AnticoagulantsAnticoagulants

1. Parenteral Anticoagulants e.g. heparin1. Parenteral Anticoagulants e.g. heparin

2. Oral anticoagulants e.g. warfarin2. Oral anticoagulants e.g. warfarin

Parenteral AnticoagulantsParenteral Anticoagulants

Indirect thrombin inhibitorsIndirect thrombin inhibitorsHigh molecular weight (HMW) heparin High molecular weight (HMW) heparin

or or unfractionated (UFH) heparinunfractionated (UFH) heparin..Low molecular weight Low molecular weight (LMW) heparin(LMW) heparin..

Direct thrombin inhibitorsDirect thrombin inhibitors

HeparinHeparinChemistryChemistryHeterogeneous mixture of sulfated Heterogeneous mixture of sulfated

mucopolysaccharides (mucopolysaccharides (glycosaminoglycan).. Strongly acidic nature. Strongly acidic nature. Extracted from porcine intestinal mucosa &Extracted from porcine intestinal mucosa &

bovine lung. bovine lung.

Mechanism of ActionMechanism of Action Has anticoagulant effect that depends upon Has anticoagulant effect that depends upon

antithrombinantithrombin Antithrombin:Antithrombin: is an endogenous anticoagulant is an endogenous anticoagulant

that inhibits activated clotting factors especially that inhibits activated clotting factors especially (IIa, IXa, Xa, XIa).(IIa, IXa, Xa, XIa).

This inhibition is slow but increased 1000 fold in This inhibition is slow but increased 1000 fold in presence of heparin.presence of heparin.

Heparin Heparin inhibits activated clotting factors in inhibits activated clotting factors in blood by blood by activity of activity of antithrombin IIIantithrombin III against against activated clotting factors as (IIa, IXa, Xa, XIIa) activated clotting factors as (IIa, IXa, Xa, XIIa) inhibits blood clotting.inhibits blood clotting.

PharmacokineticsPharmacokinetics Given only parenerally (S.C. or I.V) Given only parenerally (S.C. or I.V) Not I.MNot I.M

(hematoma).(hematoma). Immediate anticoagulant effect (t ½ = 60 - 90 Immediate anticoagulant effect (t ½ = 60 - 90

min).min). Metabolized in the liver (80 %) - 20 % excreted Metabolized in the liver (80 %) - 20 % excreted

unchanged in urine (not by microsomes).unchanged in urine (not by microsomes). Does not cross placenta & not excreted in Does not cross placenta & not excreted in

milk.milk.

Pharmacological ActionsPharmacological Actions

1. 1. Heparin has anticoagulant activity Heparin has anticoagulant activity in vivo & in vivo & in vitro.in vitro.

2. Increase activity of lipoprotein lipase from 2. Increase activity of lipoprotein lipase from tissues tissues lipemia after fatty meals ( clearing lipemia after fatty meals ( clearing factor). factor).

Control of Heparin TherapyControl of Heparin Therapy

1. Activated partial thromboplastin 1. Activated partial thromboplastin time (time (aPTTaPTT) 1.5 - 2.5 times that of the ) 1.5 - 2.5 times that of the normal value (30 sec).normal value (30 sec).

2.2. Whole blood clotting time (Whole blood clotting time (WBCTWBCT) : ) : 2 - 3 times the normal value ( 5 - 7 min).2 - 3 times the normal value ( 5 - 7 min).

Uses of HeparinUses of Heparin Initiation of anticoagulant therapyInitiation of anticoagulant therapy

1. Pulmonary embolism1. Pulmonary embolism2. Deep vein thrombosis2. Deep vein thrombosis3. Post - operative venous thrombosis3. Post - operative venous thrombosis4. Stroke4. Stroke5. Myocardial infarction5. Myocardial infarction6. Hemodialysis6. Hemodialysis7. Pregnancy7. Pregnancy

Side EffectsSide Effects

1.1. BleedingBleeding2.2. Heparin-induced thrombocytopenia (HIT)Heparin-induced thrombocytopenia (HIT)3.3. Hypersensitivity reactions: Hypersensitivity reactions: (Antigenicity due

to animal source) rarely occurring reactions include urticaria, rash, rhinitis.

4.4. Reversible alopecia & osteoporosis (long Reversible alopecia & osteoporosis (long term, term, for 6 months or longer).).

