Antiplatelets & Fibrinolytics

HARSHIT SHETH

Thrombosis

• Arterial Thrombosis : – Adherence of platelets to arterial walls

- White in color - Often associated with MI, stroke and ischemia

• Venous Thrombosis :– Develops in areas of stagnated blood

flow (deep vein thrombosis), Red in color- Associated with Congestive Heart Failure, Cancer, Surgery.

HOW PLAQUES ARE FORMED?

Basic concepts• PGI2- inhibit platelet aggregation• TXA2- platelet aggregation• Elevated c-AMP- inhibit platelet

aggregation & vice versa• ADP receptors(P2Y1,P2Y2)-changes

shape & platelet aggregation• GPIIb/IIIa receptors- binds

fibrinogen & platelets• 5-HT-vasocostriction• Collagen,Thrombin- platelet

aggregation agonist

ANTIPLATELETS: Classification• Aspirin• Phospodiesterase inhibitors-

Dipyridamol, - Cilostazole• ADP antagonist-

Clopidogrel,Ticlopidine• GPIIb/IIIa Antagonist-

Abciximab,Eptifibatide,Tirofiban , Lamifiban

• Synthetic PGI2- Epoprostenol

Aspirin(ASA):Mechanism

Vascular endothelial cells can synthesize new PGI2 but platelets cannot synthesize new TXA2. Thus action of aspirin on platelet is permanent lasting for the lifetime of platelet i.e. 7-10 days. Balance between TXA2 (promoter of aggregation) & PGI2 ( inhibitor of aggregation) is altered.

As higher doses of aspirin are needed to inhibit COX in vascular endothelium than in platelets, antiplatelet effect can be achieved at low doses ( 75- 150 mg per day orally) Other NSAIDs are reversible inhibitors.

Limitations of Aspirin•Multiple pathways of platelet activation in vivoThrombin, collagen, high shear stress activateplatelets via non-cyclooxygenase pathwaysCatecholamines can overcome antiplatelet effectPlatelet adhesion and thrombus formation notblockedProthrombotic effect at higher dosesInhibition of vascular prostacyclin generationInhibition of tPA (at doses >300 mg)

Adverse effects• At lower dose mainly GIT adv.

Effect: A)GI mucosa damage B)High risk of bleeding C)Suppression of GI protective

action of PGs

Phosphodiaster Inhibitors:• Dipyridamol:• It inhibits Phosphodiasterase &

blocks uptake of adenosine to increase cAMP which potentiate PGI2 & interfere with aggregation

• Dipyridamol+Aspirin-used in TIA

ADP antagonist:

Clopidogrel • Pro Drug • Slow onset of action • Fewer side effects than Ticlodipine • Dose dependent action – within 5 hrs of oral loading dose 80% of platelet activity inhibited. • Duration of antiplatelet effect 7- 10 days.

Ticlodipine • Pro Drug • 8-11 days to show maximal effect. • Nausea, vomiting, diarrhoea. • Thrombocytopenia • Neutropenia • Thrombotic Thrombocytopenic Purpura – rare. • Due to distinct MOA combo with aspirin has additive or synergistic effect. • Used for sec. prevention of stroke and unstable angina.

GPIIb/IIIa Antagonist

Abciximab • Human murine chimeric monoclonal antibody Fab fragment • Binds with high affinity and slow dissociation rate. • Immediate and profound inhibition of platelet activity extending for 12-36 hrs after termination of infusion. • 0.25mg/kg bolus followed by 0.125μg/kgper min for 12hrs

Eptifibatide/ Tirofiban• • Prevent binding of fibrinogen to• the receptor complex• • Used to treat unstable angina• • Used for angioplastic coronary• interventions.• • ADRs• - Haemorrage• - Thrombocytopenia

Clinical uses of antiplatelet drugs The main drug is aspirin. Other drugs

with distinct actions (e.g. dipyridamole, clopidogrel) can have additive effects, or be used in patients who are intolerant of aspirin.

Uses of antiplatelet drugs relate mainly to arterial thrombosis and include uses in:

acute myocardial infarction high risk of myocardial infarction, including

a history of myocardial infarction, angina – unstable Angina (clopidogrel is added to

aspirin)

following coronary artery bypass grafting

– following coronary artery angioplasty (PCI) – abciximab(I.V), are used in some patients in addition to aspirin)

– transient cerebral ischaemic attack ('ministrokes') or thrombotic stroke, to prevent recurrence (dipyridamole can be added to aspirin)

– atrial fibrillation, if oral anticoagulation is contraindicated.

• epoprostenol [PGI2]; have specialised clinical applications in haemodialysis or haemofiltration in cases in which heparin is contraindicated.

FIBRINOLYTICS• These drugs dissolve the Thrombi

in blood vessel(mainly coronary artery) by activating fibrinolytic system

Fibrinolytics Agents1st GEN:• Streptokinase• Urokinase2nd GEN• Alteplase3rd GEN• Reteplase• Tenecteplase

Streptokinase :1st GEN:• Streptokinase is a protein• synthesized by streptococci that• combines with proactivator• plasminogen. Caution in patients• with previous history of fibrinolytic• therapy due to formation of• antibodies.• • Streptokinase- loading dose of• 250,000 units followed by• 100,000 units/hr for 24-72 hrs.• • It is antigenic & can cause

hypersensitivity rxn when used second time in pts.

Urokinase• Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to

plasmin.• Plasminogen can be activated endogenously by t-PA. Preferentially activate plasminogen bound to fibrin Non-antigenic Indicated in pts. With sensitivity to

strepokinase

FIBRINOLYTICS• 2ND GEN: ALTEPLASE (TPA)

– Cleaves plasminogen plasmin fibrinolysis

– Specific activity in thrombus, less systemic fibrinolysis

– Weight-based IV infusion over 60-90min

– Half-life<5 min– Heparin commonly administered

shortly after

• 2ND GEN: ALTEPLASE (TPA)– Cleaves plasminogen plasmin

fibrinolysis– Specific activity in thrombus, less

systemic fibrinolysis– Weight-based IV infusion over 60-

90min– Half-life<5 min– Heparin commonly administered

shortly after DOSE- 60 mg i.v. over the first hour followed by 40 mg at a rate of 20 mg/hr.

Adv.Of alteplase in TIA(mini stroke)

Comparision

FIBRINOLYTICS• 3RD GEN: modifications of TPA

– RETEPLASE• Half-life= 18 min• Double bolus regimen

– TENECTEPLASE (TNK)• Half life= 20 min• Single-weight tiered bolus dosing over 5-

10s

*bolus-doses fewer med errors* No absol mortality benefit in AMI

FIBRINOLYTICS: Clinical uses • The main use is in acute myocardial

infarction, with ST segment elevation on the ECG within 12 hours of onset (the earlier the better!)

• Other uses include: – acute thrombotic stroke within 3 hours

of onset (tPA), in selected patients – clearing thrombosed shunts and

cannulae – acute arterial thromboembolism – life-threatening deep vein thrombosis

and pulmonary embolism (streptokinase, given promptly).

Adv. Effect : These agents do not distinguish b/w pathological thrombi & fibrin deposit at site of vascular injury

Books To Be Referred:• Lippincott• F.s.k Barar• Rang & Dale• Goodman & Gillman• K D Tripathi• H L Sharma• R K Goyal• Photographs from Medical books• Internet

Good ideas are not adopted

automatically.They must be driven into practice

with courageous patience.

--Hyman RickoverUS Admiral(1900-1986)

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