Anti platelet agents

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  • Normal hemostasis is the result of a set of well-regulated processes that accomplish two important functions: (1) They maintain blood in a fluid, clot-free state in normal vessels; and (2) They are poised to induce a rapid and localized hemostatic plug at a site of vascular injury.thrombosis; it can be considered an inappropriate activation of normal hemostatic processes
  • On activation platelets spread podia leading to dramatic increase in surface area
  • Platelets first adhere to macromolecules in the subendothelial regions of the injured blood vessel, where they become activated. Adherent platelets release substances that activate nearby platelets, thereby recruiting them to the site of injury. Activated platelets then aggregate to form the primary hemostatic plugPlatelet adhesion and aggregation. GPIa/IIa and GPIb are platelet receptors that bind to collagen and von Willebrand factor (vWF), causing platelets to adhere to the subendothelium of a damaged blood vessel. PAR1 and PAR4 are protease-activated receptors that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP; when stimulated by agonists, these receptors activate the fibrinogen-binding protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to promote platelet aggregation and secretion. Thromboxane A2 (TxA2) is the major product of COX-1 involved in platelet activation. Prostaglandin I2(prostacyclin, PGI2), synthesized by endothelial cells, inhibits platelet activation.
  • Because platelets do not synthesize new proteins, the action of aspirin on platelet COX-1 is permanent, lasting for the life of the platelet (7-10 days)
  • The unique sensitivity of platelets to inhibition by such low doses of aspirin is related to their presystemic inhibition in the portal circulation before aspirin is deacetylated to salicylate on first pass through the liver (Pedersen and FitzGerald, 1984). In contrast to aspirin, salicylic acid has no acetylating capacity
  • Other NSAIDs that are reversible inhibitors of COX-1 have not been shown to have anti-thrombotic efficacy and in fact may even interfere with low-dose aspirin regimenssingle 325-mg dose of aspirin approximately doubles the mean bleeding time of normal persons for 4-7 days
  • cAMP potentiates PGI2andinterfereswith aggregation
  • converted to the active thiol metabolite by a hepatic CYP
  • Mechanism  of  action  of  the  P2Y12  antagonists.  P2Y1  and  P2Y12  are  G-­coupled  receptors,  which  utilize  ADP  as  an  agonist.  P2Y1  is  a Gq-­coupled  receptor,  which  initiates  ADP-­induced  platelet  aggregation  through  the  stimulation  of  PLC  and  phosphatidylinositol-­signaling pathway.  P2Y12  is  a  Gi-­coupled  7-­transmembrane  domain  receptor,  which  mediates  platelet  activation  by  inhibiting  an  AC-­mediated signaling  pathway  and  decreasing  the  cAMP  intracellular  levels.  It  also  inhibits  PI3K  and  induces  Akt  kinase  activation.  The  decrease  in cAMP  intracellular  levels  reduces  the  rate  of  phosphorylation  of  VASP,  thus  inducing  activation  of  the  GPIIb/IIIa  receptor  and  platelet aggregation.  AC:  Adenyl  cyclase;;  PLC:  Phospholipase  C;;  VASP:  Vasodilator-­stimulated  phosphoprotein;;  VASP-­P:  Vasodilator-­ stimulated  phosphoprotein  phosphorylation.
  • Loading doses of 500 mg sometimes are given to achieve a more rapid onset of actionThe plasma t1/2 after single doseis 8 hr, but after multiple dosesit is 8 days
  • (absolute neutrophil count <500/L) , seen in 2.4% of stroke patients given the drug during premarketing clinical trials
  • Ttp has high mortality
  • Becauseof its potential for serious adverse reactions, use of ticlopidine is restricted to supplementing aspirin or when aspirin is contraindicated.
  • Even patients with the reduced-function CYP2C19*3, *4, or *5 alleles may derive less benefit from clopidogrel than those with the full-function CYP2C19*1 allele
  • Metabolism  of  ADP  P2Y12  antagonists.  The  thienopyridines  clopidogrel  and  prasugrel  are  prodrugs,  requiring  hepatic  metabolism  to  form their  active  metabolites,  which  irreversibly  bind  to  P2Y12.  After  intestinal  absorption,  clopidogrel  prodrug  is  metabolized  into  inactive metabolites  by  ubiquitous  esterases.  The  remainder  (15%)  undergoes  activation  in  the  liver  by  the  hepatic  CYP450  enzymatic  pathway. Clopidogrel  activation  requires  a  two-­step  oxidative  process  conversion,  first  to  2-­oxo-­clopidogrel  and  then  to  its  active  thiol  metabolite. Both  steps  involve  several  hepatic  CYP  isoenzymes.  PON-­1  may  also  participate  in  the  formation  of  clopidogrel's  active  thiol metabolite.  Prasugrel  is  a  prodrug  that  first  undergoes  a  rapid  de-­esterification  to  an  intermediate  thiolactone,  which  is  then  converted  in the  liver  to  the  active  metabolite  by  CYP  isoenzymes  in  a  single  CYP-­dependent  process.  Clopidogrel  and  prasugrel  are  irreversible antagonists  of  the  P2Y12  receptor.  Ticagrelor  is  a  direct-­acting,  reversible,  noncompetitive  antagonist  of  the  P2Y12  receptor,  which  does not  need  metabolic  activation.  Cangrelor  and  elinogrel  cause  reversible  inhibition  of  the  P2Y12  receptor  as  well.  Both  drugs  directly  and competitively  antagonize  ADP  binding  to  the  P2Y12  receptor  without  the  need  for  any  metabolic  activation.  CYP:  Cytochrome  P450;; PON-­1:  Paraoxonase-­1.
  • Thrombocytopenia with a platelet count <50,000 occurs in about 2% of patients and may be due to development of neo-epitopes induced by bound antibodyfree antibody concentrations fall rapidly after cessation of infusion
  • It also binds to the vitronectin receptor on platelets, vascular endothelial cells, and smooth muscle cells.
  • Recent trials comparing cangrelor with placebo during coronary interventions or comparing cangrelor with clopidogrel after such procedures revealed little or no advantages of cangrelo
  • Anti platelet agents

