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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