Dyslipidemia, Hyperlipidemia, and
Hyperlipoproteinemia.
Antihyperlipidemic Drugs
Anticoagulants, Antiplatelets
and Thrombolytic drugs
• Dyslipidemia: aberrations in the level of serum lipids and/or lipoproteins.
• Can lead to negative cardiovascular events, specifically, atherosclerosis and CHD.
• Primary dyslipidemias result from genetic predisposition.
• Secondary dyslipidemias result from pathologic conditions or lifestyle choices.
• Hyperlipidemia: elevation of serum cholesterol, cholesterol esters, triglycerides, and/or phospholipids.
• Increases risk of CHD.
• Hypertriglyceridemia increases risk of pancreatitis.
Dr. Ahmed Belal
B.Sc. Pharm.; M.Sc. Pharm. Chem. ( University of Alexandria, Egypt)
• Hyperlipoproteinemia: elevation of the lipoproteins that transport lipids through the bloodstream.
• Involves elevated low-density lipoproteins (LDLs) or very low-density lipoproteins (VLDLs) and/or decreased
high-density lipoproteins (HDLs).
Ph. D. Chem. Biol. ( University of Alberta, Canada)
R. Ph. ( Alberta college of Pharmacists)
• Therapeutic approaches to the treatment of hyperlipidemia and hyperlipoproteinemia include:
• inhibiting intestinal reabsorption of bile acids (BAS).
• inhibiting triglyceride biosynthesis and VLDL formation (niacin).
• inhibiting intestinal absorption of dietary cholesterol (ezetimibe).
• stimulating serum triglyceride cleavage and clearance (fibrates).
• inhibiting de novo cholesterol biosynthesis (HMG-CoA reductase inhibitors).
Associate Prof. of Pharmaceutical Chemistry; Faculty of Pharmacy, University of
Alexandria.
abelaleg@gmail.com
abelal@ualberta.ca
ahmed.belal@alexu.edu.eg
Bile Acid Sequestrants (BAS)
• BAS are nonabsorbable anionic exchange resins that trade chloride anions
bound to strongly cationic centers for intestinal bile salts glycocholate and
taurocholate.
• Dietary and lifestyle modifications.
• Pharmacologic interventions.
• Bile salts have higher affinity for the resin’s cationic amines than chloride anion.
• Bile salts are held to (sequestered by) the resin through strong ion–ion bonds.
• Bound bile acids are excreted in the feces rather than being returned to the liver.
• Decrease Fat & Cholesterol Intake.
• Loss of hepatic return of bile acids stimulates 7α-hydroxylase-mediated oxidation of
hepatic cholesterol.
• Enhance Cholesterol Excretion.
• Resulting in a decrease in intracellular cholesterol concentration, which in turn
activates an increased hepatic uptake of cholesterol-containing LDL particles,
leading to fall in plasma LDL.
• Used to treat hypercholesterolemia
• Inhibit Cholesterol Biosynthesis.
• Increase HDL (good cholesterol).
• Decrease LDL (bad cholesterol) or increase their uptake by the liver.
3
Cholestyramine
HMG-CoA Reductase Inhibitors (HMGRIs) or Statins
Ezetimibe (Cholesterol absorption inhibitor)
• Ezetimibe selectively blocks a cholesterol-active transporting protein at
the intestinal brush border.
• Selectively inhibits 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.
• Due its modest LDL-lowering effects, ezetimibe is often used as an adjunct to
statin therapy or in statin-intolerant patients.
Clinical Applications
• Ezetimibe is marketed alone and in combination
with the statin prodrug simvastatin.
• The pure compound is generally well tolerated,
although it is not advised for use in patients with
moderate to severe hepatic dysfunction.
