ANTI-COAGULANTSANTI-COAGULANTS

DR.UZMA RIAZDR.UZMA RIAZ

ThrombosisThrombosis

• Venous thrombosisVenous thrombosis is associated with stasis of blood is associated with stasis of blood

• Has Has small platelet componentsmall platelet component and and large componentlarge component of of fibrinfibrin

• Arterial thrombosisArterial thrombosis is associated with atherosclerosis is associated with atherosclerosis

-initiated due to endothelial injury leads to atheromatous -initiated due to endothelial injury leads to atheromatous plaque formationplaque formation

• Plaque rupture, platelet adhesion, activation, aggregation Plaque rupture, platelet adhesion, activation, aggregation initiates thrombus growthinitiates thrombus growth

• ThrombusThrombus has has large platelet componentlarge platelet component

• Arterial thrombus may break away, emboli form leads to Arterial thrombus may break away, emboli form leads to ischemia and infarctionischemia and infarction

HemostasisHemostasis

• Spontaneous Arrest of Bleeding from a Damaged Blood Spontaneous Arrest of Bleeding from a Damaged Blood Vessel; This occurs by the following stepsVessel; This occurs by the following steps

1. Vasospasm1. Vasospasm

2. Platelet Adhesion2. Platelet Adhesion

3. Platelet Aggregation3. Platelet Aggregation

4. Platelet Plug4. Platelet Plug

5. Fibrin Reinforcement of platelet plug5. Fibrin Reinforcement of platelet plug

CoagulationCoagulation

This is the conversion of blood in the liquid form to a solid gel or This is the conversion of blood in the liquid form to a solid gel or clot.clot.

Normally there is a balance between Procoagulants Normally there is a balance between Procoagulants (thromboxane,(thromboxane,

thrombin, activated platelets etc.) and Anti-coagulantsthrombin, activated platelets etc.) and Anti-coagulants

(heparan sulfate, Antithrombin III, Nitric oxide and Prostacyclin)(heparan sulfate, Antithrombin III, Nitric oxide and Prostacyclin)

Whenever this balance is disturbed coagulation occurs: Whenever this balance is disturbed coagulation occurs:

• Procoagulants > AnticoagulantsProcoagulants > Anticoagulants

• Injury to blood vesselInjury to blood vessel

• Blood stasisBlood stasis

Clotting FactorsClotting Factors

• I - FibrinogenI - Fibrinogen• II - ProthrombinII - Prothrombin• III - Tissue ThromboplastinIII - Tissue Thromboplastin• IV - CalciumIV - Calcium• V - ProaccelerinV - Proaccelerin• VII - ProconvertinVII - Proconvertin• VIII- Antihemophilic globulinVIII- Antihemophilic globulin• IX - Christmas FactorIX - Christmas Factor• X - Stuart Power FactorX - Stuart Power Factor• XI - Plasma Thromboplastin anticedent (PTA)XI - Plasma Thromboplastin anticedent (PTA)• XII - Hageman FactorXII - Hageman Factor• XIII -Fibrin-stabilizing factorXIII -Fibrin-stabilizing factor

INITIATION OF BLOOD COAGULATIONINITIATION OF BLOOD COAGULATIONExtrinsic Pathway

Tissue traumaTissue trauma

Leakage of Tissue FactorLeakage of Tissue Factor

XX XaXa

Prothrombin activatorProthrombin activator

CaCa+2+2,, factor VII factor VII

CaCa+2+2

Prothrombin Prothrombin Thrombin Thrombin(factor II)(factor II)

CaCa+2+2

Intrinsic PathwayBlood trauma/ contact with collagenBlood trauma/ contact with collagen

Activation of factor Activation of factor XII, IX, VIIIXII, IX, VIII

XX XaXa

CaCa+2+2

ProthrombinProthrombin activatoractivator

Prothrombin Prothrombin Thrombin Thrombin(factor II)(factor II)

Activation of certain factors (VII, II, X and protein C and S) is essential for coagulation. This activation requires vit K (reduced form)

Classification Classification

A. Parenteral Anti-CoagulantsA. Parenteral Anti-Coagulants

1. Indirect Thrombin Inhibitors1. Indirect Thrombin Inhibitors

a) Heparinsa) Heparins i) High Molecular Weight Heparini) High Molecular Weight Heparin

