
resistance tend to normalize and returns to normal values or
decreases in case of patients with hypertension. Drugs, like labetolol
and carvedilol which are simultaneously α-receptor blockers, show
higher efficacy with a greater decrease of peripheral resistance.
Similar effects are seen with other receptor antagonists wich are
direct vasodilators as well as hydralazine.
The β-receptor antagonists have significant effects on cardiac
rhythm and automaticity. Although these effects were considered to
be due exclusively to blockade of β1-receptors, β2-receptors likely
also regulate heart rate in humans. Beta-3 receptors also have been
identified in normal myocardial tissue in some species, including
humans. The β-receptor antagonists reduce sinus rate, decrease the
spontaneous rate of depolarization of ectopic pacemakers, slow
conduction in the atria and in the AV node, and increase the
functional refractory period of the AV node.
Several β1 blockers have intrinsic sympathomimetic activity (act
as weak agonists at some adrenergic receptors). These drugs
stimulate β2 receptors, which reduces the likelihood that rebound
hypertension (sympathetic reflex fall in blood pressure) will develop.
Activated α2 receptors dilate large central arteries which provide a
reservoir for blood. Drugs without intrinsic sympathomimetic
activity produce an initial reduction in cardiac output and a reflexinduced rise in peripheral resistance, generally without net change in
arterial pressure. In patients who respond with a reduction in blood
pressure, peripheral resistance gradually returns to pretreatment
values or less. Generally, persistently reduced cardiac output and
possibly decreased peripheral resistance accounts for the reduction in
arterial pressure. Drugs with intrinsic sympathomimetic activity
produce lesser decreases in resting heart rate and cardiac output; the
31
fall in arterial pressure correlates with the fall in vascular resistance
below pretreatment levels, possibly because of stimulation of
vascular α2-adrenergic receptors that mediate vasodilation. The
clinical significance, if any, of these differences is unknown.
Drugs
Metoprolol is approximately equipotent to propranolol in
inhibiting stimulation of β1 adrenoceptors, such as those in the heart
but 50- to 100-fold less potent than propranolol in blocking
β2 receptors. Although metoprolol is in other respects very similar to
propranolol, its relative cardioselectivity may be advantageous in
treating hypertensive patients who also suffer from asthma, diabetes,
or peripheral vascular disease. Studies of small numbers of asthmatic
patients have shown that metoprolol causes less bronchial
constriction than propranolol at doses that produce equal inhibition
of β1-adrenoceptor responses. The cardioselectivity is not complete,
however, and asthmatic symptoms have been exacerbated by
metoprolol. For the treatment of hypertension, the usual initial dose
is 100 mg per day. The drug sometimes is effective when given once
daily, although it frequently is used in two divided doses. Dosage
may be increased at weekly intervals until optimal reduction of blood
pressure is achieved. If the drug is taken only once daily, it is
important to confirm that blood pressure is controlled for the entire
24-hour period. Metoprolol generally is used in two divided doses for
the treatment of stable angina. For the initial treatment of patients
with acute myocardial infarction, an intravenous formulation of
metoprolol tartrate is available. Oral dosing is initiated as soon as the
clinical situation permits. Metoprolol generally is contraindicated for
the treatment of acute myocardial infarction in patients with
heart rates of less than 45 beats per minute, heart block greater
than first-degree (PR interval 0.24 second), systolic blood pressure
<100 mm Hg, or moderate-to-severe heart failure. Metoprolol also
has been proven to be effective in chronic heart failure.
Nadolol and carteolol, nonselective β-receptor antagonists, and
atenolol, a β1-selective blocker, are not appreciably metabolized and
are excreted to a considerable extent in the urine. Betaxolol and
32
bisoprolol are β1-selective blockers that are primarily metabolized in
the liver but have long half-lives. Because of these relatively long
half-lives, these drugs can be administered once daily. The usual
starting dosage of nadolol is 40 mg/d, atenolol – 50 mg/d, carteolol –
2.5 mg/d, betaxolol –10 mg/d, and bisoprolol – 5 mg/d. Increases in
dosage to obtain a satisfactory therapeutic effect should take place no
more often than every 4 or 5 days. Patients with reduced renal
function should receive correspondingly reduced doses of nadolol,
carteolol, and atenolol. It is claimed that atenolol produces fewer
central nervous system-related effects than other, more lipid-soluble
β antagonists.
Pindolol, acebutolol, and penbutolol are partial agonists, i.e.,
β blockers with some intrinsic sympathomimetic activity. They lower
blood pressure by decreasing vascular resistance and appear to
depress cardiac output or heart rate less than other β blockers,
perhaps because of significantly greater agonist than antagonist
effects at β2 receptors. This may be particularly beneficial for
patients with bradyarrhythmias or peripheral vascular disease. Daily
initial doses of pindolol are 10 mg; of acebutolol – 400 mg; and of
penbutolol – 20 mg.
Labetalol is formulated as a racemic mixture of four isomers (it
has two centers of asymmetry). Labetalol has a 3:1 ratio of
β:α antagonism after oral dosing. Blood pressure is lowered by
reduction of systemic vascular resistance without significant
alteration in heart rate or cardiac output. Because of its combined
β- and α-blocking activity, labetalol is useful in treating the
hypertension of pheochromocytoma and hypertensive emergencies.
Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol
is given as repeated intravenous bolus injections of 20–80 mg to treat
hypertensive emergencies.
Carvedilol, like labetalol, is administered as a racemic mixture.
The average half-life is 7–10 hours. The usual starting dosage of
carvedilol for ordinary hypertension is 6.25 mg twice daily.
Esmolol is a β1-selective blocker that is rapidly metabolized via
hydrolysis by red blood cell esterases. It has a short half-life (9–10
minutes) and is administered by constant intravenous infusion.
33
Esmolol is generally administered as a loading dose (0.5–1 mg/kg),
followed by a constant infusion. The infusion is typically started at
50–150 mcg/kg/min, and the dose is increased every 5 minutes up to
300 mcg/kg/min as needed to achieve the desired therapeutic effect.
Esmolol is used for management of intraoperative and postoperative
hypertension and sometimes for hypertensive emergencies,
particularly when hypertension is associated with tachycardia.
Table 7 - Pharmacological parameters of β blockers
Agent
Selectivity
Lipid
solubility
T 1\2
(hr)
Metabolism
Notes
Acebtalol
β1
Moderate
2–3
Hepatic + Renal Partial agonist
Atenolol
β1
Low
6–7
Renal
Betaxolol
β1
Low
14–22 Hepatic + Renal Used in
glaucoma
Bisoprolol
β1
Low
9–12
Hepatic + Renal
Carvediol
β1+β2 and α1 High
6–10
Hepatic
Labetalol
β1+β2 and α1 Moderate
6–8
Hepatic + Renal Βeta blockade
Used mostly
for CHF
Nadolol
β1+β2
Low
Pindolol
β1+β2
Moderate
3–4
Hepatic + Renal Partial agonist
Prpranolol
β1+β2
High
4–6
Hepatic
Timolol
β1+β2
Lowmoderate
4–5
Hepatic+ Renal Used in
glaucoma
20–24 Renal
Long-acting
Provocation
of
bronchospasm
Adverse Effects
The most common adverse effects of receptor antagonists arise as
pharmacological consequences of receptor blockade; serious adverse
effects unrelated to receptor blockade are rare.
34
Cardiovascular system: Because the sympathetic nervous system
provides critical support for cardiac performance in many individuals
with impaired myocardial function, receptor antagonists may induce
congestive heart failure in susceptible patients. Thus, receptor
blockade may cause or exacerbate heart failure in patients with
compensated heart failure, acute myocardial infarction, or
cardiomegaly. It is not known whether receptor antagonists that
possess intrinsic sympathomimetic activity or peripheral vasodilating
properties are safer in these settings. Nonetheless, there is convincing
evidence that chronic administration of receptor antagonists is
efficacious in prolonging life in the therapy of heart failure in
selected patients
Bradycardia is a normal response to receptor blockade; however,
in patients with partial or complete atrioventricular conduction
defects, antagonists may cause life-threatening bradyarrhythmias.
Particular caution is indicated in patients who are taking other drugs,
such as verapamil or various antiarrhythmic agents, which may
impair sinus-node function or AV conduction.
It is not recommended to cease the use of receptor antagonists
abruptly during a long-term treatment due to the potential risks of
exacerbation of conditions like angina and increases the risk of
mortality by sudden death. The mechanism of such morbidity has
remained unclear even though it has been well established that
patients who have undergone long term treatment with any specific
kind of receptor antagonists has developed enhanced sensitivity to
adrenergic receptor antagonists after the therapy has been abruptly
ceased. For example, chronotropic responses to isoproterenol are
blunted in patients who are receiving receptor antagonists; however,
abrupt discontinuation of propranolol leads to greater-than-normal
sensitivity to isoproterenol. This increased sensitivity is evident for
several days after stopping propranolol and may persist for at least 1
week. The increased sensitivity can be reduced by gradual tapering
the dose before discontinuation. Supersensitivity to isoproterenol
also has been observed after abrupt discontinuation of metoprolol,
but not of pindolol. It has been hypothesized that this increased
sensitivity perhaps are caused due to up-regulation of receptors. The
35
number of receptors on circulating lymphocytes is increased in
subjects who have received propranolol for long periods; pindolol
has the opposite effect. Optimal strategies for discontinuation of
blockers are not known, but it is prudent to decrease the dose
gradually and to restrict exercise during this period.
Bronchospasm: A major adverse effect of receptor antagonists is
caused by blockade of β2 receptors in bronchial smooth muscle.
These receptors are particularly important for promoting
bronchodilation in patients with bronchospastic disease, and blockers
may cause a life-threatening increase in airway resistance in such
patients. Drugs with one adrenergic receptors selectivity or those
with intrinsic sympathomimetic activity at β2-adrenergic receptors
may be somewhat less likely to induce bronchospasm. Since the
selectivity of current blockers for β1 receptors is modest, these drugs
should be avoided if at all possible in patients with asthma. However,
in some patients with chronic obstructive pulmonary disease, the
potential advantage of using receptor antagonists after myocardial
infarction may outweigh the risk of worsening pulmonary function.
Central nervous system: The adverse effects of receptor
antagonists that are referable to the CNS may include fatigue, sleep
disturbances (including insomnia and nightmares), and depression.
The previously ascribed association between these drugs and
depression may not be substantiated by more recent clinical studies.
An interest has been focused on the relationship between the
incidence of the adverse effects of receptor antagonists and their
lipophilicity; however, no clear correlation has emerged.
Metabolism: As described above, adrenergic blockade may blunt
recognition of hypoglycemia by patients; it also may delay recovery
from insulin-induced hypoglycemia. Receptor antagonists should be
used with great caution in patients with diabetes who are prone to
hypoglycemic reactions; 1-selective agents may be preferable for
these patients. The benefits of receptor antagonists in type 1 diabetes
with myocardial infarction may outweigh the risk in selected
patients.
Miscellaneous: The incidence of sexual dysfunction in men with
hypertension who are treated with receptor antagonists is not clearly
36
defined. Although experience with the use of adrenergic receptor
antagonists in pregnancy is increasing, information about the safety
of these drugs during pregnancy is still limited.
Overdosage: The manifestations of poisoning with receptor
antagonists depend on the pharmacological properties of the ingested
drug, particularly its one selectivity, intrinsic sympathomimetic
activity, and membrane-stabilizing properties. Hypotension,
bradycardia, prolonged AV conduction times, and widened QRS
complexes are common manifestations of overdosage. Seizures and
depression may occur. Hypoglycemia is rare, and bronchospasm is
uncommon in the absence of pulmonary disease. Significant
bradycardia should be treated initially with atropine, but a cardiac
pacemaker often is required. Large doses of isoproterenol or receptor
agonist may be necessary to treat hypotension. Glucagon has positive
chronotropic and inotropic effects on the heart that are independent
of interactions with adrenergic receptors, and the drug has been
useful in some patients.
Drug Interactions
Both pharmacokinetic and pharmacodynamic interactions have
been noted between receptor antagonists and other drugs. Aluminum
salts, cholestyramine, and colestipol may decrease the absorption of
blockers. Drugs, such as phenytoin, rifampin, and phenobarbital, as
well as smoking, induce hepatic biotransformation of enzymes and
may decrease plasma concentrations of receptor antagonists that are
metabolized extensively (e.g., propranolol). Cimetidine and
hydralazine may increase the bioavailability of agents, such as
propranolol and metoprolol, by affecting hepatic blood flow.
Receptor antagonists can impair the clearance of lidocaine.
Other drug interactions have pharmacodynamic explanations. For
example, antagonists and Ca2+ channel blockers have additive effects
on the cardiac conducting system. Additive effects on blood pressure
between blockers and other antihypertensive agents often are
employed to clinical advantage. However, the antihypertensive
effects of receptor antagonists can be opposed by indomethacin and
other nonsteroidal anti-inflammatory drugs.
37
2.3.5. CALCIUM CHANNEL BLOCKERS (THE CALCIUM
SLOW CHANNEL BLOCKING AGENTS)
Calcium channel blockers (CCB) are recommended for patients
when the preferred first-line treatment (please reconsider this line)
against hypertension has been proved to be inefficient or ineffective.
These drugs are effective in treating hypertensive disorder in patients
with diabetes or angina as an accompanying disorder. High doses of
short-acting CCB are not recommended owing to increased risk
towards precipitation of an attack of myocardial infarction due to
excessive vasodilation and marked reflex tachycardia. The muscular
tonicity of vessels and contractile function of myocardium is
inherently dependent on the intracellular concentration of calcium.
Calcium influxes in the cell through special voltage-sensitive
calcium channels, or gates, which triggers the release of calcium ions
from the sarcoplasmic reticulum and mitochondria which, in turn,
increases further intracellular concentration of calcium. CCBs block
this influx of calcium into the cells by binding with the L-type (slow
type) calcium channels in the heart muscles and peripheral
vasculature. This causes relaxation of the smooth muscle of the
vessels and myocardium and reduction of tonus.
Calcium channel blockers have an intrinsic natriuretic effect and,
therefore, do not usually require the addition of a diuretic. These
agents are useful in the treatment of hypertensive patients who also
have asthma, diabetes, angina, and/or peripheral vascular disease.
Black hypertensives respond well to calcium channel blockers.
Classification of Calcium Channel Blockers
The calcium channel blockers are divided into three chemical
classes, each with different pharmacokinetic properties and clinical
indications.
Diphenylalkylamines: Verapamil is the only member of this class
that is currently approved. Verapamil is the least selective of any
calcium-channel blocker and has significant effects on both cardiac
and vascular smooth muscle cells. It is used to treat angina,
supraventricular tachyarrhythmias, and migraine headache.
38
Dihydropyridines: This rapidly expanding class of calcium
channel blockers includes the first-generation nifedipine and five
second-generation agents for treating cardiovascular disease:
amlodipine, felodipine, isradipine, nicardipine, and nisoldipine.
These second-generation calcium channel blockers differ in
pharmacokinetics, approved uses, and drug interactions. All
dihydropyridines have a much greater affinity for vascular calcium
channels than for calcium channels in the heart. They are therefore
particularly attractive in treating hypertension. Some of the newer
agents, such as amlodipine and nicardipine, have the advantage that
they show little interaction with other cardiovascular drugs, such as
digoxin or warfarin, which are often used concomitantly with
calcium channel blockers.
Benzothiazepines: Diltiazem is the only member of this class that
is currently approved. Like verapamil, diltiazem affects both cardiac
and vascular smooth muscle cells; however, it has a less pronounced
negative inotropic effect on the heart compared to that of verapamil.
Diltiazem has a favorable side-effect profile.
Table 8 - Cardivascular effects of calcium channel blockers
Parameter
Nifidipine
Dilteazem
Verapamil
-
-
-
Vasodilation
+++
++
++
Heart rate
++
-
+-
Contractility
0\+
0
0\ -
Coronary
vascular
resistance
-
-
-
Blood flow
+++
+++
++
Blood pressure
39
Table 9 – Clinical properties of some calcium channel blocking
drugs
Drug
Amlodipine
Felodipine
Isradipine
Nicardipine
Nifedipine
Nimodipine
Nisoldipine
Diltiazem
Verapamil
Indication
Angina,
hypertension
Hypertension,
Raynaud's
phenomenon,
congestive
heart
failure
Hypertension
Usual Dosage
5–10 mg orally
once daily
5–10 mg orally
once daily
Toxicity
Headache,
peripheral edema
Dizziness,
headache
2.5–10 mg orally Headache, fatigue
every12 hours
Angina,
20–40 mg orally Peripheral edema,
hypertension
every 8 hours
dizziness,
congestive
heart
headache, flushing
failure
Angina,
3–10 g/kg IV; 20– Hypotension,
hypertension,
40 mg orally every dizziness,
migraine,
8 hours
flushing, nausea,
cardiomyopathy,
constipation,
Raynaud's
dependent edema
phenomenon
Subarachnoid
60 mg orally every Headache,
hemorrhage,
4 hours
diarrhea
migraine
Hypertension
20–40 mg orally Probably similar
once daily
to nifedipine
Angina,
75–150 g/kg IV; Hypotension,
hypertension,
30–80
mgorally dizziness,
Raynaud's
every 6 hours
flushing,
phenomenon
bradycardia
Angina,
75–150 g/kg IV; Hypotension,
hypertension,
80–160 mg orally myocardial
arrhythmias,
every 8 hours
depression,
migraine,
constipation,
cardiomyopathy
dependent edema
40
Adverse Effects
Constipation occurs in 10% of patients treated with verapamil.
Dizziness, headache, and a feeling of fatigue caused by a decrease in
blood pressure are more frequent with dihydropyridines. Verapamil
should be avoided in patients with congestive heart failure or with
atrioventricular block due to its negative inotropic (force of cardiac
muscle contraction) and dromotropic (velocity of conduction)
effects.
Table 10 - Adverse effects of calcium channel blockers
Tachycardia
Decreased heart rate
Decreased A-V nodal
conduction
Negative inotropy
Vasodilatation (flushing,
edema,
hypotension,
headaches)
Constipation, nausea
2.4.
Nifidipine
0
+
+++
Dilteazem
0
+
++
Verapamil
+
0
0
++
+
+
+\0
0
+++
++
+
+\0
SECOND-LINE THERAPY
Sometimes effectivness of first-line therapy is not satisfectory or
patients have contraindications. We may use drugs from the second
group in these cases.
2.4.1. GANGLIONIC BLOCKING AGENTS
Ganglion blockers, such as pirylen and benzoxexonium,
competitively block nicotinic cholinoceptors on postganglionic
neurons in both sympathetic and parasympathetic ganglia. In
41
addition, these drugs may directly block the nicotinic acetylcholine
channel, in the same fashion as neuromuscular nicotinic blockers.
Ganglion blockers are used for controlled hypotension; for
treatment of pulmonary oedema and brain oedema; for interruption
of hypertensive crisis. Nowadays, ganglion blockers are used seldom
for treatment of hypertensive disease, because drugs administration
results in large number of side effects: decrease of tone and motility
of gastrointestinal tract and bladder, constipation, disturbances of
accomodation, dry mouth. Serious complication of ganglion blockers
administration is postural hypotension. Tolerance develops in case of
regular administration of ganglion blockers
Adverse Effects
Ganglion blockers exert their side effects as a direct extension of
their pharmacological effects. Sympathoplegia (excessive orthostatic
hypotension and sexual dysfunction) and parasympathoplegia
(constipation, urinary retention, precipitation of glaucoma, blurred
vision, dry mouth, etc.) are the most commonly observed side effects
in this class of drugs. The high drug toxicity and the severe drug side
effects are the main reasons as for why these are not considered as
the first-line treatment of hypertension anymore.
2.4.2. ALPHA 1-BLOCKERS
Nonselective α-adrenoceptor antagonists relax vessels owing to
blockage of both α1- and α2-adrenoceptors. But these drugs aren’t
used for systemic treatment of hypertensive disease, because they
don’t promote stable hypotensive effect. Shortness of effect is the
result of blockage of presynaptic α2-adrenoceptors which regulate
negative feedback. Blockage of these receptors results in excessive
noradrenaline
Prazosin, terazosin, and doxazosin produce most of their
antihypertensive effect by selectively blocking α1 receptors in
arterioles and venules. These agents produce less reflex tachycardia
when lowering blood pressure than do non-selective α antagonists,
such as phentolamine. Alpha 1-receptor selectivity allows
42
norepinephrine to exert unopposed negative feedback (mediated by
presynaptic α2 receptors) on its own release in contrast, phentolamine
blocks both presynaptic and postsynaptic α receptors, with the result
that reflex activation of sympathetic neurons produces greater release
of transmitter onto α- receptors and correspondingly greater cardioacceleration.
Alpha blockers reduce arterial pressure by dilating both resistance
and capacitance vessels. As expected, blood pressure is reduced more
in the upright than in the supine position. Retention of salt and water
occurs when these drugs are administered without a diuretic. The
drugs are more effective when used in combination with other
agents, such as a β blocker and a diuretic, than when used alone.
2.4.3. VASODILATORS
Within this class of drugs are the oral vasodilators, hydralazine
and minoxidil, which are used for long-term outpatient therapy of
hypertension; the parenteral vasodilators, nitroprusside, diazoxide,
and fenoldopam, which are used to treat hypertensive emergencies;
and the calcium channel blockers, which are used in both
circumstances.
Drugs
Hydralazine, a hydrazine derivative, dilates arterioles but not
veins. It has been available for many years, although it was initially
thought not to be particularly effective because tachyphylaxis to its
antihypertensive effects developed rapidly. The benefits of
combination therapy are now recognized, and hydralazine may be
used more effectively, particularly in severe hypertension.
Usual dosage ranges from 40 mg/d to 200 mg/d. The higher
dosage was selected as the dose at which there is a small possibility
of developing the lupus erythematosus-like syndrome described in
the next section. However, higher dosages result in greater
vasodilation and may be used if necessary. Dosing two or three times
daily provides smooth control of blood pressure.
43
The most common adverse effects of hydralazine are headache,
nausea, anorexia, palpitations, sweating, and flushing. In patients
with ischemic heart disease, reflex tachycardia and sympathetic
stimulation may provoke angina or ischemic arrhythmias.
Minoxidil is a very efficacious orally active vasodilator. The effect
results from the opening of potassium channels in smooth muscle
membranes by minoxidil sulfate, the active metabolite. Increased
potassium permeability stabilizes the membrane at its resting
potential and makes contraction less likely. Like hydralazine,
minoxidil dilates arterioles but not veins. Because of its greater
potential antihypertensive effect, minoxidil should replace
hydralazine when maximal doses of the latter are not effective or in
patients with renal failure and severe hypertension, who do not
respond well to hydralazine.
