COAGULANTSCOAGULANTS&&

ANTI-COAGULANTSANTI-COAGULANTS

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

Normally there is a balance b/n Procoagulants (TXA2,Normally there is a balance b/n Procoagulants (TXA2,

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)

• Imbalance occurs coagulation Imbalance occurs coagulation

• 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

Blood Vessel Injury

IX IXa

XI XIa

X Xa

XII XIIa

Tissue Injury

Tissue Factor

Thromboplastin

VIIa VII

X

Prothrombin Thrombin

Fibrinogen Fribrin insoluble

Stabilised Fibrin threads

XIIIa

Intrinsic Pathway Extrinsic Pathway

Factors affected

By Heparin

Vit. K dependent FactorsAffected by Oral Anticoagulants

ca+

ca+ ca+

HMW-Kininogen

XIIa, Xia, Kallikrein

ca+

XIII

ca+

COAGULANTSCOAGULANTS

• These are substances which promote These are substances which promote

coagulation & are indicated in coagulation & are indicated in

haemorrhagic states haemorrhagic states

ClassificationClassification

1 .Vitamin K1 .Vitamin K

• K1(from plants, fat-soluable)K1(from plants, fat-soluable)– Phytonadione (phylloquinone)Phytonadione (phylloquinone)

• K3(synthetic)K3(synthetic)– Fat-soluble :Fat-soluble :menadione,acetomenaphthone menadione,acetomenaphthone

– Water soluble :Water soluble :menadione sod.bisulphate menadione sod.bisulphate menadione sod.diphosphate menadione sod.diphosphate

2 .Miscellaneous2 .Miscellaneous– Fibrinogen (human), Antihaemophilic factor, Fibrinogen (human), Antihaemophilic factor,

Desmopressin, Adrenochrome Desmopressin, Adrenochrome monosemicorbazone, Ruti, Ethamsylatemonosemicorbazone, Ruti, Ethamsylate

VITAMIN KVITAMIN K

• ACTION:ACTION:- Acts as cofactor in the synthesis- Acts as cofactor in the synthesis of coagulation factors II, VII, IX, X of coagulation factors II, VII, IX, X

• DEFICIENCY:DEFICIENCY:- Haematuria- Haematuria- GIT & Nose Bleeding- GIT & Nose Bleeding- Ecchymoses- Ecchymoses

Use of Vitamin K:Use of Vitamin K:

• Dietary deficiencyDietary deficiency• Prolonged antimicrobial therapyProlonged antimicrobial therapy• Obstructive jaundiceObstructive jaundice• Malabsorption syndromesMalabsorption syndromes• Liver diseaseLiver disease• Premature newbornPremature newborn• To reverse effect of overdose of oralTo reverse effect of overdose of oral

anticoagulantsanticoagulants• Prolonged high dose salicylate therapyProlonged high dose salicylate therapy

Decorboxy Decorboxy prothrombinprothrombin(or VII, IX, X )(or VII, IX, X )

MOA MOA

Vit K Vit K hydroquinonehydroquinone

ProthrombinProthrombin(or VII, IX, X )(or VII, IX, X )

Vit K epoxide Vit K epoxide

NADHNADH NADNAD BLOCKED BY ORAL BLOCKED BY ORAL ANTICOAGULANTSANTICOAGULANTS

FibrinogenFibrinogen

• The fibrinogen fraction of human plasma is The fibrinogen fraction of human plasma is

employed to control bleeding in haemophilia, employed to control bleeding in haemophilia,

antihaemophilic globulin (AHG) deficiency and antihaemophilic globulin (AHG) deficiency and

acute afibrinogenemic states; 0.5 gm i.v acute afibrinogenemic states; 0.5 gm i.v

infusion infusion

MISCELLANEOUSMISCELLANEOUS

Antihaemophilic factorAntihaemophilic factor

• It concentrated human AHG prepared from It concentrated human AHG prepared from

pooled human plasma. pooled human plasma.

Indicated (along with human Indicated (along with human

fibrinogen) in haemophilia and AHG deficiency fibrinogen) in haemophilia and AHG deficiency

• Highly effective in control bleeding episodes, Highly effective in control bleeding episodes,

but action is short-lasting (1-2 days)but action is short-lasting (1-2 days)

• Dose; 5-10 U /kg by i v infu, repeated 6-12 hrlyDose; 5-10 U /kg by i v infu, repeated 6-12 hrly

DesmopressinDesmopressin

• It releases factor VIII and von Willebrand's It releases factor VIII and von Willebrand's

factor from vascular endothelium and checks factor from vascular endothelium and checks

bleeding in haemophilia and von Willebrand's bleeding in haemophilia and von Willebrand's

diseasedisease

Adrenochrome Adrenochrome monosemicarbazonemonosemicarbazone

• It believed to reduce capillary fragility, control It believed to reduce capillary fragility, control

oozing from raw surfaces and prevent oozing from raw surfaces and prevent

microvessel bleeding, ex:epistaxis, microvessel bleeding, ex:epistaxis,

haematuria, retinal haemorrhage, secondary haematuria, retinal haemorrhage, secondary

haemorrhage from wounds, etc Its efficacy is haemorrhage from wounds, etc Its efficacy is

uncertainuncertain

• Dose: 1-5 mg oral, i.m.Dose: 1-5 mg oral, i.m.