    1. 1. Anti-platelet agents Dr. J Pradeep
    2. 2. Contents • • • • • Introduction Classification Individual drugs Newer anti-platelet agents Summary
    3. 3. Introduction • Normal hemostasis – Maintenance of blood in a fluid, clot-free state in normal vessels; and – Formation of hemostaticplug at a site of vascular injury. • Opposite : Thrombosis – Thrombi are lysed and blood is made fluid by fibrinolytic system
    4. 4. Coagulation Fibrinolysis
    5. 5. • Both hemostasis and thrombosis are regulated by three general components – The vascular wall, – Platelets, and – The coagulation cascade
    6. 6. Myeloid precursors CFU-M Megacaryocytes Platelets
    7. 7. • • • • • Platelet count:150000 - 400000/mm3 Lifespan: 7-10 days No nucleus Cannot synthesise proteins Shape: biconcave discs, fully spread cells
    8. 8. • 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)
    9. 9. • 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
    10. 10. Platelet adhesion and aggregation
    11. 11. Classification • TXA2 inhibitors – Aspirin (non selective COX inhibitor) • Phosphodiesterase inhibitors – Dipyridamole • Thienopyridine derivatives – Ticlopidine, Clopidogrel, Prasugrel
    12. 12. • Glycoprotein (GP) IIb/IIIa inhibitor – Abciximab, Eptifibatide, Tirofiban • Newer anti-platelet agents – Cangrelor, Ticagrelor, SCH530348
    13. 13. 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)
    14. 14. • 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
    15. 15. TXA2 PGI2 • 50-320mg/day • Pro aggregation • Higher doses • Anti aggregation
    16. 16. • 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
    17. 17. 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 • cAMPpotentiates PGI2 and interferes with aggregation
    18. 18. • 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
    19. 19. Ticlopidine • Ticlopidine is a thienopyridineprodrug that inhibits the P2Y12receptor • Converted to the active thiol metabolite in liver • It is rapidly absorbed and highly bioavailable • It permanently inhibits the P2Y12receptor and has prolonged action
    20. 20. • 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
    21. 21. Side effects • Common: nausea, vomiting, diarrhoea • Serious adverse effect: severe neutropenia • Fatal agranulocytosis with thrombocytopenia has occurred within the first 3 months of therapy
    22. 22. • Frequent blood counts and platelet counts are advised in first few months of therapy • Discontinue therapy if counts fall • Thrombotic thrombocytopenic purpurahemolytic uremic syndrome (TTP-HUS) – rare adverse effect
    23. 23. Therapeutic uses • • • • • Prevention of stroke and TIAs Intermittent claudication Unstable angina Prevention of MI Preventing restenosis and stent thrombosis after PCI
    24. 24. 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
    25. 25. • 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
    26. 26. • 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
    27. 27. 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
    28. 28. Interactions • Proton pump inhibitors, inhibitors of CYP2C19, produce a small reduction in the inhibitory effects of clopidogrel on ADPinduced platelet aggregation • Atorvastatin, a competitive inhibitor of CYP3A4, reduced the inhibitory effect of clopidogrel on ADP-induced platelet aggregation
    29. 29. Prasugrel • Thienopyridineprodrug • Rapid onset of action • Greater inhibition of ADP induced platelet aggregation • Almost completely absorbed from the gut • Almost all of the drug is activated
    30. 30. • 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
    31. 31. • However, it has higher rates of fatal and lifethreatening bleeding • Contraindicated in those with a history of cerebrovasculardisease - high risk of bleeding • Caution is required if prasugrel is used in patients weighing <60 kg or in those with renal impairment
    32. 32. • 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
    33. 33. Glycoprotein IIb/IIIa inhibitors • Block final step in platelet aggregation induced by any agonist • Abciximab • Eptifibatide • Tirofiban
    34. 34. 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
    35. 35. • 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
    36. 36. 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
    37. 37. • Use: – Acute coronary syndrome – Angioplastic coronary interventions • Adverse effects: – Bleeding (10%) – Thrombocytopenia (0.5-1%)
    38. 38. Tirofiban • Similar to eptifibatide • Value in antiplatelet therapy after acute myocardial infarction is limited • Used in conjunction with heparin
    39. 39. GpIIb/IIIa inhibitors Features 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 Long (days) t1/2 Short (sec) Short (sec) Renal clearance Yes Yes No
    40. 40. Newer anti-platelet agents • • • • Cangrelor Ticagrelor SCH530348 E5555
    41. 41. 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
    42. 42. 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
    43. 43. SCH530348, E5555 • SCH530348 an orally active inhibitor of PAR1, 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
    44. 44. 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 cornerst one of antiplatelet therapy owing to its prove n clinical benefit and very good cost– effectiveness profile.
    45. 45. • 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
    46. 46. THANK YOU.
    47. 47. References • Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th 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 AgentsCurrent Knowledge and Future Perspectives, Expert Rev Clin Ph armacol. 2012;;5(3):319--336
    48. 48. 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.
    49. 49. PROSTACYCLINE ANALOGUES • Ex are epoprostenol, iloprost • These group of drugs block all pathway for platelet activation. • They also inhibits the expression of GPIIb/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.

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