Adverse Effects
Tachycardia, palpitations, angina and edema are observed when
doses of α blockers and diuretics are inadequate. Headache, sweating
and hirsutism which is particularly bothersome in women, are
relatively common. Minoxidil illustrates how one person's toxicity
may become another person's therapy. Topical minoxidil is used as a
stimulant to hair growth for correction of baldness.
Sodium nitroprusside is a powerful parenterally administered
vasodilator that is used in treating hypertensive emergencies as well
as severe heart failure. Nitroprusside dilates both arterial and venous
vessels, resulting in reduced peripheral vascular resistance and
venous return. The action occurs as a result of activation of guanylyl
cyclase, either via release of nitric oxide or by direct stimulation of
the enzyme. The result is increased by intracellular cGMP, which
relaxes vascular smooth muscle
In the absence of heart failure, blood pressure decreases, owing to
decreased vascular resistance, while cardiac output does not change
or decreases slightly. In patients with heart failure and low cardiac
output, output often increases owing to afterload reduction.
Infusion solutions should be changed after several hours. Dosage
typically begins at 0.5 mcg/kg/min and may be increased up to
44
10 mcg/kg/min as necessary to control blood pressure. Higher rates
of infusion, if continued for more than an hour, may result in
toxicity. Because of its efficacy and rapid onset of effect, the drug
should be administered by infusion pump and arterial blood pressure
continuously monitored via intra-arterial recording.
Diazoxide is similar chemically to the thiazide diuretics but has no
diuretic activity. It is bound extensively to serum albumin and to
vascular tissue. Drug is an effective and relatively long-acting
parenterally administered arteriolar dilator that is occasionally used
to treat hypertensive emergencies. Injection of diazoxide results in a
rapid fall in systemic vascular resistance and mean arterial blood
pressure associated with substantial tachycardia and increase in
cardiac output. Studies of its mechanism suggest that it prevents
vascular smooth muscle contraction by opening potassium channels
and stabilizing the membrane potential at the resting level. The most
significant toxicity from diazoxide has been excessive hypotension,
resulting from the recommendation to use a fixed dose of 300 mg in
all patients. Such hypotension has resulted in stroke and myocardial
infarction. The reflex sympathetic response can provoke angina,
electrocardiographic evidence of ischemia, and cardiac failure in
patients with ischemic heart disease, and diazoxide should be
avoided in this situation.
Diazoxide inhibits insulin release from the pancreas (probably by
opening potassium channels in the cell membrane) and is used to
treat hypoglycemia secondary to insulinoma. Occasionally,
hyperglycemia complicates diazoxide use, particularly in persons
with renal insufficiency.
In contrast to the structurally related thiazide diuretics, diazoxide
causes renal salt and water retention. However, because the drug is
used for short periods only, this is rarely a problem.
2.4.4. CENTRALLY ACTING ADRENERGIC DRUGS
These agents reduce sympathetic outflow from vasopressor
centers in the brainstem but allow these centers to retain or even
increase their sensitivity to baroreceptor control. Accordingly, the
45
antihypertensive and toxic actions of these drugs are generally less
dependent on posture than are the effects of drugs that act directly on
peripheral sympathetic neurons.
Methyldopa is useful in the treatment of mild to moderate severe
hypertension. It lowers blood pressure chiefly by reducing peripheral
vascular resistance, with a variable reduction in heart rate and cardiac
output.
Most cardiovascular reflexes remain intact after administration of
methyldopa, and blood pressure reduction is not markedly dependent
on maintenance of upright posture. Postural (orthostatic) hypotension
sometimes occurs, particularly in volume-depleted patients. One
potential advantage of methyldopa is that it causes reduction in renal
vascular resistance.
The most frequent undesirable effect of methyldopa is overt
sedation, particularly at the onset of treatment. With long-term
therapy, patients may complain of persistent mental lassitude and
impaired mental concentration. Nightmares, mental depression,
vertigo, and extrapyramidal signs may occur but are relatively
infrequent. Lactation, associated with increased prolactin secretion,
can occur both in men and in women treated with methyldopa. This
toxicity is probably mediated by inhibition of dopaminergic
mechanisms in the hypothalamus.
Clonidine: Hemodynamic studies indicate that blood pressure
lowering by clonidine results from reduction of cardiac output due to
decreased heart rate and relaxation of capacitance vessels, with a
reduction in peripheral vascular resistance, particularly when patients
are upright (when sympathetic tone is normally increased).
Reduction in arterial blood pressure by clonidine is accompanied
by decreased renal vascular resistance and maintenance of renal
blood flow. As with methyldopa, clonidine reduces blood pressure in
the supine position and only rarely causes postural hypotension.
Pressor effects of clonidine are not observed after ingestion of
therapeutic doses of clonidine, but severe hypertension can
complicate a massive overdose.
46
Adverse Effects
Dry mouth and sedation are frequent and may be severe. Both
effects are centrally mediated and dose-dependent and coincide
temporally with the drug's antihypertensive effect.
The drug should not be given to patients who are at risk for mental
depression and should be withdrawn if depression occurs during
therapy. Concomitant treatment with tricyclic antidepressants may
block the antihypertensive effect of clonidine. Patients exhibit
nervousness, tachycardia, headache, and sweating after omitting one
or two doses of the drug. Although the incidence of severe
hypertensive crisis is unknown, it is high enough to require that all
patients who take clonidine be carefully warned of the possibility. If
the drug must be stopped, this should be done gradually while other
antihypertensive agents are being substituted. Treatment of the
hypertensive crisis consists of reinstitution of clonidine therapy or
administration of α- and β-adrenoceptor-blocking agents.
2.4.5. HYPERTENSIVE EMERGENCY
Hypertensive emergency is a rare, but life-threatening situation in
which the diastolic blood pressure is either over 150 mm Hg (with
systolic blood pressure greater than 210 mm Hg) in an otherwise
healthy person, or 130 mm Hg in an individual with preexisting
complications, such as encephalopathy, cerebral hemorrhage, left
ventricular failure, or aortic stenosis. The therapeutic goal is to
reduce rapidly blood pressure.
Sodium
Nitroprusside:
Nitroprusside
is
administered
intravenously, and it 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 (Tl/2 of
minutes) and requires continuous infusion to maintain its
hypotensive action.
47
Sodium nitroprusside exerts few adverse effects except for those
of hypotension caused by overdose. 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.
Diazoxide: Diazoxide is a direct-acting arteriolar vasodilator. It
has vascular effects like those of hydralazine. For patients with
coronary insufficiency, diazoxide is administered intravenously with
a p-blocker, which diminishes reflex activation of the heart.
Diazoxide is useful in the treatment of hypertensive emergencies,
hypertensive encephalopathy, and eclampsia. Excessive hypotension
is the most serious toxicity.
Labetalol: Labetalol is both an α- and β-blocker that has been
successfully used in hypertensive emergencies. Labetalol does not
cause the reflex tachycardia that may be associated with diazoxide.
Labetalol carries the contraindications of a nonselective α-blocker.
3.
ANTIANGINAL DRUGS
3.1.
GENERAL PRINCIPELS IN THE TREATMENT OF
ISCHEMIC HEART DISEASE (IHD)
Angina pectoris is a symptom of ischemic heart disease that is
frequently characterized by typical chest pain usually located
substernally but sometimes perceived in the neck, shoulder, or
epigastrium. There are three basic categories of angina:
– Stable angina: Temporary myocardial ischemia and hypoxia
that do not lead to detectable damage.
Transient chest pain is induced by exertion or stress and ceases at
rest.
It is associated with atheromatous plaques that partially occlude
one or more coronaries. When cardiac work increases (e.g., in
exercise), the obstruction of flow results in the accumulation of
48
acidic metabolites and ischemic changes that stimulate myocardial
pain endings. A rest usually leads to prompt relief of the pain within
a few minutes. Atherosclerotic angina constitutes about 90% of
angina cases and, depending on the rate of progression of the
atheromas, may persist for years with little change. However, effort
angina may deteriorate into unstable angina.
– Unstable angina: Also known as acute coronary syndrome, is
characterized by increased frequency and severity of attacks caused
by repeated episodes of diminished coronary flow that result from a
combination of atherosclerotic plaques, platelet aggregation at
fractured plaques, and vasospasm. Unstable angina is thought to be
the immediate precursor of a myocardial infarction and is treated as a
medical emergency. It may develop at rest. Episodes are more severe
than those of stable angina. Occasionally it leads to permanent
myocardial damage, causes elevation or depression of the S-T
segment and inversion of the T wave on ECG traces.
– Variant (Prinzmetal's) angina: Hypoxia and ischemia to
myocardium is caused by vasospasm (rather than progressive
narrowing of coronary arteries). It involves reversible spasm of
coronaries, usually at the site of an atherosclerotic plaque. Episodes
of spasm may occur at any time, at rest, even during sleep.
Vasospastic angina may deteriorate into unstable angina.
Determinants of Cardiac Oxygen Requirement
The pharmacologic treatment of coronary insufficiency is based
on physiological factors that control the myocardial oxygen
requirement. A major determinant is myocardial fiber tension, i.e.,
the higher the tension, the greater the oxygen requirement.
Several variables contribute to fiber tension:
1. Preload: Preload (diastolic filling pressure) is a function of
blood volume and venous tone. Because venous tone is mainly
controlled by sympathetic outflow, activities that increase
sympathetic activity usually increase preload.
2. Afterload: Afterload or arterial blood pressure is one of the
systolic determinants of oxygen requirement. Arterial blood pressure
49
depends on peripheral vascular resistance, which is determined by
sympathetic outflow to the arteriolar vessels.
3. Heart rate: Heart rate contributes to time-integrated fiber
tension because at fast heart rates, fibers spend more time at systolic
tension levels. Furthermore, at faster rates, diastole is abbreviated,
and diastole constitutes the time available for coronary flow
(coronary blood flow is low or nil during systole). Systolic blood
pressure and heart rate may be multiplied to yield the double product,
a measure of cardiac work and therefore of oxygen requirement. In
patients with atherosclerotic angina, effective drugs reduce the
double product.
4. Cardiac contractility: Force of cardiac contraction is another
systolic factor controlled mainly by sympathetic outflow to the heart.
Ejection time for ventricular contraction is inversely related to force
of contraction but is also influenced by impedance to outflow.
Increased ejection time increases oxygen requirement.
Therapeutic Strategies:
Anginal pain is primarily caused to inadequate perfusion of blood
in the coronary vessels leading to a transient oxygen deficiency
relative to the myocardial oxygen demand. This situation can be
corrected in 2 different ways:
1. An increase in coronary oxygen supply
2. A reduction in myocardial load or oxygen demand.
Pharmacological therapies include the nitrates, the calcium
channel blockers, and the beta-blockers. All three groups reduce the
oxygen requirement in atherosclerotic angina: nitrates and calcium
channel blockers (but not beta-blockers) can also increase oxygen
delivery by reducing vasospasm, but only in vasospastic angina.
Myocardial revascularization corrects coronary obstruction either by
bypass grafting or by angioplasty (enlargement of the lumen by
means of a special catheter). Therapy of unstable angina differs from
that of stable angina because urgent angioplasty is the treatment of
choice in most patients and platelet clotting is the major target of
drug therapy. The platelet glycoprotein IIb/IIIa inhibitors
(eptifibatide and tirofiban) are used in this condition. Intravenous
50
nitroglycerin is sometimes of value. The drugs used in angina are
diagrammed in Table 11.
Table 11 Drugs used in the treatment of IHD
Drug
Organic nitrates
Calcium channel
blockers
Βeta-adrenergic
blockers
Most important
mechanism of
action
Decrease preload
by vasodilatation
Decrease
resistance of
peripheral and
coronary arterioles
Decrease oxygen
demand by
lowering heart
contraction
Additional effects
Decrease blood pressure
Negative inotropic effect
Contraindicated in cases of
asthma, diabetes, severe
bradycardia, peripheral
vascular disease and COPD
Nitroglycerin is the cornerstone of angina therapy. Nitroglycerin,
placed under the tongue, rapidly penetrates sublingual capillaries and
induces vasodilation within minutes. Nitroglycerin is taken at the
onset of anginal pain or prior to exertion to prevent anginal episodes.
Calcium entry blockers reduce the frequency of anginal episodes
and now play an important role in the management of patients’ prone
to anginal episodes. Beta-adrenergic blockers suppress heart activity,
thus lowering the oxygen requirements of myocardial cells; muscle is
also responsible for propulsion in the GI tract. Inhibition of
propulsion by calcium channel blockers causes constipation, a
prevalent side effect of calcium channel blocker therapy. Cardiac
muscle and conducting tissue rely on rapid influx of sodium and slow
influx of calcium through separate channels for contraction. The
slow calcium channel is particularly important in the SA and AV
nodes. Blockade of these channels slows the heart. Skeletal muscle
contraction is induced by rapid influx of sodium, which triggers the
51
release of calcium from the sarcoplasmic reticulum. Because these
cells do not require extracellular calcium for contraction, calcium
channel blockers fail to affect skeletal muscle. Direct vasodilators
relax smooth muscle cells which surround blood vessels by a
mechanism which is not yet clear, but likely involves production of
nitric oxide by vascular endothelium.
3.2.
ORGANIC NITRATES
Nitrates are the drugs of choice for relieving angina because they
decrease preload and myocardial oxygen demand by venous
dilatation. In addition, nitrates dilate coronary arteries even in the
setting of atherosclerosis.
Mechanism of Action
The two proposed mechanisms by which nitrates promote
venodilatation are stimulation of cyclic guanosine monophosphate
(GMP) production and inhibition of thromboxane synthetase.
Nitrites, organic nitrates, nitroso compounds, and a variety of
other nitrogen oxide-containing substances (including nitroprusside)
lead to the formation of the reactive free radical NO. The exact
mechanism(s) of denitration of the organic nitrates to liberate NO
remains an active area of investigation. NO can activate guanylyl
cyclase, increase the cellular level of cyclic GMP, activate PKG (the
cyclic GMP-dependent protein kinase), and modulate the activities of
cyclic nucleotide phosphodiesterases in a variety of cell types. In
smooth muscle, the net result is reduced phosphorylation of myosin
light chain, reduced Ca2+ concentration in the cytosol, and relaxation.
NOTE: Effects of cGMP are terminated by phosphodiesterase
enzymes. Sildenafil, vardenafil, and tadalafil are inhibitors of
phosphodiesterase type 5 that are used to treat erectile dysfunction,
because they potentiate NO actions in the corpora cavernosa of the
penis by this mechanism. The combination of sildenafil and other
phosphodiesterase type 5 (PDE5) inhibitors with organic nitrate
vasodilators can cause extreme hypotension.
52
Short-acting nitrates, such as sublingual (SL) tablets or
translingual sprays, are the preparation of choice for quick relief,
especially in the setting of exertional angina. Long-acting nitrates
(e.g., isosorbide dinitrate and isosorbide mononitrate) become useful
when the number, severity, and duration of anginal attacks increase.
Classification
Nitroglycerin is the most important of the nitrates and is available
in forms that provide a range of durations of action from 10–20
minutes (sublingual) to 8–10 hours (transdermal). Because treatment
of acute attacks and prevention of attacks are both important aspects
of therapy, the pharmacokinetics of these different dosage forms are
clinically significant.
Pharmacokinetics
The time to onset of action varies from one minute for
nitroglycerin to more than one hour for isosorbide mononitrate.
Significant first-pass metabolism of nitroglycerin occurs in the liver.
Therefore, it is common to give the drug either sublingually or via a
transdermal patch.
Mechanisms of Action
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.
Organ System Effects
Effects on cardiovascular system: Smooth muscle relaxation leads
to peripheral venodilation, which results in reduced cardiac size and
cardiac output through reduced preload. Reduced after load, from
arteriolar dilation, it may contribute to an increase in ejection and a
further decrease in cardiac size. Some studies suggest that of the
vascular beds; the veins are the most sensitive, arteries less so, and
53
arterioles least sensitive. Venodilation leads to decreased diastolic
heart size and fiber tension. Arteriolar dilation leads to reduced
peripheral resistance and blood pressure. These changes contribute to
an overall reduction in myocardial fiber tension, oxygen
consumption, and the double product. Thus, the primary therapy in
atherosclerotic angina is reduction of the oxygen requirement. A
secondary therapy – namely, an increase in coronary flow via
collateral vessels in ischemic areas – has also been proposed in
vasospastic angina; a reversal of coronary spasm and increased flow
can be demonstrated.
Nitrates have no direct effects on myocardium, but a significant
reflex tachycardia and increased force of contraction are predictable
when nitroglycerin reduces the blood pressure.
Other Smooth Muscle Organs
Relaxation of smooth muscle of the bronchi, gastrointestinal tract
(including biliary system), and genitourinary tract has been
demonstrated experimentally. Because of their brief duration, these
actions of the nitrates are rarely of any clinical value. During recent
years, the use of amyl nitrite and isobutyl nitrite by inhalation as
purported recreational (sex-enhancing) drugs has become popular
with some segments of the population. Nitrites release nitric oxide in
erectile tissue as well as vascular smooth muscle and activate
guanylyl cyclase. The resulting increase in cGMP causes
dephosphorylation of myosin light chains and relaxation, which
enhances erection.
Clinical Uses
As previously noted, nitroglycerin is available in several
formulations. The standard form for treatment of acute anginal pain
is the sublingual tablet, which has duration of action of 10-20
minutes. Oral (swallowed) normal-release nitroglycerin has duration
of action of 4 – 6 hours. Sustained-release oral forms have a
somewhat longer duration of action. Transdermal formulations
(ointment or patch) can maintain blood levels.
54
Table 12 -Nitrate and nitrite drugs used in the angina treatment
Drug
Short-acting
Nitroglycerin, sublingual
Isosorbide
dinitrate,
sublingual
Amyl nitrite, inhalant
Long-acting
Nitroglycerin,
oral,
sustained action
Nitroglycerin,
2%
ointment, transdermal
Nitroglycerin,
slowrelease, buccal
Nitroglycerin,
slowrelease patch, transdermal
Dose
Duration of action
0.15–1.2 mg
2.5–5 mg
10–30 minutes
10–60 minutes
0.18–0.3 mL
3–5 minutes
6.5–13 mg
per6–8 hours
1–1.5 inches
per 4 hours
1–2 mg
per 4 hours
10–25 mg
per 24 hours
(one patch per day)
Isosorbide
dinitrate, 2.5–10 mg
sublingual
per 2 hours
Isosorbide dinitrate, oral
10–60 mg
per 4–6 hours
Isosorbide
dinitrate, 5–10 mg
chewable oral
per 2–4 hours
Isosorbide
mononitrate 20 mg
oral
per 12 hours
6–8 hours
3–6 hours
3–6 hours
8–10 hours
1.5–2 hours
4–6 hours
2–3 hours
6–10 hours
Adverse Effects
The most common adverse effect of nitroglycerin, as well as of
the other nitrates, is a headache. Thirty to sixty percent of patients
receiving intermittent nitrate therapy with long-acting agents develop
headaches. High doses of organic nitrates can also cause postural
hypotension, facial flushing, and refectory tachycardia.
55
Methemoglobinemia: 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 larger doses of organic and inorganic nitrates, is too low to
cause significant methemoglobinemia in adults. However, sodium
nitrite is used as a curing agent for meats. In nursing infants, the
intestinal flora is capable of converting significant amounts of
inorganic nitrate, e.g., from well water, to nitrite ion. Thus,
inadvertent exposure to large amounts of nitrite ion can occur and
may produce serious toxicity. Methemoglobinemia, if excessive, can
be treated by giving methylene blue intravenously.
Glaucoma, once thought to be a contraindication, does not
worsen, and nitrates can be used safely in the presence of increased
intraocular pressure. Nitrates are contraindicated, however, if
intracranial pressure is elevated.
Tolerance: Tolerance to the actions of nitrates develops rapidly. It
can be overcome by provision of a daily "nitrate-free interval" to
restore sensitivity to the drug. This interval is typically 6 – 8 hours,
usually at night because there is decreased demand on the heart at
that time. Nitroglycerin patches are worn for 12 hours and removed
for 12 hours. However, Prinzimetal's or variant angina worsens early
in the morning, perhaps due to circadian catecholamine surges. These
patients' nitrate-free interval should be late afternoon.
With continuous exposure to nitrates, tolerance or the loss of
antianginal and hemodynamic effects occurs. When exposure is
discontinued, symptoms of withdrawal (severe headache, chest pain,
or sudden cardiac death) can occur. Short-acting nitrates are not
likely to lead to tolerance due to their rapid onset of action and short
duration.
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.
Nitric oxide released from nitroglycerin stimulates guanylyl
cyclase in platelets as in smooth muscle. The increase in cGMP that
56
results is responsible for a decrease in platelet aggregation.
Unfortunately, recent prospective trials have established no survival
benefit when nitroglycerin is used in acute myocardial infarction.
3.3.
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) ensues. The
relative importance of necrosis and apoptosis in myocardial cell
death in clinically distinct settings is unknown, but it has been
suggested that apoptosis may be an adaptive process in hypoperfused
regions, sacrificing some jeopardised myocytes but thereby avoiding
the disturbance of membrane function and risk of dysrhythmia
inherent in necrosis. Consequently, it is currently unknown if
pharmacological approaches to promote or inhibit this pathway could
be clinically beneficial.
Prevention of irreversible ischaemic damage following an episode
of coronary thrombosis is an important therapeutic aim. The main
possibilities among existing therapeutic groops are:
– thrombolytic and antiplatelet drugs (aspirin and clopidogrel) to
open the blocked artery and prevent their reocclusion;
– oxygen;
– opioids to prevent pain and reduce excessive sympathetic
activity;
– β-adrenoceptor antagonists;
– angiotensin-converting enzyme (ACE) inhibitors;
The latter two classes of drugs 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; they increase the risk of cardiogenic shock if given during
57
acute infarction to patients with signs of heart failure, but are started
as soon as is haemodynamically prudent. Several clinical trials have
demonstrated that ACE inhibitors improve survival if given to
patients shortly after myocardial infarction, especially if there is even
a modest degree of myocardial dysfunction. It is possible that sartans
could prove similarly beneficial.
