FIBRINOLYTIC DRUGS
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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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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


  • 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>


  • <back><cont>


    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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