Sunil Kumar Daha

Coagulation Cascade

Basic Pharmacology• Anticoagulants • limit the ability of the blood to clot• venous thrombosis fibrin rich

• Antiplatelet drugs • limit the migration or aggregation of platelets• arterial thrombosis platelet rich

• Thrombolytics / Fibrinolytics • drugs act to dissolve clots after they have formed• venous thrombosis fibrin rich

Anticoagulant drugsOral anticoagulants• Vitamin K antagonism : Warfarin/coumarins• Direct thrombin inhibition : Dabigatran• Direct Xa inhibition : Rivaroxaban, Apixaban

Injectable anticoagulants• Antithrombin-dependent inhibition of thrombin and Xa: Heparin

• Antithrombin-dependent inhibition of Xa :Fondaparinux, Idraparinux

• Direct thrombin inhibition ::Lepirudin, Argatroban, Bivalirudin

Heparin • MOA: promotes the action of antithrombin III to inactivate thrombin and factor

Xa and suppresses coagulation. Affects factor IIa, IXa, Xa, Xia,XIIa and VIIa• Uses: pulmonary embolism, DVT• Mode of administration: only IV or deep s.c.• Adverse effect Hemorrhage Heparin-induced thrombocytopenia Hypersensitivity reaction Osteoporosis(long term use)

Safe in pregnency

• Contraindication - Active bleeding - Hypertension - Tuberculosis - Renal disease - Recent surgery of brain, spinal cord, eye. - Ulcerative lesions in GIT• Half life 1-5 hrs• Antidote: protamine sulfate

Warfarin

Warfarin• Clearance is slow = 36 hrs • Delayed onset

• Oral Administration• 5-10 mg daily

• Antidote• Vitamin K infusion

• Can cross placenta• do not use during late pregnancies

Monitoring of Warfarin Therapy• INR ( International Normalized Ratio )• INR=(PT patient/PT normal)ISI

• Target INR= 2.0 TO 3.0• Every 2-3 weeks

Adverse effects of Warfarin • Bleeding• Skin necrosis• Fetal abnormalities, bleeding

Contraindications to Anticoagulant use • Previous Heparin-induced thrombocytopenia syndrome (HITS)• Coagulopathies• Hemophilia• thrombocytopenia

• Active bleeding• intracranial hemorrhage• gastrointestinal (GI) ulcers• certain cancers

Antiplatelet 1. AspirinMOA:• Cause irreversible acetylation of COX enzyme and inhibit Thromboxane A2

formation in platelet thus inhibit platelet aggregation.• Also inhibit release of ADP

Dose: 75-325 mg daily

• At high dose prostacyclin production which promotes platelet aggregation. • High dose- more A/E and toxicity

2. Dipyridamole (vasodilator)• Inhibits phosphodiesterase enzyme and block uptake of adenosine –

increase cAMP - potentiate PGI2 – inhibit platelet aggregation.• Act on platelet on the vessel wall rather than on circulating one.

Dose: 150-300 mg/day

• Used with aspirin reduces thrombus• Used with warfarin reduce incidence of thromboembolism.

3. Ticlopidine/clopidogrel/prasugrel• Inhibits the binding of ADP to platelet- inhibit activation of GPIIb/IIIa receptor required for platelet

to bind with fibrinogen or each other.

Dose: Clopidogrel- 75 mg OD Ticlopidine- 250 mg BD

A/E: Ticlopidine: diarrhoea, vomiting, rash, neutropenia, bleeding Clopidogrel: better tolerated, rarely associated with neutropenia

4. Abciximab/eptifibatide/tirofiban• Glycoprotein IIb/IIIa receptor antagonists• Inhibit platelet aggregation

Adverse effect Hemorrhage Thrombocytopenia Constipation Arrythmia

Uses of antiplatelet

• Coronary artery disease MI Unstable angina• Cerebrovascular disease Transeint ischemic attack• Coronary bypass implant

Thrombolytics/fibrinolytics• These are drugs used to lyse thrombi/ clot to recanalize occluded

blood vessels (mainly coronary artery)• work by activating the natural fibrinolytic system• Clinically important fibrinolytics are

Streptokinase Urokinase Alteplase (rt-P A), Reteplase, Tenecteplase

Fibrinolytics: MOA

Streptokinase• Side effects:

it is antigenic rash, fever, hypotension and arrhythmia

• Indication and dosageFor MI: 7.5-15 lac IV infused i.v. over 1 hr.For deep vein thrombosis and pulmonary embolism: 2.5 lac IU

loading dose over 1/2-1 hr, followed by 1 lac IU/hr for 24 hr.

Urokinase• Indication:

patients in whom streptokinase has been used for an earlier episode

• Side effectsFever(common), hypotenssion and allergic reaction are rare.

• Indications and dosagesFor MI: 2.5 lac IU iv. over 10 min followed by 5 lac IU over next 60

min (stop in between if full recanalization occurs) or 6000 IU/min for upto 2 hr.

For venous thrombosis and pulmonary embolism: 4400 IU/kg over 10 min iv. followed by 4400 IU/kg/hr for 12 hr.

Alteplase• recombinant tissue plasminogen activator (rt-PA)• short halflife: 4-5min• Side effects: nausea,fever, mild hypotension• Indications and dosages

For MI: 15 mg iv. bolus injection followed by 50 mg over 30 min, then 35 mg over the next 1 hr.

For pulmonary embolism: 100 mg i.v. infused over 2 hr.

References• Harrison’s Principle of Medicine, 18th ed.• Davidson’s Principle and Practice of Medicine, 21st ed.• Katzung’s Basic and Clinical Pharmacology, 12th ed.

Thank You