Thadani U, Lipicky R J
Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73104.
Cardiovasc Drugs Ther. 1994 Aug;8(4):611-23. doi: 10.1007/BF00877415.
Nitroglycerin (NTG) spray and sublingual tablets rapidly relieve an established attack of angina, and their infrequent use is not associated with the development of tolerance. Although, following a suitable nitrate-free interval, the first dose of oral, long-acting nitrates produces significant hemodynamic effects, increases angina free walking, and decreases exercise-induced ischemia, during continued long-term therapy tolerance limits their usefulness. Appropriate dosing regimens of controlled-release formulations of isosorbide dinitrate (ISDN) and controlled-release NTG during long-term therapy have not been established. Use of immediate-release formulation of 15-120 mg of ISDN in a qid regimen lead to a marked reduction in the size and duration of antianginal effects compared to the initial dose. Asymmetric tid therapy with 30 mg of ISDN (7 a.m., 1 p.m., and 6 p.m.) is also associated with the development of partial tolerance and appears to provide antianginal prophylaxis for only a period of 6 hours each day. Asymmetric bid therapy with ISDN at 7 a.m. and noon may give sustained effect but is supported by only a single, small study that did not examine effectiveness after the noon dose in long-term use. Isosorbide-5-mononitrate (IS-5-MN) has been the subject of more recent studies than other nitrates because of attempts to bring a number of products into the U.S. market. IS-5-MN in qid, tid, and standard bid (8 a.m. and 8 p.m.) dosing regimens produce tolerance. Asymmetric regimens of immediate-release IS-5-MN (10 and 20 mg) given bid (once in the morning and again 7 hours later) decrease the development of tolerance compared to symmetric regimens and produce an increased exercise duration after each dose of the day; the 20 mg bid dosing is more effective. Similarly, once-daily 120 and 240 mg controlled-release IS-5-MN does not produce tolerance and gives a sustained increase in daytime exercise duration. Both asymmetric bid immediate-release and once-daily controlled-release IS-5-MN preparations do not produce deterioration in exercise performance prior to the administration of the medication in the morning (i.e., no zero-hour effect). Further studies are needed to establish useful dosing regimens for ISDN, for controlled-release ISDN, and for controlled-release nitroglycerin. None of the dosing regimens of any oral, long-acting nitrate (including IS-5-MN) provide 24 hour antianginal and antiischemic effects.(ABSTRACT TRUNCATED AT 400 WORDS)
硝酸甘油喷雾剂和舌下片可迅速缓解已发作的心绞痛，且偶尔使用不会产生耐受性。虽然在经过适当的无硝酸盐间隔期后，口服长效硝酸盐的首剂会产生显著的血流动力学效应，增加无心绞痛的行走距离，并减少运动诱发的缺血，但在长期持续治疗期间，耐受性会限制其效用。长期治疗期间，硝酸异山梨酯（ISDN）控释制剂和硝酸甘油控释制剂的合适给药方案尚未确定。采用每日四次服用15 - 120毫克ISDN速释制剂的给药方案，与初始剂量相比，抗心绞痛作用的大小和持续时间会显著降低。采用每日三次服用30毫克ISDN（上午7点、下午1点和下午6点）的不对称治疗方案也会产生部分耐受性，且似乎每天仅能提供6小时的抗心绞痛预防作用。采用上午7点和中午服用ISDN的不对称每日两次治疗方案可能会产生持续效果，但仅得到一项小型研究的支持，该研究未考察长期使用中午剂量后的有效性。由于试图将多种产品推向美国市场，与其他硝酸盐相比，5 - 单硝酸异山梨酯（IS - 5 - MN）受到了更多近期研究。每日四次、每日三次以及标准每日两次（上午8点和晚上8点）服用IS - 5 - MN的给药方案都会产生耐受性。与对称给药方案相比，采用每日两次（早上一次，7小时后再一次）服用10毫克和20毫克速释IS - 5 - MN的不对称给药方案可减少耐受性的产生，且每次给药后运动持续时间会增加；每日两次服用20毫克的给药方案更有效。同样，每日一次服用120毫克和240毫克控释IS - 5 - MN不会产生耐受性，且白天运动持续时间会持续增加。每日两次速释不对称给药制剂和每日一次控释IS - 5 - MN制剂在早晨给药前均不会导致运动表现恶化（即无零时效应）。需要进一步研究以确定ISDN、控释ISDN和控释硝酸甘油的有效给药方案。任何口服长效硝酸盐（包括IS - 5 - MN）的给药方案均无法提供24小时的抗心绞痛和抗缺血作用。（摘要截取自400字）
