Fibrinolytic/thrombolytic and Antiplatelet

Drugs

Mebratu
Department of Pharmacology,
SPHMMC

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 Learning objectives
• At the end of the session, the student will
– Describe the fibrinolytic drugs
– Describe the antiplatelete drugs
– Characterize the adverse effect

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 Fibrinolysis
• Fibrinolysis refers to the process of fibrin digestion by
the fibrin-specific protease, plasmin
• Precursor form of the serine protease plasmin circulates
in an inactive form as plasminogen
• In response to injury, endothelial cells synthesize &
release tissue plasminogen activator (t-PA), which
converts plasminogen to plasmin
• Plasmin remodels the thrombus & limits its extension by
proteolytic digestion of fibrin
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Cont…

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Cont…

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 Cont…
• Regulation of the fibrinolytic system is useful in therapeutics

• Increased fibrinolysis is effective therapy for thrombotic disease

• Tissue plasminogen activator, urokinase, & streptokinase all

activate the fibrinolytic system
• Conversely, decreased fibrinolysis protects clots from lysis &
reduces the bleeding of hemostatic failure
• Aminocaproic acid is a clinically useful inhibitor of fibrinolysis

• Heparin & the oral anticoagulant drugs do not affect the

fibrinolytic mechanism

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 Cont…
• Streptokinase
– Is a protein (but not an enzyme in itself) synthesized
by streptococci that combines with the proactivator
plasminogen
– This enzymatic complex catalyzes the conversion of
inactive plasminogen to active plasmin
• Urokinase is a human enzyme synthesized by the
kidney that directly converts plasminogen to active
plasmin
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 Indications & dosage

• Pulmonary embolism
• Severe deep venous thrombosis such as the superior
vena caval syndrome
• Ascending thrombophlebitis of the iliofemoral vein
with severe lower extremity edema
– These drugs are also given intra-arterially, especially
for peripheral vascular disease

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 Cont…

• Thrombolytic therapy in the management of acute

myocardial infarction requires careful patient
selection, the use of a specific thrombolytic agent, and
the benefit of adjuvant therapy
• Streptokinase is administered by intravenous infusion of
a loading dose of 250,000 units, followed by 100,000
units/h for 24–72 hours

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 Cont…
• Adverse effects

– Hypotension, myopathy, abdominal discomfort, diarrhea, & nasal

stuffiness
• CI: bleeding of the upper tract because of the potential for excessive
clotting

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 Antiplatelet agents

Fig. Thrombus formation at the site of the damaged vascular wall (EC, endothelial cell) and
the role of platelets and clotting factors. Platelet membrane receptors include the glycoprotein
(GP) Ia receptor, binding to collagen (C); GP Ib receptor, binding von Willebrand factor
(vWF); and GP IIb/IIIa, which binds fibrinogen and other macromolecules. Antiplatelet
prostacyclin (PGI2 ) is released from the endothelium. Aggregating substances released from
the degranulating platelet include adenosine diphosphate (ADP), thromboxane A 2 (TXA2), and
serotonin (5-HT) 11
 Cont…

• Several targets for platelet inhibitory drugs have been

identified inhibition of prostaglandin synthesis (aspirin),
inhibition of ADP-induced platelet aggregation
(clopidogrel & ticlopidine), & blockade of glycoprotein
IIb/IIIa receptors on platelets (abciximab, tirofiban, &
eptifibatide)
• Dipyridamole & cilostazol are additional antiplatelet
drugs

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 Cont…
– Platelet aggregates form the initial hemostatic plug
at sites of vascular injury
– Platelets also contribute to the pathological
thrombi that lead to myocardial infarction, stroke,
and peripheral arterial thrombosis
– Potent inhibitors of platelet function have been
developed in recent years.
– These drugs act by discrete mechanisms. Thus, in
combination, their effects are additive or even
synergistic.
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 Aspirin
• Prostaglandin thromboxane A2

– Is an arachidonate product that causes platelets to change

shape, release their granules, & aggregate
– Drugs, antagonize this pathway interfere with platelet
aggregation in vitro & prolong the bleeding time in vivo
• Aspirin is the prototype of this class of drugs

