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FIBRINOLYTIC DRUGS VIJAYA LECHIMI RAJ. Learning Outcomes. On completing this lecture, you should be able to: Classify the fibrinolytic drugs Discuss the mechanism of action of fibrinolytic drugs e.g streptokinase, alteplase Discuss briefly the pharmacology of streptokinase and alteplase

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slide1

FIBRINOLYTIC DRUGS

VIJAYA LECHIMI RAJ

learning outcomes
Learning Outcomes

On completing this lecture, you should be able to:

  • Classify the fibrinolytic drugs
  • Discuss the mechanism of action of fibrinolytic drugs e.g streptokinase, alteplase
  • Discuss briefly the pharmacology of streptokinase and alteplase

Contents:

  • Classification of fibrinolytic drugs
  • Pharmacology of streptokinase and alteplase
introduction
Introduction
  • Acute thromboembolic disease maybe treated by administration of agents that activate the conversion of plasminogen to plasmin
  • Plasmin is a serine protease that hydrolyses fibrin and thus dissolves clots
slide4

Streptokinase – first to be approved

    • Causes systemic fibrinolytic state that can lead to bleeding problems
  • Alteplase – acts more locally on the thrombotic fibrin to produce fibrinolysis <fig>
  • Nearly equal efficacy between streptokinase and alteplase
  • Thrombolytic therapy is unsuccessful in 20% of infarcted arteries and 15% will close again later
  • In MI:
    • When angioplasty is not an option
    • Until pt can be taken to facility that performs percutaneous coronary interventions
  • May lyse both normal and pathologic thrombi<next>
common characteristics
Common Characteristics
  • Mechanism of action:
    • All act directly or indirectly to convert plasminogen to plasmin cleaves fibrin lyses thrombi
    • Clot dissolution and reperfusion occur with higher frequency when therapy is initiated early after clot formation
    • Clots become more resistant to lysis as they age
    • Increased local thrombi may occur as clot dissolves

Enhanced platelet aggregability and thrombosis

    • Strategy:
      • Include administration of antiplatelet drugs (aspirin) or antithrombotics (heparin)
common characteristics1
Common Characteristics
    • Therapeutic uses:
    • Originally for deep vein thrombosis (DVT), serious pulmonary embolism - Now less frequently
    • Tendency to cause bleeding has blunted their use in acute MI or peripheral arterial thrombosis
    • Helpful in restoring catheter and shunt function
      • By lysing clots that cause occlusions
  • Also used to dissolve clots that result in strokes
  • Pharmacokinetics:
  • Usually administered IV
    • Rapid
    • Inexpensive
    • Does not have risks of catheterization
common characteristics2
Common Characteristics
    • Adverse effects:
    • Do not distinguish between fibrin of unwanted thrombus and of a beneficial hemostatic plug
    • Hemorrhage is a major side effect
      • E.g. a peptic ulcer may hemorrhage after injection of a thrombolytic agent<diag>
  • C/I in pts with healing wounds, pregnancy, history of cerebrovascular accident, metastatic cancer
  • presence of thrombogenic stimuli may cause rethrombosis after lysis of the initial clot<next>
alteplase
Alteplase
  • Formerly known as tissue plasminogen activator (tPA)
  • Is a serine protease originally derived from human melanoma cells
  • Now – product of recombinant DNA technology

Mechanism of action:

  • Low affinity for free plasminogen but rapidly activates plasminogen bound to fibrin in a thrombus or hemostatic plug
  • Fibrin selective and at low doses lyses only fibrin
  • Contrasts with streptokinase
    • Acts on free plasminogen
    • Induces a general fibrinolytic state
alteplase1
Alteplase
  • Therapeutic uses:
  • Approved for treatment of myocardial infarction, massive pulmonary embolism and acute ischemic stroke
  • Superior to streptokinase in dissolving older clots
  • Administered within 3 hours of onset of ischemic stroke can significantly improve clinical outcome
alteplase2
Alteplase
  • Pharmacokinetics:
  • Very short half-life – about 5 mins
  • Usually 10% of total dose is injected IV as a bolus and remaining drug is administered over 60 minutes
  • Adverse effects
  • Bleeding complications including GI and cerebral hemorrhages may occur
streptokinase
Streptokinase
  • An extracellular protein purified from culture broths of Group C β-hemolytic streptococci
  • Mechanism of action:
  • No enzymic activity
  • Forms an active one-to-one complex with plasminogen
  • Converts uncomplexedplasminogen to the active enzyme plasmin
streptokinase1
Streptokinase
  • In addition to the hydrolysis of fibrin plugs, the complex also catalyses the degradation of fibrinogen as well as clotting Factors V and VII
streptokinase2
Streptokinase
  • Therapeutic uses:
  • Acute pulmonary embolism, deep vein thrombosis, acute myocardial infarction, arterial thrombosis and occluded access shunt
  • Pharmacokinetics:
  • Is instituted within 4 hours of a MI and is infused for 1 hour
  • Half-life is less than half an hour
  • Thromboplastin time is monitored and maintained at 2-5 fold the control value
  • On discontinuation of treatment, either heparin or oral anticoagulants may be administered
streptokinase3
Streptokinase
  • Adverse effects:
    • Bleeding disorders
    • Activation of circulating plasminogen leads to elevated levels of plasmin
    • May precipitated bleeding by dissolving hemostatic plugs<fig>
    • In the rare instance of life-threatening hemorrhage, aminocaproic acid may be administered
streptokinase4
Streptokinase
  • Adverse effects:
    • Hypersensitivity
    • Streptokinase is a foreign protein and is antigenic
    • Rashes, fever and rarely, anaphylaxis occur
    • Circulating antibodies against streptokinase are likely to be present in most patients
streptokinase5
Streptokinase
  • These antibodies can combine with streptokinase and neutralize its fibrinolytic properties
  • Sufficient quantities must be administered to overwhelm the antibodies and provide a therapeutic concentration of plasmin
  • Fever, allergic reaction and therapeutic failure may be associated with the presence of antistreptococcal antibodies
  • Incidence of allergic reactions – 3%
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