RutinRutin

• A plant glycoside claimed to reduce capillary A plant glycoside claimed to reduce capillary

bleeding bleeding

• Dose 60 mg oral BD-TDS along with vit C Dose 60 mg oral BD-TDS along with vit C

which is believed to facilitate its actionwhich is believed to facilitate its action

• Its efficacy is uncertain.Its efficacy is uncertain.

EthamsylateEthamsylate

• It reduces capillary bleeding when platelets It reduces capillary bleeding when platelets are adequate; probably exerts are adequate; probably exerts antihyaluronidase actionantihyaluronidase action

improves capillary wall stability, but does not improves capillary wall stability, but does not stabilize fibrin (not an antifibrinolytic) stabilize fibrin (not an antifibrinolytic)

• in the prevention and treatment of capillary in the prevention and treatment of capillary bleeding in menorrhagia, after abortion, PPH, bleeding in menorrhagia, after abortion, PPH, epistaxis, malena, hematuria and after tooth epistaxis, malena, hematuria and after tooth extraction, but efficacy is unsubstantiated extraction, but efficacy is unsubstantiated

• S/E:N,H, rash & S/E:N,H, rash & ↓↓ BP (only after i.v inj) BP (only after i.v inj)

• Dose: 250-500 mg TDS oral/i.vDose: 250-500 mg TDS oral/i.v

LOCAL HAEMOSTATICS(STYPTICS)LOCAL HAEMOSTATICS(STYPTICS)

• AstringentsAstringents

• Vasoconstrictors (Adrenaline)Vasoconstrictors (Adrenaline)

• ThrombinThrombin

• FibrinFibrin

• Gelatin FoamGelatin Foam

• Calcium alginateCalcium alginate

• Oxidized cellulose Oxidized cellulose

• Russell's viper venomRussell's viper venom

ANTICOAGULANTSANTICOAGULANTS

CLASSIFICATIONCLASSIFICATIONThese are drugs used to reduce the coagulability of blood These are drugs used to reduce the coagulability of blood

classified into:classified into:

USED IN VIVOUSED IN VIVO

Parenteral anticoagulantsParenteral anticoagulants

a) Heparins (ITI)a) Heparins (ITI)

• High Molecular Weight HeparinHigh Molecular Weight Heparin

Unfractionated Heparin (UFH)Unfractionated Heparin (UFH)

• Low molecular weight heparin Low molecular weight heparin (Enoxaparin, Dalteparin, Tinzaparin, (Enoxaparin, Dalteparin, Tinzaparin, Reviparin, Reviparin, Danaparoid)Danaparoid)

b) Heparinoids (DTI)-Heparan sulfate, Hirudin, b) Heparinoids (DTI)-Heparan sulfate, Hirudin, Lepirudin, Bivalirudin, ArgatrobanLepirudin, Bivalirudin, Argatroban

Oral anticoagulantsOral anticoagulants

(1)Coumarin derivatives :Bishydroxycoumarin(1)Coumarin derivatives :Bishydroxycoumarin

(dicumarol), Warfarin sod, Acenocoumarol(dicumarol), Warfarin sod, Acenocoumarol

(Nicoumalone), Ethylbiscoumacetate(Nicoumalone), Ethylbiscoumacetate

(2)Indandione derivative: Phenindione.(2)Indandione derivative: Phenindione.

USED IN VITROUSED IN VITRO

(a)Heparin(a)Heparin

(b)Sod. citrate :used in blood banks to store the blood(b)Sod. citrate :used in blood banks to store the blood

(c)Sod. oxalate :(c)Sod. oxalate :

(d)Sod. editate :(d)Sod. editate :uused as an anticoagulant in laboratory

Parenteral anticoagulantsParenteral anticoagulantsHistory of HeparinHistory of Heparin

• McLeanMcLean

• Howell and HoltHowell and Holt in 1918 named it in 1918 named it heparinheparin

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

• Commercial heparin , porcine intestinal mucosa Commercial heparin , porcine intestinal mucosa and bovine lungsand bovine lungs