– Inhibits the synthesis of thromboxane A 2 by irreversible

acetylation of the enzyme cyclooxygenase
• Other salicylates & NSAIDS also inhibit cyclooxygenase but have
a shorter duration of inhibitory action because they can not
acetylate cyclooxygenase - their action is reversible
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• Aspirin
– In platelets, the major COX-1 product is TxA2, a labile
inducer of platelet aggregation and a potent
vasoconstrictor
– Aspirin blocks production of TxA2 by acetylating a serine
residue near the active site of platelet COX-1
– Because platelets do not synthesize new proteins, the
action of aspirin on platelet COX-1 is permanent, lasting for
the lifetime of the platelet (7–10 days)
– Thus, repeated doses of aspirin produce a cumulative
effect on platelet function

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– Complete inactivation of platelet COX-1 is achieved with a
daily aspirin dose of 75 mg.
– Therefore, aspirin is maximally effective as an
antithrombotic agent at doses much lower than those
required for other actions of the drug
– Numerous trials indicated that aspirin, when used as an
antithrombotic drug, is maximally effective at doses of 50–
325 mg/d.

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– Higher doses do not improve efficacy and potentially are less
efficacious because of inhibition of prostacyclin production,
which can be largely spared by using lower doses of aspirin.
– Higher doses also increase toxicity, especially bleeding.
Therefore, daily aspirin doses of 100 mg or less are used for
most indications
– Nonsteroidal anti-inflammatory drugs that are reversible
inhibitors of COX-1 have not been shown to have
antithrombotic efficacy and in fact may even interfere with
low-dose aspirin regimen

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• Dipyridamole
– Dipyridamole interferes with platelet function by
increasing the intracellular concentration of cyclic AMP
– This effect is mediated by inhibition of phosphodiesterase
or by blockade of uptake of adenosine, thereby increasing
the dwell time of adenosine at cell surface adenosine A2
receptors that link to the stimulation of platelet adenylyl
cyclase.

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– Dipyridamole is a vasodilator that, in combination with
warfarin, inhibits embolization from prosthetic heart
valves
– Dipyridamole is approved for secondary prevention of
stroke when it is combined with low-dose aspirin.

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• P2Y12 Receptor Antagonists
• Clopidogrel
– Clopidogrel is an irreversible inhibitor of P2Y12
– It has largely replaced ticlopidine because clopidogrel is
more potent and less toxic, with thrombocytopenia and
leukopenia occurring only rarely
– Clopidogrel is a prodrug that requires metabolic activation
in the liver.
– Therefore, it has a slow onset of action
– It also has a slow offset of action because of its irreversible
effect on P2Y12.

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– Metabolic activation of clopidogrel can be affected
by polymorphisms in CYP2C19 that result in
reduced or absent CYP2C19 activity.

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• Therapeutic Uses.
– Clopidogrel is somewhat better than aspirin for secondary
prevention of stroke, and the combination of clopidogrel plus
aspirin is superior to aspirin alone for prevention of recurrent
ischemia in patients with unstable angina.
– The FDA-approved indications for clopidogrel are to reduce
the rate of stroke, myocardial infarction, and death in patients
with recent myocardial infarction or stroke, established
peripheral artery disease, or acute coronary syndrome
– Clopidogrel is often used in combination with aspirin after
coronary stent implantation.

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• Adverse Effects.
– Clopidogrel increases the risk of bleeding, particularly when
combined with aspirin or an anticoagulant.
– Thrombotic thrombocytopenic purpura (TTP) can occur but is rare.

• Drug Interactions.
– CYP2C19 inhibition by proton pump inhibitors (e.g.,
omeprazole, lansoprazole, deslansprazole, and pantoprazole)
may reduce conversion to the active metabolite of clopidogrel,
which may contribute to the lower efficacy of clopidogrel
when coadministered with proton pump inhibitors.

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 Glycoprotein IIb/IIIa Inhibitors

– Abciximab
– Abciximab is the Fab fragment of a humanized monoclonal
antibody directed against the αIIbβ3 receptor.
– It also binds to the vitronectin receptor on platelets,
vascular endothelial cells, and smooth muscle cells.

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– The antibody is administered to patients
undergoing percutaneous coronary intervention
and, when used in conjunction with aspirin and
heparin, has been shown to prevent recurrent
myocardial infarction and death

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 – The t1/2 of the circulating antibody is about 30
min, but antibody remains bound to the αIIbβ3
receptor and inhibits platelet aggregation as
measured in vitro for 18–24 h after infusion.
– It is given as a 0.25-mg/kg bolus followed by an
infusion of 0.125 μg/kg/min (maximum 10
μg/kg/min) for 12 to 24 h.
• Adverse Effects
– The major side effect of abciximab is bleeding

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