Heparin-induced thrombocytopenia (HIT)Heparin-induced thrombocytopenia (HIT)

is a life-threatening immune reaction that occurs in is a life-threatening immune reaction that occurs in up to 3% of patients on heparin therapy for 5-14 up to 3% of patients on heparin therapy for 5-14 daysdays

Venous thrombosis or arterial occlusion may Venous thrombosis or arterial occlusion may develop.develop.

Platelet count is required.Platelet count is required. Lower risk with LMWHLower risk with LMWHTreated byTreated by1.1. Heparin discontinuationHeparin discontinuation2.2. Direct thrombin inhibitor is usedDirect thrombin inhibitor is used

Heparin antidoteHeparin antidote

Protamine sulphateProtamine sulphate Basic peptideBasic peptide Given I.V. slowly (1 mg / 100 U Given I.V. slowly (1 mg / 100 U

heparin).heparin).

Contraindications of heparinContraindications of heparin

1.1. Hemophilia, thrombocytopenia. Hemophilia, thrombocytopenia. 2.2. Severe hypertension.Severe hypertension.3.3. Intra cranial hemorrhage.Intra cranial hemorrhage.4.4. Threatened abortion Threatened abortion 5.5. Ulcerative lesions of GIT.Ulcerative lesions of GIT.6.6. Threatened abortion.Threatened abortion.7.7. Advanced hepatic or renal disease.Advanced hepatic or renal disease.8.8. Hypersensitivity to heparin.Hypersensitivity to heparin.9.9. Patients who have had surgery of CNS, eye or Patients who have had surgery of CNS, eye or

spinal cord. spinal cord.

Low Molecular Weight HeparinLow Molecular Weight Heparin Enoxaparin – Enoxaparin – Dalteparin -Danaproid.Dalteparin -Danaproid.

prepared by controlled chemical or enzymatic prepared by controlled chemical or enzymatic depolymerization of standard unfractionated depolymerization of standard unfractionated heparinheparin

its action is antithrombin III-dependentits action is antithrombin III-dependent Acts via inhibition of activated Acts via inhibition of activated blood clotting factor blood clotting factor

XaXa (less effect on IIa) by increasing activity of (less effect on IIa) by increasing activity of antithrombin III.antithrombin III.

Doses: Doses: given at fixed doses once to twice daily by given at fixed doses once to twice daily by S.C. route, S.C. route, in- & out-hospitalin- & out-hospital

Control of the Doses Control of the Doses estimation of plasma factor estimation of plasma factor Xa.Xa.

LMW heparins LMW heparins Have equal anticoagulant effect to UF heparinHave equal anticoagulant effect to UF heparin

BUT LMW heparins haveBUT LMW heparins have1.1. Favorable pharmacokinetic characters.Favorable pharmacokinetic characters.2.2. Increased bioavailabilityIncreased bioavailability3.3. Longer biological half life.Longer biological half life.4.4. Less frequent dosing requirements Less frequent dosing requirements 5.5. Doses are specified in milligrams Doses are specified in milligrams 6.6. more predictable anticoagulant responsemore predictable anticoagulant response7.7. Less incidence of bleeding and thrombocytopenia.Less incidence of bleeding and thrombocytopenia.

Uses of heparinUses of heparin

1. 1. Treatment of pulmonary embolism.Treatment of pulmonary embolism.

2. Treatment of deep vein thrombosis.2. Treatment of deep vein thrombosis.3. Post-operative venous thrombosis.3. Post-operative venous thrombosis.4. Stroke.4. Stroke.5. Myocardial infarction.5. Myocardial infarction.6. Hemodialysis.6. Hemodialysis.7. Reduction of coronary artery thrombosis after 7. Reduction of coronary artery thrombosis after

thrombolytic treatmentthrombolytic treatment8. Anticoagulant of choice in pregnant women8. Anticoagulant of choice in pregnant women

DifferencesDifferencesHMWHHMWHLMWHLMWH

activity of a antithrombin activity of a antithrombin III against active factor II, III against active factor II, IX, X, XI, and XII.IX, X, XI, and XII.

activity ofactivity of antithrombin III antithrombin III against Xa against Xa

Bleeding Bleeding tendencytendency

HighHighLowLow

thrombocytopeniathrombocytopeniaHigh High LowLow

T ½T ½ShortShortLong ( double )Long ( double )

BioavailabilityBioavailabilityLowLowHighHigh

Control of doseControl of doseaPTT, WBC. aPTT, WBC. Plasma factor XaPlasma factor Xa

