Medical Pharmacology Chapter 39: Drugs that Influence Coagulation

 

Fibrolytic Drugs

• Overview:  fibrolytic drugs

  • Lyse thrombi by catalyzing plasmin (serine protease) formation from plasminogen (the zymogen precursor)

  • Lytic state induced following IV administration

  • Note: both target thromboemboli and hemostatic thrombi are dissolved

• Pharmacology: streptokinase, alteplase, tissue plasminogen activator, reteplase, urokinase

  • Streptokinase (Streptase, Kabikinase):(protein {not an enzyme} derived from streptococci)

    • Combines with plasminogen (proactivator)

    • Enzymic complex catalyzes: plasminogen → active plasmin

  • Urokinase (Abbokinase):(human enzyme; renal)

    • Catalyzes: plasminogen →active plasmin

    • Note: Plasmin cannot be directly used because of endogenous inhibitors;

      • Endogenous antiplasmins do not affect urokinase or streptokinase-proactivator complex

      • Urokinase (and streptokinase-proactivator complex) promote plasmin formation inside the thrombus →yse thrombus from within.

  • Anistreplase (APSAC, Eminase) (anisoylated plasminogen streptokinase activator complex; APSAC)

    • Purified human plasminogen - bacterial acylated streptokinase complex {upon administration deacylation activatesstreptokinase-proactivator complex}

    • Rapid IV injection

    • Enhanced clot selectivity -- more plasminogen activity clot-associated than associated with free blood plasminogen

    • More thrombolytic activity

  • Tissue Plasminogen Activators (t-PA)

    • Plasminogen activator

    • Preferential activation of fibrin-bound plasminogen

    • Human t-PA: recombinant DNA technology

    • Alteplase: unmodified human t-PA

    • Reteplase: modified human t-PA

• Clinical Uses: Fibrolytic Drugs

  • Multiple pulmonary emboli (not requiring surgery)

  • Central deep venous thrombosis

    •  Superior vena caval syndrome

    •  Ascending thrombophlebitis (iliofemoral vein)

  •  Intra-arterial use -- peripheral vascular disease

  • Acute Myocardial Infarction:

    • Careful patient selection (early intervention)

Antithrombotic -- Antiplatelet Drugs

• Overview: antithrombotic agents

  • Regulation of platelet function -- Three types of substances:

    1. Substances developed outside the platelet but interacts with platelet membrane receptors:

       •   Catecholamines

       •   Collagen

       •   Thrombin

       •   Prostacyclin

    2. Agents generated internal to the platelet and interact with membrane receptors:

       •   ADP

       •   Prostaglandin D₂

       •   Prostaglandin E₂

       •   Serotonin

    3. Agents generated internal to the platelet and interact within the platelet:

       • Prostaglandin endoperoxidases

       • Thromboxane A₂

       •   cAMP

       •   cGMP

       •   Ca²⁺

  • Pharmacological Targets:antithrombotic agents

    • Inhibition of prostaglandin metabolism: aspirin

    • inhibition of ADP-induced platelet aggregation: ticlopidine

    • Blockade of GP IIb/IIIa platelet membrane glycoprotein receptors: abciximab(ReoPro) & integrelin

• Aspirin

  • Aspirin

  • Mechanism of Action:aspirin

    • Prostaglandin thromboxane A2 (arachidonate product) causes:

      • Platelet aggregation

      • Platelet shape changing

      • Platelet degranulation

    • Inhibition of this process inhibits platelet aggregation, prolonging in vivo bleeding time

    • Aspirin inhibits thromboxane A₂ synthesis by:

      • Irreversible acetylation of cyclooxygenase

      • New cyclooxygenase cannot be synthesize during the 10-day lifespan of the platelet

      • Other cyclooxygenase inhibitors are reversible and therefore have shorter duration of action, e.g. other salicylates & other nonsteroidal anti-inflammatory drugs

  • Clinical Use --antithrombotic effects

    • Possible primary prophylaxis of myocardial infarction

    • FDA approval for this indication

  •  Adverse Effects:  aspirin

    • Increased gastrointestinal bleeding

    • Increased frequency of peptic ulcer disease.

• Dietary:  antithrombotic effects

  • Unsaturated fatty acid eicosapentaenoic acid -- generates prostaglandin I₃ and thromboxane A₃, anti-aggregation agents

• Ticlopidine

  • Ticlopidine

  • Inhibits ADP platelet pathway: reduces platelet aggregation

  • No effect on prostaglandin metabolism

  • Clinical Use-Ticlopidine: Efficacy in prevention:

    •   Strokes

    •   Unstable angina

    •   Transient ischemic attacks

  •  Adverse Effect:  ticlopidine

    • Gastrointestinal disturbance: frequency = 20%

    • Hemorrhage: frequency = 5%

    • Leukopenia (serious): frequency: = 1%

      • Requires blood testing during first three months of ticlopidine treatment

• Blockade of GP IIb/IIIa platelet membrane glycoprotein receptors: abciximab, integrelin

  • Abciximab:(ReoPro)

    • Mouse/human chimeric monoclonal antibody blocking IIb/IIIa receptors

    • Clinical Use:  abciximab

      • Adjunctive treatment in high-risk angioplasty and atherectomy

Primary Reference: O'Reilly, R.A. Drugs Used in Disorders of Coagulation, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 916-940

Handlin, R.I. Bleeding and Thrombosis, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 339-344.