CVcoagulation23-24bb.pptx

CV Pharmacology: Blood Coagulation Robert Sims HA209 [email protected]  Lecture Plan A brief background on coagulation Anticoagulants Antiplatelet drugs Fibrinolytics & procoagulants Drugs for hyperlipidaemia...

CV Pharmacology: Blood Coagulation Robert Sims HA209 [email protected]  Lecture Plan A brief background on coagulation Anticoagulants Antiplatelet drugs Fibrinolytics & procoagulants Drugs for hyperlipidaemias  Haemostasis The cessation of bleeding from damaged blood vessels Complex system of proteins and enzymes, mainly involving: Adhesion & activation of platelets Formation of fibrin Platelet activation and fibrin formation are usually concurrent  Vascular endothelium Endothelial cells are protective against haemostasis: Heparan sulfate membrane glycoproteins Signalling molecules: Prostaglandin I2 (PGI2) & NO Tissue plasminogen activator (tPA) Converts ADP to adenosine  Haemostatic plug Basement membrane Platelet Fibrin ECM proteins Platelets aggregate, activate Endothelial Smooth coagulation cascade & fibrin forms: cell muscle cell “haemostatic plug”  Thrombosis Pathological coagulation within an intact blood vessel; may cause blockage (thrombus) May detach from the vessel wall – embolus. Embolisms are often life- threatening if they become stuck in a smaller blood vessel. Differ by blood vessel: Venous thrombi are high in fibrin Arterial thrombi are high in platelets  Major causes of thrombosis Myocardial infarction Abnormal Virchow’s Atherosclerosis blood flow Triad Vasculitis Hypertension Smoking Radiation Chemical irritation Inflammation Blood vessel Hypercoagulability Hypoxia damage Infection  Coagulation pathway Intrinsic Pathway Extrinsic Pathway Tissue damage or Factors XII, XI, IX contact with external bodies sets off signalling and enzyme cascade Factor X Factor Xa End result is conversion of prothrombin to thrombin (factor IIa) Factor II Factor IIa Antithrombin III (prothrombin) (thrombin) -  Fibrin formation Thrombin is a protease, it cleaves the ends of a free-floating blood protein called fibrinogen With the ends cleaved, the new protein, fibrin, is insoluble Fibrinogen Fibrin Fibrin strands assemble into fibrils that bind to platelets and each other  Platelet aggregation Activated Unactivated platelets platelet Fibrinogen Glycoprotein IIb / IIIa receptors Collagen PAF Thrombin, ADP collagen, vWF TXA2  Antithrombosis drugs & strategies Anticoagulants inhibit initiation by limiting small scale production of thrombin Anti-platelet drugs inhibit amplification by restricting platelet activation Fibrinolytics promotes degradation of fibrin (/ thrombolytics) strands – “clot buster” Note: all antithrombotics increase risk of bleeding / haemmorhage  International Normalised Ratio (INR) Prothrombin time: lab test of blood clotting (~12-13s) INR compares prothrombin time against standardised norm State INR Normal healthy 0.8 – 1.2 Therapeutic 2 – 3 or 2.5 – 3.5 Dose reduction 5–9 Emergency >8  Anticoagulants – Warfarin Warfarin is the most used anticoagulant (UK): “Vitamin K antagonist”. Inhibits VKORC1 enzyme, blocks production of active form of Vit K Antidote available: Vit K & prothrombin (takes several hours) Problems: Teratogen, hepatotoxicity, soft tissue necrosis Requires initial administration of heparin Low therapeutic index: requires heavy monitoring. Gene polymorphisms – variations in effectiveness Numerous CYP450 drug interactions Synergistic bleeding (e.g. aspirin, heparin)  Anticoagulants – Warfarin alternatives Direct inhibitors of Factor Xa – “-xaban”: rivaroxaban, apixaban, etc. Orally administered, rapid onset Caution in renal impairment; Antidote (new) – andexanet alfa