1.
Fibrinolytic drugs
 Fibrinolytic drugs rapidly lyse thrombi
 Catalyze the formation of the serine protease plasmin
from its precursor zymogen plasminogen
 Create a generalized lytic state when administered
intravenously
 Useful for Acute myocardial Infarction
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2.
Pharmacology
 Streptokinase is a protein synthesized by streptococci
 Combines with the proactivator plasminogen
 Catalyzes the conversion of inactive plasminogen to active plasmin
 Urokinase is a human enzyme synthesized by the kidney
 Directly converts plasminogen to active plasmin
 Plasmin itself cannot be used because naturally occurring inhibitors in
plasma prevent its effects
 The absence of inhibitors for urokinase and the streptokinase-
proactivator complex permits their use clinically
 Plasmin formed inside a thrombus by these activators is protected from
plasma antiplasmins, which allows it to lyse the thrombus from within
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3.
 Plasminogen can also be activated endogenously by tissue
plasminogen activators (t-PAs)
 These activators preferentially activate plasminogen that is bound to
fibrin
 Human t-PA is manufactured as alteplase by means of recombinant
DNA technology
 Reteplase is another recombinant human t-PA from which several
amino acid sequences have been deleted
 Reteplase is less expensive to produce than t-PA.
 Because it lacks the major fibrin-binding domain, reteplase is less
fibrin specific than t-PA
 Tenecteplase is has a longer half-life, and it can be given as an
intravenous bolus
 Tenecteplase is slightly more fibrin-specific than t-PA
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4.
Antiplatelet agents
 Aspirin
 Thromboxane A 2 is an arachidonate product that causes
platelets to change shape, release their granules, and aggregate
 Drugs that antagonize this pathway interfere with platelet
aggregation and prolong the bleeding time
 Aspirin is the prototype of this class of drugs
 inhibits the synthesis of thromboxane A2 by irreversible
acetylation of the enzyme cyclooxygenase
 Other salicylates and nonsteroidal anti-inflammatory drugs also
inhibit cyclooxygenase but have a shorter duration of inhibitory
action
 because they cannot acetylate cyclooxygenase; that is, their
action is reversible
 The FDA has approved the use of 325 mg/d aspirin for primary
prophylaxis of myocardial infarction
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5.
Ticlopidine, clopidogrel & prasugrel
 Ticlopidine, clopidogrel, and prasugrel reduce platelet
aggregation by inhibiting the ADP pathway of platelets
 These drugs irreversibly block the ADP receptor on
platelets
 Unlike aspirin, these drugs have no effect on
prostaglandin metabolism
 Use of ticlopidine, clopidogrel, or prasugrel to prevent
thrombosis is now considered standard practice in
patients undergoing placement of a coronary stent
 As the indications and adverse effects of these drugs
are different, they will be considered individually
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6.
 Ticlopidine is approved for prevention of stroke in patients with a history of
a transient ischemic attack (TIA)
 Adverse effects of ticlopidine include
 nausea
 Dyspepsia
 diarrhea
 hemorrhage
 most seriously, leukopenia in 1%
 Clopidogrel is approved for patients with unstable angina
 Clopidogrel has fewer adverse effects than ticlopidine and is rarely
associated with neutropenia
 Clopidogrel is a prodrug that requires activation via the cytochrome P450
enzyme isoform CYP2C19
 Depending polymorphism inheritance pattern in CYP2C19, individuals
may be poor metabolizers of clopidogrel, and these patients may be at
increased risk of cardiovascular events
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7.
Blockade of platelet glycoprotein II b/III a receptors
 The IIb/IIIa complex functions as a receptor mainly for fibrinogen and
vitronectin but also for fibronectin and von Willebrand factor
 Activation of this receptor complex is the “final common pathway” for
platelet aggregation
 Abciximab, an antibody directed against the IIb/IIIa complex including the
vitronectin receptor, was the first agent approved in this class of drugs
 It has been approved for use in percutaneous coronary intervention and
in acute coronary syndromes
 Eptifibatide is an analog of the sequence at the extreme carboxyl
terminal of the delta chain of fibrinogen, which mediates the binding of
fibrinogen to the receptor
 Tirofiban is a smaller molecule with similar properties with others
 Eptifibatide and tirofiban inhibit ligand binding to the IIb/IIIa receptor by
their occupancy of the receptor but do not block the vitronectin receptor
 Are administered parenterally
 Oral formulations of IIb/IIIa antagonists are in various stages of
development
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8.
Drugs used in bleeding disorders
 Vitamin K
 Vitamin K confers biologic activity upon prothrombin and factors VII,
IX, and X
 Vitamin K is a fat-soluble substance found primarily in leafy green
vegetables
 The dietary requirement is low, because the vitamin is additionally
synthesized by bacteria that colonize the human intestine
 Two natural forms exist: vitamins K 1 and K 2
 Vitamin K 1 (phytonadione; is found in food
 Vitamin K 2 (menaquinone) is found in human tissues and is
synthesized by intestinal bacteria
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9.
Cont.…
 Vitamins K 1 and K 2 require bile salts for absorption from the
intestinal tract
 Vitamin K 1 is available clinically in oral and parenteral forms
 Intravenous administration of vitamin K 1 should be slow
 Rapid infusion can produce dyspnea, chest and back pain, and
even death
 Vitamin K repletion is best achieved with intravenous or oral
administration,
 its bioavailability after subcutaneous administration is erratic
 Vitamin K 1 is currently administered to all newborns to prevent
the hemorrhagic disease of vitamin K deficiency
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10.
Cont.…
 The water-soluble salt of vitamin K 3 (menadione) should never
be used in therapeutics
 K3 is particularly ineffective in the treatment of warfarin over
dosage
 Vitamin K deficiency frequently occurs in
 hospitalized patients in intensive care
 recent surgery
 multiple antibiotic therapy
 uremia
 Severe hepatic failure results in diminished protein synthesis
and a hemorrhagic disorder that is unresponsive to vitamin K
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