硝酸酯的临床应用及抗药性

硝酸酯的临床应用及抗药性２７１０００山东省泰山疗养院张作芳，宋洪发综述河北省医学科学院于占久审校１硝酸酯对心绞痛的作用硝酸酯直接作用于血管平滑肌，扩张冠状动脉，缓解冠状动脉痉挛，对劳累型和痉挛性心绞痛均有效。与其他抗心绞痛药物比较，对心脏及其他器官的...     

具有独特双重作用机制的抗心绞痛新药:尼可地尔

尼可地尔是日本研制的新一类抗心绞痛药物,具有双重抗心绞痛机制:硝酸酯类作用扩张静脉和心外膜冠状动脉,以及开放K+-ATP通道引起外周动脉和冠状动脉阻力血管扩张。其药理作用降低心脏前后负荷,增加冠状动脉血流,改善冠状循环,并防止冠状动脉痉挛。基于对线粒体的ATP敏感的钾通道的作用,尼可地尔发挥药物性预适应作用以及缺血或再灌注导致的心肌损伤的心脏保护作用。日本、欧洲和中国的临床报告提示尼可地尔具有与硝酸酯、β受体阻滞药和钙拮抗药相当的抗心绞痛作用。临床试验显示尼可地尔可预防稳定型心绞痛患者心绞痛发作及改善运动耐力。IONA和JCAD研究显示稳定型心绞痛患者长期服用尼可地尔可显著改善预后,减少主要冠状动脉事件或心血管死亡。尼可地尔耐受性好,无耐药性,不良反应轻微,如头痛、恶心、脸红和头晕。有报告尼可地尔可引起口腔、肛门及胃肠道溃疡。故尼可地尔是耐受良好的抗心绞痛新药,有血管扩张和心脏保护作用。其临床作用与当前的抗心绞痛药物不同,当其他药物控制心绞痛不满意时可加用尼可地尔。     

硝酸酯类药物耐药性及其防治对策

硝酸酯类药物已广泛用于治疗心血管疾病。但其连续应用或长期应用易发生耐药性[1],从而降低了这类药物的临床作用。如何降低或防治其耐药性的发生一直为临床研究者所关注。本文就硝酸酯类药物耐药性的发生机制及其防治对策作一介绍。1硝酸酯类药物的耐受性及其发生机制目前已有大量证据表明,长程应用硝酸酯类药物都可发生耐药性。这种耐药性的发生与临床所用的药物类型和剂型无密切关系,而与临床使用方法和剂量相关［12」。近期报道,连续应用硝酸甘油贴片可在数天内发生耐药性,间断应用每12h释放＞75mg硝酸甘油的贴片可导致夜间心绞痛…     

尼可地尔的药理和临床研究动向

<正> 很少有药物在治疗心绞痛和心衰时能与硝酸酯类药物媲美,但后者在长期应用中副作用及耐药性发生率高,因此,寻找具有同样抗心绞痛和抗心衰作用但无上述缺点的药物的研究工作一直在进行。尼可地尔(Nicorandil烟酰胺硝酸酯)是70年代日本Chugai制药公司研制的治疗冠心病和心衰的新药,其化学结构式为:     

异舒吉静滴加重心肌缺血(附5例报告)

对5例冠状动脉粥样硬化性心脏病病人,经静滴异舒吉后诱发心绞痛或加重心肌缺血进行临床分析。提示硝酸酯类药物除易产生耐药性外,还可诱发心绞痛及导致心电图ST—T缺血样改变。探讨了发生的机理,提醒临床注意。     

卡托普利对冠状动脉扩张症的治疗

目的评价卡托普利对冠状动脉扩张症的疗效。方法将冠状动脉造影证实为冠状动脉扩张的稳定性心绞痛患者,患者总数40例,随机分为硝酸异山梨酯组和卡托普利组,疗程1年,观察心绞痛发作、平板运动试验、冠状动脉造影等项的影响。结果治疗后卡托普利组总有效率87.5%,硝酸异山梨酯组总有效率17.7%,两组对比有显著差异,P〈0.05。结论卡托普利治疗冠状动脉扩张中明显改善平板运动试验的结果,减少心绞痛的发病,冠脉血流明显改善,所以卡托普利是治疗冠状动脉扩张的有效药物。     