Unfractionated Heparin (UFH)Unfractionated Heparin (UFH) ii) Low Molecular Weight Heparinsii) Low Molecular Weight Heparins

EnoxaparinEnoxaparin DalteparinDalteparinTinzaparinTinzaparin ReviparinReviparinDanaparoidDanaparoid

2. Direct Thrombin Inhibitors2. Direct Thrombin Inhibitors

HirudinHirudin LepirudinLepirudin

BivalirudinBivalirudin ArgatrobanArgatroban

B. Oral Anti-CoagulantsB. Oral Anti-Coagulants1. Coumarins1. Coumarins

WarfarinWarfarin

DicumarolDicumarol

2. Indanediones2. Indanediones

PhenindionePhenindione

Heparin,HistoryHeparin,History

• McLeanMcLean, a 2, a 2ndnd year medical student attempting to extract year medical student attempting to extract coagulant substances from various tissues during a coagulant substances from various tissues during a vacation project. But found instead a powerful vacation project. But found instead a powerful anticoagulant. He discovered in 1916 that liver contains a anticoagulant. He discovered in 1916 that liver contains a powerful anticoagulant. powerful anticoagulant.

• Howell and HoltHowell and Holt in 1918 named it in 1918 named it heparinheparin because it because it was obtained from liverwas obtained from liver

• Occurs in mast cells (richest source of mast cells are lungs, Occurs in mast cells (richest source of mast cells are lungs, liver and intestinal mucosa)liver and intestinal mucosa)

• Commercial heparin is extracted from porcine intestinal Commercial heparin is extracted from porcine intestinal mucosa and bobine lung mucosa and bobine lung

• It is a mixture of straight chain anionic (negative charge) It is a mixture of straight chain anionic (negative charge) glycosaminoglycan with a wide range of molecular weightsglycosaminoglycan with a wide range of molecular weights

• It is strongly acidic because of presence of sulfate and It is strongly acidic because of presence of sulfate and carboxylic acid groupscarboxylic acid groups

Heparin-KineticsHeparin-Kinetics

• Heparin is highly charged, thus crosses cell membranes Heparin is highly charged, thus crosses cell membranes very poorly, hence given Parenterallyvery poorly, hence given Parenterally

• Low dose: Subcutaneous Low dose: Subcutaneous • High Dose: Subcutaneous or IV InjectionHigh Dose: Subcutaneous or IV Injection• Metabolized by liver, half life depends on doseMetabolized by liver, half life depends on dose

Heparin-Mechanism of ActionHeparin-Mechanism of Action• Once the coagulation pathways are activated, factors IXa, Xa, XIa, XIIa and Once the coagulation pathways are activated, factors IXa, Xa, XIa, XIIa and

IIa (especially IIa (especially IIa,IXa,XaIIa,IXa,Xa), need to be neutralized by Anti-thrombin III (AT ), need to be neutralized by Anti-thrombin III (AT III).III).

• Heparin accelerates the interaction of the active clotting factors with AT Heparin accelerates the interaction of the active clotting factors with AT III. III.

• The negatively charged heparin molecule binds to the positively charged The negatively charged heparin molecule binds to the positively charged lysine sites on AT IIIlysine sites on AT III

• This causes a conformational change in AT III and exposing its active This causes a conformational change in AT III and exposing its active arginine sitearginine site

• The serine active sites of the active clotting factors bind to the reactive The serine active sites of the active clotting factors bind to the reactive arginine site of AT IIIarginine site of AT III

• The resulting complex is removed by the reticuloendothelial systemThe resulting complex is removed by the reticuloendothelial system• This process is accelerated 1000-3000 times by heparinThis process is accelerated 1000-3000 times by heparin

• The active heparin molecules bind tightly to antihormbin and The active heparin molecules bind tightly to antihormbin and cause a conformational change in this inhibitor. The cause a conformational change in this inhibitor. The conformational change of antithrombin exposes its active site for conformational change of antithrombin exposes its active site for more rapid interaction with the proteases (the activated clotting more rapid interaction with the proteases (the activated clotting factors) Heparin functions as a cofactor for the antithrombin factors) Heparin functions as a cofactor for the antithrombin protease reactio without being consumed. Once the antithrombin protease reactio without being consumed. Once the antithrombin protease complex is formed, heparin is released intact for protease complex is formed, heparin is released intact for renewed binding to more antithrombin.renewed binding to more antithrombin.