HO
H3C
SCoA
•
•
•
1,4-diaryl-β-lactam
structure is important
to activity
COOH
O
HMG-CoA
•
•
•
•
•
Cholesterol
HMG CoA
reductase
inhibitors
2 NADP+
2 NADPH
O
HMG-CoA
reductase CoA
HO
H3C
COOH
OH
Mevalonic acid
Statins are competitive inhibitors of HMGR, the rate-limiting enzyme in cholesterol biosynthesis.
Statins successfully compete with the endogenous 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
substrate for access to the HMGR active site.
The dihydroxyheptan(en)oic acid segment of the statins mimics the chemistry of HMG and binds
in a similar fashion to HMGR.
An ion–ion bond between anionic statins and cationic Lys735 is the anchoring interaction.
The remainder of the statin structure (ring component) binds to hydrophobic and polar residues in a
flexible receptor pocket.
Affinity is enhanced 1000- to 10,000-fold compared to HMG-CoA, ensuring effective enzyme
inhibition.
LDL reuptake receptor expression is augmented, leading to increased LDL clearance.
6
The two most potent statins (rosuvastatin, atorvastatin) also lower serum triglycerides.
Rosuvastatin
• Statins must be anionic to anchor to HMGR Lys735. The dihydroxyheptan(en)oic acid
segment is essential.
• Hydroxyls at chiral C3 and C5 have important interactions at HMGR and must have the
proper absolute configuration.
• C3 requires the R configuration.
• Optimal configuration at C5 depends on C6–C7 saturation status. Dihydroxyheptanoic
acid statins have 5R stereochemistry and dihydroxyheptenoic acids have the 5S
configuration.
• The ring component of statins is of two general types:
• Naturally occurring statins have a 2’,6’-dimethylhexahydronaphthylene ring system
substituted with a methylbutyrate ester at C8’.
• Addition of an α-CH3 to the methylbutyrate group (lovastatin vs. simvastatin) increases
activity two-fold.
Ester group is
important
Ether decreases
activity
Natural
Semi-synthetic
• Synthetic statins have heteroaromatic ring systems. Isopropyl (or cyclopropyl) and pfluorophenyl substituents contribute to receptor affinity.
• Statins with polar functional groups positioned to bind to Arg568 and Ser565
(rosuvastatin) show significant increases in affinity and potency.
• Studies have shown that statins with a lower hydrophobic character (such as rosuvastatin) are
more selective for liver cells, where most cholesterol synthesis takes place, and that
such statins have fewer side effects.
ü A polar sulphonamide group was added to rosuvastatin to make it more hydrophilic and
more tissue selective.
p-fluorophenyl cannot
be coplanar with
central aromatic ring
Five membered or
six membered
heterocyclic
Double bond has
optimal activity in
synthetic statins
Rosuvastatin is unique among the
statins in having an extra binding
interaction between the sulphone
group of the drug and Arg-568,
making it the most strongly bound
statin.
2 carbon
distance
between C5 and
ring system
Statins metabolism
• CYP3A4 and 2C9 metabolize some statins.
• With one exception (pravastatin), saturated
dihydroxyheptanoic acid statins are metabolized by
CYP3A4.
• Unsaturated dihydroxyheptenoic acids are metabolized
by CYP2C9.
• Pravastatin is CYP resistant. It is oxidized/decomposed in
gut and liver to a less active major metabolite
• CYP3A4:
• Catalyzes inactivating alicyclic hydroxylation and ω-1
hydroxylation of lovastatin and simvastatin acids.
• Catalyzes the aromatic hydroxylation of atorvastatin.
• These two metabolites are equally active with the
parent drug.
Statins metabolism
• CYP2C9:
• Catalyzes the N-demethylation of rosuvastatin.
• The metabolite retains activity but is
formed in low amounts (5% to 10% of the
dose).
• Catalyzes aromatic hydroxylation and Ndealkylation of fluvastatin.
• Catalyzes the inactivating aromatic
hydroxylation of pitavastatin.
• Pitavastatin toxicity can increase if
coadministered with CYP3A4 inhibitors.