不同剂型与剂量硝酸酯类药物分时给药方案比较研究

硝酸酯类药物是冠心病心绞痛治疗中常用的一类药物.在临床实践中,由于硝酸酯类药物长时间静脉滴注产生的耐药性及患者的烦躁情绪、疲劳感等,使该药疗效与患者用药依从性之间产生矛盾.为此,我们经过探索,找到了一套既能保证该类药物疗效又能提高患者依从性的用药方案,报告如下.     

硝酸酯类药物快速耐受性机制的研究进展

有机硝酸酯类药物仍广泛用于冠心病(包括稳定型和不稳定型心绞痛及心肌梗死)和充血性心力衰竭等心血管疾病的治疗中.这类药物在体内进行生物转化,不断释放一氧化氮(NO),经过一系列的生物学过程,最终引起血管平滑肌舒张及其他效应.短期应用时,硝酸酯类药物能够扩张血管和对抗缺血症状,但其长期应用时的疗效因快速耐受性而受到质疑,耐受性发生于连续使用的1～3 d内,这使其在临床上的应用受到一定限制.多年来,硝酸酯类药物的耐受性机制一直在被广泛地讨论,同时发展了几种学说,如巯基耗竭学说、神经激素反馈激活学说、血容量扩张学说、NO转导过程障碍等,本文就硝酸酯类药物的作用机制与耐受机制作一综述.     

浅谈硝酸酯类药物耐药问题

硝酸酯类药作为急性冠状动脉综合征（ACS）治疗中最常用的缓解心绞痛一类药物,安全有效性已经得到广泛临床验证,目前几乎是临床医生每天使用的药物,其中近年来大剂量硝酸异山梨酯在ACS中的应用为ACS治疗提供更可靠的手段。因此,目前国内外仍然不断有新的硝酸酯剂型研制和问世。但是硝酸酯类药物连续应用或频繁给药时迅速发生耐药。主要涉及到神经内分泌系统调整和细胞内硝酸甘油代谢障碍两个方面。     

不同给药周期对硝酸酯类药物耐药性的影响

目的 通过观察冠脉血管的扩张程度来研究不同的给药周期对耐药性产生的影响。方法 将120例冠心病并拟进行冠状动脉造影术的患者分为4组：间断给药组、短程持续给药组、长程持续给药组、空白对照组。进行冠状动脉造影术时冠脉内注射硝酸异山梨酯1 mg,测量给药前及给药2 min后前降支(left anterior descending coronary artery,LAD)近端及回旋支(left circumflex branch of coronary artery,LCX)近端管径,计算平均扩张程度,进而评价患者硝酸酯药物的耐药程度。结果 单因素方差分析显示各组LAD和LCX及平均扩张度不完全相同,长程持续用药组扩张度明显低于间断给药组及空白对照组(P<0.05或0.01),短程持续用药组扩张度与其他3组均无明显差异,空白对照组与间断用药组无明显差异。结论 硝酸酯类药物长期使用(>72 h)会产生一定的耐药性,短时程持续使用也可出现不显著的耐药性,间断使用(每天8~10 h空白期)可避免耐药的发生。     

Hypothyroidism complicated by angina pectoris: therapeutic approaches.

The association of hypothyroidism and coronary artery disease is not uncommon. The precipitation of angina pectoris, cardiac arrhythmia, and even myocardial infarction may occur in patients when initiating rapid replacement therapy for hypothyroidism. This is particularly true when replacement therapy is instituted in elderly persons or in patients with preexisting coronary artery disease. A starting daily dose of 12.5 to 25 micrograms and increments of 25 micrograms every 2 to 3 weeks is recommended. Close monitoring of cardiac symptoms is essential to avoid side effects. Medical management of angina pectoris includes administration of beta-blockers, nitrates, or at times combination antianginal therapy may be most effective. Persistence of angina in these patients may require coronary angiography with subsequent angioplasty or coronary artery bypass surgery.     