• Heparin catalyzes the reaction without being consumedHeparin catalyzes the reaction without being consumed

• Once antithrombin-clotting factor complex is formed, Once antithrombin-clotting factor complex is formed, heparin is released for renewed binding to more heparin is released for renewed binding to more antithrombinantithrombin

• High molecular weight Heparins accelerates the inactivation High molecular weight Heparins accelerates the inactivation of clotting factors of clotting factors IIa and XaIIa and Xa..

• Low molecular weight heparins accelerate the inactivation Low molecular weight heparins accelerate the inactivation of only Factor of only Factor XaXa

MechanismMechanism

No heparinNo heparin

Active clotting factorsActive clotting factors

Slow Slow Antithrombin Antithrombin IIIIII

Inactive clotting factorsInactive clotting factors

Heparin Heparin

Active clotting factorsActive clotting factors

Fast Fast Antithrombin Antithrombin IIIIII

++ HeparinHeparin

Inactive clotting factorsInactive clotting factors

CharacterCharacter HMW HeparinsHMW Heparins LMW HeparinsLMW Heparins

Molecular WeightMolecular Weight HighHigh

(30000 Daltons)(30000 Daltons)LowLow

(5000 Daltons)(5000 Daltons)

BiotransformationBiotransformation LowLow High (90%)High (90%)

Half LifeHalf Life Shorter-depends on Shorter-depends on dosedose

Longer-independent Longer-independent of doseof dose

Mechanism of ActionMechanism of Action Inactivate both factor Inactivate both factor IIa and factor XaIIa and factor Xa

Inactivate only factor Inactivate only factor XaXa

Anti-coagulant effectAnti-coagulant effect More effectiveMore effective less effectiveless effective

MonitoringMonitoring By aPTTBy aPTT Can be given once or twice Can be given once or twice daily without monitoring, but daily without monitoring, but requires special assay if requires special assay if necessarynecessary

Adverse Adverse

EffectsEffectsLess chance of Less chance of thrombocytopenia and long thrombocytopenia and long term osteoporosisterm osteoporosis

ExcretionExcretion Cleared by the Cleared by the Reticuloendothelial Reticuloendothelial systemsystem

Cleared unchanged by Cleared unchanged by kidneyskidneys

ReversalReversal By protamineBy protamine Not fully reversed by Not fully reversed by protamineprotamine

ExpenseExpense Not expensiveNot expensive ExpensiveExpensive

Dose Dose

ResponseResponseLess predictable dose Less predictable dose response because of response because of binding to plasma proteins, binding to plasma proteins, macrophages and macrophages and endothelial cellsendothelial cells

Has a more predictable Has a more predictable dose-response because dose-response because it does not bind to it does not bind to plasma proteins, plasma proteins, macrophages, or macrophages, or endothelial cells.endothelial cells.

UseUse More effective forMore effective for

a) Orthopaedic a) Orthopaedic procedures on lower limbprocedures on lower limb

b) Pulmonary Embolismb) Pulmonary Embolism

c) Unstable Anginac) Unstable Angina

Advantages of LMWH over UFHAdvantages of LMWH over UFH

• Better subcutaneous bioavailability(70-90%) compared to Better subcutaneous bioavailability(70-90%) compared to UFH(20-30%)UFH(20-30%)

• Longer and more consistent half life: once daily Longer and more consistent half life: once daily subcutaneous administrationsubcutaneous administration

• Since aPTT/clotting times are not prolonged, lab. monitoring Since aPTT/clotting times are not prolonged, lab. monitoring is not neededis not needed

• Lower incidence of haemorrhagic complicationsLower incidence of haemorrhagic complications

• Appear to have lesser antiplatelet action so less Appear to have lesser antiplatelet action so less interference with haemostasissinterference with haemostasiss

Uses of Heparin (Anti-coagulants in Uses of Heparin (Anti-coagulants in General)General)

1.Treatment & Prevention of Deep Venous Thrombosis1.Treatment & Prevention of Deep Venous Thrombosis in in

• Bedridden (Immobilized patients)Bedridden (Immobilized patients)

