s3

• 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