AdministrationAdministration3 - 4 dose / day 3 - 4 dose / day

( I.V. or S.C )( I.V. or S.C )

1 - 2 dose / day 1 - 2 dose / day

S.C. S.C. onlyonly

EfficacyEfficacyEqualEqualEqualEqual

MWMW5000 - 30.0005000 - 30.0002000 - 90002000 - 9000

Direct Thrombin Inhibitor anticoagulantsDirect Thrombin Inhibitor anticoagulantsLepirudinLepirudin-Bivalirudin -Bivalirudin

acts via direct binding to active site on acts via direct binding to active site on activated factor II (thrombin) activated factor II (thrombin) is antithrombin III- independent.is antithrombin III- independent.

Prepared by recombinant DNA technology Prepared by recombinant DNA technology Given I.V.Given I.V.

Has short duration of action (1 hr)Has short duration of action (1 hr)Used for treatment of thrombosis inUsed for treatment of thrombosis in

HIT patients.HIT patients.

LepirudinLepirudin

Is accumulated in renal insufficiency.Is accumulated in renal insufficiency. It is monitored by aPTTIt is monitored by aPTT

Oral anticoagulantsOral anticoagulants

Coumarin anticoagulants e.g. Coumarin anticoagulants e.g. warfarinwarfarin are vitamin K antagonists (vitamin K epoxide are vitamin K antagonists (vitamin K epoxide

reductase inhibitors). reductase inhibitors). reduced vitamin K is required for hepatic reduced vitamin K is required for hepatic

synthesis of several clotting factors II, VII, IX, X synthesis of several clotting factors II, VII, IX, X ((gamma carboxyglutamic acid residuesgamma carboxyglutamic acid residues).).

This results in the production of inactive clotting This results in the production of inactive clotting factors lacking ɣ-carboxyglutamyl residuesfactors lacking ɣ-carboxyglutamyl residues

Vitamin K AntagonistsVitamin K AntagonistsWarfarinWarfarin

The reduced vit K is converted into vitamin K epoxide which is reduced back by vitamin K vitamin K reductasereductase the target enzyme which warfarin inhibits

PharmacokineticsPharmacokinetics

Taken orally.Taken orally. Highly bound to plasma protein (low Vd).Highly bound to plasma protein (low Vd).

Long plasma half life (36 h).Long plasma half life (36 h). Cross placenta Cross placenta (# pregnancy).(# pregnancy).

Metabolized in the liver by cytochrome Metabolized in the liver by cytochrome P450 P450

Excreted in urine and stool.Excreted in urine and stool. Delayed onset of action (12 h).Delayed onset of action (12 h).

Acts in vivo only.Acts in vivo only.

Side effectsSide effects

1.1. Hemorrhage : treated by vitamin K 1Hemorrhage : treated by vitamin K 1

2.2. Soft tissue necrosisSoft tissue necrosis

3.3. Drug interactionsDrug interactions

4.4. Teratogenicity: Teratogenicity: hemorrhagic disorderhemorrhagic disorder abnormal bone formation in the fetusabnormal bone formation in the fetus..

5.5. slow onset of actionslow onset of action

Drug interactionsDrug interactions1.Broad spectrum antibiotics1.Broad spectrum antibiotics sulfonamides increase sulfonamides increase

warfarin actionwarfarin action2. Hepatic P450 Inhibitors2. Hepatic P450 Inhibitors increase warfarin actionincrease warfarin action

Cimetidine, erythromycinCimetidine, erythromycin3. Hepatic P450 Inducers3. Hepatic P450 Inducers decrease warfarin actiondecrease warfarin action

rifampicin, phenobarbitonerifampicin, phenobarbitone4. NSAIDs, aspirin 4. NSAIDs, aspirin

ContraindicationsContraindicationsPregnancyPregnancy

Hypoprothrombinemia (Liver disease).Hypoprothrombinemia (Liver disease).

Control of warfarin TherapyControl of warfarin Therapy

Prothrombin time (PT) Prothrombin time (PT) (10-12 seconds) 2-4 (10-12 seconds) 2-4 timestimes

International normalized ratio (INR)International normalized ratio (INR)Ratio between patients PT and normal Ratio between patients PT and normal standard PT (2-3).standard PT (2-3).

UsesUses for Maintenance of anticoagulant activity for Maintenance of anticoagulant activity in venous thromboembolic disorder.in venous thromboembolic disorder.