• Old peopleOld people

• Post-operativePost-operative

• Post-stroke patientsPost-stroke patients

• Leg fracturesLeg fractures

• Elective SurgeryElective Surgery

2. 2. Ischemic Heart DiseaseIschemic Heart DiseaseUnstable anginaUnstable anginaAfter MIAfter MIAfter angioplasty CABG, stent replacement; Prevent After angioplasty CABG, stent replacement; Prevent

recurrencerecurrence

3. 3. Rheumatic Heart Disease/ Atrial FibrillationRheumatic Heart Disease/ Atrial FibrillationWarfarin, heparin, low dose aspirin, Warfarin, heparin, low dose aspirin, Decrease stroke due to emboliDecrease stroke due to emboli

4. 4. Cerebrovascular DiseasesCerebrovascular DiseasesCerebral Emboli (Prevention of recurrence)Cerebral Emboli (Prevention of recurrence)

5. 5. Vascular Surgery, Prosthetic heart valves, HemodialysisVascular Surgery, Prosthetic heart valves, HemodialysisTo prevent thromboembolismTo prevent thromboembolism

6. 6. DICDICAbruptio placenta, malignancies, infections; increased Abruptio placenta, malignancies, infections; increased consumption of clotting factorsconsumption of clotting factors

Adverse EffectsAdverse Effects

1.Bleeding(most common)1.Bleeding(most common)

2. Allergy and Anaphylaxis2. Allergy and Anaphylaxis

3. Increased hair loss, alopecia3. Increased hair loss, alopecia

4. Long term-Osteoporosis, spontaneous fractures4. Long term-Osteoporosis, spontaneous fractures

5. Thrombocytopenia5. Thrombocytopenia

Heparin-induced Thrombocytopenia Heparin-induced Thrombocytopenia HIT)HIT)

• 22ndnd most common side effect after bleeding most common side effect after bleeding• Occurs in 3-5% of patients 5 to 10 days after initiation of Occurs in 3-5% of patients 5 to 10 days after initiation of

therapy of standard heparintherapy of standard heparin• Lower incidence in low molecular wt heparin. Lower incidence in low molecular wt heparin. • In 1/3 of pts is preceded by thrombosisIn 1/3 of pts is preceded by thrombosis• Can be life-threatening.Can be life-threatening.• Due to production of IgG against complexes of heparin Due to production of IgG against complexes of heparin

with platelet (platelet factor 4) with platelet (platelet factor 4) • The complexes activate more platelets with the release of The complexes activate more platelets with the release of

more platelet factor 4 or other cytokines.more platelet factor 4 or other cytokines.• This stimulates the formation of more IgG.This stimulates the formation of more IgG.• This snow-ball effect uses up platelets and also leads to This snow-ball effect uses up platelets and also leads to

thrombosis. Systemic bleeding and localized infarction thrombosis. Systemic bleeding and localized infarction (due to thrombosis) occur. (due to thrombosis) occur.

• Once thrombocytopenia is determined, heparin must be Once thrombocytopenia is determined, heparin must be stopped. Direct thrombin inhibitor should be givenstopped. Direct thrombin inhibitor should be given

• Platelets must NOT be given because they will react with Platelets must NOT be given because they will react with antibody already being produced against them, causing antibody already being produced against them, causing greater chance of thrombosis. greater chance of thrombosis.

3

Heparin and PregnancyHeparin and Pregnancy

• Heparin does not cross the placenta, therefore it must be Heparin does not cross the placenta, therefore it must be used instead of warfarin in cases of requiring anticoagulant used instead of warfarin in cases of requiring anticoagulant therapy in pregnancy.therapy in pregnancy.

• Warfarin crosses the placenta and induces changed in the Warfarin crosses the placenta and induces changed in the fetus to produce the fetal warfarin syndrome – not good.fetus to produce the fetal warfarin syndrome – not good.

ContraindicationsContraindications

1.1. HypersensitivityHypersensitivity

2. Bleeding Disorders like Hemophilia2. Bleeding Disorders like Hemophilia

3. Thrombocytopenia3. Thrombocytopenia

4-. Intracranial Hemorrhage4-. Intracranial Hemorrhage

5. GIT Ulcerations5. GIT Ulcerations

6. Threatened abortion6. Threatened abortion

7. Advanced renal or hepatic disease7. Advanced renal or hepatic disease

Antidote –Protamine SulfateAntidote –Protamine Sulfate

• Protamine is a highly basic peptide that combines with Protamine is a highly basic peptide that combines with heparin as an ion pair to form a stable complex devoid of heparin as an ion pair to form a stable complex devoid of anticoagulant activityanticoagulant activity

• Hemorrhage – can be reversed by protamine sulfate Hemorrhage – can be reversed by protamine sulfate titrated so that 1 mg of protamine sulfate is administered titrated so that 1 mg of protamine sulfate is administered for every 100 U of heparin remaining in the patient.for every 100 U of heparin remaining in the patient.