• Competition for organic anion transporting
protein (OATP) 1B1 may be responsible.
• All statins can be glucuronidated at either the
original or the hydrolysis generated COOH prior to
biliary (predominant) or urinary excretion.
Physicochemical and pharmacokinetic Prop.
• Lipophilic statins (log P > 3) include fluvastatin, pitavastatin, atorvastatin, lovastatin, and simvastatin.
Carbon-rich ring systems override the impact of any polar substituent.
• Hydrophilic statins (log P < 1.5) include pravastatin and rosuvastatin. They are carbon-poor and contain a
polar functional group.
• Lipophilic, but not hydrophilic, statins are absorbed across gastrointestinal, hepatic, and muscle cell
membranes primarily by passive diffusion.
• Prodrug statins are unionized and have no affinity for OATP.
• Statins that are anionic at intestinal pH can be actively transported across gastrointestinal membranes by
OATP2B1.
Physicochemical and pharmacokinetic Prop.
• Hydrophilic statins are actively transported across hepatic membranes predominantly by OATP1B1.
• Lipophilic statins utilize this carrier system to lower extent.
• OATP2B1 on muscle cell membranes actively transport some anionic statins into myocytes. Muscle
toxicity can result.
• Atorvastatin, fluvastatin, and rosuvastatin have the highest affinity for muscle cell OATP2B1.
• Pitavastatin and pravastatin bind to OATP2B1 in intestine (pH 6.0), but not on muscle (pH 7.0)
• Hydrophilic statins (pravastatin, rosuvastatin) are considered among the most hepatoselective.
• Hydrophilic statins enter hepatocytes almost exclusively by one-way OATP1B1 carrier
mediated transport.
• Hydrophilic statins cannot exit hepatocytes by passive diffusion and are trapped at the site of
action.
• Fluvastatin is also highly hepatoselective.
• Adverse Effects
• They may elevate serum levels of hepatic enzymes and cause hepatitis.
• They may cause muscle weakness (myopathy).
• Side effects are thought to be caused by the inhibition of HMGR in other
tissues, particularly muscle cells, where a condition known as myalgia can
occur.
• A severe form of muscle toxicity is a condition known as rhabdomyolysis,
which can be fatal.
16
• Rosuvastatin bioavailability decreases in the presence of antacids
due to chelation of divalent and trivalent metal ions.
Niacin
• The liver normally uses circulating free fatty acids
as a major precursor for triglyceride synthesis.
• At gram doses, niacin strongly inhibits lipolysis
in adipose tissue, thereby reducing production
of free fatty acids.
• Pleiotropic Statins
• Statins are pleiotropic drugs that have multiple beneficial
effects.
• Statins decrease levels of C-reactive protein (CRP), a
major biomarker of inflammation, and they have shown
promise in the treatment of inflammation-based
diseases, including CAD and vascular dysfunction
secondary to diabetic insulin resistance.
• Lipophilic statins may have a positive impact on bone
density
• Statin–NSAID
cotherapy
has
demonstrated
a
chemoprotective effect for some cancers.
• Reduced liver triglyceride levels decrease hepatic
VLDL production, which in turn reduces LDL-C
plasma concentrations.
• Niacin must be anionic to be an effective antihyperlipidemic.
• The carboxylic acid is essential.
• Nonionizable amides (e.g., nicotinamide) are inactive.
• Essentially, any change made on the niacin structure results
in inactivation.
Fibrates
Clinical Applications:
• When used as an antihyperlipidemic, niacin is dosed up to 6 g/day. Niacin
nuclear receptor family that regulates lipid metabolism.
administered as vitamin B3 is dosed at 13 to 20 mg/day.
üNiacin induces cutaneous vasodilation when given in multigram doses (activates
phospholipase A2).
to
combating
• PPARs function as ligand-activated transcription factors.
• Upon
vasodilation
include
pretreatment
with
OTC
nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin or indomethacin.
