s3

Cards (41)

  • Antiplatelets and anticoagulants
    Drugs developed to prevent and/or reverse thrombus formation
  • Classes of drugs to prevent thrombus formation

    • Anticoagulants
    • Antiplatelet agents
    • Fibrinolytic agents
  • Anticoagulants
    • Modify blood clotting mechanisms
  • Antiplatelet agents
    • Inhibit COX-1 activity to inhibit platelet aggregation
  • Fibrinolytic agents

    • Break down fibrin
  • Classes of anticoagulant drugs
    • Selective factor Xa inhibitors - Apixaban
    • Direct thrombin inhibitors - Dabigatran
    • Heparin and low molecular weight heparins
    • Vitamin K antagonists - Warfarin
  • Anticoagulants
    Target various factors in the coagulation cascade preventing formation of a stable fibrin framework
  • Venous thromboembolism: Treatment

    1. Apixaban or rivaroxaban
    2. Low molecular weight heparin (LMWH) followed by dabigatran etexilate or edoxaban or LMWH given with a vitamin K antagonist
    3. Thromboprophylaxis for patients undergoing surgery (NICE guidelines)
  • Direct-acting oral anticoagulants (DOACs)
    • apixaban, dabigatran etexilate, edoxaban, and rivaroxaban
  • Dabigatran etexilate

    Reversible inhibitor of thrombin
  • Apixaban, edoxaban, and rivaroxaban
    Reversible inhibitors of activated factor X (factor Xa)
  • Idarucizumab
    Reversal agent for dabigatran
  • Andexanet alfa

    Reversal agent for apixaban, edoxaban, and rivaroxaban
  • Indications for DOACs
    • Prevention of stroke
    • Secondary prevention of DVT and/or PE
    • Prevention of venous thromboembolism following surgery
    • Prevention of atherothrombotic events in patients with coronary or peripheral artery disease following an acute myocardial infarction
  • Contra-indications for apixaban
    • Avoid in conditions with significant risk of bleeding
    • Gastrointestinal ulceration
    • Malignant neoplasms with high risk of bleeding
    • Oesophageal varices
  • Elderly - prescription of apixaban potentially inappropriate
    Risk of bleeding e.g. severe hypertension
  • Side-effects of apixaban - Common or very common
    • Anaemia
    • Haemorrhage
  • Heparin
    Family of sulphated mucopolysaccharides, found in the secretory granules of mast cells
  • Heparin
    Inhibits coagulation by activating antithrombin III (AT III)
  • AT III
    Naturally occurring inhibitor of thrombin and clotting factors IX, Xa, XI and XII
  • In the presence of heparin, AT III becomes ~1000x more active and inhibition of clotting factors is instantaneous
  • Low molecular weight heparins (LMWH)

    Fragments or synthetic heparin with more consistent activity
  • LMWH
    Inactivate factor Xa (and thrombin) via activation of antithrombin III
  • Heparin and LMWH have immediate onset of action
  • Examples of LMWH
    • dalteparin sodium, enoxaparin sodium, and tinzaparin sodium
  • Heparin and LMWH: Pharmacokinetics

    • Inactive given orally (not absorbed from GI tract)
    • Administered IV or SC (SC for LMWHs)
    • Heparin has a short half life (t ½ <1h low doses, 2h large doses)
    • Heparin must be given frequently or as a continuous infusion
    • LMWH have longer duration of action (t ½ ~4-5h)
    • Allows once daily dosing
    • Eliminated mainly by renal excretion
    • Care needed in patients with renal disease
    • Side effects include bleeding and hypersensitivity
    • LMWH have lower risk of heparin-induced thrombocytopenia
    • Overdose treated by IV protamine (strongly basic protein)
  • Vitamin K antagonists

    Inhibit the activation of Vitamin K dependent clotting factors II, VII, IX and X
  • At least 48 to 72 hours for the anticoagulant effect of vitamin K antagonists to develop
  • A small population of patients is genetically resistant to warfarin, due to reduced binding to Vitamin K reductases
  • Vitamin K antagonists

    • Warfarin, acenocoumarol, phenindione
  • Side effects of vitamin K antagonists
    • Haemorrhage
    • Skin necrosis
  • Warfarin: Pharmacokinetics

    • Rapidly and almost totally absorbed from the GI tract
    • Levels peak in blood ~0.5-4h after administration
    • Low volume of distribution as ~ 99% plasma protein bound (mainly to albumin)
    • Action is terminated by metabolism in the liver by CYP450 enzymes (e.g. CYP2C9, 2C19, 3A4)
    • Metabolites are conjugated to glucuronide and excreted in urine and faeces
    • Half life – 15-80 hours
    • Dose is highly variable - (2-112 mg/week)
  • Platelets
    Provide the initial haemostatic plug at sites of vascular injury
  • Antiplatelet drugs
    Inhibition of platelet function is a useful prophylactic and therapeutic strategy against MI and stroke caused by thrombosis
  • Aspirin
    • Irreversibly inhibits COX-1, therefore inhibits the synthesis of TXA2
    • Platelets do not contain DNA or RNA so cannot synthesise new COX-1
    • The inhibition is irreversible and effective for the life of the circulating platelet (7-10 days)
  • Clinical use of aspirin
    • Used prophylactically to prevent arterial thrombosis leading to: transient ischemic attack, stroke, myocardial infarction
  • Other antiplatelet drugs

    • Ticlopidine - TIA prevention
    • Clopidogrel - post MI/stroke
  • Thromboses
    Dynamic - balance between breakdown (fibrinolysis) and formation
  • Thrombolytic drugs

    • Potentiate the effects of the fibrinolytic system
    • Activate conversion of plasminogen to plasmin which breaks down fibrin, thus dissolves clots
  • Fibrinolytic (thrombolytic) drugs

    • e.g. streptokinase, alteplase