• Protamine sulfate is also an anticoagulant because it Protamine sulfate is also an anticoagulant because it interacts with platelets, fibrinogen, and other clotting interacts with platelets, fibrinogen, and other clotting factors – so it can make hemorrhage worse if more is given factors – so it can make hemorrhage worse if more is given than necessary. than necessary.

Direct Thrombin Inhibitors (DTIs)Direct Thrombin Inhibitors (DTIs)

• The DTIs bind thrombin without additional binding proteins, The DTIs bind thrombin without additional binding proteins, such as anti-thrombin, and they do not bind to other plasma such as anti-thrombin, and they do not bind to other plasma proteins such as platelet factor 4.proteins such as platelet factor 4.

• Hirudin and Bivalirudin bind at both the catalytic or active Hirudin and Bivalirudin bind at both the catalytic or active site of thrombin as well as at a substrate recognition sitesite of thrombin as well as at a substrate recognition site

• Argatroban bind only at the thrombin active siteArgatroban bind only at the thrombin active site

LepirudinLepirudin

• Monitored by aPTTMonitored by aPTT

• Action independent of antithrombinAction independent of antithrombin

• Use in thrombosis related to heparin induced Use in thrombosis related to heparin induced thrombocytopeniathrombocytopenia

• No antidoteNo antidote

• Adverse effect: Antibody formation against thrombin-Adverse effect: Antibody formation against thrombin-lepirudin complexlepirudin complex

Bivalirudin:Bivalirudin: Inhibits platelet activation also Inhibits platelet activation also

Use in percutaneous coronary angiographyUse in percutaneous coronary angiography

Argatroban:Argatroban: Used in heparin induced thrombocytopenia with Used in heparin induced thrombocytopenia with or without thrombosisor without thrombosis

Monitored by aPTTMonitored by aPTT

Dose reduction in liver diseaseDose reduction in liver disease

Oral Anti-Coagulants,HistoryOral Anti-Coagulants,History

• Following the report of a hemorrhagic disorder in cattle that Following the report of a hemorrhagic disorder in cattle that resulted from the ingestion of spoiled sweet clover silage, resulted from the ingestion of spoiled sweet clover silage, Campbell and Link, in 1939, identified the hemorrhagic Campbell and Link, in 1939, identified the hemorrhagic agent as bishydroxycoumarin (dicoumarol). agent as bishydroxycoumarin (dicoumarol).

• In 1948, a more potent synthetic congener was introduced In 1948, a more potent synthetic congener was introduced as an extremely effective rodenticide; the compound was as an extremely effective rodenticide; the compound was named named warfarinwarfarin as an acronym derived from the name of as an acronym derived from the name of the patent holder, Wisconsin Alumni Research Foundation. the patent holder, Wisconsin Alumni Research Foundation.

• Warfarin's potential as a therapeutic anticoagulant was Warfarin's potential as a therapeutic anticoagulant was recognized but not widely accepted, partly due to fear of recognized but not widely accepted, partly due to fear of unacceptable toxicity. unacceptable toxicity.

• However, in 1951, an Army inductee uneventfully survived However, in 1951, an Army inductee uneventfully survived an attempted suicide with massive doses of a preparation an attempted suicide with massive doses of a preparation of warfarin intended for rodent control. of warfarin intended for rodent control.

• Since then, these anticoagulants have become a mainstay Since then, these anticoagulants have become a mainstay for prevention of thromboembolic disease for prevention of thromboembolic disease

WWisconsin isconsin AAlumni lumni RResearch esearch FFoundation oundation CoumCoumarin--Warfarinarin--Warfarin

Warfarin-PharmacokineticsWarfarin-Pharmacokinetics1. Rapidly and completely absorbed after oral administration1. Rapidly and completely absorbed after oral administration2. 100% Bioavailability 2. 100% Bioavailability 3. Highly plasma protein bound (99%)3. Highly plasma protein bound (99%)4. Crosses the placenta (teratogenic)4. Crosses the placenta (teratogenic)5. Appears in milk; infants given Vitamin K5. Appears in milk; infants given Vitamin K6. Variable but slow clearance;depends on hepatic P450s6. Variable but slow clearance;depends on hepatic P450s

