anti coagulants pharmacology

7/31/2019 Anti Coagulants Pharmacology

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ANTI-COAGULANTSANTI-COAGULANTS

DR.UZMA RIAZDR.UZMA RIAZ


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ThrombosisThrombosis

is associated with stasis of bloodis associated with stasis of blood

HasHas andand ofof

is associated with atherosclerosisis associated with atherosclerosis

-initiated due to endothelial injury leads to atheromatous plaque-initiated due to endothelial injury leads to atheromatous plaqueformationformation

Plaque rupture, platelet adhesion, activation, aggregation initiatesPlaque rupture, platelet adhesion, activation, aggregation initiatesthrombus growththrombus growth

hashas

Arterial thrombus may break away, emboli form leads to ischemiaArterial thrombus may break away, emboli form leads to ischemiaand infarctionand infarction


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HemostasisHemostasis

Spontaneous Arrest of Bleeding from a Damaged Blood Vessel;Spontaneous Arrest of Bleeding from a Damaged Blood Vessel;This occurs by the following stepsThis 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


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CoagulationCoagulation

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

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


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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


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Extrinsic Pathway

Tissue traumaTissue trauma

Leakage of Tissue FactorLeakage of Tissue Factor

XX XaXa

Prothrombin activatorProthrombin activator

CaCa+2+2,, factor VIIfactor VII

CaCa+2+2

ProthrombinProthrombin ThrombinThrombin

(factor II)(factor II)

CaCa+2+2

Intrinsic Pathway

Blood trauma/ contact with collagenBlood trauma/ contact with collagen

Activation of factorActivation of factor

XII, IX, VIIIXII, IX, VIII

XX XaXa

CaCa+2+2

ProthrombinProthrombin

activatoractivator

ProthrombinProthrombin ThrombinThrombin

(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)


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ClassificationClassification

1. Indirect Thrombin Inhibitors1. Indirect Thrombin Inhibitors

a) Heparinsa) Heparins

i) High Molecular Weight Heparini) High Molecular Weight HeparinUnfractionated Heparin (UFH)Unfractionated Heparin (UFH)

ii) Low Molecular Weight Heparinsii) Low Molecular Weight Heparins

EnoxaparinEnoxaparin DalteparinDalteparin

TinzaparinTinzaparin ReviparinReviparin

DanaparoidDanaparoid


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2. Direct Thrombin Inhibitors2. Direct Thrombin Inhibitors

HirudinHirudin LepirudinLepirudin

BivalirudinBivalirudin ArgatrobanArgatroban

1. Coumarins1. Coumarins

WarfarinWarfarinDicumarolDicumarol

2. Indanediones2. Indanediones

PhenindionePhenindione


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Heparin,HistoryHeparin,History

, a 2, a 2ndnd year medical student attempting to extract coagulantyear medical student attempting to extract coagulantsubstances from various tissues during a vacation project. But foundsubstances from various tissues during a vacation project. But foundinstead a powerful anticoagulant. He discovered in 1916 that liverinstead a powerful anticoagulant. He discovered in 1916 that livercontains a powerful anticoagulant.contains a powerful anticoagulant.

in 1918 named itin 1918 named it because it wasbecause it wasobtained from liverobtained from liver Occurs in mast cells (richest source of mast cells are lungs, liver andOccurs in mast cells (richest source of mast cells are lungs, liver and

intestinal mucosa)intestinal mucosa)

Commercial heparin is extracted from porcine intestinal mucosa andCommercial heparin is extracted from porcine intestinal mucosa andbobine lungbobine 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 carboxylicIt is strongly acidic because of presence of sulfate and carboxylic

acid groupsacid groups


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Heparin-KineticsHeparin-Kinetics

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

Low dose: SubcutaneousLow 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


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Heparin-Mechanism of ActionHeparin-Mechanism of Action

Once the coagulation pathways are activated, factors IXa, Xa, XIa, XIIa and IIaOnce the coagulation pathways are activated, factors IXa, Xa, XIa, XIIa and IIa(especially(especially ), need to be neutralized by Anti-thrombin III (AT III).), need to be neutralized by Anti-thrombin III (AT III).