Despite several encouraging small trials of organic nitrates, a
large randomised controlled trial (the Fourth International Study of
Infarct Survival, ISIS-4, 1994) showed that these drugs do not
improve outcome in patients with myocardial infarction, although
they are useful in preventing or treating anginal pain. Calcium
antagonists, which reduce cardiac work (via arteriolar vasodilatation
and afterload reduction) and block Ca2+ entry into cardiac myocytes,
have been disappointing, and several clinical trials of short-acting
dihydropyridines (e.g., nifedipine ) were halted when adverse trends
were evident. Trimetazidine, a 3-ketoacyl-CoA thiolase inhibitor, is
believed to protect the heart from ischaemia by switching cardiac
metabolism from fatty acid to glucose oxidation, but its place (if
any) in therapeutics is yet to be established.
4.
ANTIHYPERLIPEDEMIC DRUGS
Coronary artery disease (CAD) is the cause of about half of all
deaths in the world. CAD has been shown to be correlated with the
levels of plasma cholesterol- and/or triacylglycerol-containing
lipoprotein particles. These particles, which are the key to the
development of atherogenesis, are initially synthesized by the
intestinal mucosa and the liver, and undergo extensive metabolism in
the plasma. They also play an essential role in the transport of lipids
between tissues. Because lipids are insoluble in aqueous solutions,
they must be transported in the plasma from tissue to tissue, bound to
proteins, hence the name, lipoprotein. Their levels can be elevated by
environmental causes, such as diet, or by inherited genetic defects in
the appropriate synthesis or degradation of these compounds. Drugs
used in the treatment of elevated serum lipids (hyperlipidemias)
58
generally are targeted to (1) decrease production of a lipoprotein by
the tissues, (2) increase catabolism of a lipoprotein in the plasma, or
(3) increase removal of cholesterol from the body. Such treatments
lead to a decline in the progression of coronary plaque and a possible
regression of pre-existing lesions.
The main agents used clinically are:
Statins: 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase inhibitors inhibit synthesis of cholesterol, increasing
expression of low-density lipoprotein (LDL) receptors on
hepatocytes and hence LDL cholesterol (LDL-C) uptake.
Fibrates activate PPARα receptors, increase activity of lipoprotein
lipase, decrease hepatic very low-density lipoprotein production, and
enhance clearance of LDL-C by the liver. They markedly lower
serum triglycerides and modestly increase high-density lipoprotein
cholesterol. Adverse effects include muscle damage.
Inhibitors of cholesterol absorption: Agents that interfere with
cholesterol absorption, usually as an adjunct to diet plus statin:
– ezetimibe;
– stanol-enriched foods;
– bile acid-binding resins (e.g., colestyramine).
Nicotinic acid or its derivatives: Flushing is the main adverse
effect.
Essential phospholipids (Essenciale).
Fish oil derivatives: Omega-3-acid ethyl esters.
4.1.
PRINCIPLES OF TREATMENT IN ACCORDANCE WITH
THE TYPES OF DYSLIPIDEMIA
Before the start of correction of dyslipidemia, levels of different
types of lipoproteins, chylomicrons, triacylglycerols and total
cholesterol in patient’s blood must be examined. The doctor detects
the type of dyslipidemia and only after that begins the treatment. The
classification by Fredricsson is used more often in the word.
Type I [familial hyperchylomicronemia]:
59
– Massive fasting hyperchylomicronemia even following normal
dietary fat intake, resulting in greatly elevated serum triacylglycerol.
– Deficiency of Ilpoprotein lipase or deficiency of normal
apolipoprotein CII (rare).
– Type I is not associated with an increase in coronary heart
disease.
– Treatment: Low fat diet. No drug therapy is effective for Type
I hyperlipidemia.
Type IIA [familial hypercholesterolemia]:
– Elevated LDL with normal VLDL levels due to block in LDL
degradation, therefore increased serum cholesterol but normal
triacylglycerol.
– Caused by decreased numbers of normal LDL receptors.
– Ischemic heart disease is greatly accelerated.
– Treatment: Low cholesterol and low saturated fat in the diet.
Heterozygotes: Cholestyramine or colestipol, and/or, Iovastatin or
mevastatin. Homozygofes: As above, plus niacin.
Type IIb [familial combined (mixed) hyperlipidemia]:
– Similar to IIA except VLDL are also increased, resulting in
elevated serum triacylglycerol as well as cholesterol.
– Caused by overproduction of VLDL by the liver.
– Relatively common.
– Treatment: dietary restriction of cholesterol and saturated fat
and alcohol. Drug therapies similar to IIA except heterozygotes also
to receive niacin.
Type III [familial dysbetalipoproteinemia]:
– Serum concentrations of IDL are increased resulting in
increased triacylglycerol and cholesterol levels.
– The cause is either overproduction or underutilization of IDL,
due to mutant apelipeprotein E.
60
– Xanthomas and accelerated coronary and peripheral vascular
disease develop in patients by middle age.
– Treatment: weight reduction (if necessary). Dietary restriction
of cholesterol and alcohol. Drug therapy includes niacin and
clofibrate (or gemfibrozil), or lovastatin (or mevastatin).
Type IV [familial hypertriglyceridemia]:
– VLDL levels are increased, while LDL levels are normal or
decreased, resulting in normal to elevated cholesterol and greatly
elevated circulating triacylglycerol levels.
– The cause is an overproduction and/or decreased removal of
VLDL triacylglycerol in serum.
– This is a relatively common disease. It has few clinical
manifestations other than accelerated ischemic heart disease. Patients
with this disorder are frequently obese, diabetic, and hyperuricemic.
Also seen in individuals undergoing estrogen therapy, or are in their
third trimester of pregnancy, or are alcoholic.
– Treatment: weight reduction (if necessary) is of primary
importance. Dietary restriction of controlled carbohydrate, modified
fat, low alcohol consumption. If necessary, drug therapy includes
niacin and/or gemfibrozil (or clofibrate), or lovastatin (or
mevastatin).
Type V [familial mixed hypertriglyceridemia]:
– Serum VLDL and chylomicrons are elevated. LDL is normal or
decreased. This results in elevated cholesterol and greatly elevated
triacylglycerol levels.
– The cause is either increased production or decreased clearance
of VLDL and chylomicrons. Usually a genetic defect.
– Occurs most commonly in adults who are obese and/or
diabetic.
– Treatment: weight reduction (if necessary) is important. Diet
should include protein, low fat and controlled carbohydrate, and no
61
alcohol. If necessary, drug therapy includes niacin, clofibrate and/or
gemfibrozil, or lovastatin (or mevastatin).
The hyperlipidemias form a complex group of diseases that can be
designated either primary or secondary, depending on their causes.
Primary hyperlipidemias can result from a single inherited gene
defect, or more commonly, are caused by a combination of genetic
and environmental factors. Secondary, hyperlipidemias are the result
of more generalized metabolic disorders, such as diabetes mellitus,
excessive alcohol intake, hypothyroidism, or primary biliary
cirrhosis. Therapeutic strategies for treating secondary
hyperlipidemia caused by one of these disorders include dietary
intervention plus a regimen of drugs used to treat the primary cause
of the hyperlipidemia.
4.2.
HMG CoA REDUCTASE INHIBITORS
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
inhibitors (commonly known as statins) lower elevated LDL
cholesterol levels resulting in a substantial reduction in coronary
events and death from CHD. This group of antihyperlipidemic agents
inhibits the first committed enzymatic step of cholesterol synthesis,
and they are the first-line and more effective treatment for patients
with elevated LDL cholesterol. Therapeutic benefits include plaque
stabilization, improvement of coronary endothelial function,
inhibition of platelet thrombus formation, and anti-inflammatory
activity. The value of lowering the level of cholesterol with statin
drugs has now been demonstrated in 1) patients with CHD with or
without hyperlipidemia, 2) men with hyperlipidemia but no known
CHD, and 3) men and women with average total and LDL
cholesterol levels and no known CHD.
Inhibition of HMG-CoA reductase: lovastatin, simvastatin,
pravastatin, atorvastatin, fluvastatin, and rosuvastatin are analogs of
HMG, the precursor of cholesterol. Lovastatin and simvastatin are
lactones that are hydrolyzed to the active drug. Pravastatin and
fluvastatin are active as such. Because of their strong affinity for the
enzyme, all compete effectively to inhibit HMG-CoA reductase, the
62
rate-limiting step in cholesterol synthesis. By inhibiting de novo
cholesterol synthesis, they deplete the intracellular supply of
cholesterol. Rosuvastatin and atorvastatin are the most potent LDL
cholesterol lowering statin drugs, followed by simvastatin,
pravastatin and then lovastatin and fluvastatin.
Increase in LDL receptors: Depletion of intracellular cholesterol
causes the cell to increase the number of specific cell-surface LDL
receptors that can bind and internalize circulating LDLs. Thus, the
end result is a reduction in plasma cholesterol, both by lowered
cholesterol synthesis and by increased catabolism of LDL. Because
these agents undergo a marked first-pass extraction by the liver, their
dominant effect is on that organ. The HMG-CoA reductase
inhibitors, like the bile acid sequestrant cholestyramine, can increase
plasma HDL levels in some patients, resulting in an additional
lowering of risk for CHD. Decreases in triglyceride also occur.
Therapeutic uses: These drugs are effective in lowering plasma
cholesterol levels in all types of hyperlipidemias. Indications are:
– Primary prevention of arterial disease in patients who are at
high risk because of elevated serum cholesterol concentration,
especially if there are other risk factors for atherosclerosis. Tables
(available for example in the British National Formulary) are used to
target treatment to those at greatest risk.
– Secondary prevention of myocardial infarction and stroke in
patients who have symptomatic atherosclerotic disease (e.g., angina,
transient ischaemic attacks, or following myocardial infarction or
stroke).
However, patients who are homozygous for familial
hypercholesterolemia lack LDL receptors and, therefore, benefit
much less from treatment with atorvastatin. Sometimes these drugs
are often given in combination with other antihyperlipidemic drugs.
It should be noted that in spite of the protection afforded by
cholesterol lowering, about one-fourth of the patients treated with
these drugs still present with coronary events. Thus, additional
strategies, such as diet, exercise, or additional agents, may be
warranted.
63
Pharmacokinetics: Pravastatin and fluvastatin are almost
completely absorbed after oral administration; oral doses of
lovastatin and simvastatin are from 30% to 50% absorbed. Similarly,
pravastatin and fluvastatin are active as such, whereas lovastatin and
simvastatin must be hydrolyzed to their acid forms. Due to first-pass
extraction, the primary action of these drugs is on the liver. All are
biotransformed, with some of the products retaining activity.
Excretion takes place principally through the bile and feces, but some
urinary elimination also occurs. Their half-lives range from 1.5 to 2
hours.
Adverse Effects
Statins are well tolerated; mild unwanted effects include myalgia,
gastrointestinal disturbance, and raised concentrations of liver
enzymes in plasma, insomnia and rash. Therefore, it is prudent to
evaluate liver function and measure serum transaminase levels
periodically. These return to normal on suspension of the drug.
Hepatic insufficiency can cause drug accumulation.
More serious adverse effects are rare but include severe myositis
(rhabdomyolysis – disintegration or dissolution of muscle) and
angio-oedema. Myositis is a class effect of statins, occurs also with
other lipid-lowering drugs (especially fibrates) and is dose-related. It
is more common in patients with small lean body mass or
uncorrected hypothyroidism. It s very important to measure regularly
serum creatine kinase levels.
HGM-CoA reductase inhibitors are metabolized by the
cytochrome P450 system; drugs or foods (e.g., grapefruit juice) that
inhibit cytochrome P450 activity may increase the risk of
epatotoxicity and myopathy. Because of evidence that the HMGCoA reductase inhibitors are teratogenic, these drugs should be
avoided in pregnancy.
Drug interactions: The HMG CoA reductase inhibitors may also
increase warfarin levels. Thus, it is important to monitor INR times
frequently.
64
Contraindications: These drugs are contraindicated during
pregnancy and in nursing mothers. They should not be used in
children or teenagers.
4.3.
NIACIN (NICOTINIC ACID)
Niacin is a water-soluble B-complex vitamin that functions as a
vitamin only after its conversion to NAD or NADP, in which it
occurs as an amide. Both niacin and its amide may be given orally as
a source of niacin for its functions as a vitamin, but only niacin
affects lipid levels. The hypolipidemic effects of niacin require larger
doses than are required for its vitamin effects.
Niacin can reduce LDL levels by 10–20% and is the most
effective agent for increasing HDL levels. Niacin can be used in
combination with statins, and a fixed-dose combination of lovastatin
and long-acting niacin is available.
Mechanism of Action
Niacin inhibits VLDL secretion, in turn decreasing production of
LDL. Increased clearance of VLDL via the LPL pathway contributes
to triglyceride reduction. Niacin has no effect on bile acid
production. Excretion of neutral sterols in the stool is increased
acutely as cholesterol is mobilized from tissue pools and a new
steady state is reached. The catabolic rate for HDL is decreased.
Fibrinogen levels are reduced, and levels of tissue plasminogen
activator appear to increase. Niacin inhibits the intracellular lipase of
adipose tissue via receptor-mediated signaling, possibly reducing
VLDL production by decreasing the flux of free fatty acids to liver.
Sustained inhibition of lipolysis has not been established, however.
Therapeutic uses: Niacin lowers plasma levels of both cholesterol
and triacylglycerol. Therefore, it is particularly useful in the
treatment of familial hyperlipidemias. Niacin is also used to treat
other severe hypercholesterolemias, often in combination with other
antihyperlipidemic agents. In addition, it is the most potent
antihyperlipidemic agent for raising plasma HDL levels, which is the
most common indication for its clinical use.
65
Pharmacokinetics: Niacin is administered orally. It is converted in
the body to nicotinamide, which is incorporated into the cofactor
nicotinamide-adenine dinucleotide (NAD+). Niacin, its nicotinamide
derivative, and other metabolites are excreted in the urine. [Note:
Nicotinamide alone does not decrease plasma lipid levels.]
Adverse Effects
Cutaneous flushing (accompanied by an uncomfortable feeling of
warmth) and pruritus are common adverse effects. NSAIDs (aspirin)
reduces the intensity of this flushing, suggesting that it is mediated
by prostaglandin. Tolerance to the flushing reaction usually develops
within a few days. Some patients also experience nausea and
abdominal pain. It is a dose-dependent reaction. NA inhibits tubular
secretion of uric acid and, thus, predisposes to hyperuricemia and
gout. Hyperuricemia occurs in about 20% of patients, and
carbohydrate tolerance may be moderately impaired. Impaired
glucose tolerance and hepatotoxicity have also been repor. Moderate
elevations of liver enzymes and even severe hepatotoxicity may
occur.
4.4.
FIBRIC ACID DERIVATIVES (FIBRATES)
Fenofibrate and gemfibrozil are derivatives of fibric acid that
lower serum triacylglycerols and increase HDL levels. Both have the
same mechanism of action. However, fenofibrate is more effective
than gemfibrozil in lowering plasma LDL cholesterol and
triglyceride levels.
Mechanism of Action
They are agonists for a subset of lipid-controlled gene regulatory
elements (PPARs4), PPARα, which are members of the superfamily
of nuclear receptors; in humans, the main effects are to increase
transcription of the genes for lipoprotein lipase, apoA1 and apoA5.
They increase hepatic LDL-C uptake. In addition to effects on
lipoproteins, fibrates reduce plasma C-reactive protein and
fibrinogen, improve glucose tolerance, and inhibit vascular smooth
66
muscle inflammation by inhibiting the expression of the transcription
factor NF-κB. As with the pleiotropic effects of statins (see above),
there is great interest in these actions, although again it is unknown if
they are clinically important. These drugs are useful in
hypertriglyceridemias, in which VLDL predominate and in
dysbetalipoproteinemia. They also may be of benefit in treating the
hypertriglyceridemia that results from treatment with viral protease
inhibitors. The dosage of fenofibrate is one to three 54 mg tablets (or
a single 160 mg tablet) daily. Absorption of both drugs is improved
when they are taken with food.
Clinical Uses of Fibrates:
– Mixed dyslipidaemia (i.e., raised serum triglyceride as well as
cholesterol), provided this is not caused by excessive alcohol
consumption. Fenofibrate is uricosuric, which may be useful where
hyperuricaemia coexists with mixed dyslipidaemia.
– In patients with low high-density lipoprotein and high risk of
atheromatous disease (often type 2 diabetic patients).
– Combined with other lipid-lowering drugs in patients with
severe treatment-resistant dyslipidaemia. This may, however,
increase the risk of rhabdomyolysis.
Pharmacokinetics: Both drugs are completely absorbed after an
oral dose. Gemfibrozil and fenofibrate distribute widely, bound to
albumin. Both drugs undergo extensive biotransformation and are
excreted in the urine as their glucuronide conjugates.
Adverse Effects
Gastrointestinal effects: The most common adverse effects are
mild gastrointestinal disturbances. Gastrointestinal symptoms,
pruritus and rash are more common than with statins. All of these
lessen as the therapy progresses.
Lithiasis: Because these drugs increase biliary cholesterol
excretion, there is a predisposition to the formation of gallstones.
Muscle: Myositis (inflammation of a voluntary muscle) can occur
with both drugs; thus, muscle weakness or tenderness should be
67
evaluated. Myositis is unusual but can be severe (rhabdomyolysis)
with myoglobinuria and acute renal failure. Myopathy and
rhabdomyolysis have been reported in a few patients taking
gemfibrozil and lovastatin together.
Drug interactions: Both fibrates compete with the coumarin
anticoagulants for binding sites on plasma proteins, thus transiently
potentiating anticoagulant activity. INR times should therefore be
monitored when a patient is taking both drugs. Similarly, these drugs
may transiently elevate the levels of sulfonylureas.
Contraindications: The safety of these agents in women during
pregnancy or lactation has not been established. They should not be
used in patients with severe hepatic and renal dysfunction or in
patients with preexisting gallbladder disease.
4.5. BILE ACID BINDING RESINS
Bile acid sequestrants (resins) have significant LDL cholesterol
lowering effects, although the benefits are less than those observed
with statins.
Mechanism of Action
Cholestyramine, colestipol, and colesevelam are anion-exchange
resins that bind negatively charged bile acids and bile salts in the
small intestine. The resin/bile acid complex is excreted in the feces,
thus preventing the bile acids from returning to the liver by the
enterohepatic circulation. Lowering the bile acid concentration
causes hepatocytes to increase conversion of cholesterol to bile acids,
resulting in a replenished supply of these compounds, which are
essential components of the bile. Consequently, the intracellular
cholesterol concentration decreases, which activates an increased
hepatic uptake of cholesterol-containing LDL particles leading to a
fall in plasma LDL. This increased uptake is mediated by an upregulation of cell-surface LDL receptors. In some patients, a modest
rise in plasma HDL levels is also observed. The final outcome of this
sequence of events is a decreased total plasma cholesterol
concentration.
68
Pharmacokinetics: Cholestyramine, colestipol, and colesevelam
are taken orally. Because they are insoluble in water and are very
large (molecular weights are greater than 106), they are neither
absorbed nor metabolically altered by the intestine. Instead, they are
totally excreted in the feces.
Therapeutic uses: The bile acid binding resins are the drugs of
choice (often in combination with diet or niacin) in treating Type IIa
and Type IIb hyperlipidemias. Cholestyramine can also relieve
pruritus caused by accumulation of bile acids in patients with biliary
obstruction.
Adverse Effects
The most common side effects are gastrointestinal disturbances,
such as constipation, nausea, and flatulence. Colesevelam has fewer
gastrointestinal side effects than other bile acid sequestrants.
Impaired absorptions: At high doses, cholestyramine and
colestipol (but not colesevelam) impair the absorption of the fatsoluble vitamins (A, D, E, and K).
Drug interactions: Cholestyramine and colestipol interfere with
the intestinal absorption of many drugs, for example, tetracycline,
phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin, and
thiazide diuretics. Therefore, drugs should be taken at least 1-2 hours
before, or 4-6 hours after the bile acid binding resins.
4.6.
CHOLESTEROL ABSORPTION INHIBITORS
Ezetimibe selectively inhibits intestinal absorption of dietary and
biliary cholesterol in the small intestine, leading to a decrease in the
delivery of intestinal cholesterol to the liver. This causes a reduction
of hepatic cholesterol stores and an increase in clearance of
cholesterol from the blood. Ezetimibe lowers LDL cholesterol by
17% and triacylglycerols by 6 %, and it increases HDL cholesterol
by 1.3%. Ezetimibe is primarily metabolized in the small intestine
and the liver via glucuronide conjugation (a Phase II reaction), with
subsequent biliary and renal excretion. Both ezetimibe and
ezetimibe-glucuronide are slowly eliminated from plasma, with a
69
half-life of approximately 22 hours. Ezetimibe has no clinically
meaningful effect on the plasma concentrations of the fat-soluble
vitamins A, D, and E. Patients with moderate to severe hepatic
insufficiency should not be treated with ezetimibe.
Adverse Effects
GIT effects: The most common side effects are gastrointestinal
disturbances, such as constipation, nausea, and flatulence.
Impaired absorptions: Absorption of the fat-soluble vitamins, A,
D, E, and K can be impaired if high doses of the resin are present.
Folic acid and ascorbic acid absorption may also be reduced.
Drug interactions: Cholestyramine and colestipol interfere with
the intestinal absorption of many drugs, for example, tetracycline,
phenobarbital digoxin, warfarin, pravastatin, fluvastatin, aspirin, and
thiazide diuretics. Therefore, drugs should be taken at least 1–2 hours
before, or 4–6 hours after the bile acid binding resins.
4.7.
COMBINATION DRUG THERAPY
It is often necessary to employ two antihyperlipidemic drugs
to achieve treatment goals in plasma lipid levels. For example, in
Type II hyperlipidemias, patients are commonly treated with a
combination of niacin plus a bile acidв binding agent, such as
cholestyramine.
Table 12 - Principles of correction of hyperlipedemias
.
Drugs
Therapy
level
I
Lovastatin
Simvastatin
Fenofibrate
Cyprofibrate
Cholesteramine
+
+
+
+
+
II
+
+
Primary
Severe ↓Choleste- ↓Cholestehyperlipi- hyperlipirol
rol
demia
demia
absorption synthesis
+
+
+
+
+
+
+
+
+
+
+
+
70
Cholestyramine causes an increase in LDL receptors that clears
the plasma of circulating LDL, whereas niacin decreases synthesis of
VLDL and, therefore, also the synthesis of LDL. The combination of
an HMG-CoA reductase inhibitor with a bile acid binding agent has
also been shown to be very useful in lowering LDL cholesterol
levels. A low-dose statin in combination with ezetimibe achieves
comparable or even greater LDL cholesterol reduction than a veryhigh-dose statin. Simvastatin and ezetimibe are currently available
combined in one pill to treat elevated LDL cholesterol.
5.
DRUGS FOR ASTHMA OR COPD TREATMENT
Asthma is the commonest chronic disease characterized by
hyperresponsive airways. It is increasing in prevalence and severity.
