Clotting Mechanism 2-Antithrombotic Therapy PDF

CLOTTING MECHANISM 2- ANTITHROMBOTIC AGENTS Dr Syed Imran Ahmed; MClinPharm, PhD, FHEA, FRSPH Senior Lecturer in Clinical Pharmacy School of Health and Care Sciences, College of Health & Science University of Lincoln [email protected]  Learning Objectives At the end of the session, you should...

CLOTTING MECHANISM 2- ANTITHROMBOTIC AGENTS Dr Syed Imran Ahmed; MClinPharm, PhD, FHEA, FRSPH Senior Lecturer in Clinical Pharmacy School of Health and Care Sciences, College of Health & Science University of Lincoln [email protected]  Learning Objectives At the end of the session, you should be able to understand and describe; different classes of drugs that affect blood coagulation, and their mechanism of action. various indications and therapeutic uses of anticoagulants and antiplatelet agents. pros and cons of using various antithrombotic agents, adverse drug reactions, contraindications and monitoring. Inhibitors of Clotting Mechanism Inhibitors Target Antithrombin Inhibits factors IIa, IXa and Xa Protein S Co factor for activation of protein C Protein C Inactivate factors Va and VIIIa Tissue factor pathway inhibitor Inhibits activity of factor VIIa Plasminogen Converted to plasmin via t-PA which causes lysis of fibrin, to fibrin degradation products Selection of agents The anticoagulants heparin (UFH), low-molecular-weight heparins (LMWH), Warfarin and others are used in the treatment and prevention of both arterial and venous thrombi. Platelet aggregation inhibitors (e.g. aspirin, clopidogrel), alone or in combination with anticoagulants, are used in the prevention of arterial thrombi. Fibrinolytic agents (e.g. Streptokinase) are used in the rapid dissolution of thromboembolism, notably during myocardial infarction (MI). Overview of Drugs Affecting Blood Coagulation  Antiplatelet Agents Antiplatelet drugs inhibit platelet aggregation They are used in the management of Arterial thrombosis – They are not used in the management of venous thromboembolism (VTE) – fibrin dominant The main types of antiplatelet drugs include: – Thienopyridines Clopidogrel, Prasugrel and Ticlopidine – Glycoprotein IIb/IIIa inhibitors Abciximab, Eptifibatide and Tirofiban – Others Aspirin (low dose), Dipyridamole, Ticagrelor Thromboxane TXA₂ promotes platelet aggregation while prostacyclin PGI₂ inhibits it. – Both are produced by cyclooxygenase enzyme and balance is important. Prostacyclin is generated by vascular endothelium.  Antiplatelet agents Aspirin inhibits cyclo-oxygenase irreversibly resulting in altering balance between TXA2 (promotes aggregation), and PGI2 (inhibits aggregation). -Mainly used for arterial thrombosis ( AMI, history of AMI and angina, CABG, transient ischemic attack, thrombotic stroke etc. Clopidogrel and Ticlopidine inhibits ADP-dependant aggregation of platelet. Their actions are additives with aspirin. Antagonist of glycoprotein (GP IIb/IIIa) receptors (Abciximab, Tirofiban, Eptifibatide) inhibits diverse agonists e.g. ADP and TXA2 , because different pathways of activation converge on GP IIb/IIIa receptors. Platelet Aggregation Inhibition  Aspirin Mode of action – Irreversibly inhibits cyclooxygenase reducing synthesis of thromboxane A2 for the life of the platelet Low dose aspirin (75-325mg daily) recommended for the prevention of serious vascular events (MI, stroke) in high-risk patients (post MI, angina, PVD, previous stroke, etc) In patients with no previous cardiovascular disease benefits in terms of CV prevention should be weighed against risks (GI and intracranial bleeding) Common side effects – GI irritation, increased bleeding time, allergy (bronchospasm, urticaria and rhinitis – arguably due to excipients used) Rarer side effects – GI and intracranial bleed Category C in pregnancy, low doses considered safe, though should be avoided, when possible, in the third trimester.  Clopidogrel and Prasugrel Clopidogrel and Prasugrel block the platelet ADP receptor (P2Y12) which prevents activation of the platelet glycoprotein IIb/IIIa complex preventing platelet aggregation and thrombus formation. Platelets are affected for their whole lifespan by these drugs They prolong bleeding time therefore used with caution in patients with bleeding disorders Clopidogrel is used in patients for whom aspirin is contraindicated or in combination with aspirin in patients who either have a CV event on aspirin or after stenting (see ACS in Module 302) – Diarrhoea is a common side effect.  