Especially for atrial fibrillation, DVT, pulmonary embolism post-surgical venous thromboembolism Direct thrombin inhibitor – dabigatran Orally active, increasingly popular Has specific antidote (idarucizumab)  IV anticoagulants Heparins – including fondaparinux Fondaparinux generally superior to conventional LMWHs e.g. enoxaparin Useful in acute situations; injection only. Bridging to warfarin treatment Activates antithrombin III Thrombocytopenia, hypersensitivity Hirudins (e.g. lepirudin, bivalirudin) Heparin monomer Thrombin inhibitors; injection only Useful if patients intolerant to heparin  Anti-platelet drugs: P2Y & PAR AD Thromb P in Giα GPCR activation by ADP and P2Y PAR thrombin receptor receptor ↓cAMP → release of Ca2+ from internal Gi α Gi α stores ↓cAMP Ca2+ triggers release of procoagulative Ca2+ Ca2+ molecules from Ca2+ Ca2+ granules (e.g. ADP) Ca2+ Ca 2+  Antiplatelet drugs – P2Y12 & PAR antagonists P2Y12 antagonists: “-grel-” Clopidogrel second in class; irreversible. prodrug: ineffective in some poor metabolisers Prasugrel & Ticagrelor: prasugrel irreversible, ticagrelor reversible PAR antagonists: Very new; not yet available in UK e.g. vorapaxar (approved FDA, 2014)  Dipyridamole Phosphodiesterase inhibitor: ↑ cAMP, cGMP Sometimes prescribed with aspirin; most favoured for stroke prevention and after transient ischaemic attack (TIA). Anti-platelet drug with chronic administration. Use declining; lower efficacy observed than alternatives Vasodilator (especially high dose for short periods): Cautions with hypotension, MI, migraine  Anti-platelet drugs: TXA2 & GPIIb Arachidonic acid (AA) PAR receptor produced downstream of GPII PAR activation b AA converted to thromboxane A2 (TXA2) by cyclooxygenase TXA AA iPLA2 2 TXA2 activates COX1 glycoprotein IIb (GPIIb) receptor GPIIb & GPIIIa combine to form fibrinogen-binding complex  Aspirin Cyclooxygenase inhibitor (non-specific, but COX-1 in platelets) Irreversible inhibitor Low dose (~1/4 of analgesic); very low side effect risks Aspirin resistance in some patients Often administered with other drugs e.g. clopidogrel  GPIIb/IIIa receptor inhibitors Specialist use only during or after cardiac surgery; used as adjuncts to heparin. Prevent binding of fibrinogen to activated GPIIb/IIIa receptors Abciximab – monoclonal antibody; injection only. Also eptifibatide, tirofiban: peptides, also injection only.  Summary: Anti-platelet drugs AD Vorapaxar Abciximab P Eptifibatide Clopidogrel Thrombin Tirofiban Prasugrel Ticagrelor P2Y PAR GPII b TX AA A2 COX1 Ca2+ Ca2+ Ca2+ Ca 2+ Ca2+ Dipyradimole Platelet granule Aspirin  Fibrinolytics (/thrombolytics) tPA Fibrinogen Fibrinolytic pathway also initiated with coagulation Tranexamic acid system Plasminogen Plasminogen activated to – Fibrin protease plasmin, which degrades fibrin + Plasmin Coagulation v. fibrinolysis Fibrin Degradation controlled by competing Fibrinolytics signalling Products  Fibrinolytics Streptokinase: bacterial plasminogen-activating enzyme Acute thrombotic / embolic events such as deep vein thrombosis; post-MI Recombinant tPA: Alteplase (and others e.g. tenecteplase) Only recommended stroke medication; also other acute throbotic / embolic events, post-MI All fibrinolytics administered IV, usually in acute cases for occluded arteries. Tranexamic acid as antifibrinolytic (procoagulant); orally available.  Stroke Complex and frequently devastating cerebrovascular disorder Loss of blood flow to brain (ischaemia) caused by thrombosis / embolism, cardiac arrest (~85%); haemorrhage (~15%). Transient ischaemic attack (TIA): brief ischaemia without cell loss; indicator of high stroke risk Treated with tPA – time to treatment essential (