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Platelets for anaesthetists—Part 2: pharmacology

2015; Elsevier BV; Volume: 16; Issue: 4 Linguagem: Inglês

10.1093/bjaed/mkv035

2058-5357

Ganesh Ramalingam, Nicola Jones, Martin Besser,

Coronary Interventions and Diagnostics

Key points•Aspirin is the most widely used antiplatelet agent.•The thienopyridine group of antiplatelet agents block platelet activation by inhibiting the adenosine diphosphate receptors.•Good understanding of the pharmacodynamics and pharmacokinetics of antiplatelet agents provides us an insight into the perioperative management of patients with antiplatelet agents.•Perioperative management of patients with antiplatelet agents comprises a fine balance between the risk of cardiovascular events on stopping the medication and the bleeding complications due to the continuation of the antiplatelet agent. •Aspirin is the most widely used antiplatelet agent.•The thienopyridine group of antiplatelet agents block platelet activation by inhibiting the adenosine diphosphate receptors.•Good understanding of the pharmacodynamics and pharmacokinetics of antiplatelet agents provides us an insight into the perioperative management of patients with antiplatelet agents.•Perioperative management of patients with antiplatelet agents comprises a fine balance between the risk of cardiovascular events on stopping the medication and the bleeding complications due to the continuation of the antiplatelet agent. Platelets play a major role in the pathogenesis of atherosclerosis and thrombotic diseases. Antiplatelet agents are widely used to prevent complications of the atherosclerotic disease process. As anaesthetists, we encounter patients on antiplatelet therapy regularly and more frequently. This review describes the pharmacokinetics and pharmacodynamics of various antiplatelet agents. Platelet activation and aggregation occurs due to the binding of various ligands and agonists to several platelet receptors. The receptors of interest in relation to antiplatelet therapy are TP (thromboxane A2 receptor), ADP (adenosine diphosphate) receptor, PAR (protease-activated receptor), and GP IIb/IIIa receptor. TP, PAR, and ADP receptors all belong to the G-protein family of receptors. There are two types of ADP receptors, P2Y1 and P2Y12. Both P2Y1 and P2Y12 are G-protein-coupled receptors. Thrombin activates platelets via PAR receptors. There are four types of PAR, of which PAR-1 and PAR-4 are present in humans. GP IIb/IIIa receptor (αIIb/β3) is a transmembrane receptor present in the surface of platelets and belongs to the integrin group of receptors. The most commonly used antiplatelet agent is aspirin, which is a cyclooxygenase (COX) enzyme inhibitor. This enzyme converts arachidonic acid to prostaglandin H2 (PGH2), which itself is a precursor for the formation of other prostaglandins, in particular thromboxane A2 (TXA2) by thromboxane synthase and Prostacyclin (PGI2) by prostacyclin synthase. TXA2 is responsible for stimulation of platelet aggregation and localized vasoconstriction, while PGI2 is responsible for inhibition of platelet aggregation and localized vasodilatation. Cyclooxygenase enzyme exists in two isoforms, COX-1 and COX-2. COX-1 is mainly responsible for TXA2 synthesis and COX-2 is mainly responsible for PGI2 synthesis. COX-2 enzyme is abundant in endothelium and exerts its antiplatelet actions. Aspirin at low doses (75–300 mg) selectively inhibits COX-1 enzyme and is responsible for its antiplatelet actions. However, at high doses (1 g day−1), it inhibits COX-2 enzyme as well. Low-dose aspirin is preferred as high doses cause increased incidence of upper gastrointestinal bleeding without an increase in efficacy (Fig. 1).1Ferreiro JL Angiolillo DJ New directions in antiplatelet therapy.Circ Cardiovasc Interv. 