Trimetazidine. A review of its use in stable angina pectoris and other coronary conditions.

The orally administered antianginal agent trimetazidine increases cell tolerance to ischaemia by maintaining cellular homeostasis. In theory, this cytoprotective activity should limit myocyte loss during ischaemia in patients with angina pectoris. Data from studies in patients with coronary artery disease indicate that, unlike the effects of other antianginals, the anti-ischaemic effects of trimetazidine 20 mg are not associated with alterations in haemodynamic determinants of myocardial oxygen consumption such as heart rate, systolic blood pressure and the rate-pressure product. Furthermore, limited evidence suggests trimetazidine may improve left ventricular function in patients with chronic coronary artery disease or ischaemic cardiomyopathy and in patients experiencing acute periods of ischaemia when undergoing percutaneous transluminal coronary angioplasty. Clinical studies have shown that oral trimetazidine 20 mg 3 times daily reduces the frequency of anginal attacks and nitroglycerin use and increases exercise capacity when used as monotherapy in patients with angina pectoris. Its clinical effects are broadly similar to those of nifedipine 40 mg/day and propranolol 120 to 160 mg/day but, unlike these agents, trimetazidine does not affect the rate-pressure product during peak exercise or at rest. Adjunctive trimetazidine 60 mg/day reduces the frequency of anginal attacks and nitroglycerin use and improves exercise capacity in patients with angina pectoris not sufficiently controlled by conventional antianginal agents. Furthermore, the drug appears to be more effective than isosorbide dinitrate 30 mg/day when used adjunctively in patients with angina pectoris poorly controlled by propranolol 120 mg/day. The tolerability profile of trimetazidine 60 mg/day was similar to that of placebo when used as add-on therapy in patients with angina pectoris insufficiently controlled by other antianginal agents and was superior to that of either nifedipine 40 mg/day or propranolol 120 to 160 mg/day when used as monotherapy. The most frequently reported adverse events in trimetazidine recipients were gastrointestinal disorders, although the incidence of these events was low. CONCLUSIONS: Trimetazidine is an effective and well tolerated anti-ischaemic agent which, in addition to providing symptom relief and functional improvement in patients with angina pectoris, has a cytoprotective action during ischaemia. The drug is suitable for initial use as monotherapy in patients with angina pectoris and, because of its different mechanism of action, as adjunctive therapy in those with symptoms not sufficiently controlled by nitrates, beta-blockers or calcium antagonists. The role of trimetazidine in other coronary conditions has yet to be clearly established.     

Glyceryl trinitrate (nitroglycerin) and the organic nitrates. Choosing the method of administration

Nitrate usage worldwide is on the increase as the indications for therapy expand. Present indications for nitrate therapy include chronic stable angina pectoris, unstable angina pectoris, complications of acute myocardial infarction, and 'unloading' therapy for acute and chronic congestive heart failure. Nitrates are also being used in the operating suite by anaesthesiologists to control systolic blood pressure during various surgical procedures. New nitrate delivery systems have recently become available which provide considerable dosing flexibility, further increasing the interest in this group of compounds. The dominant action of nitrates is a direct effect on vascular smooth muscle, producing vasodilation of the veins and arteries. These drugs decrease myocardial work by lowering systolic blood pressure, systemic vascular resistance, and reducing intracardiac dimensions. In addition, nitrates have a potent effect on cardiac preload as a result of systemic venodilatation. There is also some evidence that nitrates exert direct effects on the coronary circulation (vasodilatation of coronary arteries and coronary collateral vessels, and direct atherosclerotic stenosis dilatation). These actions may play a role in relieving myocardial ischaemia. Adverse sequelae of nitrate therapy are well known and serious adverse reactions are uncommon. Headache and dizziness are the most frequent side effects. Nitrate tolerance is a definite problem - present evidence indicates that long acting formulations, high doses, or frequent dosing regimens are particularly likely to induce vascular tolerance to nitrates. Consequently, provision of a nitrate-free interval has taken on increasing significance as a strategy to avoid tolerance. Nitrate delivery systems are numerous. Although availability varies from country to country, in most countries there are a wide variety of formulations of glyceryl trinitrate (nitroglycerin) available, including sublingual and oral tablets, oral spray, topical ointment as well as discs or patches for transdermal administration, a transmucosal tablet and an intravenous formulation. Similar formulations of isosorbide dinitrate, except buccal tablets, are available in some countries. Isosorbide 5-mononitrate, a potent metabolite of isosorbide dinitrate, is achieving increasing popularity as an antianginal drug. Optimum nitrate therapy requires a good understanding of the properties of the various formulations, particularly onset and duration of action and propensity to induce tolerance.(ABSTRACT TRUNCATED AT 400 WORDS)     

