Antiplatelet Drugs PDF

Antiplatelet Drugs Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 1 Learning Objectives At the end of the lectures you should be able to:...

Antiplatelet Drugs Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 1 Learning Objectives At the end of the lectures you should be able to: List the major drugs used as antiplatelet agents. Explain the mechanisms of action of antitplatelet agents, their major side effects, their clinical indications, how their activity is monitored, and their antidotes, if any. Recall drug interactions where these drugs are involved, and explain the mechanisms of interactions. 2 2 1  Thrombosis Formation of occluding thrombi Heart – myocardial infarction Brain – stroke Leading cause of death High incidence groups – prevention 3 3 Rupturedplaque thrombus injury formation 4 4 2  Anti-Thrombotic Therapy - Anti-coagulant and anti-platelet therapy: Prevent thrombus propagation Isingtire Prevent thrombus formation formingintnefr.tt face - Thrombolytic therapy: Targetsexistingclot Lysis of existing thrombi (fibrinolysis) - Antiplatelet Drugs prevent platelet activation - Anticoagulants prevent fibrin formation - Procoagulants enhance coagulation 5 5 6 6 3  Antiplatelet Drugs 7 7 Antiplatelet Drugs Paizendotheliacells TX A2plateletcells targetadifferentpathwaysofplateletactivation Platelet activation can be inhibited via: admit Prevent TXA2 synthesis ith atavate Antagonize ADP receptors panorpanicreceptor platelets Antagonize the platelet glycoprotein GPIIb/IIIa Inhibit Phosphodiesterase (PDE) w tum i mate FE.tt nn activation serotonin vasoconstrictors enhancesplatelet ADPactivatesplatelets slotformation enhances 8 8 4  Platelet Activation  When platelets adhere to the subendothelial tissues, they undergo degranulation (secretion; or release reaction) and release cytoplasmic granules, which contain: serotonin, a vasoconstrictor ADP  platelet activation and aggregation  enhance clot formation siteofinjury plateletswithin  Platelets will also synthesize: Thromboxane A2  platelet activation and aggregation  enhance clot formation 9 9 How to prevent platelet activation? 2 thrombin 3 1 Goodman & Gilman: PBT, 11th Edn 10 10 5  Major Drug Targets for Inhibiting Platelet Function I. ADP receptors (P2Y1/ P2Y12) – Activates GPIIb/IIIa receptors – Activates COX-1 enzyme producesTXA2 II. COX-1 enzyme – Produces TxA2 III. Fibrinogen receptors (GPIIb/IIIa) – When activated by other factors, fibrinogen binds to these receptors  platelet aggregation IV. Phosphodiesterases – Cyclic nucleotide PDEs degrades cAMP that inhibits platelet activation. 11 11 copia.gr Major Antiplatelet Drug Classes iiii Prasugrel Effien Ticogrelor I. ADP Receptor Antagonists Brillinta Clopidogrel (Plavix®) Prasugrel (Effient®) Ticagrelor (Brilinta®) II. Anti-thromboxane Drugs Knowthebrandnames a 101 in Aspirin GPIb 111AAntagonist III. GPIIb/IIIa Antagonists Abciximab (ReoPro®; antibody) AbciximabReoproAntibody Eptifibatide (Integrilin®) – Peptide-based EptitibatideCintegrilin Tirofiban (Aggrastat®) – non-peptide TirofibanAggrastat IV. Phosphodiesterase Inhibitors Dipyridamole (Persantine®) viagra 12 persanting 12 6  ADP blocking receptor the blows L campproduction platelet ADP Antagonists activation  É p and 2412 ADP receptor activation causes platelet activation  clot formation  ADP antagonists can therefore reduce clot formation. Useful in aspirin intolerant patients.  ADP activates purinergic receptors  Major subtypes: P2Y1, P2Y12  Clinically used ADP antagonists: – Clopidogrel (Plavix ®) – Prasugrel (Effient®) – Ticagrelor (Brilinta®) 13 13 ADP Antagonists-Mechanism of Action These Clopidogrel drugs P2Y12 receptor target Prasugrel 72412 Ticagrelor receptor ADP Adenosine diphosphate 14 14 7  PRODRUG coated mettabolite Clopidogrel (Plavix®) (1) byCYP2019primary  Noncompetitive (irreversible) ADP (P2Y12) and or CYP3A4 receptor antagonist, and is a prodrug that requires activation via metabolism in the liver by CYP2C19 and CYP 3A4 (note: gene polymorphisms exist for the 2C19) by polymorphism cantake CYP2C19 Active enymenonfunctional Clopidogrel metabolite  Patients who are 2C19 poor metabolizers may produce less of the active form and poormetabolizerof display resistance to the antiplatelet effects cypenzyme of this agent. let it it 15 15 Clopidogrel (Plavix®) (2)  Reduces platelet activation. May be combined with aspirin  Clopidogrel requires a loading dose to achieve a maximal antiplatelet effect rapidly.  