Manejo perioperatorio de pacientes usuarios de antiagregantes plaquetarios / Perioperative management of patients using antiplatelet agents

Resumen El uso de fármacos antiagregantes plaquetarios para prevención primaria y secundaria de eventos cardiovasculares es una práctica común en clínica. La terapia antiagregante plaquetaria disminuye significativamente la incidencia de eventos cardiovasculares, incluyendo infarto agudo al miocardio y accidente cerebro-vascular. Cada vez es más frecuente enfrentarse a pacientes en terapia antiagregante plaquetaria que serán sometidos a algún procedimiento quirúrgico, por tanto es fundamental conocer el manejo perioperatorio de estos fármacos, para disminuir los riesgos y complicaciones asociados a la suspensión o mantención de estas drogas en el período perioperatorio. Los antiagregantes plaquetarios de mayor uso en Chile son la aspirina y las tienopiridinas, siendo el clopidogrel el fármaco más utilizado en este grupo. El enfrentamiento perioperatorio de estos fármacos está supeditado al riesgo trombótico individual de cada paciente y al riesgo hemorrágico de cada cirugía. En cirugías no cardiacas, se sugiere mantener la aspirina, excepto en pacientes con bajo-moderado riesgo trombótico que serán sometidos a cirugías con alto riesgo de sangrado, en los cuales se recomienda suspenderla 5-7 días previo a la intervención quirúrgica. El clopidogrel se sugiere suspenderlo 5 días antes de la cirugía, excepto en pacientes con alto riesgo trombótico que se someterán a procedimientos quirúrgicos con riesgo hemorrágico bajo-moderado. En cirugías de revascularización miocárdica, se recomienda mantener aspirina y suspender clopidogrel 5 días antes del procedimiento. En relación al reinicio postquirúrgico de estos fármacos, se sugiere reanudar aspirina 6 h posterior a la cirugía y clopidogrel durante las primeras 24 h postoperatorias, asegurando previamente una adecuada hemostasia quirúrgica.

The use of antiplatelet drugs for primary and secondary prevention of cardiovascular disease events is a common clinical practice. Antiplatelet therapy significantly decreases the incidence of cardiovascular disease events, including acute myocardial infarction and cerebrovascular accident. It is increasingly common to face patients on antiplatelet therapy who will undergo some surgical procedure, so it is essential to know the perioperative management of these drugs, to reduce the risks and complications associated with the suspension or maintenance of these therapies in the perioperative period. The most common antiplatelet agents used in Chile are acetylsalicylic acid and thienopyridines, of which clopidogrel is the most frequent one. The perioperative management of these drugs has to be based on the individual thrombotic risk of each patient and the risk of hemorrhage of each surgery. In noncardiac surgeries, it is suggested to maintain acetylsalicylic acid, except in patients with low to moderate thrombotic risk who will undergo surgeries with a high risk of bleeding, in which case it is recommended to suspend it 5 to 7 days before surgery. Clopidogrel is suggested to be discontinued 5 days before surgery, except in patients with high thrombotic risk who will undergo surgical procedures with low to moderate risk of hemorrhage. In myocardial revascularization surgeries, it is recommended to maintain acetylsalicylic acid and to suspend clopidogrel 5 days before the procedure. Once assuring adequate surgical hemostasis, it is suggested to reinitiate acetylsalicylic acid 6 hours after surgery and to reinitiate clopidogrel during the first 24 postoperative hours.

Oral antiplatelet agent hypersensitivity and cross-reactivity managed by successful desensitisation

Oral platelet aggregation inhibitors are widely used for the treatment and prevention of cardiovascular diseases, including coronary stent thrombosis. Premature discontinuation following percutaneous coronary intervention would pose a grave risk of in-stent thrombosis, acute myocardial infarction and eventual death. Although they share the same mechanism of adenosine diphosphate P2Y12 platelet receptor inhibition, they belong to either the chemical class of thienopyridines (clopidogrel, prasugrel, and ticlopidine) or cyclopentyl-triazolo-pyrimidines (ticagrelor and cangrelor). This case describes the first documented cross-reactive hypersensitivity of clopidogrel towards both its fellow thienopyridine, prasugrel, as well as the structurally dissimilar ticagrelor, and its subsequent successful desensitisation.

Receptores plaquetários P2Y12: importância na intervenção coronariana percutânea / P2Y12 platelet receptors: importance in percutaneous coronary intervention

As plaquetas estão envolvidas em vários processos biológicos, desde o combate a agentes infecciosos até a coordenação do controle da permeabilidade vascular e angiogênese. Entretanto, o seu principal foco de ação consiste na modulação da cascata de coagulação. A intervenção coronariana percutânea é um procedimento com alto risco trombogênico, que induz a ativação plaquetária e de monócitos, devido à lesão direta do endotélio e pelo contato de estruturas trombogênicas com o sangue, levando ao aumento da atividade inflamatória, tanto no local do dano vascular coronariano como de forma sistêmica. Os receptores plaquetários P2Y12 desempenham papel central na amplificação da agregação induzida por todos os agonistas plaquetários, como a adenosina difosfato, o colágeno, tromboxano A2, adrenalina e serotonina. Por esse motivo, têm sido o principal alvo das drogas antiplaquetárias. Apesar de atuarem no mesmo receptor, características farmacocinéticas e farmacodinâmicas distintas conferem peculiaridades a cada agente.