It is a specific (allergic) inflammatory condition in which there is
recurrent reversible airway obstruction in response to irritant stimuli
that are too weak to affect non-asthmatic subjects. The obstruction
usually causes wheeze and merits drug treatment, although the
natural history of asthma includes spontaneous remissions.
Reversibility of airways obstruction in asthma contrasts with COPD,
where the obstruction is either not reversible or at best incompletely
reversible, by bronchodilators.
Bronchoconstriction, inflammation (increasing mucous secretion)
and loss of lung elasticity are the three most common processes that
result in bronchial obstruction. Therapy for obstructive lung disease
is aimed at preventing or reversing these processes.
Bronchoconstriction is the result of the effects of acetylcholine,
histamine, and inflammatory mediators released within the bronchial
walls. The vagus nerve releases acetylcholine in response to
stimulation of upper airway mucosa by irritants. As a result,
acetylcholine also triggers release of pulmonary secretions which
further reduce air flow by plugging airways. Adrenergic agonists,
cholinergic antagonists, methylxanthines and corticosteroids relax
smooth muscles of small bronchi. Spasmolitics can be given for this
indication too. Chronic inflammation is caused by prolonged
71
exposure to airway irritants such as pollution and cigarette smoke.
Bronchiolar inflammation results in narrowed airways, increased
secretions, epithelial proliferation, loss of ciliated epithelium and
fibrosis. Corticosteroids inhibit the inflammatory response and
decrease immunological system, but their use is at the expense of
systemic side effects. Loss of lung elasticity results in terminal
bronchiole enlargement, changes in lung compliance and the collapse
of airways which are normally tethered open by surrounding lung
tissue. Specific therapy to reverse or prevent proteolytic destruction
of lungs is not readily available. For diagnostic and treatment
purposes, obstructive lung disease is subclassified as either reactive
airway disease or chronic obstructive lung disease (COPD). In
practice, it is often difficult to distinguish these two diseases on the
basis of pathophysiology or clinical course.
Reactive airway disease (RAD, asthma): The trachea and bronchi
of patients with reactive airway disease are particularly sensitive to
stimulants, such as cigarette smoke, dust, cold air, and allergens.
Patients present with wheezing, coughing and chest tightness.
Decreased oxygenation of the lungs secondary to tracheobronchial
constriction, mucus production, inflammation and edema cause these
symptoms.
5.1.
GENERAL PRINCIPLES IN THE TREATMENT OF
BRONCHIAL OBSTRUCTIVE SYNDROME
There are two categories of antiasthma drugs: bronchodilators and
anti-inflammatory agents. The main drugs used as bronchodilators
are β2-adrenoceptor agonists; others include xanthines, cysteinyl
leukotriene receptor antagonists and muscarinic receptor antagonists.
The method of treatment depends on the severity of the attack and
the patient's response to previous therapy. Selective agents are
preferred to nonselective β-blockers because they are less likely to
cause tachycardia (mediated by βl-receptors).
– Methylxanthines increase cAMP and inhibit adenosine-induced
bronchoconstriction. Oral theophylline is used for outpatient
management of asthma.
72
– An intravenous bolus of aminophylline, the watersoluble salt of
theophylline, produces therapeutic serum levels faster than oral
theophylline. Aminophyline is therefore used in acute management.
– Cholinergic antagonists block bronchoconstriction caused by
parasympathetic transmission. Ipratroprium bromide is a drug of
choice for the treatment of non-asthmatic COPD in adults and is a
secondary drug in the treatment of asthma.
– Corticosteroids decrease peribronchial inflammation.
Corticosteroids «bursts» (high doses for a few days) are sometimes
used when adrenergic antagonists and theophylline fail to control
asthma. The benefits of steroids must be balanced against their
considerable toxicity if they are to be administered chronically at
high doses.
– Cromolyn is a prophylactic agent. It inhibits the release of
mediators from inflammatory cells, such as mast cells. It is used
exclusively in asthma.
Most of these agents are administered by inhalation. With
thoughtful teaching, asthmatic patients become proficient at
delivering their own medication.
Consider improper administration of bronchodilators as an
explanation for therapeutic failure.
5.2.
ADRENOMIMETICS
Beta-adrenergiс agonists bind to β2 receptors on bronchial smooth
muscle, causing an increase in the biochemical messenger, cyclic
AMP (cAMP). Increased levels of cAMP cause relaxation of
bronchial muscle cells, resulting in bronchodilation. They also inhibit
mediator release from mast cells and TNF-α release from monocytes
and increase mucus clearance by an action on cilia. These drugs are
usually given by inhalation of aerosol (metered-dose inhaler),
powder or nebulised solution, but some may be given orally or by
injection.
Classification: Two categories of β2-adrenoceptor agonists are
used in asthma:
73
Short-acting agents: salbutamol and terbutaline. These drugs are
given by inhalation; the maximum effect occurs within 30 minutes
and the duration of action is 3–5 hours; they are usually used on an
'as needed' basis to control symptoms.
Longer-acting agents, e.g., salmeterol and formoterol are given by
inhalation, and the duration of action is 8–12 hours. They are not
used “as needed” but are given regularly, twice daily, as adjunctive
therapy in patients whose asthma is inadequately controlled by
glucocorticoids.
They act as physiological antagonists of the spasmogenic
mediators but have little or no effect on the bronchial hyperreactivity.
Adverse Effects
At higher doses, therefore, these drugs may lead to increased heart
rate, cardiac arrhythmias, and central nervous system (CNS) effects
associated with adrenergic receptor activation such as tachycardia,
hyperglycemia, hypokalemia, and hypomagnesemia are minimized
with dosing via inhalation versus systemic routes. Although tolerance
to the effects of β2 agonists on non-airway tissues occurs, it is
uncommon with normal dosages. All patients with asthma should be
prescribed a quick-relief inhaler and regularly assessed for
appropriate inhaler technique.
5.3.
ANTIMUSCARINIC AGENTS
Interest in the potential value of antimuscarinic agents increased
with demonstration of the importance of the vagus nerves in
bronchospastic responses of laboratory animals and by the
development of a potent atropine analog that is poorly absorbed after
aerosol administration and that is therefore relatively free of systemic
atropine-like effects. Its effectivness is less than that of adrenergic
agents.
74
Mechanism of Action
In the airways, acetylcholine is released from efferent endings of
the vagus nerves, and muscarinic antagonists block the contraction of
airway smooth muscle and the increase in secretion of mucus that
occurs in response to vagal activity. Very high concentrations well
above those achieved even with maximal therapy are required to
inhibit the response of airway smooth muscle to nonmuscarinic
stimulation. This selectivity of muscarinic antagonists accounts for
their usefulness as investigative tools in examining the role of
parasympathetic pathways in bronchomotor responses but limits their
usefulness in preventing bronchospasm. In the doses given,
antimuscarinic agents inhibit only that portion of the response
mediated by muscarinic receptors, which varies by stimulus, and
which further appears to vary among individuals in responses to the
same stimulus.
Antimuscarinic agents are effective bronchodilators. When given
intravenously, atropine, the prototypical muscarinic antagonist,
causes bronchodilation at a lower dose than that needed to cause an
increase in heart rate. The selectivity of atropine's effect can be
increased further by administering the drug by inhalation or by use of
a more selective quaternary ammonium derivative of atropine,
ipratropium bromide. Ipratropium can be delivered in high doses by
this route because it is poorly absorbed into the circulation and does
not readily enter the central nervous system. Studies with this agent
have shown that the degree of involvement of parasympathetic
pathways in bronchomotor responses varies among subjects. In
some, bronchoconstriction is inhibited effectively; in others - only
modestly. The failure of higher doses of the muscarinic antagonist to
further inhibit the response in these individuals indicates that
mechanisms other than parasympathetic reflex pathways must be
involved.
Ipratropium appears to be at least as effective in patients with
COPD that includes a partially reversible component. A longeracting, selective antimuscarinic agent, tiotropium, is approved as a
treatment for COPD. This drug is also taken by inhalation, and a
single dose of 18 mcg has 24-hour duration of action. Daily
75
inhalation of tiotropium has been shown not only to improve
functional capacity of patients with COPD, but also to reduce the
frequency of exacerbations of their condition.
Adverse Effects
Ipratropium is virtually devoid of the CNS side effects associated
with atropine.The most prevalent peripheral side effects are dry
mouth, headache, nervousness, dizziness, nausea, and cough. Unlike
atropine, ipratropiumdoes does not inhibit mucociliary clearance and
thus does not promote the accumulation of secretions in the lower
airways.
5.4.
CORTICOSTEROIDS
Mechanism of Action
There are many effects of corticosteroids than have been used to
treat asthma. More important are its anti-inflammatory efficacy,
mediated in part by inhibition of production of inflammatory
cytokines and bronchodilatating action. They do not relax airway
smooth muscle directly but reduce bronchial reactivity and reduce
the frequency of asthma exacerbations if taken regularly. Their effect
on airway obstruction may be due in part to their contraction of
engorged vessels in the bronchial mucosa and their potentiation of
the effects of β-receptor agonists, but their most important action is
inhibition of the lymphocytic eosinophilic mucosal inflammation of
asthmatic airways.
Clinical studies of corticosteroids consistently show them to be
effective in improving all indices of asthma control severity of
symptoms, tests of airway caliber and bronchial reactivity, frequency
of exacerbations, and quality of life. Urgent treatment is often begun
with an oral dose of 30–60 mg prednisone per day or an intravenous
dose of 1 mg/kg methylprednisolone every 6 hours; the daily dose is
decreased after airway obstruction has improved. In most patients,
systemic corticosteroid therapy can be discontinued in a week or 10
days, but in other patients symptoms may worsen as the dose is
decreased to lower levels. Because adrenal suppression by
76
corticosteroids is related to dose and because secretion of
endogenous corticosteroids has a diurnal variation, it is customary to
administer corticosteroids early in the morning after endogenous
ACTH secretion has peaked. For prevention of nocturnal asthma,
however, oral or inhaled corticosteroids are most effective when
given in the late afternoon.
Because of severe adverse effects when given chronically, oral
and parenteral corticosteroids are reserved for patients who require
urgent treatment, ie, those who have not improved adequately with
bronchodilators or who experience worsening symptoms despite
maintenance therapy. Regular or "controller" therapy is maintained
with aerosol corticosteroids.
Adverse Effects
Aerosol treatment is the most effective way to avoid the systemic
adverse effects of corticosteroid therapy. The introduction of
corticosteroids such as beclomethasone, budesonide, flunisolide,
fluticasone, mometasone, and triamcinolone has made it possible to
deliver corticosteroids to the airways with minimal systemic
absorption. Although these high doses of inhaled steroids may cause
adrenal suppression, the risks of systemic toxicity from chronic use
appear negligible compared with those of the oral corticosteroid
therapy they replace.
A special problem caused by inhaled topical corticosteroids is the
occurrence of oropharyngeal candidiasis. The risk of this
complication can be reduced by having patients gargle water and spit
after each inhaled treatment.
A novel approach to minimizing the risk of toxicity from systemic
absorption of an inhaled corticosteroid underlays the development of
ciclesonide. This investigational corticosteroid is inhaled as a
prodrug activated by cleavage by esterases in bronchial epithelial
cells. When absorbed into the circulation, the active product is tightly
bound to serum proteins, and so has little access to glucocorticoid
receptors in skin, eye, and bone, minimizing its risk of causing
cutaneous thinning, cataracts, osteoporosis, or temporary slowing of
growth.
77
Chronic use of inhaled corticosteroids effectively reduces
symptoms and improves pulmonary function in patients with mild
asthma. Such use also reduces or eliminates the need for oral
corticosteroids in patients with more severe disease. In contrast to
β-stimulant agents and theophylline, chronic use of inhaled
corticosteroids reduces bronchial reactivity. Because of the efficacy
and safety of inhaled corticosteroids, they are now routinely
prescribed for patients who require more than occasional inhalations
of a β agonist for relief of symptoms. This therapy is continued for
10-12 weeks and then withdrawn to determine whether more
prolonged therapy is needed. Inhaled corticosteroids are not curative.
In most patients, the manifestations of asthma return within a few
weeks after stopping therapy even if they have been taken in high
doses for 2 years or longer.
5.5.
MAST CELL STABILIZERS
As other anti-inflammatory agents, the cell membrane stabilizers
can be used. Cromolyn sodium (disodium cromoglycate) and
nedocromil sodium are stable but extremely insoluble salts. When
used as aerosols (by nebulizer or metered-dose inhaler), they
effectively inhibit both antigen- and exercise-induced asthma, and
chronic use (four times daily) slightly reduces the overall level of
bronchial reactivity. However, these drugs have no effect on airway
smooth muscle tone and are ineffective in reversing asthmatic
bronchospasm; they are only of value when taken prophylactically.
Cromolyn sodium and nedocromil sodium are used almost
exclusively for the prophylactic treatment of mild to moderate
asthma and should not be used to control acute bronchospasm.
Adverse Effects
Cromolyn sodium and nedocromil sodium are the least toxic of
available therapies for asthma. Adverse reactions are rare and
generally minor and include transient bronchospasm, cough or
wheezing, dryness of throat, laryngeal edema, swollen parotid gland,
78
angioedema, joint swelling and pain, dizziness, dysuria, nausea,
headache, nasal congestion, rash, and urticaria.
5.6.
LEUKOTRIENE MODULATORS
Zafirlukast and montelukast are cysteinyl leukotriene (CysLT)
receptor antagonists, and zileuton is a leukotriene synthesis inhibitor.
CysLTs include leukotrienes C4, D4, and E4. These mediators are
products of arachidonic acid metabolism and make up the
components of slow reacting substance of anaphylaxis. Montelukast
and zafirlukast are competitive antagonists of these receptors. In
contrast, zileuton suppresses synthesis of the leukotrienes by
inhibiting 5-lipoxygenase, a key enzyme in the bioconversion of
arachidonic acid to the leukotrienes. Zileuton also blocks the
production of leukotriene B4, another arachidonic acid metabolite
with proinflammatory activity.
Montelukast, zafirlukast, and zileuton are prescribed for the
prophylaxis and treatment of chronic asthma, but not in treating
attacks of asthma. All these drugs are administered orally.
Adverce Effects
Liver transaminase levels may be elevated sometimes. Zileuton
inhibits the metabolism of theophylline. Dyspepsia is the most
common side effect of zileuton. Zafirlukast and montelukast are well
tolerated.
5.7.
METHYLXANTINE DRUGS
Methylxanthines increase cAMP and inhibit adenosine-induced
bronchoconstriction. Oral theophylline is used for outpatient
management of asthma. An intravenous bolus of aminophylline, the
watersoluble salt of theophylline, produces therapeutic serum levels
faster than oral theophylline.
Aminophyline is therefore used in acute management.
The three important methylxanthines are theophylline,
theobromine, and caffeine. Their major source is beverages (tea,
79
cocoa, and coffee, respectively). The importance of theophylline as a
therapeutic agent in the treatment of asthma has waned as the greater
effectiveness of inhaled adrenoceptor agents for acute asthma and of
inhaled anti-inflammatory agents for chronic asthma has been
established, but theophylline's very low cost is an important
advantage for economically disadvantaged patients in societies in
which health care resources are limited.
6.
GENERAL
THERAPY
PRINCIPLES
OF
ANTIMICROBIAL
Antibacterial drugs can either kill infecting organism
(bacteriacidal) or slow their growth (bacteriostatic), depending on
many factors, including the specific drugs and dosage, the particular
microorganism, and tissue location of the infection.
Classification and Mechanism of Action
Antimicrobial agents are classified based on chemical structure
and proposed mechanism of action as follows:
1) agents that inhibit synthesis of bacterial cell walls, including
the β-lactam class (e.g., penicillins, cephalosporins, and
carbapenems) and dissimilar agents, such as cycloserine,
vancomycin, and bacitracin;
2) agents that act directly on the cell membrane of the
microorganism, increasing permeability and leading to leakage of
intracellular compounds, including detergents, such as polymyxin,
polyene antifungal agents (e.g., nystatin and amphotericin B) which
bind to cell-wall sterols, and the lipopeptide daptomycin;
3) agents that disrupt function of 30S or 50S ribosomal subunits to
reversibly inhibit protein synthesis, which generally are bacteriostatic
(e.g., chloramphenicol, tetracyclines, erythromycin, clindamycin,
streptogramins, and linezolid);
4) agents that bind to the 30S ribosomal subunit and alter protein
synthesis, which generally are bactericidal (e.g., the
aminoglycosides);
80
5) agents that affect bacterial nucleic acid metabolism, such as the
rifamycins (e.g., rifampin and rifabutin), which inhibit RNA
polymerase, and the quinolones, which inhibit topoisomerases;
6) the antimetabolites, including trimethoprim and the
sulfonamides, which block essential enzymes of folate metabolism.
6.1.
BETA-LACTAM COMPOUNDS AND OTHER CELL
WALL INHIBITORS
PENICILLINS
The penicillins are classified as β-lactam drugs because of their
unique four-membered lactam ring. They share features of chemistry,
mechanism of action, pharmacological and clinical effects, and
immunologic characteristics with cephalosporins, monobactams,
carbapenems, and β-lactamase inhibitors, which also are β-lactam
compounds.
These drugs have the greatest activity against gram-positive
organisms, Gram-negative cocci, and non-β-lactamase-producing
anaerobes. However, they have little activity against Gram-negative
rods. They are susceptible to hydrolysis by β lactamases.
Antistaphylococcal penicillins: These penicillins are resistant to
staphylococcal β-lactamases. They are active against staphylococci
and streptococci but inactive against enterococci, anaerobic bacteria,
and Gram-negative cocci and rods. These drugs retain the
antibacterial spectrum of penicillin and have improved activity
against Gram-negative organisms, but they are destroyed by β
lactamases. Methicillin, nafcillin, oxacillin and dicloxacillin are
penicillinase-resistant penicillins. Their use is restricted to the
treatment of infections caused by penicillinase-producing
staphylococci. Methicillin resistant Staphyilococcus aureus (MRSA)
is currently a serious source of nosocomial (hospital-acquired)
infections. This organism is usually susceptible to vancomycin and,
rarely, to ciprofloxacin or rifampin.
Extended-spectrum penicillins: Ampicillin and amoxicillin have an
antibacterial spectrum similar to that of penicillin G, but are more
effective against Gram-negative bacilli. They are therefore referred
81
to as extended-spectrum penicillins. Ampicillin is the drug of choice
for the Gram-positive bacillus Listeria monocytogenes. These agents
are also widely used in the treatment of respiratory infections, and
amoxicillin is employed prophylactically by dentists for patients with
abnormal heart valves who are to undergo extensive oral surgery.
Resistance to these antibiotics is now a major clinical problem
because of inactivation by plasmid-mediated penicillinase.
Formulation with a β-lactamase inhibitor, such as clavulanic acid or
sulbactam, protects amoxicillin or ampicillin, respectively, from
enzymatic hydrolysis and extends their antimicrobial spectrum.
Antipseudomonal penicillins: Carbenicillin, ticarcillin, and
piperacillin are called antipseudomonal penicillins because of their
activity against Pseudomonas aeruginosa. Piperacillin is the most
potent. These antibiotics are effective against many Gram-negative
bacilli but not against Klebsiella, because of its constitutive
penicillinase. Formulation of ticarcillin or piperacillin with
clavulanic acid or tazobactam, respectively, extends the antimicrobial
spectrum of these antibiotics to include penicillinase-producing
organisms. Mezlocillin and azlocillin (sometimes referred to as
acylureido penicillins) are also effective against Pseudomonas
aeruginosa, and a large number of Gram-negative organisms. They
are susceptible to β-lactamase breakdown.
Penicillins, like all β-lactam antibiotics, inhibit bacterial growth
by interfering with a specific step in bacterial cell wall synthesis.
Adverse Reactions
Penicillins are among the safest drugs, and blood levels are not
monitored, although adverse reactions do occur.
1. Hypersensitivity: This is the most important adverse effect of
the penicillins. The major antigenic determinant of penicillin
hypersensitivity is its metabolite, penicilloic acid, which reacts with
proteins and serves as a hapten to cause an immune reaction.
Approximately 5% of patients have some kind of reaction, ranging
from maculopapular rash to angioedema (marked swelling of lips,
tongue, and periorbital area) and anaphylaxis. Cross-allergic
reactions do occur among the 13-1actam antibiotics. Although rashes
82
can develop with all the penicillins, maculopapular rashes are most
common with ampicillin. Among patients with mononucleosis who
are treated with ampicillin, the incidence of maculopapular rash
approaches 100%.
2. Diarrhea: This effect, which is caused by a disruption of the
normal balance of intestinal microorganisms, is a common problem.
It occurs to a greater extent with those agents that are incompletely
absorbed and have an extended antibacterial spectrum.
3. Nephritis: All penicillins, but particularly methicillin, have the
potential to cause acute interstitial nephritis.
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.
5. Platelet dysfunction: This side effect, which involves decreased
agglutination, is observed with the antipseudomonal penicillins
(carbenicillin and ticarcillin) and, to some extent, with penicillin G. It
is generally a concern when treating patients predisposed to
hemorrhage or those receiving anticoagulants.
6. Cation toxicity: Penicillins are generally administered as the
sodium or potassium salt. Toxicities may be caused by the large
quantities of sodium or potassium that accompany the penicillin.
Sodium excess may result in hypokalemia. This can be avoided by
using the most potent antibiotic, which permits lower doses of drug
and accompanying cations.
CEPHALOSPORINS AND CEPHAMYCINS
Cephalosporins and cephamycins are similar to penicillins
chemically, in mechanism of action, and in toxicity. Cephalosporins
are more stable than penicillins to produced by some bacteria βlactamases and therefore usually have a broader spectrum of activity.
Cephalosporins are not active against enterococci and Listeria
monocytogenes.
Cephalosporins can be classified into four major groups or
generations, depending mainly on the spectrum of antimicrobial
activity. As a general rule, first-generation compounds have better
83
activity against Gram-positive organisms, and the later compounds
exhibit improved activity against Gram-negative aerobic organisms.
Classification
First generation – narrow spectrum, sensitive to β-lactamases:
cephalexin (Keflex), cefazolin (Kefzol), cephalothin (Keflin),
cephradine (Anspor), cephadroxil (Duricef), cephaprin (Cephadyl).