Available as clopidogrel bisulfate whyisloadingdosegiven ofactionor Shortening onset canreachmintherapeuticconcfate 16 16 8  Clopidogrel (Plavix®) (3) 51 forall  Side effects anti thrombotic – Hemorrhage agents beleding – Neutropenia (reduced white blood cell count; serious ADR)  Slightly more favorable toxicity profile than ticlopidine (especially bone marrow toxicity) FInames  Drug-drug interactions: With drugs that are metabolized by CYP 3A4 (e.g., statins atorvastatin) ?? --- PPIs** (omeprazole) may decrease activity via CYP 2C19 interaction ?? Dinhibitscuraciaso to iii nai Note: Prescription of a PPI is recommended in all patients taking dual antiplatelet therapy to reduce the risk of gastrointestinal tract bleeding ** JAMA. 2009;301(9):937-944 17 PPIs: proton pump inhibitors 17 iii ii Clopidogrel (Plavix®) (4) iiiiiiiii.it E Antidote/ pre-op, preprocedure, washout (if indicated) Platelet transfusion suggested Washout: five to seven days It if 18 18 9  FYI Research data generated by Harold Ting, M.S. , WesternU (11/11/2009) 19 19 Note: New evidence suggests that patients using a PPI have increased baseline cardiovascular and GI risk profiles. 20 20 10  CYP2C19/Clopidogrel Gene Testing** ** FYI 21 21 Clopidogrel (Plavix®) Boxed Warning (1)** CYP2C19 Loss of Function ** FYI 22 22 11  Clopidogrel (Plavix®) Boxed Warning (2)** ** FYI 23 23 Prasugrel (Effient®)  Approved by FDA on July 2009 in intestine  Noncompetitive (irreversible) iii as ADP (P2Y12) receptor antagonist, and is also a prodrug that first undergoes hydrolysis in the intestine and then activation via metabolism in the liver (CYP3A4 and CYP2B6 (thus, no interaction with PPIs that inhibit CYP2C19)  Requires a loading dose pttakingPPIgivePrasugrel Higher risk of bleeding compared to clopidogrel telling g.ieclopidogrel 24 24 12  irreversible ClopidogrelandPrasugrelnoncompetitive Ticagrelor (Brilinta®) reiiiitiimii.ie In December 2010, the FDA declined to approve this agent, but approved it on July 20, 2011  A competitive (reversible) ADP (P2Y12) receptor antagonist. Thus, no persistent platelet inhibition after drug stoppage. Ticagrelorisnot aprodrug i fft Ticagrelor is metabolized to an active equipotent metabolite mainly by CYP3A4similartoPlavix Tydountchangeafter m etabolized  Consider for patients with reduced CYP2C19 activity  Requires a loading dose 25 25 Cangrelor (Kengreal®) - Fast-acting, potent intravenous P2Y12 inhibitor - Approved by FDA on June 22 2015 (after being initially rejected in 2014) 26 26 13  Antithromboxane Drugs  COX-1 enzyme mediates production of Thromboxane A2 (TXA2 ) that activates platelets  Therefore to inhibit platelet activation: -- Prevent formation of (TXA2 ) - COX-1 inhibitors (aspirin, non-specific) ftp.teuethtspYdfonofTxA2 splateeetnotactivated i iodcox.s Blockade of TXA2 receptors?? iiif Experimental: – KP-496 - NCX-4016 – S18886 - BM-573 Note: No TXA2 receptor antagonist is currently available for clinical use 27 27 Aspirin o Acetyl salicylic acid (ASA) o Derived from salicylic acid (Willow tree) o Inhibits both COX-1 and COX-2 (non-selective COX inhibitor) acetylationcontenereside o Irreversibly/covalently acetylates serine residue of COX enzymes iiI i iii cannot.am o Because platelets cannot synthesize new cyclooxygenase, the inhibitory es VALLETERSPLE effect of aspirin lasts the life span of the platelets. IE aasth o Inhibits the production of TXA2 in platelets splateletactivation cheat m e o Reduces platelet activation, aggregation  inhibit clot formation o Low doses (baby aspirin; 81 mg once/day) are used clinically for prevention of MI 28 28 14  Major Drawback of Aspirin Therapy  Aspirin is a non-selective inhibitor of COX, inhibiting both COX-1 and COX-2  COX-1 also produces prostaglandins which are gastro- protective (e.g. PGE2) Aspirin riskofulcer cox blocked Gastric blocked prostaglandin regionunprotected bleeding  By inhibiting the gastro-protective PGs, aspirin (and all other risk non-specific COX inhibitors) can cause gastric mucosal damage  bleeding  However at low-doses used for antiplatelet effect, these side effects are minimal kidneyd amage  ADRs: GI bleeding, nephropathy, hepatic injury, aspirin-induced airway hyperreactivity in asthmatics; Reye's syndrome (with viral disease) 29 29 Baby Aspirin Use in Prevention of MI Aspirin  Aspirin reduces platelet aggregation and hence chances of PYEE.IE coronary artery blockade in patients with CAD (esp. unstable angina) bydeactivating  Why baby aspirin (low dose)? Coxenzyme – Cumulative (intermittent) low doses of aspirin can irreversibly acetylate and deactivate COX-1 enzyme required for the production of TXA2 (platelet activator). Platelets cannot make new COX-1. On the other hand, endothelial cell can make new COX-1, and thus can make PGI2 (which inhibits platelets). – Low doses have minimal effect on the synthesis of gastro- protective prostacyclins (e.g., PGE2) and hence reduced risk of GI bleeding.  