2012; 5: 433-445Crossref PubMed Scopus (62) Google Scholar Aspirin is widely used in the secondary prevention of coronary events and stroke in patients with coronary artery disease, cerebrovascular disease, and peripheral vascular disease. The important adverse event with aspirin is bleeding complications in the gastrointestinal tract. This can be reduced by co-administration of proton pump inhibitor or a H2 blocker. Aspirin is contraindicated in children and adolescents 99%). The primary route of elimination is by biliary secretion. No dosage adjustment is necessary for patients with renal impairment. The terminal half-life of the drug is 7 and 9 h for the active metabolite. Apart from bleeding complication associated with all antiplatelet agents, ticagrelor is associated with transient dyspnoea. The PLATO6Wallentin L Becker RC Budaj A et al.Ticagrelor versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2009; 361: 1045-1057Crossref PubMed Scopus (5522) Google Scholar (Platelet Inhibition and patient outcomes) trial compared ticagrelor with clopidogrel in patients with acute coronary syndrome; 18 624 patients were enrolled of which 35% had STEMI (ST Elevation Myocardial Infarction). Ticagrelor showed significant reductions in cardiovascular events when compared with clopidogrel. Cangrelor (an ATP analogue) is a short-acting i.v. P2Y12 ADP-receptor antagonist. It has a rapid onset of action. It is given as an i.v. loading dose of 30 μg kg−1 followed by 2–4 μg kg−1 min−1 i.v. The maximal inhibition occurs within 15 min and a rapid reversal after discontinuation of the drug.7Wallentin L P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use.Eur Heart J. 2009; 30: 1964-1977Crossref PubMed Scopus (258) Google Scholar The elimination half-time is under 9 min and platelet function tends to come to normal in 60 min. Metabolism of the drug is through dephosphorylation and is not dependent on the liver or kidneys. Cangrelor appears as an effective drug for bridge therapy during the perioperative period or even during ACS when possibility of surgery exists. Although the drug appeared promising in bridging therapy, the FDA this year refused marketing approval citing inconclusive phase III clinical trials.8Waite LH Phan YL Spinler SA Cangrelor: a novel intravenous antiplatelet agent with a questionable future.Pharmacotherapy. 2014; 34: 1061-1076Crossref PubMed Scopus (17) Google Scholar GP IIb/IIIa receptors play a crucial role in platelet aggregation. GP IIb/IIIa receptors are present on the surface of platelets normally in an inactive form. When the platelets are activated, they undergo a conformational change resulting in binding of fibrinogen and von Willebrand factor (vWF). These molecules function as a bridge for the platelet aggregation. GP IIb/IIIa receptor blocking drugs bind to the GP IIb/IIIa receptor and inhibit platelet aggregation by preventing the binding of vWF and fibrinogen. Abciximab is a monoclonal antibody, while the other two are synthetic derivatives. Abciximab, the Fab fragment of chimeric murine (humanized form) monoclonal antibody, binds with the GP IIb/IIIa receptor and prevents platelet aggregation. It also binds and inhibits vitronectin receptor found in platelets and endothelial and smooth muscle cells. Abciximab is given as an i.v. loading dose of 0.25 mg kg−1 followed by an i.v. infusion of 0.125 μg kg−1 min−1. After a bolus dose, the plasma levels reduce very rapidly with a half-life of 10 min due to the rapid binding of abciximab to platelets and phase II half-life of 30 min. It takes 48 h for the platelet function to recover after cessation of the medication. Abciximab can be found in the circulation even after 15 days. It is not necessary to adjust the dose of abciximab in patients with renal impairment. Eptifibatide is a cyclic heptapeptide. It selectively binds to GP IIb/IIIa receptors and inhibits platelet aggregation. Unlike abciximab, eptifibatide does not bind to any other receptors. It is given as an i.v. bolus dose of 180 μg kg−1 followed by an i.v. infusion of 2 μg kg−1 min−1.9Oprea AD Popescu WM Perioperative management of antiplatelet therapy.Br J Anaesth. 2013; 111: i3-17Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar It inhibits platelet aggregation in a dose-dependent and concentration-dependent manner, resulting in 80% IPA within 15 min.9Oprea AD Popescu WM Perioperative management of antiplatelet therapy.Br J Anaesth. 2013; 111: i3-17Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Eptifibatide dissociates from platelets rapidly on discontinuation of infusion and is mostly excreted unchanged in urine. The plasma elimination half-life is 2.5 h. Since the drug is eliminated unchanged in urine, the dose needs to be reduced in renal impairment. If the creatinine clearance is <60 ml min−1, the dose should be reduced to 1 μg kg−1 min−1. Tirofiban is a reversible non-peptide antagonist of the GP IIb/IIIa receptor. It is given as an i.v. loading dose of 25 μg kg−1 over 3 min followed by an i.v. infusion of 0.15 μg kg−1 min−1.9Oprea AD Popescu WM Perioperative management of antiplatelet therapy.Br J Anaesth. 