Cephalexin, cephradine and cefadroxil are administered orally,
others IV/IM. Oral drugs reach therapeutic levels in urine but not
serum. They all fail to penetrate into the CNS. They all are destroyed
by β-lactamases, but may be administered with clavulinate to
circumvent this problem: metabolized by liver, excreted by kidney. E
Effective against most Staphylococcal and Streptococcal species that
do not produce β-lactamases, they cover most strains of enteric
Gram-negatives (E. coil, Proteus, Klebsiella) and some anaerobes
perioperatively to reduce risk of surgical infections. Cephalexin and
cefadroxil are often used for urinary tract infections.
Second generation - increased activity against Gram-negatives:
cefaclor (Ceclor), cefuroxime (Zinacef), cephamandole (Mandol),
efoxitin (Mefoxin), cefotetan (Cefotan), cefonicid (Monocid),
ceforanide (Precef), cefmetazole (Zefazone).
Cefaclor and cefuroxime are administered orally; cefuroxime is
administered also IV/IM. Others are administered IV/IM only.
Cefuroxime enters CSF in concentrations suitable for the treatment
of meningitis, others do not. Cefuroxime is also used as monotherapy
for Gram-positive cocci and H. influenzae infections in infants and
small children. It has increased activity against Gram-negatives
(including H. influenza) but not effective for Pseudomonas
aeruginosa or B. fragilis (except cefoxitin, which has good activity
against B. fragilis), slightly less effective for treating Gram-positive
infections than first generation agents, not drugs of choice for any
infections. Cefoxitin, cefotetan, and cefmetazole are used primarily
for abdominal and pelvic infections.
Third generation - broad spectrum, resistant to most
cephalosporins: cefotaxime (Claforan), ceftriaxone (Rocephin),
84
cefixime (Suprax), ocftizoxime (Cefizox), cefoperazone (Cefobid),
moxalactam (Moxam), ceftazidime (Fortaz).
Cefixime is precribed PO, others – IV/IM. Good CNS penetration
(except cefoperazone). Ceftriaxone has the longest half-life. This
generation is the most effective against Gram-negatives but is less
effective against S. aureus than first or second generation drugs.
They are not well suited for pseudomonal infections, although
ceftazidime may be effective. Moxolactam is used less frequently
than the others because it is associated with hemorrhagic side effects
and is less effective against Gram-positive cocci.
Fourth generation - Cefepime (Maxipim), cefirom (Keyten),
cefelidine, and Cefoselis. Cefepime is the most clinically useful
fourth generation cephalosporin and must be administered
parenterally. Cefepime has a wide antibacterial spectrum being active
against Streptococci and Staphylococci (only those that are
methicillin susceptible). It is also effective against aerobic Gramnegative organisms, such as Enterobacter, Escherichia coli,
Klebsiella pneumoniae, and Proteus mirabilis.
Adverse Effects
The cephalosporins produce a number of adverse affects, some of
which are unique to particular members of the group.
Allergic manifestations: The cephalosporins should be avoided or
used with caution in individuals allergic to penicillins (about 5–15%
show cross-sensitivity). In contrast, the incidence of allergic
reactions to cephalosporins is 1–2% in patients without a history of
allergy to penicillins.
A Disulfiram-like effect: When cefamandole or cefoperazone is
ingested with alcohol or alcohol-containing medications, a
disulfiram-like effect is seen, because these cephalosporins block the
second step in alcohol oxidation, which results in the accumulation
of acetaldehyde 1.
Bleeding: Bleeding can occur with cefamandole or cefoperazone,
because of antivitamin K effects; administration of the vitamin
corrects the problem.
85
MONOBACTAMS
These are drugs with a monocyclic β-lactam ring. They are
relatively resistant to lactamases and active against Gram-negative
rods (including pseudomonas and serratia). They are not active
against Gram-positive bacteria or anaerobes. Aztreonam resembles
aminoglycosides in its spectrum of activity. Aztreonam is given
intravenously every 8 hours in a dose of 1–2 g, providing peak serum
levels of 100 g/mL. The half-life is 1–2 hours and is greatly
prolonged in renal failure.
Adverse Effects
Aztreonam is relatively nontoxic, but it may cause phlebitis, skin
rash, and occasionally, abnormal liver function tests. Aztreonam has
a low immunogenic potential and shows little cross-reactivity with
antibodies induced by other β-lactams. Thus, aztreonam may offer a
safe alternative for treating patients allergic to penicillins and/or
cephalosporins.
BETA-LACTAMASE
INHIBITORS
(Clavulanic
Acid,
Sulbactam, and Tazobactam)
These substances resemble β-lactam molecules but have very
weak antibacterial action. They are potent inhibitors of many but not
all bacterial lactamases and can protect hydrolyzable penicillins from
inactivation by these enzymes. Beta-lactamase inhibitors are most
active against the Ambler class A β-lactamases, such as those
produced 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 by enterobacter,
citrobacter, serratia, and pseudomonas, but they do inhibit
chromosomal β-lactamases of legionella, bacteroides, and
branhamella.
The indications for penicillin-β-lactamase inhibitor combinations
are empirical therapy for infections caused by a wide range of
potential
pathogens
in
both
immunocompromised
and
immunocompetent patients and treatment of mixed aerobic and
86
anaerobic infections, such as intra-abdominal infections. Doses are
the same as those used for the single agents except that the
recommended dosage of piperacillin in the piperacillin-tazobactam
combination is 3 g every 6 hours. This is less than the recommended
3–4 g every 4–6 hours for piperacillin alone, raising concerns about
the use of the combination for treatment of suspected pseudomonal
infection. Adjustments for renal insufficiency are made based on the
penicillin component.
A) CARBAPENEMS
The carbapenems (ertapenem, imipenem, and meropenem) are
structurally related to β-lactam antibiotics. Imipenem has a wide
spectrum with good activity against many Gram-negative rods,
including Pseudomonas aeruginosa, Gram-positive organisms, and
anaerobes. It is resistant to most β-lactamases but not metallo-βlactamases.
Enterococcus
faecium,
methicillin-resistant
strains
of
staphylococci, Clostridium difficile, Burkholderia cepacia, and
Stenotrophomonas maltophilia are resistant. Imipenem is inactivated
by dehydropeptidases in renal tubules, resulting in low urinary
concentrations. Consequently, it is administered together with an
inhibitor of renal dehydropeptidase, cilastatin, for clinical use.
Meropenem is similar to imipenem but has slightly greater activity
against Gram-negative aerobes and slightly less activity against
Gram-positives. It is not significantly degraded by renal
dehydropeptidase and does not require an inhibitor. Ertapenem is less
active than meropenem or imipenem against Pseudomonas
aeruginosa and acinetobacter species. It is not degraded by renal
dehydropeptidase.
Carbapenems penetrate body tissues and fluids well, including the
cerebrospinal fluid. All are cleared renally, and the dose must be
reduced in patients with renal insufficiency. The usual dose of
imipenem is 0.25–0.5 g given intravenously every 6–8 hours (halflife 1 hour). The usual adult dose of meropenem is 1 g intravenously
every 8 hours. Ertapenem has the longest half-life (4 hours) and is
administered as a once-daily dose of 1 g intravenously or
87
intramuscularly. Intramuscular ertapenem is irritating, and for that
reason the drug is formulated with 1% lidocaine for administration
by this route.
A carbapenem is indicated for infections caused by susceptible
organisms that are resistant to other available drugs and for treatment
of mixed aerobic and anaerobic infections. Carbapenems are active
against many highly penicillin-resistant strains of pneumococci. A
carbapenem is the β-lactam antibiotic of choice for treatment of
enterobacter infections, since it is resistant to destruction by the
lactamase produced by these organisms. Strains of Pseudomonas
aeruginosa may rapidly develop resistance to imipenem or
meropenem, so simultaneous use of an aminoglycoside is
recommended for infections caused by those organisms. Ertapenem
is insufficiently active against P aeruginosa and should not be used to
treat infections caused by that organism. Imipenem or meropenem
with or without an aminoglycoside may be effective treatment for
febrile neutropenic patients.
Adverse effects are nausea, vomiting, diarrhea, skin rashes, and
reactions at the infusion sites. Excessive levels of imipenem in
patients with renal failure may lead to seizures. Meropenem and
ertapenem are less likely to cause seizures than imipenem. Patients
allergic to penicillins may be allergic to carbapenems as well.
B) VANCOMYCIN
Vancomycin is an antibiotic produced by Streptococcus orientalis.
With the single exception of flavobacterium, it is active only against
Gram-positive bacteria, particularly staphylococci. Vancomycin
inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala
terminus of nascent peptidoglycan pentapeptide. Vancomycin is
bactericidal for Gram-positive bacteria in concentrations of 0.5–
10 g/mL. Most pathogenic staphylococci, including those producing
lactamase and those resistant to nafcillin and methicillin, are killed
by 4 g/mL or less. Vancomycin kills staphylococci relatively slowly
and only if cells are actively dividing; the rate is less than that of the
penicillins both in vitro and in vivo. Vancomycin is synergistic with
88
gentamicin and streptomycin against E. faecium and E. faecalis
strains that do not exhibit high levels of aminoglycoside resistance.
Vancomycin is poorly absorbed from the intestinal tract and is
administered orally only for the treatment of antibiotic-associated
enterocolitis caused by Clostridium difficile. Parenteral doses must
be administered intravenously. A 1 hour intravenous infusion of 1 g
produces blood levels of 15–30 g/mL for 1–2 hours. The drug is
widely distributed in the body. Cerebrospinal fluid levels 7–30% of
simultaneous serum concentrations are achieved if there is meningeal
inflammation.
Ninety percent of the drug is excreted by glomerular filtration.
The main indication for parenteral vancomycin is sepsis or
endocarditis caused by methicillin-resistant staphylococci. However,
vancomycin is not as effective as antistaphylococcal penicillin for
treatment of serious infections, such as endocarditis, caused by
methicillin-susceptible strains.
Vancomycin in combination with gentamicin is an alternative
regimen for treatment of enterococcal endocarditis in a patient with
serious penicillin allergy. Vancomycin (in combination with
cefotaxime, ceftriaxone, or rifampin) is also recommended for
treatment of meningitis suspected or known to be caused by a highly
penicillin-resistant strain of pneumococcus (i.e., MIC > 1 g/mL).
The recommended dosage is 30 mg/kg/d in two or three divided
doses. A typical dosing regimen for most infections in adults with
normal renal function is 1 g every 12 hours. The dosage in children
is 40 mg/kg/d in three or four divided doses. Oral vancomycin,
0.125–0.25 g every 6 hours, is used to treat antibiotic-associated
enterocolitis caused by Clostridium difficile. However, because of
the emergence of vancomycin-resistant enterococci and the strong
selective pressure of oral vancomycin for these resistant organisms,
metronidazole is strongly preferred as initial therapy and vancomycin
should be reserved for treatment of refractory cases.
Adverse effects are encountered in about 10% of cases. Most
reactions are minor. Vancomycin is irritating to tissue, resulting in
phlebitis at the site of injection. Chills and fever may occur.
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Ototoxicity is rare and nephrotoxicity uncommon with current
preparations. However, administration with another ototoxic or
nephrotoxic drug, such as an aminoglycoside, increases the risk of
these toxicities. Among the more common reactions is the so-called
"red man" or "red neck" syndrome. This infusion-related flushing is
caused by release of histamine. It can be largely prevented by
prolonging the infusion period to 1–2 hours or increasing the dosing
interval.
6.2.
PROTEIN SYNTHESIS INHIBITORS (Tetracyclines,
Macrolides, Aminoglycosides, Chloramphenicol,
Clindamycin)
A) TETRACYCLINES
Tetracyclines are broad-spectrum bacteriostatic antibiotics that
inhibit protein synthesis.. The group includes tetracycline,
oxytetracycline, demeclocycline, lymecycline, doxycycline and
minocycline They are active against many Gram-positive and Gramnegative bacteria, including anaerobes, rickettsiae, chlamydiae,
mycoplasmas, and L. forms; and against some protozoa, e.g.,
amebas. The antibacterial activities of most tetracyclines are similar
except that tetracycline-resistant strains may be susceptible to
doxycycline, minocycline, and tigecycline, all of which are poor
substrates for the efflux pump that mediates resistance. Differences
in clinical efficacy for susceptible organisms are minor and
attributable largely to features of absorption, distribution, and
excretion of individual drugs.
The oral dosage for rapidly excreted tetracyclines, equivalent to
tetracycline hydrochloride, is 0.25–0.5 g four times daily for adults
and 20–40 mg/kg/d for children (8 years of age and older). For
severe systemic infections, the higher dosage is indicated, at least for
the first few days. The daily dose is 600 mg for demeclocycline or
methacycline, 100 mg once or twice daily for doxycycline, and 100
mg twice daily for minocycline. Doxycycline is the oral tetracycline
of choice because it can be given as a once-daily dose and its
absorption is not significantly affected by food. All tetracyclines
90
chelate with metals, and none should be orally administered with
milk, antacids, or ferrous sulfate. To avoid deposition in growing
bones or teeth, tetracyclines should be avoided in pregnant women
and children under 8 years of age.
Several tetracyclines are available for intravenous injection in
doses of 0.1–0.5 g every 6–12 hours (similar to oral doses) but
doxycycline is the usual preferred agent, at a dosage of 100 mg every
12–24 hours. Intramuscular injection is not recommended because of
pain and inflammation at the injection site.
Adverse Effects
Gastric discomfort: Epigastric distress commonly results from
irritation of the gastric mucosa and is often responsible for noncompliance in patients treated with these drugs. The discomfort can
be controlled if the drug is taken with foods other than dairy
products.
Effects on calcified tissues: Deposition in the bone and primary
dentition occurs during calcification in growing children; this causes
discoloration and hypoplasia of the teeth and a temporary stunting of
growth.
Fatal hepatotoxicity: This side effect has been known to occur in
pregnant women who received high doses of tetracyclines, especially
if they are experiencing pyelonephritis.
Phototoxicity: Phototoxicity, for example, a severe sunburn,
occurs when the patient receiving a tetracycline is exposed to sun or
ultraviolet rays. This toxicity is encountered most frequently with
tetracycline, doxycycline, and demeclocycline.
Vestibular problems: These side effects (for example, dizziness,
nausea, vomiting) occur with minocycline, which concentrates in the
endolymph of the ear and affects function.
Pseudotumor cerebri: Benign intracranial hypertension
characterized by headache and blurred vision, may occur in adults.
Though discontinuation of the drug reverses the condition; it is not
clear whether permanent sequelae may occur.
Organs and tissue toxicity: Tetracyclines can probably impair
hepatic function, especially during pregnancy, in patients with
91
preexisting hepatic insufficiency and when high doses are given
intravenously. Hepatic necrosis has been reported with daily doses of
4 g or more intravenously.
Renal tubular acidosis and other renal injury resulting in nitrogen
retention have been attributed to the administration of outdated
tetracycline preparations. Tetracyclines, given along with diuretics,
may produce nitrogen retention. Tetracyclines, other than
oxycycline, may accumulate to toxic levels in patients with impaired
kidney function.
Intravenous injection can lead to venous thrombosis.
Intramuscular injection produces painful local irritation and should
be avoided.
Superinfections: Candida overgrowths (for example in the vagina)
or increase in resistant staphylococci (in the intestine) may occur.
Contraindications: Renally-impaired patients should not be
treated with any of the tetracyclines except doxycycline and
minocycline. Accumulation of tetracyclines may aggravate preexisting azotemia by interfering with protein synthesis, thus
promoting amino acid degradation The tetracyclines should not be
employed in pregnant or breast-feeding women, or in children under
8 years of age.
B) MACROLIDES
The macrolides are a group of closely related compounds
characterized by a macrocyclic lactone ring (usually containing 14
or 16 atoms) to which deoxy sugars are attached. The prototype
drug, erythromycin, which consists of two sugar moieties attached
to a 14-atom lactone ring, was obtained in 1952 from Streptomyces
erythreus. The newer members of this family, clarithromycin (a
methylated form of erythromycin) and azithromycin (having a
larger lactone ring), have some features in common with, and others
that improve on, erythromycin. Recently, dirithromycin, a
macrolide similar to erythromycin in antibacterial spectrum but
with the advantage of one-daily dosage, has been approved.
Erythromycin has activity against many species of
campylobacter, chlamydia, mycoplasma, legionella, Gram-positive
92
cocci, and some Gram-negative organisms. The spectrums of
activity of azithromycin and clarithromycin are similar but include
greater activity against Chlamydia, M avium complex (MAC),
Haemophilus influenzae and Moraxella catarrhalis and toxoplasma.
Azithromycin: Except for its cost, it is now the preferred therapy
for urethritis caused by Chlamydia trachomatis. Its activity against
Mycobacterium avium intracellulare complex has not proven to be
clinically important except in AIDS patients with disseminated
infections.
Resistance to the macrolides in Gram-positive organisms
involves production of a methylase that adds a methyl group to the
ribosomal binding site. Resistance in enterobacteria is the result of
formation of drug-metabolizing esterases. Cross-resistance between
the individual macrolides is complete.
Adverse Effects
Epigastric Distress: This side effect is common and can lead to
poor patient compliance for erythromycin. The new macrolides
seem to be better tolerated by the patient; gastrointestinal problems
are their most common side effects.
Cholestatic Hepatitis: This side effect occurs, especially with the
estolate form of erythromycin, presumably as the result of a
hypersensitivity reaction to the estolate form (the lauryl salt of the
propionyl ester of erythromycin). It has also been reported for other
forms of the drug.
Ototoxicity: Transient deafness has been associated with
erythromycin, especially at high dosages.
Skin Rashes, and Eosinophilia, Cardiac Arrhythmias.
Erythromycin inhibits several forms of hepatic cytochrome P450
and can increase the plasma levels of anticoagulants,
carbamazepine, cisapride, digoxin, and theophylline.
Contraindications: Patients with hepatic dysfunction should not
be treated with erythromycin since the drug accumulates in the
liver.
93
C) CLYNDAMICINE
The lincosamides lincomycin and clindamycin inhibit bacterial
protein synthesis via a mechanism similar to that of the macrolides,
though they are not chemically related. Mechanisms of resistance
include methylation of the binding site on the 50S ribosomal subunit
and enzymatic inactivation. Cross-resistance between lincosamides
and macrolides is common. Good tissue penetration occurs after oral
absorption. The fincosamides are eliminated partly by metabolism
and partly by biliary and renal excretion. The main use of
clindamycin is in the treatment of severe infections due to certain
anaerobes such as bacteroides. Clindamycin has been used as a
backup drug against Gram-positive cocci and is currently
recommended for prophylaxis of endocarditis in valvular disease
patients who are penicillin-allergic. The drug is also active against
Mocystis carinii pneumonia and Toxoplasmjsis. The toxicity of
clindamycin includes gastrointestinal irritation, skin rashes,
neutropenia, hepatic dysfunction, and possible superinfections.
D) CHLORAMPHENICOL
Chloramphenicol is a bacteriostatic broad-spectrum antibiotic that
is active against both aerobic and anaerobic Gram-positive and
Gram-negative organisms. It is active also against rickettsiae but not
chlamydiae. Most Gram-positive bacteria are inhibited at
concentrations of 1–10 mcg/mL, and many Gram-negative bacteria
are inhibited by concentrations of 0.2–5 mcg/mL. H. influenzae,
N. meningitidis, and some strains of bacteroides are highly
susceptible, and for them chloramphenicol may be bactericidal.
However, because of its toxicity, its use is restricted to lifethreatening infections for which no alternatives exist.
Adverse Effects
Gastrointestinal disturbances: Adults occasionally develop
nausea, vomiting, and diarrhea. This is rare in children. Oral or
vaginal candidiasis may occur as a result of alteration of normal
microbial flora.
94
Bone marrow disturbances: Chloramphenicol commonly causes a
dose-related reversible suppression of red cell production at dosages
exceeding 50 mg/kg/d after 1–2 weeks. Aplastic anemia, a rare
consequence (1 in 24,000 to 40,000 courses of therapy) of
chloramphenicol administration by any route, is an idiosyncratic
reaction unrelated to dose, although it occurs more frequently with
prolonged use. It tends to be irreversible and can be fatal.
Toxicity for newborn infants: The drug may accumulate, resulting
in the Gray Baby Syndrome with vomiting, flaccidity, hypothermia,
gray color, shock, and collapse. To avoid this toxic effect,
chloramphenicol should be used with caution in infants and the
dosage limited to 50 mg/kg/d or less (during the first week of life) in
full-term infants more than 1 week old and 25 mg/kg/d in premature
infants.
Interaction with other drugs: Chloramphenicol inhibits hepatic
microsomal enzymes that metabolize several drugs. Half-lives are
prolonged, and the serum concentrations of phenytoin, tolbutamide,
chlorpropamide, and warfarin are increased. Like other bacteriostatic
inhibitors of microbial protein synthesis, chloramphenicol can
antagonize bactericidal drugs, such as penicillins or aminoglycosides.
E) AMINOGLICOSIDES
The aminoglycosides are a group of antibiotics of complex
chemical structure resembling each other in antimicrobial activity,
pharmacokinetic characteristics and toxicity. The main agents are
gentamicin, streptomycin, amikacin, tobramycin, netilmicin and
neomycin. Aminoglycoside antibiotics had been the mainstays for
treatment of serious infections due to aerobic Gram-negative bacilli.
They are most widely used against Gram-negative enteric organisms
and in sepsis. However, because their use is associated with serious
toxicities, they have been replaced to some extent by safer
antibiotics, such as the third- and fourth-generation cephalosporins,
the fluoroquinolones, and the carbapenems. They may be given
together with penicillin in streptococcocal infections caused by
Listeria spp. and P. aeruginosa. Gentamicin is the aminoglycoside
most commonly used, although tobramycin is the preferred member
95
of this group for P. aeruginosa infections. Amikacin has the widest
antimicrobial spectrum and, along with netilmicin, can be effective in
infections with organisms resistant to gentamicin and tobramycin.
The aminoglycoside antibiotics are rapidly bactericidal.
Bacteria may be resistant to aminoglycosides because of failure of
the antibiotic to penetrate intracellularly, low affinity of the drug for
the bacterial ribosome, or inactivation of the drug by microbial
enzymes. Clinically, drug inactivation is the most common
mechanism for acquired microbial resistance to aminoglycosides.
The genes encoding aminoglycoside-modifying enzymes are
acquired primarily by conjugation and transfer of resistance
plasmids.
Adverse Effects
It is important to monitor plasma levels of gentamicin,
tobramycin, and amikacin to avoid concentrations that cause doserelated toxicities
Ototoxicity: Ototoxicity (vestibular and cochlear) is directly
related to high peak plasma levels and the duration of treatment.
Vertigo and loss of balance (especially in patients receiving
streptomycin) may also occur, because these drugs affect the
vestibular apparatus.