Side effects of using nitrates to treat heart failure and the acute coronary syndromes, unstable angina and acute myocardial infarction

Nitrates are potent venous dilators and anti-ischemic agents. They are widely used for the relief of chest pain and pulmonary congestion in patients with acute coronary syndromes and heart failure. Nitrates, however, do not reduce mortality in patients with acute coronary syndromes. Combination of nitrates and hydralazine when given in addition to beta-blockers and angiotensin-converting enzyme (ACE) inhibitors reduce mortality and heart failure hospitalizations in patients with heart failure due to left ventricular systolic dysfunction who are of African-American origin. Side effects during nitrate therapy are common but are less well described in the literature compared with the reported side effects in patients with stable angina pectoris. The reported incidence of side effects varies highly among different studies and among various disease states. Headache is the most commonly reported side effect with an incidence of 12% in acute heart failure, 41-73% in chronic heart failure, 3-19% in unstable angina and 2-26% in acute myocardial infarction. The reported incidence of hypotension also differs: 5-10% in acute heart failure, 20% in chronic heart failure, 9% in unstable angina and < 1-48% in acute myocardial infarction, with the incidence being much higher with concomitant nitrate therapy plus angiotensin-converting enzyme inhibitors. Reported incidence of dizziness is as low as 1% in patients with acute myocardial infarction to as high as 29% in patients with heart failure. Severe headaches and/or symptomatic hypotension may necessitate discontinuation of nitrate therapy. Severe life threatening hypotension or even death may occur when nitrates are used in patients with acute inferior myocardial infarction associated with right ventricular dysfunction or infarction, or with concomitant use of phosphodiesterase-5 inhibitors or N-acetylcysteine. Despite the disturbing observational reports in the literature that continuous and prolonged use of nitrates may lead to increased mortality and recurrent myocardial infarction in patients with stable coronary artery disease, no such adverse effects of nitrates have been reported in the large randomized trials in patients with acute myocardial infarction or chronic heart failure.     

Restoration of flow-dependent coronary dilation by ACE inhibition improves papaverine-induced maximal coronary blood flow in hypertensive patients: demonstration that large epicardial coronary arteries are more than conductance vessels

Restoration of flow-dependent coronary artery dilation by angiotensin-converting enzyme inhibition (ACEI) has been demonstrated in patients with hypertension. The aim of the present study was to evaluate whether dilation of conductance coronary arteries may alter maximal coronary blood flow (CBFmax) and minimal coronary resistance (CRmin) in hypertensive patients with reversible impairment of flow-dependent coronary artery dilation. Thirteen hypertensive patients with angiographically normal coronary arteries and no other risk factors were studied. Cross-sectional areas (CSAs) of proximal and distal left anterior descending (LAD) coronary arteries were determined by quantitative angiography. Coronary flow velocity was recorded in the distal LAD with an intracoronary Doppler catheter. Estimates of coronary blood flow and resistance were calculated at rest and during maximal increase in blood flow induced by papaverine injected in the midportion of the LAD, both before and after ACEI. Flow-dependent dilation of the proximal LAD, abolished before ACEI, was restored after (26.7 +/- 11.2%; p < 0.001). The increase in CSA of the distal LAD exposed to papaverine was significantly higher after ACEI than before (from 33.4 +/- 20.5% to 51.5 +/- 23.4%; p < 0.001). After restoration of proximal LAD flow-dependent dilation, CBFmax was increased by +21.0 +/- 10.3% (p < 0.001), and CRmin was reduced by 19.3 +/- 9.5% (p < 0.001). Thus, dilation of epicardial coronary arteries participates substantially in the coronary resistance in hypertensive patients. Restoration of flow-dependent coronary artery dilation by ACEI may improve the ability of coronary circulation to deliver its maximal myocardial blood flow in hypertensive patients.     

