ANTICOAGULANTS

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ANTICOAGULANTS:

ANTICOAGULANTS Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC.

Anticoagulants :

Anticoagulants Parenteral Anticoagulants Heparin Low Molecular Weight Heparins - Enoxaparin Dalteparin , Tinzaparin , Ardeparin , Nadroparin , Reviparin Synthetic Heparin Derivatives- Fondaparinux Thrombin Inhibitors- lepirudin , Bivalirudin , Desirudin , Argatroban , Danaparoid , Drotecogin Alfa (All Parentral ), Rivaroxiban , Dabigatran (Oral)

Oral Anticoagulants :

Oral Anticoagulants Coumarin derivatives: warfarin, acenocumarol , ethyl biscoumacetate and dicumarol Indanedione group: phenindione and anisindione

Coagulation :

Coagulation Factor Name  I Fibrinogen II Prothrombin III Tissue Factor or thromboplastin IV Ca++ V Proaccelerin VII Proconvertin VIII Antihemophilic A factor IX Christmas factor or X Stuart factor XI Plasma thomboplastin antecedent XII Hageman factor XIII Fibrin stabilizing factor

Clotting Cascade:

Clotting Cascade

What’s the difference?:

What’s the difference? Intrinsic Pathway All clotting factors are within the blood vessels Clotting slower Activated partial thromboplastin test ( aPTT ) Extrinsic Pathway Initiating factor is outside the blood vessels - tissue factor Clotting - faster - in Seconds Prothrombin test (PT)

Sites of drug action:

Sites of drug action

Standard Unfractionated Heparin (UFH) :

Standard Unfractionated Heparin (UFH) Heparin is a non-uniform mixture of straight chain mucopolysaccharide molecules The mean molecular weight of heparin is 15,000 D Strongest organic acid present in body Source- mast cells  lung, liver, Int.mucosa Actions –acts both in-vivo and invitro Antithrombin III (ATIII) binding is necessary for its anticoagulant activity

Heparin-Mechanism of action :

Heparin-Mechanism of action Antithrombin III (ATIII) is a slow endogenous progressive inhibitor of thrombin and other clotting enzymes. Higher doses inhibits platelet aggregation and Prolongs bleeding time. Lipaemia clearing

Pharmacokinetics :

Pharmacokinetics Large, highly ionised molecule, Bioavailability- sc -variable, IV Does not cross –BBB or placenta Excreted in urine T 1/2 -1-4 hrs 1000, 5000 u/ml 5ml vials Should not be mixed with pencillins , tetracyclines .

Adverse effects:

Adverse effects Bleeding: they both lead to bleeding but the bleeding is less in LMWH To treat bleeding: inject antidote protamine sulphate (1mg IV for each 100 units of UFH) (reversal effect) Thrombosis: heparin  ↓ ATIII  ↑risk of thrombosis

Adverse effects:

Adverse effects Thrombocytopenia: Heparin-induced thrombocytopenia (HIT) is a life threatening immune reaction HIT  ↑ platelet activation  platelet aggregation  thrombosis. HIT  endothelial damage HIT may occur in the early stages of treatment (within 5 days) but it’s non-immune reaction (not life threatening) LMWHs, though of lower risk, are contraindicated with HIT. Osteoporosis, hyperkalemia , hypersensitivity

Contraindications :

Contraindications Bleeding or hemophilia Severe hypertension Thrombocytopenia or purpura-HIT Intracranial hemorrhage Recent surgery- occular , neuro , lumbar Hypersensitivity to heparin TB GIT ulcer Hepatic or renal disease, chronic alcoholics Use of digoxin

Low molecular weight heparins(LMW):

Low molecular weight heparins(LMW) M.Wt 2000-8000 Da ( avg 4500 Da )- prepared from SH by fractionation & enzymatic degradation . Commercial preprn : Enoxaparin, Dalteparin , Ardeparin , Tinzaparin , Reviparin , Nadroparin Routes : SC (OD) High anti-Xa and low anti- IIa activity↔ greater antithrombotic and lower anticoag activity Low anti- IIa activity, hence, aPTT , TT are not ideal for monitoring. Anti-Xa assay ideal Less complicated, dose independent clearance and more predictable anticoagulant response than UFH.

