anti platelet agents
DESCRIPTION
TRANSCRIPT
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Anti-platelet agents
Dr. J Pradeep
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Contents
• Introduction• Classification• Individual drugs• Newer anti-platelet agents• Summary
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Introduction
• Normal hemostasis – Maintenance of blood in a fluid, clot-free state in
normal vessels; and– Formation of hemostatic plug at a site of vascular
injury.• Opposite : Thrombosis– Thrombi are lysed and blood is made fluid by
fibrinolytic system
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• Both hemostasis and thrombosis are regulated by three general components
– The vascular wall, –Platelets, and – The coagulation cascade
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• Platelet count:150000 - 400000/mm3• Lifespan: 7-10 days• No nucleus• Cannot synthesise proteins• Shape: biconcave discs, fully spread cells
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• Receptors on platelets: – GpIa/IIa: receptors for collagen – GpIb: receptor for vWF– GpIIb/IIIa: receptor for fibrinogen– P2Y1/P2Y12: purinergic receptors for ADP– PAR1/PAR4: protease activated receptors for
thrombin (IIa)
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• Platelets provide the initial hemostatic plug at sites of vascular injury
• They also participate in pathological
thromboses that lead to myocardial infarction, stroke, and peripheral vascular thromboses
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Platelet adhesion and aggregation
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Classification
• TXA2 inhibitors – Aspirin (non selective COX inhibitor)
• Phosphodiesterase inhibitors – Dipyridamole
• Thienopyridine derivatives – Ticlopidine, Clopidogrel, Prasugrel
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• Glycoprotein (GP) IIb/IIIa inhibitor – Abciximab, Eptifibatide, Tirofiban
• Newer anti-platelet agents – Cangrelor, Ticagrelor, SCH530348
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Aspirin
• Aspirin blocks production of TxA2by acetylating a serine residue near the active site of platelet cyclooxygenase-1 (COX-1)
• The action of aspirin on platelet COX-1 is permanent
• Action lasts for the life of the platelet (7-10 days)
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• Cumulative effect on repeated doses • Should be stopped atleast one week prior to
any surgical procedure• Complete inactivation of platelet COX-1 is
achieved with a daily aspirin dose of 75 mg• Maximal effective doses is 50-320 mg/day
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• Anti-thrombotic dose is much lower than doses required for other actions
• Higher doses do not improve efficacy• Potentially less efficacious because of
inhibition of prostacyclin production• Higher doses also increase toxicity, especially
bleeding
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Dipyridamole
• Interferes with platelet function by increasing the cellular concentration of cyclic AMP
• This effect is mediated by inhibition of cyclic nucleotide phosphodiesterases and Blockade of uptake of adenosine
• cAMP potentiates PGI2 and interferes with aggregation
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• Dipyridamole alone has little clinically significant effect
• Inhibits embolization from prosthetic heart valves when used in combination with warfarin
• May potentiate the action of aspirin in preventing strokes in patients with TIA,
• No additional benefit as combination with aspirin in preventing MI
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Ticlopidine
• Ticlopidine is a thienopyridine prodrug that inhibits the P2Y12 receptor
• Converted to the active thiol metabolite in liver
• It is rapidly absorbed and highly bioavailable• It permanently inhibits the P2Y12 receptor and
has prolonged action
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• Cumulative effect is seen• Maximal inhibition of platelet aggregation is
not seen until 8-11 days after starting therapy• The usual dose is 250 mg twice daily• Like aspirin it has short half life and inhibition
of platelet aggregation lasts for few days after stopping drug
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Side effects
• Common: nausea, vomiting, diarrhoea• Serious adverse effect: severe neutropenia• Fatal agranulocytosis with thrombocytopenia
has occurred within the first 3 months of therapy
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• Frequent blood counts and platelet counts are advised in first few months of therapy
• Discontinue therapy if counts fall• Thrombotic thrombocytopenic purpura-
hemolytic uremic syndrome (TTP-HUS) – rare adverse effect
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Therapeutic uses
• Prevention of stroke and TIAs• Intermittent claudication• Unstable angina• Prevention of MI• Preventing restenosis and stent thrombosis
after PCI
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Clopidogrel
• Similar to ticlopidine• Theinopyridine pro drug with slow onset of
action (only 15% is activated by CYP3A4)• Irreversible inhibitor of platelet P2Y12
• More potent and lesser side effects• Usual dose is 75 mg/day with or without an
initial loading dose of 300 or 600 mg
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• Secondary prevention of stroke : somewhat better than aspirin
• Prevention of recurrent ischemia in patients with unstable angina: better as combination with aspirin
• Synergistic with aspirin since mechanism of action is different
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• Wide inter-individual variability in efficacy of clopidogrel is seen
• Genetic polymorphism in CYP2C19• Patients with reduced function of CYP219*2
allele show less inhibition of platelets by clopidogrel and have higher rate of cardiovascular events
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Uses
• To reduce the rate of stroke, myocardial infarction, and death in – Patients with recent myocardial infarction or
stroke– Established peripheral arterial disease– Acute coronary syndrome
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Interactions
• Proton pump inhibitors, inhibitors of CYP2C19, produce a small reduction in the inhibitory effects of clopidogrel on ADP-induced platelet aggregation
• Atorvastatin, a competitive inhibitor of CYP3A4, reduced the inhibitory effect of clopidogrel on ADP-induced platelet aggregation