• A mixture of straight chain anionic (negative A mixture of straight chain anionic (negative charge) glycosaminoglycan with a wide range of charge) glycosaminoglycan with a wide range of mol wtmol wt

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

PK of HeparinPK of Heparin

• Heparin is highly charged, thus crosses cell Heparin is highly charged, thus crosses cell

membranes very poorly, hence given membranes very poorly, hence given

ParenterallyParenterally

• Low dose: S.c Low dose: S.c

• High Dose: S.c /IV InjHigh Dose: S.c /IV Inj

• Metabolized by liver, half life depends on doseMetabolized by liver, half life depends on dose

Blood Vessel Injury

IX IXa

XI XIa

X Xa

XII XIIa

Tissue Injury

Tissue Factor

Thromboplastin

VIIa VII

X

Prothrombin Thrombin

Fibrinogen Fribrin insoluble

Stabilised Fibrin threads

XIIIa

Intrinsic Pathway Extrinsic Pathway

Factors affected

By Heparin

Vit. K dependent FactorsAffected by Oral Anticoagulants

ca+

ca+ ca+

HMW-Kininogen

XIIa, Xia, Kallikrein

ca+

XIII

ca+

MechanismMechanism

No heparinNo heparin

Active clotting factorsActive clotting factors

SlowSlow AT IIIAT III

Inactive clotting factorsInactive clotting factors

Heparin Heparin

Active clotting factorsActive clotting factors

Fast Fast AT IIIAT III ++

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 & XaIIa & Xa

Inactivate XaInactivate Xa

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) Orthopedic a) Orthopedic procedures procedures on lower limb on lower limb

b) Pulmonary Embolismb) Pulmonary Embolism

c) Unstable Anginac) Unstable Angina

Advantages of LMWH over UFHAdvantages of LMWH over UFH

• Better S.c, BA (70-90%) compared to UFH(20-30%)Better S.c, BA (70-90%) compared to UFH(20-30%)

• Longer and more consistent half life: once daily S.c Longer and more consistent half life: once daily S.c

administrationadministration

• Since aPTT/clotting times are not prolonged, lab. Since aPTT/clotting times are not prolonged, lab.

monitoring is not neededmonitoring is 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 haemostasisinterference with haemostasis

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 Disease

Unstable anginaUnstable angina

After MIAfter MI

After angioplasty CABG, stent replacement; After angioplasty CABG, stent replacement; Prevent Prevent recurrencerecurrence

3. 3. Rheumatic Heart Disease/ Atrial FibrillationRheumatic Heart Disease/ Atrial Fibrillation

Warfarin, heparin, low dose aspirin, Warfarin, heparin, low dose aspirin,

Decrease stroke due to emboliDecrease stroke due to emboli

4. 4. Cerebrovascular DiseasesCerebrovascular Diseases

Cerebral Emboli (Prevention of recurrence)Cerebral Emboli (Prevention of recurrence)

5. 5. Vascular Surgery, Prosthetic heart valves, Retinal Vascular Surgery, Prosthetic heart valves, Retinal vessel thrombosis, Extracorporeal circulation, vessel thrombosis, Extracorporeal circulation, HemodialysisHemodialysis

To prevent ThromboembolismTo prevent Thromboembolism

6. 6. Defibrination syndrome or DICDefibrination syndrome or DIC

Abruptio placenta, malignancies, infections; Abruptio placenta, malignancies, infections; increased consumption of clotting factorsincreased consumption 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 3. Increased hair loss

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

fracturesfractures

5. Thrombocytopenia5. Thrombocytopenia

• Once thrombocytopenia is determined, Once thrombocytopenia is determined,

heparin must be stopped. Direct thrombin heparin must be stopped. Direct thrombin

inhibitor should be giveninhibitor should be given

• Platelets must NOT be given because they Platelets must NOT be given because they

will react with antibody already being will react with antibody already being

produced against them, causing greater produced against them, causing greater

chance of thrombosis. chance of thrombosis.

Heparin-induced ThrombocytopeniaHeparin-induced Thrombocytopenia

Heparin in PregnancyHeparin in Pregnancy

• It not cross placenta, it must be used instead It not cross placenta, it must be used instead

of warfarin in cases of requiring anticoagulant of warfarin in cases of requiring anticoagulant

therapy in pregnancy.therapy in pregnancy.

• Warfarin cross placenta and induces changed Warfarin cross placenta and induces changed

in the fetus to produce the fetal warfarin in the fetus to produce the fetal warfarin

syndrome – not good.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

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

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

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

Direct Thrombin Inhibitors (DTIs) Direct Thrombin Inhibitors (DTIs) or Heparinoidsor Heparinoids

• The DTIs bind thrombin without additional The DTIs bind thrombin without additional

binding proteins, such as anti-thrombin, and binding proteins, such as anti-thrombin, and

they do not bind to other plasma proteins such they do not bind to other plasma proteins such

as platelet factor 4.as platelet factor 4.