Uses :

Uses Heparin –IV -5000-10000 units Low dose regimen-sc-DVT LMWH- Prophylaxis and trmt of DVT, pulm . Embolism-enoxaparin -30mg sc Unstable angina and MI- To maintain patency of canula and shunts RHD Cerebrovascular diseases DIC Anticoagulation in pregnancy Treatment of peripheral embolism

Oral direct thrombin inhibitor- Dabigatran etexilate, Rivaroxiban:

Oral direct thrombin inhibitor- Dabigatran etexilate , Rivaroxiban Dabigatran etexilate is a new oral direct thrombin inhibitor and the prodrug of dabigatran Rivaroxaban is an orally available, small-molecule, active site-directed factor Xa inhibitor Knee repalacement surgeries Equivalent to LMWH

Synthetic heparin derivative-Fondaparinux:

Synthetic heparin derivative-Fondaparinux first selective factor Xa inhibitor, 55% better than enoxaparin (LMWH) at reducing risk of VTE synthetic pentasaccharide: “represents the oligosaccharide consensus sequence of heparin” Indirect inhibition: binds to antithrombin and increases antithrombin’s affinity for factor Xa by 300-fold Fondaparinux is given –sc- once daily Long elimination t 1/2 (20 hrs). Renal clearance Initial treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and for venous thromboembolism prevention in patients undergoing surgery for hip fracture or hip/knee replacement

Thrombin inhibitors:

Thrombin inhibitors Lepirudin (DTI) derived from hirudin from leech salivary glands. -ischemic conditions associated with unstable angina Better in hepatic insufficiency patients Bivalirudin (DTI) approved for use during heparin-induced thrombocytopenia (HIT) & percutaneous coronary interventions Argatroban (DTI) can be used in patients with risk of (HIT) Desirudin -DVT

Direct thrombin inhibitors:

Direct thrombin inhibitors Danaparoid -84% heparan sulphate+12% dermatan sulphate + 4% chondroitin sulphate Drotrecogin Alfa Human recombinant activated protein C used in patients with sepsis; recombinant form of activated protein C that inhibits f Va and f VIIIa

Oral Anticoagulants :

Oral Anticoagulants Vitamin K Antagonists (The Coumarins ) Vitamin K is co-factor for the hepatic synthesis of clotting factors II, VII, IX & X Warfarin inhibits Vit . K reductase  no active form of Vit . K  no synthesis of clotting factors Clinical anticoagulant activity needs several days to develop (due to the already circulating clotting factors) So the action of warfarin will appear after the elimination of prior clotting factors.

Warfarin :

Warfarin Onset: starts after 12-16 hours lasts for 4-5 days Elimination time (factor II needs: 60 hours factor X: 40 hours) Overlap heparin & warfarin therapy taken together until the effect of warfarin appears (after 5 days) then stop taking heparin.

Pharmacokinetics:

Pharmacokinetics Warfarin has 100% oral bioavailability, plasma protein binding-99% & long plasma t1/2 of 36 hours A high loading dose followed by an adjusted maintenance dose Contraindicated with pregnancy -is teratogenic in the first trimester & and induce intracranial hemorrhage in the baby during delivery Warfarin is metabolized by hepatic Cytochrome P450 enzymes with half-life of 40 hrs

Oral anticoagulants:

Oral anticoagulants Dicumerol - bishydroxycoumarin - slowly, unpredictably t 1/2 -prolonged GI-intolerance Acenocumarol -t 1/2 -8hrs active metabolite-24hrs rapid action 1, 2, 4mg Ethyl biscoumoacetate -rapid and brief action Indandione derivative- Phenindione -S/E-leucopenia, agranulocytosis, haemorrhage Anisindione - S/E- vasculitis , haemorrhage , hematuria

Uses :

Uses Prophylaxis and/or treatment of: Venous thrombosis and its extension-2-2.5 Pulmonary embolism Thromboembolic complications associated with AF and cardiac valve replacement- Post MI, to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization-3-3.5 Prevention and treatment of cardiac embolism.

PowerPoint Presentation:

INR= patients PT in seconds mean normal PT in seconds ISI INR = International Normalized Ratio ISI = International Sensitivity Index INR Equation

Problems with Warfarin:

Problems with Warfarin Food and drug interactions Genetic variation in metabolism narrow therapeutic window slow onset of action overlap with parenteral drugs dosage adjustments & freq. monitor with INR

Drug Interactions :

Drug Interactions Induce microsomal enzymes (barbiturates, meprobamate and other sedative-hypnotic drugs; griseofulvin). Inhibition of metabolism (e.g., allopurinol disulfiram. Displaced from binding sites by phenylbutazone, phenytoin, sulfinpyrazone, clofibrate and other drugs . Salicylates, indomethacin, Oral Contraceptives Acetaminophen  inhibits warfarin degradation Effect of anticoagulants on other drugs -Coumarin agents prolong and intensify action of chlorpropamide, tolbutamide, phenytoin and phenobarbital .

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