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Prasugrel
• Thienopyridine prodrug• Rapid onset of action• Greater inhibition of ADP induced platelet
aggregation• Almost completely absorbed from the gut• Almost all of the drug is activated
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• Irrversible inhibitor of P2Y12 receptor• Has prolonged effect after discontinuation• Better than clopidogrel in reducing incidence
of non fatal MI• The incidence of stent thrombosis also was
lower with prasugrel than with clopidogrel
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• However, it has higher rates of fatal and life-threatening bleeding
• Contraindicated in those with a history of cerebrovascular disease - high risk of bleeding
• Caution is required if prasugrel is used in patients weighing <60 kg or in those with renal impairment
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• After a loading dose of 60 mg, prasugrel is given once daily at a dose of 10 mg
• Patients >75 years of age or weighing <60 kg may do better with a daily prasugrel dose of 5 mg
• It is reasonable alternative to clopidogrel in patients with the loss-of-function CYP2C19 allele because there is no association with decreased anti platelet action in prasugrel
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Glycoprotein IIb/IIIa inhibitors
• Block final step in platelet aggregation induced by any agonist
• Abciximab• Eptifibatide• Tirofiban
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Abciximab
• Abciximab is the Fab fragment of a humanized monoclonal antibody directed against the GpIIb/IIIa receptor
• Uses:– percutaneous angioplasty for coronary
thromboses– prevent restenosis, recurrent myocardial
infarction, and death: used in combination with aspirin and heparin
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• T1/2: 30 min• Duration of action: 18 – 24 hrs• Dose: 0.25-mg/kg bolus followed by 0.125
g/kg/min for 12 hours or longer, IV• Adverse effects: – Hemorrhage (1-10%)– Thrombocytopenia (2%)
• Platelet transfusions can reverse the aggregation defect
• Expensive
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Eptifibatide • Cyclic peptide inhibitor of the fibrinogen
binding site on GpIIb/IIIa receptor• Dose: 180 g/kg IV bolus followed by 2
g/kg/min for up to 96 hours• Short duration of action: 6-12 hrs• Given with aspirin and heparin
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• Use:– Acute coronary syndrome– Angioplastic coronary interventions
• Adverse effects:– Bleeding (10%)– Thrombocytopenia (0.5-1%)
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Tirofiban
• Similar to eptifibatide• Value in antiplatelet therapy after acute
myocardial infarction is limited• Used in conjunction with heparin
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GpIIb/IIIa inhibitorsFeatures Abciximab Eptifibatide Tirofiban
Description Fab fragment of humanized mouse monoclonal antibody
Cyclical heptapeptide
Nonpeptide
Specific for GPIIb/IIIa
No Yes Yes
Plasma t1/2 Short Long (2.5h) Long (2.0h)
Platelet-bound t1/2
Long (days) Short (sec) Short (sec)
Renal clearance
No Yes Yes
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Newer anti-platelet agents
• Cangrelor• Ticagrelor• SCH530348 • E5555
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Cangrelor
• Adenosine analogue• Reversible inhibitor of P2Y12 receptor• T1/2: 3-6 min• Duration of action: 60 min• Administration: IV bolus followed by infusion• Little or no advantage over other drugs
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Ticagrelor
• Orally active reversible inhibitor of P2Y12 receptor
• Rapid onset and offset of action• Twice daily dosage• First new antiplatelet drug to demonstrate a
reduction in cardiovascular death compared with clopidogrel in patients with acute coronary syndromes
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SCH530348, E5555
• SCH530348 an orally active inhibitor of PAR-1, is under investigation as an adjunct to aspirin or aspirin plus clopidogrel.
• Two large phase III trials are under way. • E5555 is an oral PAR-1 antagonist in early
developement
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Summary
• Potent inhibitors of platelet function have been developed in recent years
• These drugs act by discrete mechanisms; thus, in combination, their effects are additive or even synergistic
• Aspirin has remained, for over 50 years, the cornerstone of antiplatelet therapy owing to its proven clinical benefit and very good cost–effectiveness profile.
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• Their availability has led to a revolution in cardiovascular medicine, whereby angioplasty and vascular stenting of lesions now are feasible with low rates of restenosis and thrombosis when effective platelet inhibition is employed
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THANK YOU.
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References • Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12 th
edition, Section III. Modulation of Cardiovascular Function, Chapter 30. Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs
• Robbins and Cotran’s Pathologic basis of disease, 8th edition, Section IV, Hemodynamic disorders, Thromboembolic disease and shock. Hemostasis and thrombosis.
• Tripathi K D, essentials of medical pharmacology, 6th edition, Section ten, Drugs affecting blood and blood formation. Drugs affecting coagulation, bleeding and thrombosis.
• Kallirroi I Kalantzi, Maria E Tsoumani, ET. AL. Pharmacodynamic Properties of Antiplatelet Agents -Current Knowledge and Future Perspectives , Expert Rev Clin Pharmacol. 2012;;5(3):319- 336
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Dazoxiben
• It inhibits the enzyme thromboxane synthetase so reduces the concentration of thromboxane A2
• Its antiplatelet action is not satisfactory, when used alone.
• However may be useful when used with aspirin.
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PROSTACYCLINE ANALOGUES
• Ex are epoprostenol, iloprost• These group of drugs block all pathway for platelet
activation.• They also inhibits the expression of GP IIb/IIIa
receptor.• Epoprostenol has a very short half life of 3 mins so it
has to be used by iv infusion. • It causes headache and flushing due to vasodilation.• iloprost is similar to epoprostenol but iloprost is
longer acting.