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