Aspirin Resistance: Up to 20% of the population may not respond (are resistant) to aspirin therapy 30 30 Aspirin prevention of MI low dose every otherday dosing 15  Why not Celecoxib or Ibuprofen? 1. Why not ibuprofen? - Inhibition of the cyclooxygenase is not permanent. 2. Why not Celebrex® (celecoxib) for preventing clotting? - COX-2 not expressed in platelets  drug will not have an effect cardiovascular TXAzPlateletattivation 3. Why Rofecoxib (VIOXX ®) caused CVS problems? - most likely because these agents inhibit endothelial production of Palz plateletinhibition PGI2 without inhibiting platelet generation of TXA2. Thus, there is lack of inhibition of platelets by the TXA2 ”physiologic antagonist” PGI2. am 4. Why Celebrex ® is still in the market? iiifii – CVS adverse effects are claimed to be drug specific and not class specific. 31 31 I LP heart'attack GPIIb/IIIa Antagonists  GPIIb/IIIa receptors activated by other factors such as GP receptors, ADP/PAR/TXA2 receptors  bind to fibrinogen  mediate platelet aggregation (i.e., fibrinogen acts as a molecular bridge between activated platelets). Thus, blocking fibrinogen interaction with GPIIb-IIIa will prevent this final common pathway of platelet aggregation.  GPIIb/IIIa antagonists reduce platelet activation 32 32 16  GPIIb/IIIa Antagonists (2)  Common antagonists – Abciximab (Reopro®; monoclonal antibody) – Eptifibatide (Integrelin®; synthetic cyclic peptide) – Tirofiban (Aggrastat®; non-peptide) Pstcannot Disadvantage: All good for parenteral (i.v.) administration only begiven orally 33 33 GPIIb/IIIa Antagonists (2) ii as ii  GPIIb/IIIa antagonists reduce platelet activation independent of the agonist activating them (broad-spectrum inhibition). 34 34 CAMP is another broad spectruminhibitor 17  GPIIb/IIIa Antagonists - Mechanism abciximab is Abciximab prevents the binding of fibrinogen to activated GPIIb/IIIa receptors  inhibit platelet aggregation  reduce clot formation 35 35 Abciximab (ReoPro®) incsible  Monoclonal antibody Fab (fragment) directed against GPIIb/IIIa (essentially irreversible antagonist)  Administered intravenously  Reduces risk of restenosis, but at the risk of causing bleeding as an adverse drug reaction shuttingdownplatelets completely  Drawbacks: Immunogenicity limits the use to single administration; has to be administered parenterally Ptmaybecomeallergictodrug afteradministered once 36 36 18  PDE breaks cAMP less CAMP platelet activity whatades Phosphodiesterase Inhibitors (PDEI) InhibitPDE less AMP - cAMP inhibits platelet activity. brokendown Phosphodiesterases degrade morecAMP cAMP  increase platelet activation. PDEIs letsplatelet - Phosphodiesterase inhibitors activation prevent the degradation and, thus, lead to an increase in cAMP levels, thereby inhibiting platelet activity  reduced platelet aggregation (independent of agonist; broad spectrum inhibition) and, hence reduce clot formation MOA: Ca2+ is an important mediator of intracellular signal events that leads to platelet activation. Cyclic AMP (cAMP) has an opposing effect of Ca2+ by sequestering cytosolic Ca2+ to its storage site. 37 37 Wepaelet Dipyridamole (Persantine®) inhibitor Inhibits cyclic nucleotide phosphodiesterase  ↑ cAMP  inhibit platelet activity (weak effect if used alone) Recommended use: in combination with warfarin ADRs: Coronary vasodilation 38 38 19  US Pharmacist, 2004, Vol. No: 29:02 39 39 PAR-1 Antagonist Zontivity® (Vorapaxar): Is a first-in- class approved antiplatelet medication that acts as a protease-activated receptor 1 (PAR-1) antagonist Approved on May 8 2014 40 40 20  Platelet Function Testing and Implications for Clinical Practice* so - While low responsiveness to antiplatelet therapy (as measured in various platelet function assays) correlates with a high rate of ischemic events, tailoring treatment based on platelet response remains to be definitively proven in clinical trials. - Additional studies are needed to determine whether changes in therapy based on results of platelet function testing improve clinical outcomes, and thus will determine whether broader use of platelet function testing in clinical practice is warranted. J Cardiovasc Pharmacol Ther. 2009 Sep;14(3):157-69. * FYI 41 41 Any questions? The End 42 42 21