Silber S
Division of Cardiovascular Disease, University of Alabama, Birmingham.
Eur J Clin Pharmacol. 1990;38 Suppl 1:S35-51. doi: 10.1007/BF01417564.
Nitrates are highly effective both in terminating acute attacks of angina pectoris and in the prophylaxis of symptomatic and asymptomatic myocardial ischemia. Preload reduction by venodilatation is the prevailing mechanism of nitrates in patients with chronic stable angina and is the unique feature distinguishing them from beta and calcium-channel blockers. Nitrates dilate coronary arteries not only in pre- and poststenotic vessels, but also in eccentric lesions. In patients with endothelial dysfunction, nitrates seem to be the physiological substitute for endothelium-derived relaxing factor. During the past decade, however, there has been substantial evidence of a clinically relevant loss of the anti-ischemic effects ("nitrate tolerance"). Many studies with oral dosing of isosorbide dinitrate or isosorbide-5-mononitrate at least three times daily have proven nitrate tolerance in patients with coronary artery disease and/or congestive heart failure. Complete loss of anti-ischemic effects after repetitive, continuous patch attachments has also been found. As we first showed in 1983, intermittent therapy with once-daily ingestion of high-dose sustained-release isosorbide dinitrate was successful in preventing the development of tolerance. Similarly, tolerance to isosorbide-5-mononitrate also does not develop when it is ingested once daily. It is now generally accepted that a daily low-nitrate interval is required to prevent tolerance development. Although the minimal patch-free interval required to prevent tolerance needs further investigation, a 12-h patch-free interval should prevent tolerance in most patients. The prolonged duration of action of once-daily high-dosage administration of sustained-release formulations, the improved patient compliance with a single daily administration, and the increased likelihood of maximal anti-ischemic effects are important reasons for recommending high single daily doses of isosorbide dinitrate or isosorbide-5-mononitrate.
硝酸盐在终止心绞痛急性发作以及预防有症状和无症状心肌缺血方面都非常有效。通过静脉扩张减少前负荷是硝酸盐类药物在慢性稳定型心绞痛患者中的主要作用机制，也是将它们与β受体阻滞剂和钙通道阻滞剂区分开来的独特特征。硝酸盐不仅能扩张狭窄前和狭窄后的冠状动脉，还能扩张偏心性病变部位的冠状动脉。在存在内皮功能障碍的患者中，硝酸盐似乎是内皮源性舒张因子的生理替代物。然而，在过去十年中，有大量证据表明临床上存在与抗缺血作用相关的丧失（“硝酸盐耐受性”）。许多关于每日至少三次口服二硝酸异山梨酯或5-单硝酸异山梨酯的研究已证实，冠心病和/或充血性心力衰竭患者存在硝酸盐耐受性。重复、持续贴敷贴片后也发现抗缺血作用完全丧失。正如我们在1983年首次表明的那样，每日一次摄入高剂量缓释二硝酸异山梨酯进行间歇治疗成功地预防了耐受性的发展。同样，每日一次摄入5-单硝酸异山梨酯时也不会产生耐受性。现在人们普遍认为，需要每日有一个低硝酸盐间隔期来防止耐受性的发展。虽然预防耐受性所需的最短无贴片间隔期还需要进一步研究，但12小时的无贴片间隔期应该能防止大多数患者产生耐受性。每日一次高剂量服用缓释制剂的作用持续时间延长、患者对每日一次给药的依从性提高以及最大抗缺血作用的可能性增加，是推荐每日单次高剂量使用二硝酸异山梨酯或5-单硝酸异山梨酯的重要原因。