Heparin accelerates the interaction of the active clotting factors with AT III.Heparin accelerates the interaction of the active clotting factors with AT III. The negatively charged heparin molecule binds to the positively charged lysine sitesThe negatively charged heparin molecule binds to the positively charged lysine sites

on AT IIIon AT III

This causes a conformational change in AT III and exposing its active arginine siteThis causes a conformational change in AT III and exposing its active arginine site The serine active sites of the active clotting factors bind to the reactive arginine siteThe serine active sites of the active clotting factors bind to the reactive arginine site

of AT IIIof 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 cause aThe active heparin molecules bind tightly to antihormbin and cause aconformational change in this inhibitor. The conformational change ofconformational change in this inhibitor. The conformational change of

antithrombin exposes its active site for more rapid interaction with theantithrombin exposes its active site for more rapid interaction with theproteases (the activated clotting factors) Heparin functions as a cofactor forproteases (the activated clotting factors) Heparin functions as a cofactor forthe antithrombin protease reactio without being consumed. Once thethe antithrombin protease reactio without being consumed. Once theantithrombin protease complex is formed, heparin is released intact forantithrombin protease complex is formed, heparin is released intact forrenewed binding to more antithrombin.renewed binding to more antithrombin.


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

Once antithrombin-clotting factor complex is formed, heparin isOnce antithrombin-clotting factor complex is formed, heparin isreleased for renewed binding to more antithrombinreleased for renewed binding to more antithrombin

High molecular weight Heparins accelerates the inactivation ofHigh molecular weight Heparins accelerates the inactivation ofclotting factorsclotting factors ..

Low molecular weight heparins accelerate the inactivation of onlyLow molecular weight heparins accelerate the inactivation of onlyFactorFactor


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Character HMW Heparins LMW Heparins

Molecular Weight High

(30000 Daltons)

Low

(5000 Daltons)

Biotransformation Low High (90%)

Half Life Shorter-depends on dose Longer-independent of dose

Mechanism of Action Inactivate both factor IIaand factor Xa

Inactivate only factor Xa

nti-coagulant effect More effective less effective

Monitoring By aPTT Can be given once or twice daily


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Monitoring By aPTT Can be given once or twice dailywithout monitoring, but requiresspecial assay if necessary

dverse

Effects

Less chance of thrombocytopeniaand long term osteoporosis

Excretion Cleared by theReticuloendothelial system

Cleared unchanged by kidneys

Reversal By protamine Not fully reversed by protamine

Expense Not expensive Expensive

Dose Less predictable dose response Has a more predictable dose


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Dose

Response

Less predictable dose responsebecause of binding to plasmaproteins, macrophages andendothelial cells

Has a more predictable dose-response because it does notbind to plasma proteins,macrophages, or endothelialcells.

Use More effective for

a) Orthopaedic procedures onlower limb

b) Pulmonary Embolism

c) Unstable Angina


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Advantages of LMWH over UFHAdvantages of LMWH over UFH

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

Longer and more consistent half life: once daily subcutaneousLonger and more consistent half life: once daily subcutaneous

administrationadministration

Since aPTT/clotting times are not prolonged, lab. monitoring is notSince aPTT/clotting times are not prolonged, lab. monitoring is notneededneeded

Lower incidence of haemorrhagic complicationsLower incidence of haemorrhagic complications

Appear to have lesser antiplatelet action so less interference withAppear to have lesser antiplatelet action so less interference with

haemostasisshaemostasiss


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

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

Bedridden (Immobilized patients)Bedridden (Immobilized patients)

Old peopleOld people

Post-operativePost-operative Post-stroke patientsPost-stroke patients

Leg fracturesLeg fractures

Elective SurgeryElective Surgery


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2.2. Ischemic Heart DiseaseIschemic Heart Disease

Unstable anginaUnstable angina

After MIAfter MI

After angioplasty CABG, stent replacement; Prevent recurrenceAfter angioplasty CABG, stent replacement; Prevent recurrence

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


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4.4. Cerebrovascular DiseasesCerebrovascular Diseases

Cerebral 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. DICDIC

Abruptio placenta, malignancies, infections; increased consumption ofAbruptio placenta, malignancies, infections; increased consumption of

clotting factorsclotting factors


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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 fractures5. Thrombocytopenia5. Thrombocytopenia


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

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

of standard heparinof 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 withDue to production of IgG against complexes of heparin with

platelet (platelet factor 4)platelet (platelet factor 4)

The complexes activate more platelets with the release of moreThe complexes activate more platelets with the release of moreplatelet factor 4 or other cytokines.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 toThis snow-ball effect uses up platelets and also leads to

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


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

Platelets must NOT be given because they will react with antibodyPlatelets must NOT be given because they will react with antibodyalready being produced against them, causing greater chance ofalready being produced against them, causing greater chance ofthrombosis.thrombosis.

3


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Heparin and PregnancyHeparin and Pregnancy

Heparin does not cross the placenta, therefore it must be usedHeparin does not cross the placenta, therefore it must be usedinstead of warfarin in cases of requiring anticoagulant therapy ininstead of warfarin in cases of requiring anticoagulant therapy inpregnancy.pregnancy.