üNSAIDs inhibit cyclooxygenase and block conversion of arachidonic acid
released by phospholipase A2 to PGD2.
binding
to
their
natural
ligands
(fatty
acids
or
eicosanoids)
or
antihyperlipidemic drugs, PPARs are activated.
üProstaglandin D2 (PGD2) is responsible for adverse effects.
üApproaches
• The peroxisome proliferator–activated receptors (PPARs) are members of the
• They then bind to peroxisome proliferator response elements (PPARα), which
ultimately leads to decreased triglyceride concentrations through increased
expression of lipoprotein lipase.
• Fenofibrate is more effective than gemfibrozil in lowering triglyceride levels.
• Fibrates also increase the level of HDL cholesterol
O
SAR
[Aromatic ring]-O-[Spacer group]
H3C
OH
CH3
Hydrolysis
• The pharmacophore for fibrates is phenoxyisobutyric acid.
• The fibrate anion predominates at pH 7.4.
• Fibrate esters must hydrolyze to release the active anion.
• PPARα is flexible. A spacer of up to three carbons between isobutyrate and aryloxy groups is
permitted.
• Spacer groups augment molecular lipophilicity and promote gastrointestinal and hepatic membrane
penetration.
Fenofibrate
prodrug
Propan-2-yl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate
Gemfibrozil
5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid
Anticoagulants, Antiplatelets and
Thrombolytics
• Blood Coagulation (Normal Hemostasis)
• There are 3 mechanisms that work together to stop the flow of
blood, namely: Vasoconstriction, platelet plug formation and
clotting of blood
1. Vasoconstriction
• Vasoconstriction of a damaged blood vessel slows the flow of blood
and thus helps to limit blood loss. This process is mediated by:
• Local controls. Vasoconstrictors such as thromboxane are released
at the site of the injury.
• Systemic control. Epinephrine released by the adrenal glands
stimulates general vasoconstriction.
•
•
•
•
2. Formation of a Platelet Plug.
When a blood vessel is damaged, the blood is exposed to collagen fibers
in the basement membrane of the vessel.
Platelets (thrombocytes) stick to collagen and become activated.
Activated platelets release chemicals such as adenosine diphosphate
(ADP), and thromboxane A2 (TXA2), that cause the aggregation of more
platelets to the site of injury.
Platelet aggregation results in the formation of a platelet plug, which acts
to stop the flow of blood from the broken vessel. (Note: Healthy vessels
secrete an enzyme called prostacyclin that functions to inhibit platelet
activation and aggregation).
3. Clotting of Blood
•
Blood clotting is the transformation of liquid blood into a semisolid gel. Blood contains about a
dozen clotting factors.
•
These factors are proteins that exist in the blood in an inactive state but can be activated when
tissues or blood vessels are damaged.
•
The activation of clotting factors occurs in a sequential manner.
•
The first factor in the sequence activates the second factor, which activates the third factor and so
on. This series of reactions is called the clotting cascade.
•
Control of the Clotting Cascade:
•
Thrombin is the key to the clotting mechanism, i.e. if thrombin is present then clotting will
proceed.
•
Thrombin is derived from an inactive precursor called prothrombin.
•
There are two pathways that lead to the conversion of prothrombin to thrombin; the intrinsic
pathway and the extrinsic pathway.
• Blood clots can be life-threatening if they form inappropriately in critical
locations.
1.
• Clots that block coronary arteries cause heart attacks, while clots that
block arteries in the brain cause stroke.
• Drugs that retard the blood clot formation, “anticoagulants”, are used to
prevent the occurrence or enlargement of venous thrombosis and
embolism.
Anticoagulants; inhibit the action of the coagulation factors (heparin) or
interfere with the synthesis of the coagulation factors (for example, vitamin K
antagonists such as warfarin).
a) Coumarin derivatives: Warfarin
b) Heparin-based: Fondaparinux
c) Direct Thrombin Inhibitors (DTIs): Dabigatran etexilate
d) Direct Factor Xa Inhibitors: Rivaroxaban
2.