7. 7. Biotransformation by the liver: Oxidation, GlucuronidationBiotransformation by the liver: Oxidation, Glucuronidation8. Takes 12-16 hours before effect is observed8. Takes 12-16 hours before effect is observed

Vitamin KVitamin K

Synthesis of Synthesis of Functional Functional

Coagulation Coagulation FactorsFactors

VIIVII

IXIX

XX

IIII

Vitamin K-Dependent Vitamin K-Dependent Clotting FactorsClotting Factors

WarfarinNo Synthesis No Synthesis of Functional of Functional Coagulation Coagulation

FactorsFactors

Antagonismof

Vitamin K

Warfarin Mechanism of ActionWarfarin Mechanism of Action

Vitamin K

VIIVII

IXIX

XX

IIII

Mechanism of ActionMechanism of Action

• Coumarins block the Gamma Carboxylation of glutamic acid Coumarins block the Gamma Carboxylation of glutamic acid residues of Clotting factors residues of Clotting factors II,VII, IX, XII,VII, IX, X as well as the as well as the endogenous anti-coagulants endogenous anti-coagulants C & S.C & S.

• This is coupled with oxidative deactivation of Vitamin KThis is coupled with oxidative deactivation of Vitamin K

• Coumarins and Indanediones inhibit the enzyme Coumarins and Indanediones inhibit the enzyme Vitamin KVitamin K epoxideepoxide reductasereductase that converts Vitamin K epoxide back that converts Vitamin K epoxide back into the active hydroquinone (reduced form)into the active hydroquinone (reduced form)

• Thus they prevent the activation of Vitamin K and hence Thus they prevent the activation of Vitamin K and hence along with it carboxylations of clotting factor residuesalong with it carboxylations of clotting factor residues

Why Carboxylation is necessary?Why Carboxylation is necessary?

• Carboxylation is necessary for ability of clotting factors to Carboxylation is necessary for ability of clotting factors to bind Ca and to get bound to phospholipid surfaces which is bind Ca and to get bound to phospholipid surfaces which is necessarynecessary

for coagulationfor coagulation

• Factor VII affected first, then IX, X, and finally Factor II Factor VII affected first, then IX, X, and finally Factor II (depends(depends upon half lives of circulating factors)upon half lives of circulating factors)

CH3

R

OH

OH O

O

CH3

R

O

O

O

CH3

R

NH

O

H

COOH

NH

O

COOH

COOHGlu residues Gla residuesin prothrombin in prothrombin

vitamin K vitamin Khydroquinone 2,3-epoxide

vitamin K vitamin Kreductase epoxide reductase

vitamin K

Anticoagulant coumarinsand 1,3-indandiones

UsesUses

• Same as Heparin and other AnticoagulantsSame as Heparin and other Anticoagulants

• Monitoring necessary because of its low therapeutic indexMonitoring necessary because of its low therapeutic index

• PT (Prothrombin time is noted; time taken for blood to clot)PT (Prothrombin time is noted; time taken for blood to clot)

• Patients on Heparin are shifted to oral warfarin after 3-5 Patients on Heparin are shifted to oral warfarin after 3-5 daysdays

Adverse EffectsAdverse Effects

1. 1. BleedingBleedingMost common and most serious adverse effect;Most common and most serious adverse effect;

Epistaxis, hematuria, GIT Bleeding, internal hemorrhagesEpistaxis, hematuria, GIT Bleeding, internal hemorrhages

2. 2. Cutaneous NecrosisCutaneous Necrosis This is due to decreased activity of Protein CThis is due to decreased activity of Protein C Protein C and Protein S found in bone & other tissues also Protein C and Protein S found in bone & other tissues also

require Gamma carboxylationsrequire Gamma carboxylations

3. 3. InfarctionInfarction of breast, fatty tissues, intestine and extremities of breast, fatty tissues, intestine and extremities due to venous thrombosis caused by again decreased due to venous thrombosis caused by again decreased activity of Protein Cactivity of Protein C

Antidote of WarfarinAntidote of Warfarin

• Stop WarfarinStop Warfarin

• Give Vitamin K (Antidote)Give Vitamin K (Antidote)

• Also Fresh frozen plasma, Prothrombin complex Also Fresh frozen plasma, Prothrombin complex concentrates and Recombinant factor VIIa can be concentrates and Recombinant factor VIIa can be administeredadministered

