10. Pharmacology of Thrombosis 2

Pharmacology of Thrombosis II

Instructor Information

  • Dr. Declan McKernan

  • Contact: declan.mckernan@universitygalway.ie

  • Course: PM309 Cardiovascular Drugs


Learning Outcomes

  • Objective 1: Compare and contrast different types of anticoagulant drugs

    • Mechanisms of action

    • Pharmacokinetics

    • Side effects

  • Objective 2: Compare and contrast different types of fibrinolytic drugs

    • Mechanisms of action

    • Pharmacokinetics

    • Side effects


Anti-coagulants

  • Definition: Drugs used to treat and prevent thrombotic diseases

  • Classes of anti-coagulants:

    1. Vitamin K Antagonists (e.g., Warfarin)

    2. Unfractionated & Low Molecular Weight Heparins (LMWHs)

    3. Selective Factor Xa Inhibitors

    4. Direct Thrombin Inhibitors

  • Selectivity:

    • Least selective: Warfarin & Heparin

    • Most selective: Factor Xa & Thrombin inhibitors

  • Mechanism: Prevent the formation of a stable fibrin meshwork

  • Action duration:

    • Heparins & thrombin inhibitors: Immediate effect

    • Warfarin: Takes several days


Vitamin K Antagonists

  • Definition: Fat-soluble vitamin necessary for coagulation factor synthesis

  • Mechanism of Action:

    • Inhibits Vitamin K epoxide reductase (VKORC1) preventing coagulation factor synthesis

    • Delayed action due to half-lives of coagulation factors (6-60 hrs)

  • Clinical Uses:

    • Prevent thrombosis in high-risk patients (DVT, PE, prosthetic valves)


Pharmacokinetics of Vitamin K Antagonists

  • Absorption & Binding: Orally bioavailable, rapid absorption, small volume of distribution

  • Binding: 99% bound to albumin

  • Metabolism: CYP2C9 polymorphism leading to variable half-life (~36 hrs)

  • Monitoring: Requires regular INR checks (2-4 INR target) due to narrow therapeutic index

  • Contraindications: Pregnancy and breastfeeding; significant drug-drug interactions


International Normalized Ratio (INR)

  • Definition: Standardized measure of prothrombin time adjusted for sensitivity index

  • Purpose: Adjust warfarin dosing to maintain INR within therapeutic range


Heparins

  • Description: Family of glycosaminoglycans derived from liver

  • Mechanism of Action:

    • Activates antithrombin III (AT III) to inhibit thrombin (IIa) and factor Xa

    • Unfractionated heparin (UFH) has a broader mechanism than LMWHs

  • Clinical Uses: Treatment and prevention of thrombosis (DVT, PE, atrial fibrillation)


Pharmacokinetics of Heparins

  • Administration: Given IV or SC; not absorbed from GIT

  • Action time: Immediate after IV administration

  • Monitoring: Activated partial thromboplastin time (APTT) for dosing

  • Side Effects: Hemorrhage, heparin-induced thrombocytopenia, hypoaldosteronism, and osteoporosis


Factor Xa Inhibitors

  • Mechanism of Action: Selectively inhibit factor Xa, no effect on thrombin

  • Examples: Fondaparinux, rivaroxaban, apixaban

  • Clinical Uses: DVT prevention and treatment; can be used in heparin-induced thrombocytopenia cases

  • Pharmacokinetics: Fondaparinux given SC; rivaroxaban & apixaban are orally available

  • Side Effects: Bleeding, anemia, nausea


Direct Thrombin Inhibitors

  • Mechanism of Action: Directly inhibit thrombin, negligible effect on factor Xa

  • Examples: Dabigatran, argatroban, lepirudin

  • Clinical Uses: Specific thrombosis types, particularly post-hospitalization

  • Pharmacokinetics: Some administered IV; dabigatran is an orally bioavailable prodrug

  • Side Effects: Bleeding, hypersensitivity reactions


Fibrinolytic Drugs

  • Mechanism of Action: Activators that convert plasminogen to plasmin, degrading fibrin

  • Examples: Streptokinase, alteplase, tenecteplase

  • Clinical Uses: Acute myocardial infarction management; should be administered promptly

  • Side Effects: Risk of bleeding, particularly hemorrhagic stroke


Inhibitors of Anticoagulants & Fibrinolytics

  • Inhibitors of Anticoagulants:

    • Mechanism: Heparin antagonist (protamine) for reversing heparin effects

    • Use: Life-threatening hemorrhage or heparin excess

  • Anti-fibrinolytics:

    • Mechanism: Inhibit plasmin and plasminogen (e.g., tranexamic acid)

    • Use: Reduce perioperative bleeding


Platelet Interaction and Thrombus Formation

  • Thrombus Components:

    • Fibrin forms the framework; trapped blood cells create the thrombus

  • Coagulation Mechanism: Involves platelet activation, coagulation factors, and vascular endothelial cells

  • Fibrinolytic Control: Tissues and plasma contain activators and inhibitors that regulate fibrinolysis

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