Organic nitrate-induced oxidant stress and cardiovascular therapy

First clinically introduced in the 19th century, organic nitrates are likely to remain the mainstay of nitrovasodilator-based therapy of angina pectoris, acute myocardial infarction and congestive heart failure well into the future. However, the utility and affordability of continuous cardiovascular disease management with organic nitrates has historically been compromised by the rapid development of nitrate tolerance, the requirement for nitrate-free periods and rebound phenomena. While recent landmark research has proposed a novel nitrate-induced oxidant stress mechanism of nitrate tolerance that may be readily modifiable in the clinic, the implications of these findings for the future of nitric oxide (NO) pharmacotherapy in cardiovascular disease have yet to be fully explored. In particular, organic nitrate-induced oxidant stress may not only have a pivotal role in attenuating organic nitrate bioconversion and vascular NO bioavailability vis-à-vis nitrate tolerance development, but may also potentially aggravate both endothelial dysfunction and insulin resistance in cardiovascular disease and Type 2 diabetes. Such deleterious actions may now help account for the disappointing neutral effects of organic nitrate therapy on mortality in coronary care documented in large-scale clinical trials.     

硝酸盐类联合恬尔心治疗心绞痛的疗效

目的评价静脉应用硝酸盐类联合恬尔心治疗心绞痛的疗效及耐受性。方法选择100例心绞痛患者,在应用硝酸酯类、抗凝药物基础上加用恬尔心治疗,观察1个月,比较治疗前后心绞痛发作次数、时间、心电图指标等的变化。结果硝酸酯类对心绞痛总有效率为85%,硝酸酯类加恬尔心总有效率为90%。结论恬尔心治疗心绞痛有一定效果,硝酸酯类联合恬尔心治疗心绞痛效果更好。     

冠心病心绞痛（气虚血瘀证）症状疗效评分量表的研究

目的：建立冠心病心绞痛（气虚血瘀证）症状疗效评分量表。方法：症状评分与其发生率（频率）、重要性（专家评定）及严重性（轻中重）有关,根据以上3种因素（因子）的症状评分数学模型,形成冠心病心绞痛（气虚血瘀证）中医症状的评分量表,通过信度、效度、反应度的评价,确认其可行性和合理性。结果：6个症状（胸痛、胸闷、心悸、气短、神疲乏力、唇色紫暗）作为疗效评分症状群,根据其发生率、重要性和严重性确定了各自权重因子和量表等级分值。信度结果可靠,一致性良好,反应灵敏。结论：冠心病心绞痛（气虚血瘀证）中医症状疗效评分量表,可为此类临床研究提供一个应用工具。     

Methemoglobin levels produced by organic nitrates in patients with coronary artery disease

To determine if ordinary doses of nitrates produce a significant increase in methemoglobin, methemoglobin levels were measured in 59 randomly selected patients with coronary artery disease and unstable angina pectoris who were receiving organic nitrate therapy. Patients were taking isosorbide dinitrate, 2% nitroglycerin ointment, or a combination of the two. Patients were subdivided according to whether they were using one (group A) or more than one (group B) organic nitrate preparations. These results were compared with 17 control patients. Mean methemoglobin levels in group B were 1.78 +/- 1.29%, and this differed significantly (P less than 0.05) from both group A mean methemoglobin, 1.13 +/- 0.92%, and controls, 0.99 +/- 0.55%. The proportion of patients with elevated methemoglobin concentration increased from the control to group A to group B. It is concluded that commonly used dosages of nitrates are capable of causing elevations of methemoglobin which are probably not of routine clinical significance. However, these elevations may be of import in certain patient populations such as those with coronary insufficiency or anemia.