Antiplatelets;
• Drugs that interfere with the synthesis or activity of the mediators of
platelet aggregation, “antiplatelet drugs”, are used to prevent and treat
arterial thromboembolic disorders.
a) COX-1 inhibitor: Aspirin
• Drugs that can mediate the removal of clots, "clot busters, fibrinolytics,
thrombolytic", are used in cases of heart attack and stroke to decrease
the damage caused by the clot.
d) GP IIb/IIIa antagonists: Tirofiban
b) PDE3 inhibitors: Cilostazol and Dipyridamole
c) P2Y purinergic receptor inhibitors: Clopidogrel and Ticagrelor
3.
Thrombolytics: Urokinase, Streptokinase, Alteplase
• Vitamin K is essential for the post translation carboxylation of glutamic acid to
γ-carboxyglutamic acid.
• γ-carboxyglutamic acid is needed for the activation factors II, VII, IX, and X
• Warfarin blocks the interconversion of vitamin K and vitamin K 2,3epoxide (inhibit vitamin K reductase),
• specifically preventing the reduction of vitamin K 2,3-epoxide to vitamin K
quinone, the rate limiting step in the recycling of vitamin K.
• The onset of action of warfarin is delayed (3 to 5 days) until clotting factors
already present are cleared (slow acting).
• They are taken orally in small doses for long-term control of blood clotting.
O
Warfarin
4-Hydroxy-3-(3-oxo-1-phenylbutyl)- 2H-chromen-2-one
O
O
OH
• Heparin is a natural-occurring polysulfated polysaccharide found in the mucosal
tissues, produced primarily in the liver and lung (usually obtained from pigs or
cows) .
• Various forms of heparin-based products exist including:
üunfractionated heparin (UFH),
ülow molecular weight heparin (LMWH),
üsynthetic pentasaccharide fondaparinux.
• Heparin-based drugs exist as polysulfate ions at physiological pH and may
appear as various salts (e.g., Na+, Ca2+, Li+).
• Heparin-based anticoagulants for human use are all water-soluble sodium salts
administered parenterally (IV, SC).
)LJXUH6WUXFWXUHRISURWKURPELQ7KURPELQLVOLEHUDWHGWKURXJKWKHFOHDYDJHRIWKH$UJ7KUDQG$UJ
SHSWLGHERQGV LQGLFDWHGZLWKVWDUV 7KHȖFDUER[\JOXWDPDWHUHVLGXHVDUHLQWKHUHOHDVHG1WHUPLQDOSRUWLRQRISUR
DQGDUHQRWSDUWRIWKURPELQ7KH$DQG%FKDLQVRIWKURPELQDUHMRLQHGE\DGLVXOILGHERQG
• Cleavage occurs at two locations in prothrombin resulting in thrombin fragments
together by a disulfide bond (Fig. 16.2).
• Thrombin’s function is twofold: (1) catalyze the conversion of fibrinogen to solub
fibrin (fibrin monomer) and (2) catalyze the conversion of factor XIII to XIIIa (a
transamidase) which converts soluble fibrin to cross-linked insoluble fibrin (Fig. 1
• The cross-linking involves amide formation (isopeptide bond) between a side cha
amine of a lysine and a side chain carboxyl of a glutamine from separate soluble
• Heparin-based products cause a conformational change in antithrombin III
(AT or ATIII) peptide through ion–ion bond
• The conformationally modified AT exhibits an accelerated binding to thrombin
and factor Xa.
• Heparin is then released from the AT~thrombin/AT~factor Xa complex leaving an
inactive form of thrombin and/or factor Xa (heparin is a catalyst).