The nephrotoxicity consists of damage to the kidney tubules and
can be reversed if the use of the drugs is stopped. Nephrotoxicity is
more likely to occur in patients with pre-existing renal disease or in
conditions in which urine volume is reduced, and concomitant use of
other nephrotoxic agents (e.g., cephalosporins) increases the risk.
Nephrotoxicity: Retention of the aminoglycosides by the proximal
tubular cells disrupts calcium-mediated transport processes, and this
results in kidney damage ranging from mild, reversible renal
impairment to severe, acute tubular necrosis, which can be
irreversible.
Neuromuscular paralysis: This side effect most often occurs after
direct intraperitoneal or intrapleural application of large doses of
aminoglycosides. The mechanism is responsible in a decrease in both
the release of acetylcholine from prejunctional nerve endings and the
96
sensitivity of the postsynaptic site. Patients with myasthenia gravis
are particularly at risk. Prompt administration of calcium gluconate
or neostigmine can reverse the block.
Allergic reactions: Contact dermatitis is a common reaction to
topically applied neomycin.
6.3.
MISCELLANEOUS ANTIBACTERIAL AGENTS
Vancomycin is a glycopeptide antibiotic, and teicoplanin is similar
but longer lasting. Vancomycin is bactericidal (except against
streptococci) and acts by inhibiting cell wall synthesis. It is effective
mainly against Gram-positive bacteria and has been used against
methicillin-resistant staphylococci. Vancomycin is not absorbed from
the gut and is only given by the oral route for treatment of
gastrointestinal infection with C. difficile. For parenteral use, it is
given intravenously and has a plasma half-life of about 8 hours.
Adverse effects include fever, rashes and local phlebitis at the site
of injection. Ototoxicity and nephrotoxicity can occur, and
hypersensitivity reactions are occasionally seen.
Nitrofurantoin is a synthetic compound active against a range of
Gram-positive and Gram-negative organisms. The development of
resistance in susceptible organisms is rare, and there is no crossresistance. Its mechanism of action is not known. It is given orally
and is rapidly and totally absorbed from the gastrointestinal tract and
just as rapidly excreted by the kidney. The clinical use of
nitrofurantoin is confined to the treatment of urinary tract infections.
The polymixin antibiotics in use are polymixin B and colistin
(polymixin E). They have cationic detergent properties and exert
their antibacterial action by disrupting the cell membrane
phospholipids. They have a selective, rapidly bactericidal action on
Gram-negative bacilli, especially pseudomonads and coliform
organisms. They are not absorbed from the gastrointestinal tract.
Clinical use of these drugs is limited by their toxicity (see below) and
is confined largely to gut sterilisation and topical treatment of ear,
eye or skin infections caused by susceptible organisms.
97
Adverse effects may be serious and include neurotoxicity and
nephrotoxicity.
Metronidazole was introduced as an antiprotozoal agent, but it is
also active against anaerobic bacteria such as Bacteroides, Clostridia
sp. and some streptococci. It is effective in the therapy of
pseudomembranous colitis, a clostridial infection sometimes
associated with antibiotic therapy (see above), and is important in the
treatment of serious anaerobic infections (e.g. sepsis secondary to
bowel disease).
6.4.
ANTIMICROBIAL
TOPOISOMERASE
AGENTS
AFFECTING
A) FLUOROQUINOLONES
The fluoroquinolones include the broad-spectrum agents
ciprofloxacin, levofloxacin, ofloxacin, norfloxacin and moxifloxacin,
as well as a narrow-spectrum drug used in urinary tract infections,–
nalidixic acid (the first quinolone and not fluorinated). These agents
inhibit topoisomerase II (a bacterial DNA gyrase), the enzyme that
produces a negative supercoil in DNA and thus permits transcription
or replication. 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 Gramnegative 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,
penicillinase-producing N. gonorrhoeae, Campylobacter spp. and
pseudomonads. Amongst the Gram-positive organisms, streptococci
and pneumococci are only weakly inhibited, and there is a high
incidence of staphylococcal resistance. Ciprofloxacin should be
avoided in methicillin-resistant staphylococcal infections. Clinically,
the fluoroquinolones are best used for infections with facultative and
aerobic Gram-negative rods and cocci. Resistant strains of
Staphylococous aureus and Pseudomonas aeruginosa have emerged.
98
Given orally, the fluoroquinolones are well absorbed. The half-life
of ciprofloxacin and norfloxacin is 3 hours, and that of ofloxacin is 5
hours. The drugs accumulate in several tissues, particularly in the
kidney, prostate and lung. All quinolones are concentrated in
phagocytes. Most fail to cross the blood-brain barrier, but ofloxacin
penetrates the CSF and attains 40% of its serum concentrations.
Aluminium and magnesium antacids interfere with the absorption of
the quinolones. Elimination of ciprofloxacin and norfloxacin occurs
partly by hepatic metabolism by P450 enzymes (which they can
inhibit, giving rise to interactions with other drugs) and partly by
renal excretion. Ofloxacin is excreted in the urine.
Adverse Effects
Unwanted effects are infrequent, usually mild and disappear when
the drugs are withdrawn. The most frequent manifestations are
gastrointestinal disorders and skin rashes. Arthropathy has been
reported in young individuals. Central nervous system symptomsheadache and dizziness have occurred as well as, less frequently,
convulsions associated with central nervous system pathology or
concurrent use of theophylline or a NSADs. There is a clinically
important interaction between ciprofloxacin and this drug (through
inhibition of P450 enzymes), which can lead to theophylline toxicity
in asthmatics treated with the fluoroquinolones.
Gastrointestinal: The most common adverse effects of the
fluoroquinolones are nausea, vomiting, and diarrhea, which occur in
3–6% of patients.
Central nervous system problems: The most prominent central
nervous system (CNS) effects of fluoroquinolone treatment are
headache and dizziness or lightheadedness. Thus, patients with CNS
disorders, such as epilepsy, should be treated cautiously with these
drugs.
Phototoxicity: Patients taking fluoroquinolones are advised to
avoid excessive sunlight and to apply sunscreens. However, the latter
may not protect completely. Thus, it is advisable that the drug intake
should be discontinued at the first sign of phototoxicity.
99
Connective tissue problems: Fluoroquinolones should be avoided
in pregnancy, in nursing mothers, and in children under 18 years of
age, because articular cartilage erosion (arthropathy) occurs in
immature experimental animals. Children with cystic fibrosis who
receive ciprofloxacin have had few problems, but careful monitoring
is indicated. In adults, fluoroquinolones can infrequently cause
ruptured tendons.
Contraindications: Moxifloxacin may prolong the QTc interval
and, thus, should not be used in patients who are predisposed to
arrhythmias or are taking antiarrhythmic medications.
Drug interactions: The effect of antacids and cations on the
absorption of these agents was considered above. Ciprofloxacin and
ofloxacin can increase the serum levels of theophylline by inhibiting
its metabolism. This is not the case with the third- and fourthgeneration fluoroquinolones, which may raise the serum levels of
warfarin, caffeine, and cyclosporine.
6.5.
ANTIFOLATE DRUGS
SULFONAMIDES
The sulfonamides are weakly acidic compounds that have a
common chemical nucleus resembling p-aminobenzoic acid (PABA).
Members of this group differ mainly in their pharmacokinetic
properties and clinical uses. Pharmacokinetic features include modest
tissue penetration, hepatic metabolism, and excretion of both intact
drug and acetylated metabofites in the urine. Solubility may be
decreased in acidic urine, resulting in precipitation of the drug or its
metabolites. Because of the solubility limitation, a combination of
three separate sulfonamides (triple sulfa) has been used to reduce the
likelihood that any one drug will precipitate. The sulfonamides may
be classified as short-acting (e.g., sulfisoxazole), intermediate-acting
(e.g., sulfamethoxazole), and long-acting (e.g., sulfadoxine).
Sulfonamides bind to plasma proteins at sites shared by bilirubin and
by other drugs.
The sulfonamides may be classified into three groups on the basis
of the rapidity with which they are absorbed and excreted:
100
1) agents that are absorbed and excreted rapidly, such as
sulfisoxazole and sulfadiazine;
2) agents that are absorbed very poorly when administered orally
and hence are active in the bowel lumen, such as sulfasalazine;
3) agents that are used mainly topically, such as sulfacetamide,
mafenide, and silver sulfadiazine;
4) long-acting sulfonamides, such as sulfadoxine, that are
absorbed rapidly but slowly excreted.
Sulfonamides are infrequently used as single agents. Many strains
of formerly susceptible species, including meningococci,
pneumococci, streptococci, staphylococci, and gonococci, are now
resistant. The fixed-drug combination of trimethoprimsulfamethoxazole is the drug of choice for infections, such as
Pneumocystis jiroveci (formerly P carinii) pneumonia,
toxoplasmosis, nocardiosis, and occasionally other bacterial
infections.
ORAL ABSORBABLE AGENTS
Sulfisoxazole and sulfamethoxazole are short- to medium-acting
agents used almost exclusively to treat urinary tract infections. The
usual adult dosage is 1 g of sulfisoxazole four times daily or 1 g of
sulfamethoxazole two or three times daily.
Sulfadiazine in combination with pyrimethamine is first-line
therapy for treatment of acute toxoplasmosis. The combination of
sulfadiazine with pyrimethamine, a potent inhibitor of dihydrofolate
reductase, is synergistic because these drugs block sequential steps in
the folate synthetic pathway blockade. The dosage of sulfadiazine is
1 g four times daily, with pyrimethamine given as a 75-mg loading
dose followed by a 25-mg once-daily dose. Folinic acid, 10 mg orally
each day, should also be administered to minimize bone marrow
suppression.
Sulfadoxine is the only long-acting sulfonamide currently
available in the United States and only as a combination formulation
with pyrimethamine, a second-line agent in treatment for malaria
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Oral nonabsorbable agents: Sulfasalazine (salicylazosulfapyridine) is
widely used in ulcerative colitis, enteritis, and other inflammatory
bowel diseases.
TOPICAL AGENTS
Sodium sulfacetamide ophthalmic solution or ointment is effective
treatment for bacterial conjunctivitis and as adjunctive therapy for
trachoma. Another sulfonamide, mafenide acetate, is used topically
but can be absorbed from burn sites. The drug and its primary
metabolite inhibit carbonic anhydrase and can cause metabolic
acidosis, a side effect that limits its usefulness. Silver sulfadiazine is
a much less toxic topical sulfonamide and is preferred to mafenide
for prevention of infection of burn wounds.
Trimethoprim: This drug is structurally similar to folic acid. It is a
weak base and is trapped in acidic environments, reaching high
concentrations in prostatic and vaginal fluids. A large fraction of
trimethoprim is excreted unchanged in the urine. The half-life of this
drug is similar to that of sulfamethoxazole (10–12 hours).
Adverse Effects
Crystalluria: Nephrotoxicity develops as a result of crystalluria.
Adequate hydration and alkalinization of urine prevent the problem
by reducing the concentration of drug and promoting its ionization.
Agents, such as sulfisoxazole and sulfamethoxazole, are more
soluble at urinary pH than the older sulfonamides (for example,
sulfadiazine) and less liable to cause crystalluria.
Hypersensitivity: Hypersensitivity reactions, such as rashes,
angioedema, and Stevens-Johnson syndrome, are fairly common.
The latter occurs more frequently with the longer-acting agents.
Hemopoietic Disturbances: Hemolytic anemia is encountered in
patients with glucose 6-phosphate dehydrogenase deficiency.
Granulocytopenia and thrombocytopenia can also occur.
Miscellaneous Reactions Anorexia, nausea, and vomiting occur in
1-2% of persons receiving sulfonamides, and these manifestations
probably are central in origin. The administration of sulfonamides to
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newborn infants, especially if premature, may lead to the
displacement of bilirubin from plasma albumin.
Kernicterus: This disorder may occur in newborns, because sulfa
drugs displace bilirubin from binding sites on serum albumin. The
bilirubin is then free to pass into the CNS, because the baby's bloodbrain barrier is not fully developed.
7.
DRUGS USED IN THE TREATMENT OF GIT
DISORDERS
The gastrointestinal tract serves several functions: digestive,
excretory, endocrine, exocrine, etc. These functions provide
numerous important drug targets, and many of the drugs used in
gastrointestinal disease have been discussed in earlier chapters of this
book. However, several important drugs used in common
gastrointestinal diseases do not fall into the drug groups discussed
earlier; these agents are described in this chapter.
Acid-peptic diseases include gastroesophageal reflux, peptic ulcer
(gastric and duodenal), and stress-related mucosal injury. In all these
conditions, mucosal erosions or ulceration arise when the caustic
effects of aggressive factors (acid, pepsin, bile) overwhelm the
defensive factors of the gastrointestinal mucosa (mucus and
bicarbonate secretion, prostaglandins, blood flow, and the processes
of restitution and regeneration after cellular injury). Over 99% of
peptic ulcers are caused by infection with the bacterium Helicobacter
pylori or by use of nonsteroidal anti-inflammatory drugs (NSAIDs).
Drugs used in the treatment of acid-peptic disorders may be divided
into two classes: agents that reduce intragastric acidity and agents
that promote mucosal defense.
7.1.
GENERAL PRINCIPLES IN THE TREATMENT OF
PEPTIC ULCER DISEASE
Although the pathogenesis of peptic ulcer disease is not fully
understood, several major causative factors are recognized:
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nonsteroidal anti-inflammatory drug (NSAID) use, infection with
Gram-negative Helicobacter pylori, increased hydrochloric acid
secretion, and inadequate mucosal defense against gastric acid.
Chronic infection with Helicobacter pylori is present in the great
majority of patients with recurrent non-NSAID-induced peptic
ulcers, and eradication of this organism greatly reduces the rate of
recurrence of ulcer in these patients. The regimens of choice consist
of a proton pump inhibitor plus a course of bismuth, tetracycline, and
metronidazole or a course of amoxicillin plus clarithromycin.
Compared with H2 antagonists, proton pump inhibitors afford
more rapid symptom relief and faster ulcer healing for duodenal
ulcers and, to a lesser extent, gastric ulcers. All of the pump
inhibitors heal more than 90% of duodenal ulcers within 4 weeks and
a similar percentage of gastric ulcers within 6–8 weeks.
1. H. pylori-associated ulcers: For H. pylori-associated ulcers,
there are two therapeutic goals: to heal the ulcer and eradicate the
organism. The most effective regimens for H. pylori eradication are
combinations of two antibiotics and a proton pump inhibitor. PPIs
promote eradication of H. pylori through several mechanisms: direct
antimicrobial properties (minor); raising intragastric pH and lowering
the minimal inhibitory concentrations of antibiotics against H. pylori.
The best treatment regimen consists of a 10-14 day regimen of
"Triple therapy": a proton pump inhibitor twice daily;
clarithromycin, 500 mg twice daily; and amoxicillin, 1 g twice daily.
For patients who are allergic to penicillin, metronidazole, 500 mg
twice daily, should be substituted for amoxicillin. After completion
of triple therapy, the proton pump inhibitor should be continued once
daily for a total of 4-6 weeks to ensure complete ulcer healing.
2. NSAID-associated ulcers: For patients with ulcers caused by
aspirin or other NSAIDs, either H2 antagonists or proton pump
inhibitors provide rapid ulcer healing so long as the NSAID is
discontinued; continued use of the NSAID impairs ulcer healing.
Treatment with a once-daily proton pump inhibitor promotes ulcer
healing despite continued NSAID therapy.
PPIs are also given to prevent ulcer complications from NSAIDs.
Asymptomatic peptic ulceration develops in 10–20% of people
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taking frequent NSAIDs, and ulcer-related complications (bleeding,
perforation) develop in 1–2% of persons per year. Proton pump
inhibitors taken once daily are effective in reducing the incidence of
ulcers and ulcer complications in patients taking aspirin or other
NSAIDs.
3. Prevention of rebleeding from peptic ulcers: In patients with
acute gastrointestinal bleeding due to peptic ulcers, the risk of
rebleeding from ulcers that have a visible vessel or adherent clot is
increased. Rebleeding in this subset of high-risk ulcers is reduced
significantly with use of proton pump inhibitors administered for 3–5
days either as high-dose oral therapy (eg, omeprazole, 40 mg orally
twice daily) or as a continuous intravenous infusion. It is believed
that an intragastric pH higher than 6 may enhance coagulation and
platelet aggregation. The optimal dose of intravenous proton pump
inhibitor needed to achieve and maintain this level of near-complete
acid inhibition is unknown; however, initial bolus administration
(60–80 mg) followed by constant infusion (8 mg/h) commonly is
recommended.
Pharmacological Therapeutic Classification of Drugs
Treatment approaches are:
1) drugs to eradicate the H. pylori infection;
2) agents to reduce secretion of gastric acid with the use of H2receptor antagonists or proton pump ingibitors;
3) provision of agents that protect the gastric mucosa from
damage, such as misoprostol and sucralfate.
Gastric acid secretion by parietal cells of the gastric mucosa is
stimulated by
– gastrin (a stimulatory hormone);
– acetylcholine (a stimulatory neurotransmitter);
– histamine (a stimulatory local hormone);
– prostaglandins E2 and I2 (local hormones that inhibit acid
secretion).
The receptor-mediated binding of acetylcholine, histamine or
gastrin results in the activation of protein kinases which, in turn,
stimulate the H+/K+ adenosine triphosphatase (ATPase) proton pump
105
to secrete hydrogen ions in exchange for K+ into the lumen of the
stomach. A Cl- channel couples chloride efflux to the release of H+.
In contrast, receptor binding of prostaglandin E2 and somatostatin
diminish gastric acid production. Histamine binding causes
activation of adenylyl cyclase, whereas binding of prostaglandin E2
inhibits this enzyme. Gastrin and acetylcholine act by inducing an
increase in intracellular calcium levels.
7.1.1. INHIBITORS OF THE H+/K+-ATPase PROTON PUMP
Omeprazole is the first of a class of drugs that bind to the H+/K+ATPase enzyme system (proton pump) of the parietal cell, thereby
suppressing secretion of hydrogen ions into the gastric lumen. The
membrane-bound proton pump is the final step in the secretion of
gastric acid. Four additional PPIs are now available: lansoprazole,
rabeprazole, pantoprazole, and esomeprazole. These agents are
prodrugs with an acid-resistant enteric coating to protect them from
premature degradation by gastric acid. The coating is removed in the
alkaline duodenum, and the prodrug, a weak base, is absorbed and
transported to the parietal cell canaliculus. There, it is converted
to the active form, which reacts with a cysteine residue of
the H+/K+-ATPase, forming a stable covalent bond. It takes about 18
hours for the enzyme to be resynthesized. At standard doses, all PPIs
inhibit both basal and stimulated gastric acid secretion by more than
90%. Acid suppression begins within 1-2 hours after the first dose of
lansoprazole and slightly earlier with omeprazole. There is also an
oral product containing omeprazole combined with sodium
bicarbonate for faster absorption. It is available in powder to be
dissolved in water and taken orally as well as in capsule form.
Therapeutic uses: The superiority of the PPIs over the H2 blockers
for suppressing acid production and healing peptic ulcers has made
them the preferred drugs for treating erosive esophagitis and active
duodenal ulcer and for long-term treatment of pathologic
hypersecretory conditions (for example, Zollinger-Ellison syndrome,
in which a gastrin-producing tumor causes hypersecretion of HCl).
They are approved for the treatment of GERD. Clinical studies have
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shown that PPIs reduce the risk of bleeding from an ulcer caused by
aspirin and other NSAIDs. They are also successfully used with
antimicrobial regimens to eradicate H. pylori. For maximum effect,
PPIs should be taken 30 minutes before breakfast or the largest meal
of the day. If an H2-receptor antagonist is also needed, it should be
taken well after the PPI for best effect. The H2 antagonists will
reduce the activity of the proton pump, and PPIs require active
pumps to be effective. In patients with GERD in whom once-daily
PPI is partially effective, increasing to a twice-daily regimen or
keeping the PPI in the morning and adding an H2 antagonist in the
evening may improve symptom control.
Pharmacokinetics: All these agents are delayed-release
formulations and are effective orally. Some are also available for
intravenous injection. Metabolites of these agents are excreted in
urine and feces.
Adverse Effects
The PPIs are generally well tolerated, but concerns about longterm safety have been raised due to the increased secretion of gastrin.
Omeprazole inhibits the metabolism of warfarin, phenytoin,
diazepam, and cyclosporine. However, drug interactions are not a
problem with the other PPIs. Prolonged therapy with agents that
suppress gastric acid, such as the PPIs and H2 antagonists, may result
in low vitamin B12, because acid is required for its absorption. Some
studies have reported an increased risk of both community-acquired
respiratory infections and nosocomial pneumonia among patients
taking proton pump inhibitors.
7.1.2. H2-RECEPTOR ANTAGONISTS
Although antagonists of the histamine H 2 receptor block
electively the actions of histamine at all H 2 receptors in the
stomach, blood vessels, and other sites, their chief clinical use is to
inhibit gastric acid secretion, being particularly effective against
nocturnal acid secretion. By competitively blocking the binding of
histamine to H2 receptors, these agents reduce the intracellular
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concentrations of cyclic adenosine monophosphate and, thereby,
secretion of gastric acid. The four drugs used in Ukraine now:
cimetidine, ranitidine, famotidine, and nizatidine potently inhibit
(greater than 90 %) basal, food-stimulated, and nocturnal secretion
of gastric acid after a single dose. Cimetidine is the prototype
histamine H2-receptor antagonist; however, its utility is limited by
its adverse effect profile and drug interactions.
The common indications are gastroesophageal disease, peptic
ulcer desease, nonulcer dyspepsia, prevention of bleeding from
stress-related gastritis. H2 blockers are given orally, distribute
widely throughout the body (including into breast milk and across
the placenta), and are excreted mainly in the urine. Cimetidine
normally has a short serum half-life, which is increased in renal
failure.
Approximately 30% of a dose of cimetidine is slowly inactivated
by the liver's microsomal mixed-function oxygenase system and
can interfere in the metabolism of many other drugs; the other 70%
is excreted unchanged in the urine. The dosage of all these drugs
must be decreased in patients with hepatic or renal failure.
Cimetidine inhibits cytochrome P450 and can slow metabolism
(and, thus, potentiate the action) of several drugs (for example,
warfarin, diazepam, phenytoin, quinidine, carbamazepine,
theophylline, and imipramine), sometimes resulting in serious
adverse clinical effects.
