Anticoagulants. Pathological formation of a haemostatic plug Arterial associated with atherosclerosis Venous blood stasis e.g. DVT
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1 Haemostasis Thrombosis Phases Endogenous anticoagulants Stopping blood loss Pathological formation of a haemostatic plug Arterial associated with atherosclerosis Venous blood stasis e.g. DVT Vascular Platelet Coagulation Fibrin formation Fibrin removal Antithrombin III cofactor heparin sulphate Prostacyclin (PGI 2 ) inhibits platelet aggregation Endothelium e.g. nitric oxide
2 Symptoms of DVT Sharp pain when foot is flexed upwards. Tenderness and swelling in leg. Fever, rapid heartbeat. Sudden unexplained cough and joint pain. Leg may become reed and warm to touch.
3 Anticoagulants Type Mechanism Indications Adverse effects Contraindications Response Drug interactions Heparin (injectable, p.o.) Acute use Bruising, pain Haemorrhage Low MW heparins (subcut.) Enoxaparin Warfarin (p.o.) Antithrombin III binds to serine site of clotting factors IIa (thrombin), IXa XIIa inhibit clotting steps Heparin binds to ATIII catalyses inhibition Increase inactivation by AT III of factor Xa (not thrombin) Greater bioavailability than heparin Longer t ½ than heparin Less effect on platelet function than heparin Vitamin K cofactor in activation of various factors Warfarin structurally similar to vitamin K vitamin K antagonist, active in vivo only Plasma protein bound, variable t ½, slow onset, drug interactions, diet variable response drug monitoring important Acute treatment e.g. surgery, IV device patency, unstable angina Prevent arterial thrombosis during coronary angioplasty Chronic therapy Treatment/prophylaxis of thromboembolic disorders and cardiac complications e.g. pulmonary embolism, DVT, unstable angina, atrial fibrillation (for stroke) Often heparin immediately, followed by warfarin (slow onset) Thrombocytopaenia ( platelets) less with low MW Overdose stop therapy, give protamine (forms inactive complex with heparin) Bleeding, nose bleeds, red/dark urine or faeces Haemorrhage Dose monitoring in vitro clotting assay (INR) Overdose stop therapy, give vitamin K via i.v. or p.o. Bleeding disorders Major trauma Severe hypertension Thrombocytopaenia Same as heparin Alcoholism Increased by: Vitamin K deficiency Liver disease Ageing Decreased by: Pregnancy Poor compliance Increased by: Barbiturates Alcohol Green leafy vegetables Decreased by: Cimetidine Salicyclates
4 International normalised ratio (INR) Normal range Bleeding potential 5 Clotting potential 0.5 Range on warfarin 2 4 Standardised PT assay between labs Plasma + thromboplastin (tissue factor) time to clot (~15sec) standardised factor INR = (PT patient / PT untreated )
5 Antiplatelet drugs Impair or prevent the aggregation of platelets Treat consequences of arterial thrombosis Type Drug Mechanism Indications Adverse effects Contraindications COX inhibitors Aspirin Cyclo-oxygenase convert arachidonic acid cycloendoperoxides thromboxane, prostacyclin, prostaglandin GI (dyspepsia, nausea, vomiting, bleeding) Phosphodiesterase inhibitors Platelet binding/adhesion inhibitor Inhibition of TXA 2 >> PGI 2 Dipyridamole Phosphodiesterase inhibitor platelet camp inhibits ADP-induced platelet aggregation Clopidogrel Abciximab Inhibits TXA 2 formation Blocks ADP receptor on platelets inhibits ADP-induced platelet aggregation Antagonist of glycoprotein IIb/IIIa receptor on platelets block pathway of platelet activation Prevents binding of fibrinogen to platelets Prevention of stroke Prevention of MI High risk patients (unstable angina) Post MI Following surgery (bypass, angioplasty) Thromboembolic disorders and cardiac complications e.g. pulmonary embolism, unstable angina, atrial fibrillation, coronary angioplasty, stents Monoclonal antibody hospital use only Gout Headache Nausea Severe bleeding Develop antibodies Thrombocytopaenia Aspirin intolerance Haemophilia History of GIT bleeding or peptic ulcer Bleeding disorders Caution when combined with aspirin
6 Fibrinolytic drugs (plasminogen activators) Facilitate fibrinolysis by catalysing the production of plasmin. Some selectivity conferred by targetting plasminogen adsorbed to fibrin. Streptokinase Alteplase recombinant tissue plasminogen activator (rtpa). Most fibrin selective. Indications acute MI, pulmonary embolism, acute thrombotic stroke. Adverse effects bleeding (GIT), stroke, allergic reactions, hypotension (streptokinase).
7
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