Warfarin crosses the placenta and induces changed in the fetus toWarfarin crosses the placenta and induces changed in the fetus toproduce the fetal warfarin syndrome not good.produce the fetal warfarin syndrome not good.


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ContraindicationsContraindications

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


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Antidote Protamine SulfateAntidote Protamine Sulfate

Protamine is a highly basic peptide that combines with heparin asProtamine is a highly basic peptide that combines with heparin asan ion pair to form a stable complex devoid of anticoagulant activityan ion pair to form a stable complex devoid of anticoagulant activity

Hemorrhage can be reversed by protamine sulfate titrated so thatHemorrhage can be reversed by protamine sulfate titrated so that1 mg of protamine sulfate is administered for every 100 U of1 mg of protamine sulfate is administered for every 100 U of

heparin remaining in the patient.heparin remaining in the patient. Protamine sulfate is also an anticoagulant because it interacts withProtamine sulfate is also an anticoagulant because it interacts with

platelets, fibrinogen, and other clotting factors so it can makeplatelets, fibrinogen, and other clotting factors so it can makehemorrhage worse if more is given than necessary.hemorrhage worse if more is given than necessary.


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

The DTIs bind thrombin without additional binding proteins, such asThe DTIs bind thrombin without additional binding proteins, such asanti-thrombin, and they do not bind to other plasma proteins suchanti-thrombin, and 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 or active site ofHirudin and Bivalirudin bind at both the catalytic or active site ofthrombin as well as at a substrate recognition sitethrombin as well as at a substrate recognition site

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


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LepirudinLepirudin

Monitored by aPTTMonitored by aPTT

Action independent of antithrombinAction independent of antithrombin

Use in thrombosis related to heparin induced thrombocytopeniaUse in thrombosis related to heparin induced thrombocytopenia

No antidoteNo antidote Adverse effect: Antibody formation against thrombin-lepirudinAdverse effect: Antibody formation against thrombin-lepirudin

complexcomplex


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Bivalirudin:Bivalirudin: Inhibits platelet activation alsoInhibits platelet activation also

Use in percutaneous coronary angiographyUse in percutaneous coronary angiography

Argatroban:Argatroban: Used in heparin induced thrombocytopenia with or withoutUsed in heparin induced thrombocytopenia with or without

thrombosisthrombosisMonitored by aPTTMonitored by aPTT

Dose reduction in liver diseaseDose reduction in liver disease


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Oral Anti-Coagulants,HistoryOral Anti-Coagulants,History

Following the report of a hemorrhagic disorder in cattle thatFollowing the report of a hemorrhagic disorder in cattle thatresulted from the ingestion of spoiled sweet clover silage, Campbellresulted from the ingestion of spoiled sweet clover silage, Campbelland Link, in 1939, identified the hemorrhagic agent asand Link, in 1939, identified the hemorrhagic agent asbishydroxycoumarin (dicoumarol).bishydroxycoumarin (dicoumarol).

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

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

However, in 1951, an Army inductee uneventfully survived anHowever, in 1951, an Army inductee uneventfully survived anattempted suicide with massive doses of a preparation of warfarinattempted suicide with massive doses of a preparation of warfarinintended for rodent control.intended for rodent control.

Since then, these anticoagulants have become a mainstay forSince then, these anticoagulants have become a mainstay forprevention of thromboembolic diseaseprevention of thromboembolic disease


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WWisconsinisconsinAAlumnilumni RResearchesearch FFoundationoundation

CoumCoumarin--Warfarinarin--Warfarin

Warfarin-PharmacokineticsWarfarin-Pharmacokinetics

1. Rapidly and completely absorbed after oral administration1. Rapidly and completely absorbed after oral administration

2. 100% Bioavailability2. 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 K

6. 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, Glucuronidation

8. Takes 12-16 hours before effect is observed8. Takes 12-16 hours before effect is observed


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Vitamin KVitamin K

SynthesisSynthesisofof

FunctionFunctionalal

CoagulatiCoagulati

VIVI

IIIXIX

XX

IIII

Vitamin K-Dependent ClottingVitamin K-Dependent Clotting

FactorsFactors


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WarfarinNoNo

SynthesisSynthesisofof

FunctionaFunctionall

Antagonismof

VitaminK

Warfarin Mechanism of ActionWarfarin Mechanism of Action

Vitamin K

VIVIIIIXIX

XX

IIII


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Mechanism of ActionMechanism of Action

Coumarins block the Gamma Carboxylation of glutamic acid residuesCoumarins block the Gamma Carboxylation of glutamic acid residuesof Clotting factorsof Clotting factors as well as the endogenous anti-as well as the endogenous anti-

coagulantscoagulants

This is coupled with oxidative deactivation of Vitamin KThis is coupled with oxidative deactivation of Vitamin K Coumarins and Indanediones inhibit the enzymeCoumarins and Indanediones inhibit the enzyme

that converts Vitamin K epoxide back into thethat converts Vitamin K epoxide back into the

active hydroquinone (reduced form)active hydroquinone (reduced form)

Thus they prevent the activation of Vitamin K and hence along withThus they prevent the activation of Vitamin K and hence along withit carboxylations of clotting factor residuesit carboxylations of clotting factor residues


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Why Carboxylation is necessary?Why Carboxylation is necessary?