ContraindicationsContraindications

1. Pregnancy1. Pregnancy Fetal protein in bone and blood affectedFetal protein in bone and blood affected

-Causes birth defects including abnormal bone formation, -Causes birth defects including abnormal bone formation, bone hyperplasiabone hyperplasia

-CNS Defects, fetal hemorrhage, fetal hypoprothrombinemia -CNS Defects, fetal hemorrhage, fetal hypoprothrombinemia and fetal death may occurand fetal death may occur

2. Other contraindications same as heparin2. Other contraindications same as heparin

Drug Interactions of WarfarinDrug Interactions of Warfarin

A.Pharmacokinetic InteractionsA.Pharmacokinetic Interactions1. Agents that inhibit metabolism of warfarin1. Agents that inhibit metabolism of warfarin• CimetidineCimetidine• ImipramineImipramine• CotrimoxazoleCotrimoxazole• ChloramphenicolChloramphenicol• CiprofloxacinCiprofloxacin• MetronidazoleMetronidazole• AmiodaroneAmiodarone

2. Drugs that increase metabolism of Warfarin2. Drugs that increase metabolism of Warfarin• BarbituratesBarbiturates• RifampinRifampin

3. 3. Drugs that displace warfarin from binding sites Drugs that displace warfarin from binding sites on plasma albuminon plasma albumin

• Chloral hydrateChloral hydrate• NSAIDsNSAIDs

4. Drugs that decrease GIT absorption of warfarin4. Drugs that decrease GIT absorption of warfarin• CholestyramineCholestyramine

B. Pharmacodynamic InteractionsB. Pharmacodynamic Interactions

1. Synergistic effect1. Synergistic effect• HeparinHeparin

• AspirinAspirin

• Antibiotics: Decrease bacterial flora—decrease Vitamin K Antibiotics: Decrease bacterial flora—decrease Vitamin K synthesis—increased warfarin effectsynthesis—increased warfarin effect

Physiological/Pathological Factors Physiological/Pathological Factors affecting Warfarin Actionaffecting Warfarin Action

1. Increased warfarin action1. Increased warfarin action

• Malnutrition, debility (Decreased Vit. K)Malnutrition, debility (Decreased Vit. K)

• Liver disease, chronic alcoholism (Decreased Liver disease, chronic alcoholism (Decreased clotting factors)clotting factors)

• Hyperthyroidism (Increased degradation of Hyperthyroidism (Increased degradation of Clotting factors)Clotting factors)

• Newborns (Decreased vitamin K)Newborns (Decreased vitamin K)

2. Decreased Warfarin Action2. Decreased Warfarin Action• Pregnancy (Increased clotting factors)Pregnancy (Increased clotting factors)

• Nephrotic syndromeNephrotic syndrome

• Warfarin resistance (Genetic)Warfarin resistance (Genetic)

CharacterCharacter HEPARINHEPARIN WARFARINWARFARIN

Route of Route of AdministrationAdministration

ParenteralParenteral OralOral

PolarityPolarity Polar charged Polar charged moleculemolecule

UnchargedUncharged

Onset of ActionOnset of Action RapidRapid 12-16 Hours12-16 Hours

Mechanism of Mechanism of ActionAction

Accelerates Accelerates inactivation of inactivation of clotting factors by clotting factors by Antithrombin IIIAntithrombin III

Inhibits gamma Inhibits gamma Carboxylation of glutamic Carboxylation of glutamic acid residues of clotting acid residues of clotting factorsfactors

Therapeutic IndexTherapeutic Index Not low; safeNot low; safe Low; not safeLow; not safe

MonitoringMonitoring aPTTaPTT PTPT

Adverse Effect Adverse Effect DifferencesDifferences

Thrombocytopenia,,OThrombocytopenia,,Osteoporosis, alopecia, steoporosis, alopecia, anaphylaxisanaphylaxis

Cutaneous Necrosis, Cutaneous Necrosis, Infarction of breast, Infarction of breast, fatty and other fatty and other tissuestissues

Management of Management of PatientPatient

Start with HeparinStart with Heparin Switch over to Switch over to warfarin in 3-5 dayswarfarin in 3-5 days

AntidoteAntidote Protamine SulfateProtamine Sulfate Vitamin KVitamin K

ContraindicationContraindication NotNot PregnancyPregnancy

InteractionsInteractions Not significantNot significant SignificantSignificant