ANTICOAGULANTS

Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

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

Coumarin derivatives: warfarin, acenocumarol, ethyl biscoumacetate and dicumarol

Indanedione group: phenindione and Anisindione

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

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

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 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

Large, highly ionised molecule, Bioavailability- sc -variable, IV Does not cross –BBB or placenta Excreted in urine T1/2-1-4 hrs 1000, 5000 u/ml 5ml vials Should not be mixed with penicillin,

tetracyclines.

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

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

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

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

1. Heparin –IV -5000-10000 units2. Low dose regimen-sc-DVTLMWH-3. Prophylaxis and trmt of DVT, pulm. Embolism-enoxaparin

-30mg sc 4. Unstable angina and MI-5. To maintain patency of canula and shunts6. RHD7. Cerebrovascular diseases8. DIC9. Anticoagulation in pregnancy10. Treatment of peripheral embolism

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 replacement surgeries Equivalent to LMWH

Synthetic heparin derivativeFondaparinux

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

Fondaparinux is given –sc- once daily Long elimination t 1/2 (20 hrs). Renal clearanceUses1. Initial treatment of deep vein thrombosis (DVT) 2. pulmonary embolism (PE) and for 3. Venous thromboembolism prevention in patients

undergoing surgery for hip fracture or hip/knee replacement

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 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

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 factorsClinical 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 priorclotting factors.

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

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 Dicumerol-bishydroxycoumarin-slowly,

unpredictably t1/2-prolonged GI-intoleranceAcenocumarol-t1/2 -8hrs active metabolite-24hrs rapid action 1, 2, 4mg Ethyl biscoumoacetate-rapid and brief actionIndandione derivative-Phenindione-S/E-leucopenia,

agranulocytosis, haemorrhageAnisindione- S/E-vasculitis, haemorrhage, hematuria

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.

INR= patients PT in seconds mean normal PT in seconds

ISI

INR = International Normalized Ratio ISI = International Sensitivity Index

INR Equation

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

1. Induce microsomal enzymes (barbiturates, meprobamate and other sedative-hypnotic drugs; griseofulvin).

2. Inhibition of metabolism (e.g., allopurinol disulfiram.3. Displaced from binding sites by phenylbutazone,

phenytoin, sulfinpyrazone, clofibrate, Salicylates, Indomethacin, Oral Contraceptives

4. Acetaminophen inhibits warfarin degradation5. Effect of anticoagulants on other drugs -Coumarin

agents prolong and intensify action of chlorpropamide, tolbutamide, phenytoin and phenobarbital.

Walking the Dog

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