Therapeutic uses: Compared to cimetidine, ranitidine is longer
acting and is five- to ten-fold more potent. Ranitidine has minimal
side effects and does not produce the antiandrogenic or prolactinstimulating effects of cimetidine. Unlike cimetidine, it does not
inhibit the mixed-function oxygenase system in the liver and, thus,
does not affect the concentrations of other drugs. Famotidine is
similar to ranitidine in its pharmacologic action, but it is 20–50
times more potent than cimetidine, and 3–20 times more potent than
ranitidine. Nizatidine is similar to ranitidine in its pharmacologic
action and potency. In contrast to cimetidine, ranitidine, and
famotidine, which are metabolized by the liver, nizatidine is
eliminated principally by the kidney. Because little first-pass
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metabolism occurs with nizatidine, its bioavailability is nearly
100 %. No intravenous preparation is available.
Adverse Effects
The most common side effects are headache, dizziness, diarrhea,
and muscular pain. Other central nervous system effects (confusion,
hallucinations) occur primarily in elderly patients or after
intravenous administration. Cimetidine can also have endocrine
effects, because it acts as a nonsteroidal antiandrogen. These effects
include gynecomastia, galactorrhea (continuous release/discharge of
milk), and reduced sperm count. Except for famotidine, all these
agents inhibit the gastric first-pass metabolism of ethanol. Drugs,
such as ketoconazole, which depend on an acidic medium for gastric
absorption, may not be efficiently absorbed if taken with one of these
antagonists.
7.1.3. ANTACIDS
Antacids are simple physical agents that react with protons in the
lumen of the gut. Some antacids (aluminum-containing antacids)
may also stimulate the protective functions of the gastric mucosa.
The antacids effectively reduce the recurrence rate of peptic ulcers
when used regularly in the large doses needed to significantly raise
the stomach pH.
The antacids differ mainly in their absorption and effect on stool
consistency. The most popular antacids (Maalox, Almagel) consist of
magnesium hydroxide (Mg[OH]2) and aluminum hydroxide
(AI[OH]3), and Phosphalugel consists aluminum phosphate. Neither
of these weak bases is significantly absorbed from the bowel.
Magnesium hydroxide has a strong laxative effect, while aluminum
hydroxide has a constipating action. These drugs are available as
single-ingredient products and as combined preparations. Calcium
carbonate and sodium bicarbonate are also weak bases, but they
differ from aluminum and magnesium hydroxides in being absorbed
from the gut. Because of their systemic effects, calcium and
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bicarbonate salts are less popular as antacids than the magnesium and
aluminum compounds listed.
Adverse effects : Diarrhea, constipation, phosphate depletion
resulting in muscular weakness, osteoporrosis, and renal dysfunction.
7.1.4. MUCOSAL PROTECTIVE AGENTS
These compounds, known as cytoprotective compounds, have
several actions that enhance mucosal protection mechanisms, thereby
preventing mucosal injury, reducing inflammation, and healing
existing ulcers.
Sucralfate: This complex of aluminum hydroxide and sulfated
sucrose binds to positively charged groups in proteins of both normal
and necrotic mucosa. By forming complex gels with epithelial cells,
sucralfate creates a physical barrier that impairs diffusion of HCl and
prevents degradation of mucus by pepsin and acid. It also stimulates
prostaglandin release as well as mucus and bicarbonate output, and it
inhibits peptic digestion. By these and other mechanisms, sucralfate
effectively heals duodenal ulcers and is used in long-term
maintenance therapy to prevent their recurrence. Because it requires
an acidic pH for activation, sucralfate should not be administered
with H2 antagonists or antacids. Little of the drug is absorbed
systemically. It is very well tolerated, but it can interfere with the
absorption of other drugs by binding to them. This agent does not
prevent NSAID-induced ulcers, nor does it heal gastric ulcers.
Sucralfate must be taken four times daily.
Adverse Effects
Sucralfate is too insoluble to have significant systemic effects
when taken by the oral route; toxicity is very low. Constipation
occurs in 2% of patients due to the aluminum salt. Because a small
amount of aluminum is absorbed, it should not be used for prolonged
periods in patients with renal insufficiency. Patients complains dry
mouth sometimes.
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Sucralfate may bind to other medications, impairing their
absorption.
Bismuth subsalicylate: Preparations of this compound effectively
heal peptic ulcers. In addition to their antimicrobial actions, they
inhibit the activity of pepsin, increase secretion of mucus, and
interact with glycoproteins in necrotic mucosal tissue to coat and
protect the ulcer crater.
Synthetic prostaglandins: Prostaglandin E2, produced by the
gastric mucosa, inhibits secretion of HCl and stimulates secretion of
mucus and bicarbonate (cytoprotective effect). A deficiency of
prostaglandins is thought to be involved in the pathogenesis of peptic
ulcers. Misoprostol, a stable analog of prostaglandin E1, as well as
some PPIs, are approved for prevention of gastric ulcers induced by
NSAIDs. It is less effective than H2 blockers and the PPIs for acute
treatment of peptic ulcers. Although misoprostol has cytoprotective
actions, it is clinically effective only at higher doses that diminish
gastric acid secretion. Routine prophylactic use of misoprostol may
not be justified except in patients who are taking NSAIDs and are at
high risk of NSAID-induced ulcers, such as the elderly or patients
with ulcer complications. Like other prostaglandins, misoprostol
produces uterine contractions and is contraindicated during
pregnancy. Dose-related diarrhea and nausea are the most common
adverse effects and limit the use of this agent.
7.1.5. UPPER GASTROINTESTINAL PROMOTILITY DRUGS
Some diseases (diabetes and others) that damage nerves to the
viscera frequently cause a marked loss of motility in the esophagus
and stomach, resulting in gastric paralysis (gastroparesis).
Gastroparesis is associated with delayed stomach emptying, nausea,
and severe bloating. Metoclopramide and cisapride are able to
stimulate motility in gastroparesis. Metoclopramide probably acts as
an acetylcholine facilitator and dopamine receptor antagonist in the
enteric nervous system (ENS). Cisapride appears to act as a 5-HT 4
agonist in the ENS. The "prokinetic" action of metoclopramide is
also of some value in preventing emesis following surgical
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anesthesia and emesis induced by cancer chemotherapeutic drugs.
Adverse effects of metoclopramide include induction of
Parkinsonism and other extrapyramidal effects. Cisapride in high
concentrations is associated with long-QT syndrome and has caused
fatal arrhythmias. For this reason, cisapride is now available only on
a limited basis.
A variety of drugs have been found to be of some value in the
prevention and treatment of vomiting, especially cancer
chemotherapy-induced vomiting. In addition to metoclopramide,
useful antiemetic drugs include dexamethasone; some HI antihistamines; several phenothiazines; the 5-HT 3 inhibitors; and a few
neuroleptics. The 5-HT 3 inhibitors, ondansetron, granisetron, and
dolasetron, are extremely useful in preventing nausea aud vomiting
after general anesthesia and in patients receiving cancer
chemotherapy.
7.2.
DRUGS AFFECTING OTHER GIT ORGANS
Pancreatic Enzyme Replacements: Steatorrhea, a condition of
decreased fat absorption coupled with an increase in stool fat
excretion, results from inadequate pancreatic secretion of lipase. The
abnormality of fat absorption can be significantly relieved by oral
administration of pancreatic lipase (pancrelipase) obtained from pigs.
Pancreatic lipase is inactivated at a pH below 4.0; thus, up to 90% of
an administered dose will be destroyed in the stomach, unless the pH
is raised with antacids or drugs that reduce acid secretion.
Laxatives: Laxatives increase the probability of a bowel
movement by several mechanisms: an irritant or stimulant action on
the bowel wall; a bulk-forming action on the stool that evokes reflex
contraction of the bowel; a softening action on hard or impacted
stool; and a lubricating action that eases passage of stool through the
rectum.
Antidiarrheal agents: The most effective antidiarrheal drugs are
the opioids and derivatives of opioids that have been selected for
maximal antidiarrheal and minimal CNS effect. Of the latter group,
the most important are diphenoxylate and loperamide, meperidine
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analogs with very weak analgesic effects. Difenoxin, the active
metabolite of diphenoxylate, is also available as a prescription
medication. Diphenoxylate is formulated with antimuscarinic
alkaloids to reduce the already minimal likelihood of abuse;
loperamide is formulated alone and sold over the counter as such.
Drugs that inhibit the formation of gallstones: The formation of
cholesterol gallstones cau be inhibited by several drugs, though none
are dramatically effective. Such drugs include the bile acid
derivatives (chenodiol and ursodiol). Chenodiol appears to reduce the
secretion of bile acids by the liver, while the mechanism of action of
ursodiol is unknown.
Ursohol (ursodeoxycholic acid) is a naturally occurring bile acid
that makes up less than 5% of the circulating bile salt pool in humans
and a much higher percentage in bears. After oral administration, it is
absorbed, conjugated in the liver with glycine or taurine, and
excreted in the bile. Conjugated ursodiol undergoes extensive
enterohepatic recirculation. The serum half-life is approximately 100
hours. With long-term daily administration, ursodiol constitutes 30–
50% of the circulating bile acid pool. A small amount of unabsorbed
conjugated or unconjugated ursodiol passes into the colon where it is
either excreted or undergoes dehydroxylation by colonic bacteria to
lithocholic acid, a substance with potential hepatic toxicity.
The solubility of cholesterol in bile is determined by the relative
proportions of bile acids, lecithin, and cholesterol. Although
prolonged ursodiol therapy expands the bile acid pool, this does not
appear to be the principal mechanism of action for dissolution of
gallstones. Ursodiol decreases the cholesterol content of bile by
reducing hepatic cholesterol secretion. Ursodiol also appears to
stabilize hepatocyte canalicular membranes, possibly through a
reduction in the concentration of other endogenous bile acids or
through inhibition of immune-mediated hepatocyte destruction.
Ursodiol is used for dissolution of small cholesterol gallstones in
patients with symptomatic gallbladder disease who refuse
cholecystectomy or who are poor surgical candidates. At a dosage of
10 mg/kg/d for 12–24 months, dissolution occurs in up to half of
patients with small (≈ 5–10 mm) noncalcified gallstones. It is also
113
effective for the prevention of gallstones in obese patients
undergoing rapid weight loss therapy. Several trials demonstrate that
ursodiol 13–15 mg/kg/d is helpful for patients with early-stage
primary biliary cirrhosis, reducing liver function abnormalities
Adverse Effects
Ursodiol is practically free of serious adverse effects. Bile saltinduced diarrhea is uncommon. Unlike its predecessor,
chenodeoxycholate, ursodiol has not been associated with
hepatotoxicity.
8.
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
(NSAID)
Inflammation is a normal, protective response to tissue injury
caused by physical trauma, noxious chemicals, or microbiological
agents. Inflammation is the body's effort to inactivate or destroy
invading organisms, remove irritants, and set the stage for tissue
reparation. Normally, our immune system can differentiate between
self and non-self factors. Inflammatory responses occur in three
distinct temporal phases, each apparently mediated by different
mechanisms:
1. The acute phase is characterized by transient local vasodilation
and increased capillary permeability.
2. The delayed, subacute phase is characterized by infiltration of
leukocytes and phagocytic cells.
3. In the chronic proliferative phase, tissue degeneration and
fibrosis occur.
The NSAIDs including subclass of selective cyclooxygenase-2
(COX-2) inhibitors have anti-inflammatory (modifiers of the
inflammatory reaction) analgesic (reduction of certain types of pain,
especially inflammation induced) and antipyretic (lowering of body
temperature in case of fever) actions. All of the NSAIDs act by
inhibiting the synthesis of prostaglandins (PG). Thus, an
understanding of NSAIDs requires comprehension of actions and
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biosynthesis of prostaglandins from unsaturated fatty acid derivatives
containing 20 carbons that include a cyclic ring structure. PG's and
related compounds are produced in minute quantities by virtually all
tissues. They generally act locally on the tissues in which they are
synthesized, and they are rapidly metabolized to inactive products at
their sites of action. Prostaglandins of the E and F series evoke some
of the local and systemic manifestations of inflammation, such as
vasodilation, hyperemia, increased vascular permeability, swelling,
pain, and increased leukocyte migration. In addition, they intensify
the effects of inflammatory mediators, such as histamine, bradykinin,
and 5-hydroxytryptamine. Arachidonic acid, a 20-carbon fatty acid,
is the primary precursor of the prostaglandins and related
compounds. Arachidonic acid is present as a component of the
phospholipids of cell membranes. Free arachidonic acid is released
from tissue phospholipids by the action of phospholipase A2 and
other acyl hydrolases via a process controlled by hormones and other
stimuli.
There are two major pathways in the synthesis of the eicosanoids
from arachidonic acid: Cyclooxygenase- and Lipoxygenase
pathways.
PGs act primarily by inhibiting the cyclooxygenase enzymes, but
not the lipoxygenase enzymes. Cyclooxygenase-2 is a close
structural analog of COX-1 and, like the latter, catalyzes the
conversion of arachidonic acid to prostaglandin PgH2 via PgG2.
These isozymes are encoded by two different genes. COX-1 is
generally regarded to be constitutive and COX-2 inducible.
However, this is an oversimplification, since COX-2 is produced in
the kidney and brain, but is inducible in other sites, including those
that are inflamed, such as joints. Nearly all NSAIDs have a greater
selectivity for COX-I. They are used primarily for conditions which
are not considered inflammatory (for example, headache and
analgesia). Their unwanted side effect causing gastric damage is
linked to inhibition of COX-l, resulting in an inability to form
protective prostaglandins. This led to the search for a COX-2
inhibitor, commonly referred to as a "safe aspirin", reasoning that if
115
COX-1 in the stomach is unaffected by the new drug, then the
gastrointestinal effects would be minimized.
NSAIDs are a chemically heterogeneous group of compounds,
often chemically unrelated (although most of them are organic
acids), which nevertheless share certain therapeutic actions and
adverse effects. Acetylsalicylic acid (ASA) also inhibits COX
enzymes but in a manner which is molecularly distinct from the
competitive, reversible, active site inhibitors and is often
distinguished from the NSAIDs. Similarly, acetaminophen, which is
antipyretic and analgesic but largely devoid of antiinflammatory
activity, is also conventionally segregated from the group despite of
its sharing NSAID activity with other actions relevant to its clinical
action in vivo. General properties shared by ASA, the NSAIDs, and
acetaminophen as a class of COX inhibitors are considered first,
followed by determination of important differences among
representative drugs.
Picture 3 - Eicosanoid synthesis pathway
(by Charles R. Craig and others)
Salicylates and other similar agents used to treat rheumatic disease
share the capacity to suppress the signs and symptoms of
116
inflammation. These drugs also exert antipyretic and analgesic
effects, but it is their anti-inflammatory properties that make them
most useful in the management of disorders in which pain is
proportional to the intensity of the inflammatory process. ASA
(aspirin) has three therapeutic dose ranges: the low range
(< 300 mg/d) is effective in reducing platelet aggregation;
intermediate doses (300–2400 mg/d) have antipyretic and analgesic
effects; and high doses (2400–4000 mg/d) are used for their antiinflammatory effect. Aspirin is readily absorbed and is hydrolyzed in
blood and tissues to acetate and salicylic acid. Salicylate is a
reversible nonselective inhibitor of cyclooxygenase. Elimination of
salicylate is first-order at low doses, with a half-life of 3 NSAIDs are
a chemically heterogeneous group of compounds, often chemically
unrelated (although most of them are organic acids), which
nevertheless share certain therapeutic actions and adverse effects.
Acetylsalicylic acid (ASA) also inhibits COX enzymes but in a
manner which is molecularly distinct from the competitive,
reversible, active site inhibitors and is often distinguished from the
NSAIDs. Similarly, Acetaminophen, which is antipyretic and
analgesic but largely devoid of antiinflammatory activity, is also
conventionally segregated from the group despite of its sharing
NSAID activity with other actions relevant to its clinical action in
vivo. General properties shared by ASA, the NSAIDs, and
Acetaminophen as a class of COX inhibitors are considered first,
followed by determination of important differences among
representative drugs.5 hours. At high (anti-inflammatory) doses,
half-life increases to 15 hours or more and elimination becomes zeroorder. Excretion is facilitated via the kidneys.
The other NSAIDs are well absorbed after oral administration.
Ibuprofen has a half-life of about 2 hours, it is relatively safe, and is
the least expensive of the older, nonselective NSAIDs. Indomethacin
is a potent NSAID with increased toxicity. Naproxen and piroxicam
are noteworthy because of their longer half-lives (12–24 hours),
which permit less frequent dosing. These other NSAIDs are used for
the treatment of mild to moderate pain--and especially inflammatory
pain as seen in cases of rheumatoid arthritis and gout. COX-2
117
inhibitors are primarily used in inflammatory disorders. Selected
NSAIDs are also used to treat other conditions, including
dysmenorrhea, headache, and patent ductus arteriosus in premature
infants. Ketorolac is notable as a drug used mainly as a systemic
analgesic, but not as an anti-inflammatory drug (though it has typical
nonselective NSAID properties). It is the only NSAID available in a
parenteral formulation.
Although all NSAIDs are not approved for the treatment of whole
range of rheumatic diseases, all are probably effective in rheumatoid
arthritis, seronegative spondyloarthropathies (e.g., psoriatic arthritis
and arthritis associated with inflammatory bowel disease),
osteoarthritis, localized musculoskeletal syndromes (eg, sprains and
strains, low back pain), and gout (except tolmetin, which appears to
be ineffective in gout). Since aspirin, the original NSAID, has a
number of adverse effects, many other NSAIDs have been developed
in attempts to improve upon aspirin's efficacy and decrease its
toxicity.
8.1.
CLASSIFICATION OF NSAIDs
There are many classifications of this groop – by chemical
structure (derivatives), by mechanism of action (central or peripheral
action), by selectivness (selective or nonselective), by its negative
action at the joints, and so on. It is very important to remember about
pharmacokinetic and pharmacodynamic aspects of these drugs in the
practical use. This chemical diversity yields a broad range of
pharmacokinetic characteristics. Although there are many differences
in the kinetics of NSAIDs, they have some general properties in
common. All but one of the NSAIDs is a weak organic acid as an
exception, nabumetone, which is a ketone prodrug that is
metabolized to the acidic active drug. Most of these drugs are well
absorbed, and food does not substantially change their
bioavailability. Most of the NSAIDs are highly metabolized, some by
phase I followed by phase II mechanisms and others by direct
glucuronidation (phase II) alone. NSAID metabolism proceeds, in
large part, by way of the CYP3A or CYP2C families of P450
118
enzymes in the liver. While renal excretion is the most important
route for final elimination, nearly all undergo varying degrees of
biliary excretion and reabsorption (enterohepatic circulation). In fact,
the degree of lower gastrointestinal tract irritation correlates with the
amount of enterohepatic circulation. Most of the NSAIDs are highly
protein-bound (~ 98%), usually to albumin. Some of the NSAIDs
(e.g., ibuprofen) are racemic mixtures, while one, Naproxen, is
provided as a single enantiomer and a few have no chiral center (e.g.,
diclofenac).
All NSAIDs can be found in synovial fluid after repeated dosing.
Drugs with short half-lives remain in the joints longer than they
would be predicted from their half-lives, while drugs with longer
half-lives disappear from the synovial fluid at a rate proportionate to
their half-lives.
Various NSAIDs have additional possible mechanisms of action,
including inhibition of chemotaxis, down-regulation of interleukin-1
production, decreased production of free radicals and superoxide,
and interference with calcium-mediated intracellular events. ASA
irreversibly acetylates and blocks platelet cyclooxygenase, while
most non-COX-selective NSAIDs are reversible inhibitors.
Selectivity for COX-1 versus COX-2 is variable and incomplete
for the older members, but the highly selective COX-2 inhibitor,
celecoxib, is currently available, and other highly selective coxibs are
being developed. The highly selective COX-2 inhibitors do not affect
platelet function at their usual doses. In testing using human whole
blood, aspirin, indomethacin, piroxicam, and sulindac were
somewhat more effective in inhibiting COX-1; ibuprofen and
meclofenamate inhibited the two isozymes about equally. The
efficacy of COX-2-selective drugs equals that of the older NSAIDs,
while gastrointestinal safety may be improved. On the other hand,
highly selective COX-2 inhibitors may increase the incidence of
edema and hypertension.
The NSAIDs decrease the sensitivity of vessels to bradykinin and
histamine, affect lymphokine production from T lymphocytes, and
reverse the vasodilation of inflammation. To varying degrees, all
newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and
119
all (except the COX-2-selective agents and the nonacetylated
salicylates) inhibit platelet aggregation. NSAIDs are all gastric
irritants as well, although as a group the newer agents tend to cause
less gastric irritation than ASA. Nephrotoxicity has been observed
for all of the drugs for which extensive experience has been reported,
and hepatotoxicity can also occur with any NSAID. Nephrotoxicity
is due, in part, to interference with the autoregulation of renal blood
flow, which is modulated by prostaglandins.
Several NSAIDs (including acethilsalicylic acid) appear to reduce
the incidence of colon cancer when taken chronically. Several large
epidemiologic studies have shown a 50% reduction in relative risk
when the drugs are taken for 5 years or longer. The mechanism for
this protective effect is unclear.
8.2.
NONSELECTIVE NSAIDs
Acetylsalicylic acid (Aspirin)'s long use and availability without
prescription diminishes its glamour compared with that of the newer
NSAIDs. Aspirin is now rarely used as an anti-inflammatory
medication; it has been replaced by Ibuprofen and Naproxen, since
they are effective, are also available over the counter, and have good
to excellent safety records.
Salicylic acid is a simple organic acid. Sodium salicylate and
aspirin are equally effective anti-inflammatory drugs, though ASA
may be more effective as an analgesic. The salicylates are rapidly
absorbed from the stomach and upper small intestine, yielding a
peak plasma salicylate level within 1–2 hours. Aspirin is absorbed as
such and is rapidly hydrolyzed (serum half-life is 15 minutes) to
acetic acid and salicylate by esterases in tissue and blood. Salicylate
is bound to albumin, but the binding and metabolism of salicylates
are saturable so that the unbound fraction increases as total
concentration increases. Beyond a total body load of 600 mg,
increases in salicylate dosage increase salicylate concentration
disproportionately. As doses of aspirin increase, salicylate
elimination half-life increases from 3-5 hours (for 600 mg/d dosage)
to 12–16 hours (dosage ≥ 3.6 g/d). Alkalinization of the urine
120
increases the rate of excretion of free salicylate and its water-soluble
conjugates.
Mechanism of Action
A. Anti-inflammatory effects: Aspirin is a nonselective inhibitor
of both COX isoforms, but salicylate is much less effective in
inhibiting either isoform. Nonacetylated salicylates may work as
oxygen radical scavengers. Aspirin irreversibly inhibits COX and
inhibits platelet aggregation, while nonacetylated salicylates do not.
