ANTICOAGULATION THERAPY

Anticoagulants :

Anticoagulants

Anticoagulants - Classification:

Anticoagulants - Classification Oral – Coumarin derivatives - Warfarin sodium,Dicumarol(acinocumarol) Indandion derivatives- Phenindione Parentral – Heparin LMWH

Heparin:

Heparin Heparin - originally isolated from the liver Normally not detected in the blood Potentiates the action of circulating antithrombin III to provide a antithrombotic mechanism HEPARIN can be given as Continuous infusion Intermittent IV Subcutaneous

Heparin – Action:

Heparin – Action Heparin potentiates the action of circulating antithrombin III Antithrombin - rapidly inhibits thrombin only in the presence of heparin Antithrombin inhibits thrombin , Xa, IXa and to a lesser extent VIIa The above reaction goes 1000 to 3000 times faster with heparin .

Heparin:

Heparin Continuous infusion IV – 5000 U stat ,1000 U/ hr Subcutaneously – 5000 U 8 – 12 hrly Continue heparin for 7 – 10 days Keep APTT 1.5 – 2 times of control Complications – Bleeding, HIT Antidote – Protamine sulphate

Heparin Uses:

Heparin Uses To treat DVT and PE because of its rapid onset of action, maintained by oral anticoagulants later on Drug of choice for anticoagulation during pregnancy – does not cross the placenta – not associated with fetal malformations Unstable angina In IV dialysis to prevent thrombosis in the pumps Selected patients with disseminated intravascular coagulation During and after coronary angioplasty or stent placement, Cardiopulmonary bypass surgery

Heparin – Toxicity - Hemorrhage:

Heparin – Toxicity - Hemorrhage Hemorrhage – recent surgery, trauma, peptic ulcer disease, platelet dysfunction Life-threatening bleeding can be reversed by protamine sulfate - 1 mg of protamine sulfate for every 100 U of heparin - slow iv infusion – 50 mg over 10 min) Protamine sulfate interacts with platelets, fibrinogen, and other clotting factors - an anticoagulant effect – at higher doses

Heparin-induced Thrombocytopenia:

Heparin-induced Thrombocytopenia 50% decrease in platelet count - <150,000/ μ l) Antibodies against complexes of heparin with platelet factor 4 In 3-5% of patients 5 to 10 days after initiation of heparin therapy Lower incidence with LMWH Stop heparin immediately

Low Molecular Weight Heparins:

Low Molecular Weight Heparins Avg mol. wt 4,500 daltons - 15 monosaccharide units Better absorbed - higher bioavailability Longer biological half-life More predictable dose-response - does not bind to plasma proteins, macrophages, or endothelial cells Can be given s.c. without lab monitoring in an outpatient setting Cleared unchanged by kidney (do not use in renal failure!) rather than by the reticuloendothelial system Lower risks of thrombocytopenia and bleeding Safety and use during pregnancy not evaluated

LMW heparin:

LMW heparin Dalteparin Enoxaparin Raviparin Uses: 1. prevention of venous thromboembolism 2. Treatment of venous thrombosis, pulmonary embolism and unstable angina 3. prophylaxis following total knee arthroplasty, Major surgeries

LMW heparin:

LMW heparin LMWH Regimen Product Dose Frequency Dalteparin 120 IU/kg Every 12 hrs Nadroparin <55 kg, 12,500 IU 55-80 kg, 15,000 IU >80 kg, 17,500 IU Every 12 hrs Tinzaparin 175 IU/kg Every 24 hrs Dalteparin 200 IU/kg Once daily Nadroparin <50 kg, 8,200 IU 50-70 kg, 12,300 IU >70 kg, 18,400 IU Twice daily Reviparin 35-45 kg, 3,500 IU 46-60 kg, 4,200 IU >60 kg, 6,300 IU Twice daily

Other parenteral anticoagulants:

Other parenteral anticoagulants Danaparoid nonheparin glycosaminoglycans (84% heparan sulfate) Promotes Inhibition of Xa by antithrombin Prophylaxis of deep vein thrombosis In patients with heparin-induced thrombocytopenia Lepirudin recombinant derivative of hirudin (a direct thrombin inhibitor in leech) In patients with heparin-induced thrombocytopenia

Action of Coumarins:

Action of Coumarins Coumarins act here Coumarins act here Vitamin K Coumarins are competitive inhibitors Oral anticoagulants – 4-hydroxycoumarins

Oral anticoagulants – 4-hydroxycoumarins :

Oral anticoagulants – 4-hydroxycoumarins Warfarin induces Vitamin K deficiency Takes several days before full effect is seen - carboxylated factors in plasma need to be cleared Start with Heparin in acute conditions Loading dose 10 mg/day ,then slowly reduce to a maintenance dose (1,2,5)

Warfarin follow-up:

Warfarin follow-up Monitor PT / INR Usual Maintenance of INR AF – 1.5 -2 DVT – 2-3 Lupus anticoagulant -3-4 PE – 3-4 Mechanical valve 3-4

Warfarin - side effects:

Warfarin - side effects Bleeding - Antidote : Vitamin K ,FFP Skin necrosis

Warfarin – drug & other interactions:

Warfarin – drug & other interactions Decreased effect: Cholestyramine binding, hypoproteinemia Barbiturates, Phenytoin , Rifampin Chronic alcohol Vit . K-rich foods or supplements Increased effect (risk of hemorrhage): Reduced metaboilsm and/or displacement from protein binding: phenylbutazone , sulfinpyrazone , metronidazole cimetidine , allopurinol , amiodarone , disulfiram acute alcohol intake

Warfarin – Administration, Absorption, Biotransformation:

Warfarin – Administration, Absorption, Biotransformation Administered orally Completely absorbed Crosses placenta – is teratogenic – birth defects and abortion 99% bound to plasma proteins Biotransformed by the liver Oxidation Glucuronidation