• Original lead was hirudin isolated from
Hirudo medicinalis (medical leech)
Fondaparinux
• LMWHs exhibit selectivity toward factor Xa with less binding to thrombin
• Fondaparinux does not bind to thrombin but only inactivates Xa
• Dabigatran etexilate is a nonpeptidomimetic orally active DTI.
• Dabigatran is bound to thrombin through
the active site (catalytic site) of thrombin
(univalent binding).
Prodrug
• DTIs are usually capable of binding to
both free and fibrin-bound thrombins.
• Dabigatran is a reversible DTI
Ethyl N-[(2-{[(4-{N'-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-methyl-1
H-benzimidazol-5-yl)carbonyl]-N-2-pyridinyl-β-alaninate
Morpholinone greatly improves activity versus morpholine, piperazine, or pyrrolidinone
• FXa inhibitors such as rivaroxaban, are capable of inhibiting both free
(prothrombinase) as well as clot-bound FXa.
• The prothrombinase complex consists of FXa, factor Va, prothrombin, and
Ca2+, on a phospholipid surface.
• The FXa inhibitors are highly specific inhibiting at a single site, the
convergent step of the intrinsic and extrinsic pathways.
• It does not interfere with existing thrombin levels, thus improving safety.
• The direct FXa inhibitors are reversible, highly selective, and orally active
drugs.
(S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)
phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
The four classes of anticoagulants often have overlapping treatment
indications, which include:
• prevention/treatment of Venous thromboembolism (VTE)
• deep vein thrombosis (DVT)
• Pulmonary embolism (PE)
Acetylsalicylic acid (Aspirin)
• Aspirin is an irreversible inhibitor of platelet COX-1 enzyme, thus inhibiting TXA2
synthesis.
• Platelet aggregation can
be activated by vascular
wall defect and the release
of factors, which bind to GP
receptors.
• Aggregation can be
stimulated
through
secondary
chemical
messengers such as
thromboxane
A2
(TXA2), serotonin (5HT),
thrombin,
and
adenosine diphosphate
(ADP) which recruits
additional platelets, thus
amplifying
the
aggregation process.
• Of the various phosphodiesterases, PDE3 specifically
catalyzes the hydrolysis of cyclic adenosine monophosphate
(cAMP) to 5’-AMP which is a potent inducer of platelet
aggregation.
• Both drugs inhibit PDE3, thus increasing the level of cAMP in
platelets.
• Both drugs inhibit adenosine reuptake, thus increasing
adenosine binding to adenosine A2 receptors stimulating
cAMP synthesis.
• An increase in cAMP results in an increase in the active form
of protein kinase A (PKA), which is directly related with an
inhibition in platelet aggregation.
• Dipyridamole is used in combination with aspirin to treat
thrombosis.
• Also used in combination with warfarin in treating patients
with prosthetic heart valves.
• Cilostazol is approved for treating intermittent claudication.
• Off-label use of cilostazol includes prevention of secondary
strokes and intracranial atherosclerosis.
• Acetylation occurs on a serine residue deactivating the platelet for the life of this
platelet (7 to 10 days)
• In higher doses, COX-2 in the vessel wall is inhibited, decreasing production
of PGI2. This counteracts the cardiovascular benefits of platelet COX-1 inhibition.
Cilostazol is extensively metabolized (11 metabolites are known). The two major
metabolites exhibit activity.
•
Cilostazol
•
Dipyridamole
Cilostazol has a black box warning
suggesting a decrease in survival in
patients with class III/IV congestive
heart failure and is therefore
contraindicated with patients with
congestive heart failure.
This
increase
in
extracellular
adenosine
has
the
favorable
consequence of enhancing antiplatelet
and
vasodilatory
effects,
while
diminishing the positive inotropic
response caused by PDE3 inhibition
in the heart.
P2Y Purinergic Receptor Inhibitors
• ADP binds to the P2Y purinergic receptors on the platelet surface activating this
G protein–coupled receptor.