Prasugrel Newer agent Used for: – Prevention of atherothrombotic events (with aspirin) in ACS (including STEMI and NSTEACS) to be managed with PCI Comparison of Prasugrel and Clopidogrel in ACS after PCI – Prasugrel was superior in primary outcomes (death, stroke and MI) and secondary outcomes (stent thrombosis) – But had an increased risk of major (including fatal) bleeding – Overall mortality didn’t differ between the two groups Should be given with 75-150mg aspirin, and has a starting loading dose of 60mg, then reduced to 10mg daily (5mg if >75 years old or  Dipyridamole Inhibits platelet function by inhibiting phosphodiesterase thereby increasing platelet cAMP, which blocks platelet response to ADP. Uses: Combination with warfarin in patients with prosthetic heart valves Combination with aspirin for the secondary prevention of stroke – Benefit over aspirin alone unknown. Side Effects: Causes vasodilation, therefore can cause headache, hot flushes, hypotension and tachycardia. Can also cause allergic reactions (rash, urticaria, bronchospasm).  Ticagrelor New drug Binds reversibly to the P2Y12 receptor, inhibiting platelet aggregation Indicated for use in ACS (with aspirin) – 12 month study has shown that Ticagrelor plus aspirin was more effective than Clopidogrel with aspirin in preventing CV events in patients with ACS Significant reductions in MI and vascular death but a non-significant increase in stroke was noted Incidence of total bleeding was similar – but rate of intracranial haemorrhage was higher with Ticagrelor Risk-benefit of Ticagrelor was less favourable when used with aspirin doses >150mg daily Side Effects: bleeding, nausea diarrhoea, headache and non-cardiac chest pain.  Glycoprotein IIb/IIIa receptor inhibitors Abciximab (Reopro), Eptifibatide (Integrilin), Tirofiban (Aggrastat) Prevent binding of fibrinogen to platelets by occupying platelet Glycoprotein IIb/IIIa receptor → reduced platelet aggregation. Used with heparin and low-dose aspirin for prevention of ischaemic cardiac complications following percutaneous transluminal coronary interventions (PTCA, stenting) – Abciximab and Eptifibatide Treatment of unstable angina or NSTEMI – Eptifibatide and Tirofiban All given IV  Anticoagulants The Anticoagulants can be divided into: – Indirect Parenteral Anticoagulants Heparin Low Molecular Weight Heparins (LMWHs) and Danaparoid – Direct thrombin inhibitors Dabigatran Bivalirudin – Vitamin K antagonists Warfarin Phenindione – Factor Xa inhibitors Apixaban Fondaparinux Rivaroxaban  Anticoagulants Previously they used to be classified as 1. Injectable anticoagulants (UFH, LMWH) 2. Oral anticoagulants (Warfarin and related compounds) o However, the development of newer agents, including Oral Anticoagulants, has made this classification less useful. o It is also important to note that, warfarin, was once the only and most effective choice for prolonged anticoagulation therapy, as the only oral anticoagulant.  Indirect Parenteral Anticoagulants (IPAs) - Heparin Unfractionated heparin (UFH) or Heparin Is a mixture of sulfated glycosaminoglycans with a molecular weight of 5000 to 30,000 extracted commercially from porcine intestine or bovine lung Rapidly-acting, parenteral anticoagulant (immediate effect) therefore used for acute treatment or prophylaxis of thromboembolic disorders or until the anticoagulant effect of warfarin is established. Mode of action – UFH affects Thrombin indirectly by binding to Antithrombin III to cause a rapid anticoagulant effect (maximal anticoagulation occurs within minutes) after IV injection – Antithrombin III inhibits serine proteases including some blood clotting factors including Thrombin (factor IIa) and factor Xa. This complex inactivates factor IIa (thrombin) and factor Xa together with IX, XI and XII. – In the absence of heparin, Antithrombin III slowly interacts with thrombin – The binding of heparin to antithrombin III produces a conformational change allowing the antithrombin to rapidly combine and inhibit thrombin (except thrombin already bound to fibrin) – Also inactivates factor Xa (to further inhibit thrombin activity) – It requires monitoring of activated partial prothrombin time (aPTT).  Indirect Parenteral Anticoagulants (IPAs) - Heparin Practice points – Still a major antithrombotic drug for treatment and prevention of VTE/DVT etc – Useful with pregnant women as it does not cross the placenta – Heparin has the advantage of speedy onset of action plus rapid termination of action on withdrawal of therapy – Must be given SC (having low bioavailability) or IV (Do not give IM – risk of haematoma) – Often given as an IV bolus to achieve immediate anticoagulation followed by lower doses or continuous infusions  Indirect Parenteral Anticoagulants (IPAs) - Heparin Adverse effects – Chief complication is haemorrhage (up to 6% of patients) – may be managed by stopping heparin or use of Protamine sulphate – Bruising, pain at the injection site – Thrombocytopenia (HIT – Heparin-induced Thrombocytopenia) Mild, reversible form is common Immune-modulated severe thrombocytopenia occurs in