• Hirudin and Bivalirudin bind at both the catalytic Hirudin and Bivalirudin bind at both the catalytic

or active site of thrombin as well as at a or active site of thrombin as well as at a

substrate recognition sitesubstrate 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 Adverse effect: Antibody formation against

thrombin-lepirudin complexthrombin-lepirudin 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 Used in heparin induced

thrombocytopenia with or without thrombosisthrombocytopenia with or without thrombosis

Monitored by aPTTMonitored by aPTT

Dose reduction in liver diseaseDose reduction in liver disease

ORAL ANTICOAGULANTSORAL ANTICOAGULANTS

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

Warfarin-PkWarfarin-Pk1. Rapidly and completely absorbed after oral 1. Rapidly and completely absorbed after oral

administrationadministration2. 100% Bioavailability 2. 100% Bioavailability 3. Highly PPB (99%)3. Highly PPB (99%)4. Crosses the placenta (teratogenic)4. Crosses the placenta (teratogenic)5. Appears in milk; infants given Vit K5. Appears in milk; infants given Vit K6. Variable but slow clearance;depends on hepatic 6. Variable but slow clearance;depends on hepatic

P450sP450s7. Biotransformation by the liver: Oxidation, 7. Biotransformation by the liver: Oxidation,

GlucuronidationGlucuronidation8. Takes 12-16 hrs before effect is observed8. Takes 12-16 hrs 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 Coumarins block the Gamma Carboxylation of glutamic acid residues of Clotting factors glutamic acid residues of Clotting factors II,VII, II,VII, IX, XIX, X , endogenous anti-coagulants , endogenous anti-coagulants C & S.C & S.

• This is coupled with oxidative deactivation of Vit This is coupled with oxidative deactivation of Vit KK

• Coumarins and Indanediones (-) enzyme Coumarins and Indanediones (-) enzyme Vit KVit K epoxideepoxide reductasereductase that converts Vit K epoxide that converts Vit K epoxide to its active hydroquinone (reduced form)to its active hydroquinone (reduced form)

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

Why Carboxylation is necessary?Why Carboxylation is necessary?

• Necessary for ability of clotting factors to bind Necessary for ability of clotting factors to bind

CaCa++ and to get bound to phospholipid and to get bound to phospholipid

surfaces which is necessary for coagulationsurfaces which is necessary for coagulation

• Factor VII affected first, then IX, X, and finally Factor VII affected first, then IX, X, and finally

Factor II (dependsFactor II (depends upon half lives of upon half lives of

circulating factors)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 Monitoring necessary because of its low

therapeutic indextherapeutic index

• PT noted; time taken for blood to clotPT noted; time taken for blood to clot

• Pts on Heparin are shifted to oral warfarin Pts on Heparin are shifted to oral warfarin

after 3-5 daysafter 3-5 days

Adverse EffectsAdverse Effects

1. 1. BleedingBleeding Common ,serious adverse effect;Common ,serious adverse effect;

Epistaxis, hematuria, GIT Bleeding, internal Epistaxis, hematuria, GIT Bleeding, internal hemorrhageshemorrhages

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 Protein C and Protein S found in bone & other

tissues also require Gamma carboxylationstissues also require Gamma carboxylations

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

Antidote of WarfarinAntidote of Warfarin

• Stop WarfarinStop Warfarin

• Give Vit K (Antidote)Give Vit K (Antidote)

• Also Fresh frozen plasma, Prothrombin Also Fresh frozen plasma, Prothrombin

complex concentrates and Recombinant complex concentrates and Recombinant

factor VIIa can be administeredfactor VIIa can be administered

ContraindicationsContraindications

11. Pregnancy. Pregnancy

Fetal protein in bone and blood affectedFetal protein in bone and blood affected

-Causes birth defects including abnormal bone -Causes birth defects including abnormal bone

formation, bone hyperplasiaformation, bone hyperplasia

-CNS Defects, fetal hemorrhage, fetal -CNS Defects, fetal hemorrhage, fetal

hypoprothrombinemia and fetal death may hypoprothrombinemia and fetal death may

occuroccur

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

Drug Interactions of WarfarinDrug Interactions of Warfarin

A.Pharmacokinetic InteractionsA.Pharmacokinetic Interactions

1. 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 Antibiotics: Decrease bacterial flora—decrease

Vit K synthesis—increased warfarin effectVit K synthesis—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 Vit K)Newborns (Decreased Vit 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 Carboxylation of glutamic acid residues of glutamic acid residues of clotting factorsclotting factors

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