B. Analgesic effects: Aspirin is most effective in reducing pain of
mild to moderate intensity through its effects on inflammation and
because it probably inhibits pain stimuli at a subcortical site.
C. Antipyretic effects Aspirin's antipyretic effect is probably
mediated by both COX inhibition in the central nervous system and
inhibition of interleukin-1 (which is released from macrophages
during episodes of inflammation).
D. Antiplatelet effects: Aspirin irreversibly inhibits platelet COX,
so that aspirin's antiplatelet effect lasts 8-10 days (the life of the
platelet).
Therapeutic uses: Aspirin is employed for mild to moderate pain
of varied origin but is not effective for severe visceral pain. Aspirin
and other NSAIDs have been combined with opioid analgesics for
treatment of cancer pain, where their anti-inflammatory effects act
synergistically with the opioids to enhance analgesia. High-dose
salicylates are effective for treatment of rheumatic fever, rheumatoid
arthritis, and other inflammatory joint conditions.
Aspirin has antiplatelet-aggregation action by decreasing acticity
of tromboxan system and can be given to prevent of transient
ischemic attacks, unstable angina, and coronary artery thrombosis
with myocardial infarction.
The optimal analgesic or antipyretic dose of aspirin is less than
the 0.6-0.65 g oral dose commonly used. The anti-inflammatory
dose for children is 50–75 mg/kg/d in divided doses, and the average
starting anti-inflammatory dose for adults is 45 mg/kg/d in divided
doses.
121
Adverse Effects
At the usual dosage, aspirin's main adverse effects are gastric and
duodenal ulcers; hepatotoxicity, asthma, rashes, and renal toxicity
occur less frequently. A dose-related increase in fecal blood loss is
routinely associated with aspirin administration, although some
mucosal adaptation occurs in many patients, so that blood loss
declines back to baseline over 4–6 weeks.
With
higher
doses,
patients
may
experience
“salicylism” - vomiting, tinnitus, decreased hearing, and
vertigo - reversible by reducing the dosage. Still larger doses of
salicylates cause hyperpnea through a direct effect on the medulla. At
toxic salicylate levels, respiratory alkalosis followed by metabolic
acidosis (salicylate accumulation), respiratory depression, and even
cardiotoxicity and glucose intolerance can occur. Like other
NSAIDs, aspirin can cause elevation of liver enzymes (a frequent but
mild effect), hepatitis (rare), decreased renal function, bleeding,
rashes, and asthma.
The antiplatelet action of aspirin contraindicates its use by patients
with hemophilia. Although previously not recommended during
pregnancy, aspirin may be valuable in treating preeclampsiaeclampsia.
8.2.1. OTHER NONSELECTIVE DRUGS
Like aspirin, these agents may cause significant gastrointestinal
disturbance, but the incidence is lower than with aspirin. There is a
significant risk of renal damage with any of the NSAIDs, especially
in patients with preexisting renal disease. Since these drugs are
cleared by the kidney, renal damage results in higher, more toxic
serum concentrations. Phenylbutazone, an older NSAID, should not
be used chronically because it causes aplastic anemia and
agranulocytosis. Serious hematologic reactions have also been noted
with indomethacin.
1. Diclofenac: Diclofenac is a phenylacetic acid derivative that is
relatively nonselective as a COX inhibitor.
122
Adverse effects occur in approximately 20% of patients and
include gastrointestinal distress, occult gastrointestinal bleeding, and
gastric ulceration, though ulceration may occur less frequently than
with some other NSAIDs. A preparation combining diclofenac and
misoprostol decreases upper gastrointestinal ulceration but may
result in diarrhea. Another combination of diclofenac and
omeprazole was also effective with respect to the prevention of
recurrent bleeding, but renal adverse effects were common in highrisk patients. Diclofenac at a dose of 150 mg/d appears to impair
renal blood flow and glomerular filtration rate. Elevation of serum
aminotransferases may occur more commonly with this drug than
with other NSAIDs.
A 0.1% ophthalmic preparation is recommended for prevention of
postoperative ophthalmic inflammation and can be used after
intraocular lens implantation and strabismus surgery. A topical gel
containing 3% diclofenac is effective for solar keratoses. Diclofenac
in rectal suppository form can be considered a drug of choice for
preemptive analgesia and postoperative nausea. In Europe,
diclofenac is also available as an oral mouthwash and for
intramuscular administration.
1. Etodolac is a racemic acetic acid derivative with an
intermediate half-life. It is slightly more COX-2-selective than most
other NSAIDs, with a COX-2:COX-1 activity ratio of about 10.
Unlike many other racemic NSAIDs, etodolac does not undergo
chiral inversion in the body. The dosage of etodolac is 200-400 mg
three to four times daily. Etodolac provides good postoperative pain
relief after coronary artery bypass operations, although transient
impairment of renal function has been reported. There are no data to
suggest that etodolac differs significantly from other NSAIDs except
in its pharmacokinetic parameters, though it has been claimed to
cause less gastric toxicity in terms of ulcer disease than other
nonselective NSAIDs.
2. Although diflunisal is derived from salicylic acid, it is not
metabolized to salicylic acid or salicylate. It undergoes an
enterohepatic cycle with absorption of its glucuronide metabolite
followed by cleavage of the glucuronide to liberate again the active
123
moiety. Diflunisal is a subject to capacity-limited metabolism, with
serum half-lives at various dosages approximating that of salicylates.
In rheumatoid arthritis the recommended dosage is 500–1000 mg
daily in two split dosages. It is claimed to be particularly effective for
cancer pain with bone metastases and for pain control in dental (third
molar) surgery. A 2% diflunisal oral ointment is a clinically useful
analgesic for painful oral lesions.
Adverse effects: Because its clearance depends on renal function
as well as hepatic metabolism, diflunisal's dosage should be limited
in patients with significant renal impairment. Its adverse event
profile is similar to those of other NSAIDs; pseudoporphyria has also
been reported.
3. Fenoprofen, a propionic acid derivative, is the NSAID most
closely associated with interstitial nephritis and is rarely used. Its
other toxicities mirror those of other NSAIDs.
4. Flurbiprofen is a propionic acid derivative with a possibly more
complex mechanism of action than other NSAIDs. Hepatic
metabolism is extensive; its (R)(+) and (S)(-) enantiomers are
metabolized differently, and it does not undergo chiral conversion. It
does demonstrate enterohepatic circulation.
The efficacy of flurbiprofen at dosages of 200–400 mg/d is
comparable to that of aspirin and other NSAIDs in clinical trials for
patients with rheumatoid arthritis, ankylosing spondylitis, gout, and
osteoarthritis. It is also available in a topical ophthalmic formulation
for inhibition of intraoperative miosis. Flurbiprofen intravenously
has been found to be effective for perioperative analgesia in minor
ear, neck, and nose surgery and in lozenge form for sore throat.
Although its adverse effect profile is similar to that of other
NSAIDs in most ways, flurbiprofen is also associated rarely with
cogwheel rigidity, ataxia, tremor, and myoclonus.
5. Ibuprofen is a simple derivative of phenylpropionic acid. In
doses of about 2400 mg daily, ibuprofen is equivalent to 4 g of
aspirin in anti-inflammatory effect.
Oral ibuprofen is often prescribed in lower doses (<2400 mg/d), at
which it has analgesic but not anti-inflammatory efficacy. It is
available over the counter in low-dose forms under several trade
124
names. A topical cream preparation appears to be absorbed into
fascia and muscle; an (S) (-) formulation has been tested. Ibuprofen
cream was more effective than placebo cream for the treatment of
primary knee osteoarthritis. A liquid gel preparation of ibuprofen
400 mg provides prompt relief and good overall efficacy in
postsurgical dental pain. In comparison with indomethacin, ibuprofen
decreases urine output less and also causes less fluid retention than
indomethacin. Ibuprofen is effective in closing patent ductus
arteriosus in preterm infants with much the same efficacy and safety
as indomethacin. The oral and intravenous routes are equally
effective for this indication.
Adverse effects: Gastrointestinal irritation and bleeding occur,
although less frequently than with aspirin. The use of ibuprofen
concomitantly with aspirin may decrease the total anti-inflammatory
effect. The drug is relatively contraindicated in individuals with nasal
polyps, angioedema, and bronchospastic reactivity to aspirin. In
addition to the gastrointestinal symptoms (which can be modified by
ingestion with meals), rash, pruritus, tinnitus, dizziness, headache,
aseptic meningitis (particularly in patients with systemic lupus
erythematosus), and fluid retention have been reported. Interaction
with anticoagulants is uncommon.
The concomitant administration of ibuprofen antagonizes the
irreversible platelet inhibition induced by aspirin. Thus, treatment
with ibuprofen in patients with increased cardiovascular risk may
limit the cardioprotective effects of aspirin. Rare hematologic effects
include agranulocytosis and aplastic anemia. Effects on the kidney
(as with all NSAIDs) include acute renal failure, interstitial nephritis,
and nephrotic syndrome, but these occur very rarely. Finally,
hepatitis has been reported.
6. Indomethacin, introduced in 1963, 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. Probenecid prolongs indomethacin's
half-life by inhibiting both renal and biliary clearance. It differs
somewhat from other NSAIDs in its indications and toxicities.
125
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 has
been tried in numerous small or uncontrolled trials for many other
conditions, including Sweet's syndrome, juvenile rheumatoid
arthritis, pleurisy, nephrotic syndrome, diabetes insipidus, urticarial
vasculitis, postepisiotomy pain, and prophylaxis of heterotopic
ossification in arthroplasty. An ophthalmic preparation seems to be
efficacious for conjunctival inflammation and to reduce pain after
traumatic corneal abrasion. Gingival inflammation is reduced after
administration of indomethacin oral rinse. Epidural injections
produce a degree of pain relief similar to that achieved with
methylprednisolone in postlaminectomy syndrome.
Adverse effects: At higher dosages, at least a third of patients
have reactions to indomethacin requiring discontinuance. The
gastrointestinal effects may include abdominal pain, diarrhea,
gastrointestinal hemorrhage, and pancreatitis. Headache is
experienced by 15–25% of patients and may be associated with
dizziness, confusion, and depression. Rarely, psychosis with
hallucinations has been reported. Hepatic abnormalities are rare.
Serious hematologic reactions have been noted, including
thrombocytopenia and aplastic anemia. Hyperkalemia has been
reported and is related to inhibition of the synthesis of prostaglandins
in the kidney. Renal papillary necrosis has also been observed.
A number of interactions with other drugs have been reported.
7. Ketoprofen is a propionic acid derivative that inhibits both
COX (nonselectively) and lipoxygenase.. Concurrent administration
of probenecid elevates ketoprofen levels and prolongs its plasma
half-life.
The effectiveness of ketoprofen at dosages of 100–300 mg/d is
equivalent to that of other NSAIDs in the treatment of rheumatoid
arthritis, osteoarthritis, gout, dysmenorrhea, and other painful
conditions. In spite of its dual effect on prostaglandins and
leukotrienes, ketoprofen is not superior to other NSAIDs. Its major
adverse effects are on the gastrointestinal tract and the central
nervous system.
126
8. Ketorolac is an NSAID promoted for systemic use mainly as an
analgesic, not as an anti-inflammatory drug (although it has typical
NSAID properties). The 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, but an oral dose formulation is
available. When used with an opioid, it may decrease the opioid
requirement by 25–50%. An ophthalmic preparation is available for
ocular inflammatory conditions. Toxicities are similar to those of
other NSAIDs, although renal toxicity may be more common with
chronic use.
9. Meclofenamate and mefenamic acid inhibit both COX and
phospholipase A2. They are rarely used today.
10. Naproxen is a naphthylpropionic acid derivative. It is the only
NSAID presently marketed as a single enantiomer, and it is a
nonselective COX inhibitor. Naproxen's free fraction is significantly
higher in women than in men, although albumin binding is very high
in both sexes. Naproxen is effective for the usual rheumatologic
indications and is available both in a slow-release formulation and as
an oral suspension. A topical preparation and an ophthalmic solution
are also available.
The incidence of upper gastrointestinal bleeding in over-thecounter use is low but still doubles that of over-the-counter ibuprofen
(perhaps due to a dose effect). Rare cases of allergic pneumonitis,
leukocytoclastic vasculitis, and pseudoporphyria as well as the more
common NSAID-associated adverse effects have been noted.
11. Piroxicam, an oxicam, is a nonselective COX inhibitor that at
high concentrations also inhibits polymorphonuclear leukocyte
migration, decreases oxygen radical production, and inhibits
lymphocyte function. Its long half-life permits once-daily dosing.
Piroxicam can be used for the usual rheumatic indications.
Toxicity includes gastrointestinal symptoms (20% of patients),
dizziness, tinnitus, headache, and rash. When piroxicam is used in
dosages higher than 20 mg/d, an increased incidence of peptic ulcer
and bleeding is encountered. Epidemiologic studies suggest that this
127
risk is as much as 9.5 times higher with piroxicam than with other
NSAIDs.
12. 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 to 12–16 hours.
The indications and adverse reactions of sulindac are similar to
those of other NSAIDs. 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. It appears to inhibit the occurrence of gastrointestinal cancer
in rats. The latter effect may be caused by the sulfone rather than the
sulfide.
Adverse effects: Stevens-Johnson epidermal necrolysis syndrome,
thrombocytopenia, agranulocytosis, and nephrotic syndrome have all
been observed. Like diclofenac, sulindac may have some propensity
to cause elevation of serum aminotransferases; it is also sometimes
associated with cholestatic liver damage, which disappears or
becomes quiescent when the drug is stopped.
8.3.
COX-2-SELECTIVE INHIBITORS
The COX-2-selective inhibitors may have a reduced risk of
gastrointestinal effects, including gastric ulcers and serious
gastrointestinal bleeding. Celecoxib is a sulfonamide and may cause
a hypersensitivity reaction in patients who are allergic to other
sulfonamides.
1. Celecoxib is a highly selective COX-2 inhibitor – about 10–20
times more selective for COX-2 than for COX-1. Celecoxib is as
effective as other NSAIDs in rheumatoid arthritis and osteoarthritis,
and in trials it has caused fewer endoscopic ulcers than most other
NSAIDs. Because it is a sulfonamide, celecoxib may cause rashes. It
does not affect platelet aggregation. It interacts occasionally with
warfarin – as would be expected of a drug metabolized via CYP2C9.
The coxibs continue to be investigated to determine whether their
effect on prostacyclin production could lead to a prothrombotic state.
128
The frequency of other adverse effects approximates that of other
NSAIDs. Celecoxib causes no more edema or renal effects than other
members of the NSAID group, but edema and hypertension have
been documented.
2. Meloxicam is an enolcarboxamide related to piroxicam that has
been shown to preferentially inhibit COX-2 over COX-1, particularly
at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as the
other coxibs. 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. Its efficacy in this condition
and rheumatoid arthritis is comparable to that of other NSAIDs. It is
associated with fewer clinical gastrointestinal symptoms and
complications than piroxicam, diclofenac, and naproxen. Similarly,
while 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. Other toxicities are similar to those of other
NSAIDs.
3. Rofecoxib, a furanose derivative, is a potent, selective COX-2
inhibitor. Rofecoxib is approved for osteoarthritis and rheumatoid
arthritis, and it also appears to be analgesicand antipyretic – in
common with other NSAIDs. This drug does not inhibit platelet
aggregation and appears to have little effect on gastric mucosal
prostaglandins or lower gastrointestinal tract permeability. At high
doses it is associated with occasional edema and hypertension. Other
toxicities are similar to those of other coxibs.
8.4.
PRINCIPLES OF THE PRACTICAL USE
The choice of an NSAID thus requires a balance of efficacy, costeffectiveness, safety, and numerous personal factors (e.g., other
drugs also being used, concurrent illness, compliance, medical
insurance coverage), so that there is no best NSAID for all patients.
There may, however, be one or two best NSAIDs for a specific
person.
129
Contraindications and Drug Interactions: Co-morbid factors that
increase the risk of NSAID-induced GI bleeding include history of
ulcer disease, advanced age, poor health status, treatment with
certain drugs, and long duration of NSAID therapy, smoking, and
heavy alcohol use. Because of their renal effects, NSAIDs must be
used with caution in patients with renal impairment, heart failure,
hypertension, and edema. The use of NSAIDs is contraindicated in
persons who have had a hypersensitivity reaction to salicylates or
any other NSAIDs. Asthmatics are at particular risk for these
reactions. NSAIDs should be used during pregnancy only if the
potential benefit justifies the risk to the fetus. Because NSAIDs
decrease prostaglandin synthesis in the kidney, these drugs can
increase the nephrotoxicity of agents, such as aminoglycosides,
amphotericin B, cidofovir, cisplatin, cyclosporine, foscarnet,
ganciclovir, pentamidine, and vancomycin. NSAIDs can decrease the
renal excretion of drugs such as lithium. NSAIDs can decrease the
effectiveness of antihypertensive drugs, such as β-blockers and water
pills.
130
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131
CONTENTS
P.
1. GENERAL PRINCIPLES OF CLINICAL PHARMACOLOGY ........ 3
1.1. Principles of Pharmacokinetics and Pharmacodynamics .......... 3
1.2. Routes of Administration .......................................................... 5
1.3. Drugs Interections ..................................................................... 6
2. ANTIHYPERTENSIVE AGENTS ...................................................... 9
2.1. General Principles of Hypertention Treatment ......................... 9
2.2. Clinical Uses of Antihypertensive Drugs................................ 12
2.3. Classification of Antihypertensive Drugs ............................... 13
2.3.1. Diuretics ................................................................................. 15
2.3.2. Inhibitors of the Renin-Angiotensin System ......................... 18
2.3.3. Angiotensin II Receptor Antagonists ..................................... 26
2.3.4. Antiadrenergics Drugs ........................................................... 30
2.3.5. Calcium-Channel Blockers (the Calcium Slow Channel
Blocking Agents) ................................................................... 38
2.4. Second Line Therapy .............................................................. 41
2.4.1. Ganglionic Blocking Agents ................................................. 41
2.4.2. Alpha 1-Blockers .................................................................. 42
2.4.3. Vasodilators .......................................................................... 43
2.4.4. Centrally Acting Adrenergic Drugs ....................................... 45
2.4.5. Hypertensive Emergency ....................................................... 47
3. ANTIANGINAL DRUGS .................................................................. 48
3.1. General Principles in the Treatment of Ischemic Heart
Disease (IHD) ......................................................................... 48
3.2. Organic Nitrates ..................................................................... 52
3.3. Myocardial Infarction ............................................................ 57
4. ANTIHYPERLIPEDEMIC DRUGS .................................................. 58
4.1. Principles of Treatment in Accordance With the Types
of Dyslipidemia....................................................................... 59
4.2. HMG CoA Reductase Inhibitors ............................................ 62
4.3. Niacin (Nicotinic Acid)........................................................... 65
4.4. Fibric Acid Derivatives ( Fibrates ) ........................................ 66
4.5. Bile Acid Binding Resins........................................................ 68
4.6. Cholesterol Absorption Inhibitors .......................................... 69
4.7. Combination Drug Therapy ................................................... 70
5. DRUGS FOR ASTHMA OR COPD TREATMENT ......................... 71
5.1. General Principles in the Treatment of Bronchial
Obstructive Syndrome ............................................................ 72
132
5.2. Adrenomimetics ..................................................................... 73
5.3. Antimuscarinic Agents............................................................ 74
5.4. Corticostroids .......................................................................... 76
5.5. Mat Cell Stabilizers ................................................................ 78
5.6. Leukotriene Modulators .......................................................... 79
5.7. Methylxantine Drugs .............................................................. 79
6. GENERAL PRINCIPLES OF ANTIMICROBIAL THERAPY ........ 80
6.1. Bet-Lactam Compounds and Other Cell Wall Inhibitors........ 81
6.2. Protein Synthesis Inhibitors .................................................... 90
6.3. Miscellaneous Antibacterial Agents ....................................... 97
6.4. Antimicrobial Agents Affecting Topoisomerase .................... 98
6.5. Antifolate Drugs ................................................................... 100
7. DRUGS USED IN THE TREATMENT OF GIT DISORDERS ..... 103
7.1. General Principles in the Treatment of Peptic Ulcer
Disease ................................................................................. 103
7.1.1. Inhibitors of the H+/K+-ATPase Proton Pump ................... 106
7.1.2. H2-Receptor Antagonists ..................................................... 107
7.1.3. Antacids ............................................................................... 109
7.1.4. Mucosal Protective Agents .................................................. 110
7.1.5. Upper Gastrointestinal Promotility Drugs ........................... 111
7.2. Drugs Affecting Other GIT Organs ..................................... 112
8. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS ............... 114
8.1. Classification of NSAIDs ..................................................... 118
8.2. Nonselective NSAIDs ........................................................... 120
8.2.1. Other Nonselective Drugs .................................................... 122
8.3. COX-2-Selective Inhibitors .................................................. 128
8.4. Principels of the Practical Use .............................................. 129
References ............................................................................................. 131
Contents ................................................................................................. 132
133
Навчальне видання
Методичні вказівки
для самостійного вивчення курсу
«Клінічна фармакологія лікарськіх засобів, що
використовуються в лікуванні внутрішніх хвороб»
для іноземних студентів
спеціальності 7.110101 «Лікувальна справа»
денної форми навчання
(Англійською мовою)
Відповідальний за випуск І. Ю. Висоцький
Редактор С. В. Чечоткіна
Комп’ютерне верстання А. O. Рощупкін
Підписано до друку 17.08.2015, поз.
Формат 60х84/16. Ум. друк. арк. 7,91. Обл.-вид. арк. 8,20. Тираж 100 пр. Зам. №
Собівартість видання
грн к.
Видавець і виготовлювач
Сумський державний університет,
вул. Римського-Корсакова, 2, м. Суми, 40007
Свідоцтво суб’єкта видавничої справи ДК № 3062 від 17.12.2007.
134
Міністерство освіти і науки України
Міністерство охорони здоров’я України
Сумський державний університет
До друку та в світ
дозволяю на підставі
«Єдиних правил»
п. 2.6.14
Начальник організаційно-методичного
управління
В.Б. Юскаєв
CLINICAL PHARMACOLOGY OF DRUGS USED IN
TREATMENT OF INTERNAL DISSEASES
Клінічна фармакологія лікарськіх засобів що
використовуються в лікуванні внуришніх хвороб
Усі цитати, цифровий та
фактичний матеріал,
бібліографічні відомості перевірені,
запис одиниць відповідає стандартам
Укладач
Відповідальний за випуск
Директор
медичного інституту Сум ДУ
А.О. Рощупкін
І.Ю. Висоцький
В.А. Сміянов
135