Apart from their role in hemostasis and thrombosis, platelets are involved in many other biological processes such as wound healing and angiogenesis. Percutaneous coronary intervention is a highly thrombogenic procedure inducing platelets and monocytes activation through endothelial trauma and contact activation by intravascular devices. Platelet P2Y12 receptor activation by adenosine diphosphate facilitates non-ADP agonist-mediated platelet aggregation, dense granule secretion, procoagulant activity, and the phosphorylation of several intraplatelet proteins, making it an ideal drug target. However, not all compounds that target the P2Y12 receptor have similar efficacy and safety profiles. Despite targeting the same receptor, the unique pharmacologic properties of each of these P2Y12 receptor-directed compounds can lead to very different clinical effects.

A QSAR and molecular modeling study on a series of 3, 4-dihydro-1-isoquinolinamines and thienopyridines acting as nitric oxide synthase inhibitors.

A quantitative structure-activity relationship (QSAR) and molecular modeling study were performed on a series of 3,4-dihyro-1-isoquinolinamines and thienopyridines reported by Beaton et al. [Beaton et al. (2001) Bioorg Med Chem Lett 11, 1023-1026, 1027-1030] as potent, highly selective inhibitors of two isoforms of nitric oxide synthase (NOS) — neuronal NOS (nNOS) and endothelial NOS (eNOS), in order to find the physicochemical properties that governed their activity and the mode of interaction with the receptors, so that still more potent compounds in the series could be suggested. A multiple regression analysis revealed that nNOS and eNOS inhibition potency of these compounds could be controlled by their hydrophobic property and molar refractivity, respectively. Thus, nNOS and eNOS inhibition was indicated to involve the hydrophobic interaction and steric effects, respectively, suggesting some structural differences of the two isoforms of NOS. Based on the correlations obtained, some new, more potent compounds belonging to the series were predicted. These compounds were then docked into the receptors to see their interactions and find out the docking scores. The docked structures of two representative compounds, whose interaction energies with nNOS and eNOS, respectively were found to be the lowest, were given as an example to exhibit the possible orientation of the compounds to interact with the receptors.

New Oral Antiplatelet Agents / 대한내과학회지

Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Aspirin and thienopyridines comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS. Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. While clopidogrel remains in extensive use in clinical practice, it cannot meet the needs in many clinical conditions because of its pharmacological limitations. In recent years, newly developed P2Y12 antagonists, such as prasugrel and ticagrelor, have proven to be of higher efficacy and less resistance. As a third generation thienopyridine, prasugrel exerts a much more rapid and consistent inhibitory effect on platelet aggregation than clopidogrel. Treatment with ticagrelor, nonthienopyridine oral antiplatelet drug, significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding as compared with clopidogrel. The present review aims to discuss the current knowledge on the safety and efficacy of new oral antiplatelet agents including prasugrel and ticagrelor.

Synthesis of thienopyridine derivatives and its anti-platelet activity in vivo / 药学学报

To explore novel ADP receptor inhibitors with anti-thrombotic activity, eighteen compounds were synthesized and their structures were confirmed by 1H NMR and MS. The results showed that the activity of compound C1 was superior to ticlopidine in platelet aggregation inhibition tests in vivo and worthy for further investigation. Compounds A4, B2, C4 and C7 possessed moderate platelet aggregation inhibitory activities.

Hemolytic Uremic Syndrome with Clopidogrel after Coronary Angioplasty / 대한내과학회지

Thienopyridines are antiplatelet agents used in post-percutaneous coronary angioplasty patients and patients with acute coronary syndrome, stroke, and peripheral arterial disease. Ticlopidine has been shown to reduce the incidence of stent thrombosis, but it may also cause serious hematological side effects. Among the thienopyridines, clopidogrel is considered to be a safe alternative to ticlopidine because of its decreased incidence of hematological adverse effects. However, some hematological side effects can occur and may be fatal. In this case, a 47-year-old man complained of dyspnea and generalized edema. He had been taking clopidogrel after coronary angioplasty. His laboratory findings showed acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia, which were consistent with hemolytic uremic syndrome (HUS). After discontinuing clopidogrel and undergoing plasma exchange, he recovered fully. To our knowledge, this is the first reported case of clopidogrel-induced HUS in Korea.

Antiplatelet Agents in High-Risk Patients with Coronary Artery Disease

The role of platelets is well known in the atherogenesis, acute coronary syndrome and development of complications of percutaneous coronary intervention. Until recently, aspirin was the only antiplatelet agent available for the primary and secondary prevention of coronary heart disease. Over the past several years, there has been a substantial expansion in our antiplatelet armamentarium, as well as in our understanding of the clinical importance of antiplatelet therapy in patients with coronary artery disease. The benefits and limitations of the currently available antiplatelet agents, including aspirin, thienopyridines (ticlopidine and clopidogrel) and the platelet glycoprotein IIb/IIIa blockers, in the secondary prevention of coronary heart disease, and high-risk clinical situations, such as unstable angina, acute myocardial infarction and percutaneous coronary intervention, have been reported. Antiplatelet agents should be used, in proper combination, in all relevant cases, as they have been shown to improve the prognosis of various forms of high-risk patients with coronary artery disease.

Antiplate Agents

The role of platelets in atherogenesis, acute coronary syndrome and the development of complications from percutaneous coronary intervention is relatively well known. Until recently, aspirin was the only antiplatelet agent available for the primary and secondary prevention of coronary heart disease. Recently, there has been a substantial expansion in the antiplatelet armamentarium as well as in the understanding of the clinical importance of antiplatelet therapy in patients with coronary heart disease. The benefits and limitations of the currently available antiplatelet agents including aspirin, thienopyridines (ticlopidine and clopidogrel), and the platelet glycoprotein IIb/IIIa inhibitors in the primary and secondary prevention of coronary heart disease and special clinical situations, such as unstable angina, acute myocardial infarction and percutaneous coronary intervention are discussed.