Fibrinolytics, anticoagulants and antiplatelets

Anticoagulants

Drugs that interfere with blood Drugs that interfere with blood coagulation cascade are called coagulation cascade are called

anticoagulantanticoagulant

COAGULATION CASCADE

Key Clotting Factor is THROMBIN

COAGULATION CASCADE

ANTICOAGULANTS & COAGULATION CASCADE

Classification of anticoagulantsClassification of anticoagulants

1. Parenteral anticoagulants1. Parenteral anticoagulants

2. Oral anticoagulants2. Oral anticoagulants

Parenteral AnticoagulantsParenteral Anticoagulants(THROMBIN INHIBITORS)(THROMBIN INHIBITORS)

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

Indirect Thrombin InhibitorsIndirect Thrombin Inhibitors

are antithrombin III –dependent are antithrombin III –dependent thrombin inhibitorsthrombin inhibitors

High 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..

unfractionated (UFH) heparinunfractionated (UFH) heparin..

Heterogeneous mixture of sulfated Heterogeneous mixture of sulfated

mucopolysaccharides (mucopolysaccharides (glycosaminoglycanglycosaminoglycan).. Strongly acidic nature. Strongly acidic nature.

Extraction of unfractionated (UFH) Extraction of unfractionated (UFH) heparinheparin..

Extracted from porcine intestinal mucosa &Extracted from porcine intestinal mucosa &

bovine lung. bovine lung.

Mechanism of ActionMechanism of Action of of UFHUFH

Has anticoagulant effect that depends upon Has anticoagulant effect that depends upon antithrombin IIIantithrombin III

Antithrombin III:Antithrombin III: is a natural anticoagulant is a natural 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 This inhibition is slow but increased 1000 fold1000 fold in in presence of heparin.presence of heparin.

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

LMWH acts via increasing activity of LMWH acts via increasing activity of antithrombin III against antithrombin III against activated clotting activated clotting factorfactor Xa Xa ..

MECHANISM OF ACTION OF UFH

MECHANISM OF ACTION OF UFH & LMWH

Heparin

Free

Heparin

Pharmacokinetics of UFHPharmacokinetics of UFH

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.

Low Molecular Weight Heparin (LMWH)Low Molecular Weight Heparin (LMWH) Enoxaparin – Enoxaparin – Dalteparin -Danaproid.Dalteparin -Danaproid.

prepared by chemical or enzymatic prepared by chemical or enzymatic depolymerization of UFHdepolymerization of UFH

LMWHs are LMWHs are antithrombin III-dependentantithrombin III-dependent Administration: Administration: S.C. S.C. in- & out-hospitalin- & out-hospital

LMW heparins LMW heparins

1.1. Increased bioavailabilityIncreased bioavailability

2.2. Longer biological half life.Longer biological half life.

3.3. Less frequent dosing requirements Less frequent dosing requirements

4.4. Doses are specified in milligrams Doses are specified in milligrams

5.5. Favorable pharmacokinetic characters.Favorable pharmacokinetic characters.

6.6. predictable anticoagulant effectpredictable anticoagulant effect

7.7. No dose adjustment or monitoring No dose adjustment or monitoring

8.8. Less incidence of bleeding and Less incidence of bleeding and thrombocytopenia.thrombocytopenia.

Pharmacological ActionsPharmacological Actions

1. 1. Heparin& LMWH have anticoagulant activity Heparin& LMWH have anticoagulant activity in vivo & in vitro.in vivo & in vitro.

Control of TherapyControl of Therapy

Unfractionated heparin (UFH)Unfractionated heparin (UFH)

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

LMWH LMWH estimation of plasma factor Xa.estimation of plasma factor Xa.

Side Effects of HeparinSide Effects of Heparin

1.1. BleedingBleeding2.2. Thrombocytopenia & ThrombosisThrombocytopenia & Thrombosis3.3. 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 an immune reaction that occurs in up to is an immune reaction that occurs in up to 3% of patients on heparin therapy for 5-14 3% of patients on heparin therapy for 5-14 days due to formation of IgM & IgG against days due to formation of IgM & IgG against heparin-PF4 complex heparin-PF4 complex

Platelet count is required.Platelet count is required. Lower risk with LMWHLower risk with LMWHTreated byTreated by

1.1. Heparin discontinuationHeparin discontinuation2.2. Direct thrombin inhibitor is used Direct 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). Excess protamine should be avoided Excess protamine should be avoided

sincesince it has anticoagulant effect.it has anticoagulant effect.