Carboxylation is necessary for ability of clotting factors to bind CaCarboxylation is necessary for ability of clotting factors to bind Caand to get bound to phospholipid surfaces which is necessaryand to get bound to phospholipid surfaces which is necessary

for coagulationfor coagulation

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


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CH3

R

OH

OH O

O

CH3

R

O

O

O

CH3

R

NH

O

H

COOH

NH

O

COOH

COOHGlu residues Gla residues

in prothrombin in prothrombin

vitamin K vitamin Khydroquinone 2,3-epoxide

vitamin K vitamin K

reductase epoxide

reductase

vitamin K

Anticoagulant coumarinsand 1,3-indandiones


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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 daysPatients on Heparin are shifted to oral warfarin after 3-5 days


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Adverse EffectsAdverse Effects

1.1.

Most 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.

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 requireProtein C and Protein S found in bone & other tissues also requireGamma carboxylationsGamma carboxylations

3.3. of breast, fatty tissues, intestine and extremities due toof breast, fatty tissues, intestine and extremities due tovenous thrombosis caused by again decreased activity of Protein Cvenous thrombosis caused by again decreased activity of Protein C


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Antidote of WarfarinAntidote of Warfarin

Stop WarfarinStop Warfarin

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

Also Fresh frozen plasma, Prothrombin complex concentrates andAlso Fresh frozen plasma, Prothrombin complex concentrates and

Recombinant factor VIIa can be administeredRecombinant factor VIIa can be administered


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ContraindicationsContraindications

1. Pregnancy1. Pregnancy

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

-Causes birth defects including abnormal bone formation, bone-Causes birth defects including abnormal bone formation, bonehyperplasiahyperplasia

-CNS Defects, fetal hemorrhage, fetal hypoprothrombinemia and fetal-CNS Defects, fetal hemorrhage, fetal hypoprothrombinemia and fetaldeath may occurdeath may occur

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


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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


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

3.3. Drugs that displace warfarin from binding sites on plasmaDrugs that displace warfarin from binding sites on plasmaalbuminalbumin Chloral hydrateChloral hydrate NSAIDsNSAIDs

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

CholestyramineCholestyramine


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B. Pharmacodynamic InteractionsB. Pharmacodynamic Interactions

1. Synergistic effect1. Synergistic effect

HeparinHeparin

AspirinAspirin Antibiotics: Decrease bacterial floradecrease Vitamin K synthesisAntibiotics: Decrease bacterial floradecrease Vitamin K synthesis

increased warfarin effectincreased warfarin effect


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Physiological/Pathological Factors affectingPhysiological/Pathological Factors affecting

Warfarin ActionWarfarin Action

1. Increased warfarin action1. Increased warfarin action

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

Liver disease, chronic alcoholism (Decreased clottingLiver disease, chronic alcoholism (Decreased clottingfactors)factors)

Hyperthyroidism (Increased degradation of ClottingHyperthyroidism (Increased degradation of Clottingfactors)factors)

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


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2. Decreased Warfarin Action2. Decreased Warfarin Action

Pregnancy (Increased clotting factors)Pregnancy (Increased clotting factors)

Nephrotic syndromeNephrotic syndrome

Warfarin resistance (Genetic)Warfarin resistance (Genetic)

Character HEPARIN WARFARIN


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Character HEPARIN WARFARIN

Route ofdministration

Parenteral Oral

Polarity Polar charged molecule Uncharged

Onset of Action Rapid 12-16 Hours

Mechanism of Action Accelerates inactivation ofclotting factors byAntithrombin III

Inhibits gamma Carboxylationof glutamic acid residues ofclotting factors

Therapeutic Index Not low; safe Low; not safe


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Monitoring aPTT PT

Adverse Effect DifferencesThrombocytopenia,,Osteop

orosis, alopecia,anaphylaxis

Cutaneous Necrosis,

Infarction of breast, fattyand other tissues

Management of Patient Start with Heparin Switch over to warfarin in

3-5 days

Antidote Protamine Sulfate Vitamin K

Contraindication Not Pregnancy

Interactions Not significant Significant


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anti coagulants pharmacology

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