2013; 111: i3-17Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Ninety per cent IPA is achieved within 10 min. It is excreted unchanged in urine and faeces. The half-life of tirofiban is 2 h. Similar to eptifibatide, the dose of tirofiban should be reduced to half in patients with reduced creatinine clearance (<60 ml min−1). GP IIb/IIIa receptor antagonists were associated with increasing bleeding complications when compared with other antiplatelet agents. Thrombocytopenia has been reported to occur with all three GP IIb/IIIa receptor antagonists. GP IIb/IIIa antagonists are not effective when used as the only antiplatelet agent, with the only significant benefit obtained from infusion of these drugs being during PCI. In patients undergoing PCI, GP IIb/IIIa receptor antagonists were reserved for specific patient populations as mentioned below. Vorapaxar, a tricyclic himbacine-derived drug, selectively inhibits thrombin-mediated platelet aggregation. FDA recently (May 2014) approved this drug for marketing purposes after phase III trials. Although it is a reversible antagonist to PAR-1 receptor, it behaves like an irreversible drug due to its long half-life. It has no effect on ADP-mediated platelet aggregation. It is given as a 2.5 mg once-daily dose. The bioavailability of this drug is almost 100%. It achieves 80% IPA within 1 week. It is metabolized by the CYP3A4 enzyme system. The main route of elimination is through the faeces. No dosage adjustment is necessary for patients with renal impairment or for mild-to-moderate hepatic impairment, but it is contraindicated in patients with severe hepatic impairment due to increased bleeding problems. The terminal half-life of vorapaxar is 8 days. Even after weeks of stopping the drug, the IPA can be as high as 50%. It is currently approved for use with either aspirin or clopidogrel for secondary prevention in patients with history of myocardial infarction (MI) or peripheral vascular disease. There are several antiplatelet drugs currently under various stages of development. (i)Terutuban, a thromboxane receptor antagonist.(ii)Elinogrel, a P2Y12 receptor blocker, it can be administered both orally and i.v.(iii)Atoxapar, PAR-1 antagonist. There are several reasons a patient could be on antiplatelet therapy. They may be either on a platelet monotherapy or on dual antiplatelet therapy. The following list would summarize the common indications for antiplatelet therapy. (i)Aspirin (a)In patients with MI (indefinitely),10Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events.http://www.nice.org.uk/guidance/TA210Google Scholar(b)peripheral vascular disease (not much evidence),(c)primary prevention for cerebral vascular disease (not licensed),(d)atrial fibrillation (no longer recommended),(e)vascular dementia.(ii)Dipyridamole monotherapy10Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events.http://www.nice.org.uk/guidance/TA210Google Scholar (a)Ischaemic stroke if aspirin and clopidogrel is contraindicated.(b)TIA if aspirin is contraindicated.(iii)Clopidogrel monotherapy10Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events.http://www.nice.org.uk/guidance/TA210Google Scholar (a)All patients with MI if aspirin is contraindicated.(b)To prevent occlusive vascular events in patients who have had an ischaemic stroke or who have peripheral arterial disease.(c)Multivascular disease.(iv)Aspirin+dipyridamole10Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events.http://www.nice.org.uk/guidance/TA210Google Scholar (a)Patients with history of TIA.(b)Patients with history of ischaemic stroke if clopidogrel is contraindicated.(v)Aspirin+clopidogrel11MI—secondary prevention. Secondary prevention in primary and secondary care for patients following a myocardial infarction.http://www.nice.org.uk/guidance/cg172Date: 2013Google Scholar (a)At least 12 months for patients with NSTEMI (Non-ST elevation MI).(b)At least 12 months for patients with STEMI (ST Elevation MI) with drug-eluting stent (DES) or bare metal stent (BMS).(c)At least 1 month for patients with STEMI who had medical treatment with fibrinolytic agent.(vi)Aspirin+prasugrel12Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention.http://www.nice.org.uk/guidance/TA182Date: 2009Google Scholar (a)Patients with ACS for PCI if •Immediate primary percutaneous coronary intervention (PPCI) for STEMI.•Stent thrombosis on patients with clopidogrel therapy.•Patients with diabetes mellitus.