• Binding to P2Y12 sustains platelet aggregation by inhibiting adenylyl cyclase
resulting in a decrease in cAMP.
• Clopidogrel belongs to thienopyridine-class of antiplatelet agent
• It is a prodrug which following metabolic activation (CYP oxidation) yields
irreversible inhibitor of P2Y12.
• The thio metabolite bind irreversibly with a cysteine, thus blocking ADP binding
(irreversible inhibition).
Thio metabolite
Active
P2Y12
FDA has a boxed warning of a potential
for reduced effectiveness among poor
metabolizers using clopidogrel.
Clopidogrel
2-Oxo clopidogrel
Glycoprotein IIb/IIIa Receptor Antagonists
Major metabolite (active)
Ticagrelor
• Ticagrelor and its O-deethylation metabolite are reversible inhibitors of P2Y12.
• The binding of ticagrelor occurs at a site distinct from that of the irreversible inhibitor of
P2Y12 and ADP (allosteric site), and acts as a noncompetitive antagonist
Clinical Application of P2Y Purinergic Receptor Inhibitors
• Reduction of MI and stroke in patients with a history of recent MI or stoke.
• The platelet surface is covered with inactive GP IIb/IIIa receptors.
• GP IIb/IIIa receptors exist in an inactive conformation, but conformational
change can be initiated by various platelet agonists including thrombin,
collagen, and TXA2.
• Activation of the receptor results in cross-linking of platelets through
bonding to fibrinogen thus mediating aggregation.
• Chemically diverse antagonists are capable of bonding to GP IIb/IIIa
receptors to block the platelet aggregation.
• Tirofiban is a non-peptide that binds to GP IIb/IIIa at the site that interacts
with the arginine–glycine–aspartic acid (RGD) sequence of fibrinogen.
• Acute coronary syndromes (commonly used in combination with aspirin).
Ø Major adverse effect of clopidogrel, and ticagrelor is bleeding which could lead to fatal/lifethreatening outcomes.
N-(Butylsulfonyl)-O-(4-(4-piperidyl)butyl)-L-tyrosine
Tirofiban
Thrombolytic Drugs
• Acute MI or stroke requires the digestion of insoluble fibrin clots.
• The common standard of treatment calls for the use of thrombolytic drugs for
these and other conditions associated with clot formation.
• These drugs act through their catalytic role as tissue plasminogen activators
(tPAs) in generating plasmin
• Blood clots are designed to be temporary.
After the vessel is healed and the blood
clot is no longer needed. The clot is
removed in the following way:
• The clot itself stimulates the secretion of
tissue plasminogen activator (tPA),
which catalyzes the activation of
plasminogen to plasmin which is an
enzyme that dissolves clots (cleaves
fibrin).
•
•
Alteplase (tPA)
It is produced commercially using recombinant DNA technology. It is used clinically to dissolve clots in
coronary arteries following a heart attack. It is also used to dissolve clots in the brain following stroke.
Alteplase is very specific for plasminogen bound to fibrin with a preference for older clots (clot
selective).
•
•
•
•
Streptokinase
It is a protein purified from culture broths of Group C β–hemolytic
streptococci bacteria. Alone, it has no enzymatic activity. To be active, it
must form 1:1 complex with plasminogen, which then converts
Streptokinase
Plasminogen
uncomplexed plasminogen to the active enzyme, plasmin. Streptokinase
Streptokinase-plasminogen
is not a human enzyme and might initiate immune response
complex
(hypersensitivity reactions).
Urokinase
It is isolated from cultures of human fetal kidney cells.
Urokinase is usually employed in patients who are sensitive to
streptokinase (Note: Urokinase is not a foreign protein and is therefore
nonantigenic).
• Streptokinase and urokinase which act on free (circulating)
plasminogen inducing a generalized thrombolytic state.
Plasminogen
+
Plasmin
+
Fibrin
Degradation
Products
Mechanism of action of
streptokinase.