Uses of heparinUses of heparinfor the prevention offor the prevention of

1. Pulmonary embolism.1. Pulmonary embolism.2. Deep vein thrombosis.2. 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 7. Reduction of coronary artery thrombosis

after thrombolytic treatmentafter thrombolytic treatment8. Anticoagulant of choice in pregnant women8. Anticoagulant of choice in pregnant women

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 Patients who have had surgery of CNS, eye

or spinal cord. or spinal cord.

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 No antagonists are available. No antagonists are available.

ORAL ANTICOAGULANTSORAL ANTICOAGULANTS

Coumarin anticoagulants Coumarin anticoagulants e.g. e.g. warfarinwarfarin

WarfarinWarfarinMechanism of actionMechanism of action

Warfarin is vitamin K antagonist (vitamin K epoxide Warfarin is vitamin K antagonist (vitamin K epoxide reductase inhibitor). reductase inhibitor).

Reduced vitamin K is required for Reduced vitamin K is required for γ-carboxylation of glutamate residues in clotting factors.

Warfarin acts by inhibiting the activation of several clotting factors (II, VII, IX, X ) by blocking γ-carboxylation of glutamate residues in clotting factors in the liver.

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 reductase

The reduced vit K is converted into vitamin K epoxide which is reduced back by vitamin K reductase 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 (8-12 h).Delayed onset of action (8-12 h).

Acts in vivo only.Acts in vivo only.

Side effectsSide effects

1.1. slow onset of action slow onset of action

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

3.3. Soft tissue necrosisSoft tissue necrosis

4.4. Drug interactionsDrug interactions

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

Warfarin Drug interactionsWarfarin Drug interactions

Warfarin action is increased by:Warfarin action is increased by:

Broad spectrum antibioticsBroad spectrum antibiotics

Cyt P450 inhibitors: Cyt P450 inhibitors: Cimetidine, erythromycinCimetidine, erythromycin

Aspirin Aspirin

Diseases Diseases Hyperthyroidism & liver diseaseHyperthyroidism & liver disease

Warfarin Drug interactionsWarfarin Drug interactions

Warfarin action is decreased byWarfarin action is decreased by

Cyt P450 inducers: Cyt P450 inducers:

Phenobarbitone, rifampicin, phenytoinPhenobarbitone, rifampicin, phenytoin

ContraindicationsContraindicationsPregnancy Pregnancy

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

Overdose of warfarinOverdose of warfarinTreated by vitamin KTreated by vitamin K

Control of warfarin TherapyControl of warfarin Therapy

Prothrombin time (PT)Prothrombin time (PT)Time required for plasma clotting with Time required for plasma clotting with calcium and thromboplastin (10-12 calcium and thromboplastin (10-12 seconds) 2-4 times expressed as INRseconds) 2-4 times expressed as INR

International normalized ratio (INR)International normalized ratio (INR)Ratio between patients PT and standard PT Ratio between patients PT and standard PT

(2-4).(2-4).

UsesUses for Maintenance of anticoagulant for Maintenance of anticoagulant activity.activity.

Uses of anticoagulantsUses of anticoagulants for the prevention offor the prevention of

1. Pulmonary embolism recurrence1. Pulmonary embolism recurrence2. Deep vein thrombosis2. Deep vein thrombosis3. Post - operative venous thrombosis3. Post - operative venous thrombosis4. Stroke4. Stroke5. Myocardial infarction5. Myocardial infarction6.6. During hemodialysisDuring hemodialysis7.7. Unstable anginaUnstable anginaHeparin (LMW) Heparin (LMW) for short term actionfor short term actionWarfarin Warfarin is used for prolonged therapyis used for prolonged therapy

Contraindications of anticoagulantsContraindications of anticoagulants

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 Patients who have had surgery of CNS, eye

or spinal cord. or spinal cord.