(vii)Aspirin+ticagrelor13Ticagrelor for the treatment of acute coronary syndromes.http://www.nice.org.uk/guidance/TA23Date: 2011Google Scholar (a)For 12 months on patients •STEMI if the patients have PPCI•NSTEMI•Unstable angina(viii)I.V. eptifibatide or i.v. tirofiban14Unstable angina and NSTEMI. The early management of unstable angina and non-ST-segment-elevation myocardial infarction.http://www.nice.org.uk/guidance/cg94Date: 2013Google Scholar (a)Patients with unstable angina who are undergoing angiography within 96 h of admission. (i)Prevention of eclampsia and its complications15Duley L Henderson-Smart DJ Meher S King JF Antiplatelet agents for preventing pre-eclampsia and its complications.Cochrane Database Syst Rev. 2007; : CD004659PubMed Google Scholar,16Henderson JT Whitlock EP O'Connor E Senger CA Thompson JH Rowland MG Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force.Ann Intern Med. 2014; 160: 695-703Crossref PubMed Scopus (269) Google Scholar(ii)Thrombocytosis (controversial and uncertain)17Harrison CN Bareford D Butt N et al.Guideline for investigation and management of adults and children presenting with a thrombocytosis.Br J Haematol. 2010; 149: 352-375Crossref PubMed Scopus (223) Google Scholar(iii)Anticancer therapy (animal studies) Surgery on patients with dual antiplatelet therapy poses a significant challenge to anaesthetists. On the one hand, continuing dual antiplatelet therapy increases the risk of bleeding, on the other hand, stopping the antiplatelet can lead to cardiovascular events such as stent thrombosis, MI, and death. Each patient should be managed individually. It should be a multidisciplinary approach between surgeon, anaesthetist, cardiologist, and haematologist. The following factors should be taken into consideration. Aspirin can be continued until the day of surgery in most circumstances but may need to be stopped for some specific surgeries such as intracranial surgery. (i)Emergency or urgent (cancer related) surgery, elective surgery.(ii)Type of surgery: low risk, intermediate risk, or high risk for bleeding.(iii)Time duration from the occurrence of acute coronary syndrome or PCI to the surgery and if patient had a primary PCI, type of stent, that is, DES or BMS.(iv)Type of lesion—global coronary disease or specific coronary lesions. Platelet transfusions may not provide rapid reversal of the antiplatelet effects. Some antiplatelet drugs have a long half-life, so they remain in circulation for a considerable period of time. When platelets are transfused on these patients, the circulating drug will also inhibit the transfused platelets. Figure 2 illustrates the algorithm for the management of antiplatelets during surgery. There is no evidence that aspirin needs to be stopped for performing regional anaesthetic techniques. For all other antiplatelet agents, sufficient time should be allowed for the platelet function to recover. This time duration depends upon the elimination half-life and mechanism of action of the antiplatelet agents as shown in Table 1.Table 1Antiplatelets and regional anaesthesia. Adapted (with permission) from the AAGBI guidelines on regional anaesthesia and patients with abnormalities of coagulation, 2013DrugElimination half-lifeAcceptable time after the drug for performing blockAdministration of drug while spinal or epidural catheter in placeAcceptable time after spinal block performance or catheter removal for next drug doseAspirinNot significant irreversibleNo additional precautionsNo additional precautionsNo additional precautionsDipyridamole10 hNo additional precautionsNo additional precautions6 hTiclopidine4–5 days14 daysNot recommended6 hClopidogrelNot significant irreversible7 daysNot recommended6 hPrasugrelNot significant irreversible7 daysNot recommended6 hTicagrelor8–12 h5 daysNot recommended6 hAbciximab24–48 h48 hNot recommended6 hEptifibatide4–8 h8 hNot recommended6 hTirofiban4–8 h8 hNot recommended6 hVorapaxar8 daysNo dataNot recommendedNo data Open table in a new tab The list of antiplatelet agents in the market is growing constantly. Newer antiplatelet agents are being developed continuously to overcome the shortcomings of existing antiplatelet agents. As anaesthetists, we should continue to update ourselves with these newer antiplatelet agents to manage the patients effectively and safely during the perioperative period. A haematologist or cardiologist should be contacted in complex and difficult situations.