Burrell L M
University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.
Drug Saf. 1997 Jan;16(1):56-65. doi: 10.2165/00002018-199716010-00004.
Losartan potassium is the first of a new class of orally active antihypertensive drugs which antagonise the action of angiotensin (AT) II at the AT1 receptor subtype. Losartan potassium is converted by the liver to the active metabolite E-3174, which is a more potent antagonist at the AT1 receptor. E-3174 is responsible for most of the pharmacological effects of losartan potassium, and its long half-life contributes to the extended duration of action of the drug. Losartan potassium is effective as a once-daily antihypertensive agent. In mild to moderate hypertension, losartan potassium has similar efficacy to enalapril, atenolol and felodipine extended release. When losartan potassium is combined with hydrochlorothiazide there is a further reduction in blood pressure. Losartan potassium is well tolerated in mild, moderate and severe essential hypertension, with dizziness being reported as the only drug-related adverse effect. The overall rate of patient withdrawal from therapy due to adverse experiences with losartan potassium is lower (2.3%) than that of placebo (3.7%). First-dose hypotension is uncommon, perhaps due to the slower onset of action of the drug, and cough does not appear to be a significant problem. A number of areas concerning the safety and efficacy of losartan potassium remain to be clarified. In particular, long term tolerability studies are needed; cough only became apparent as an adverse effect of ACE inhibitors after 3 to 4 years of use. Postmarketing surveillance has shown that angioedema, a rare but life-threatening adverse effect of ACE inhibitors, also occurs with losartan potassium. Further data are needed on the use of losartan potassium in patients with renal impairment before accepting the recommendation that dosage adjustment is not necessary. The pharmacokinetics and pharmacodynamics of losartan potassium in patients with hepatic disease also require further investigation. Losartan potassium increases uric acid secretion and lowers plasma uric acid levels, which may be of benefit when losartan potassium is combined with a thiazide diuretic, but which may otherwise lead to uric acid stone formation and possibly to nephropathy. Simple control of blood pressure is no longer an adequate goal in the management of hypertension. Any new antihypertensive agent should also reduce cardiovascular events, prevent or cause regression of end-organ damage such as left ventricular hypertrophy, atherosclerosis and renal failure, and should not impair quality of life. Such data on losartan potassium are not currently available. Losartan potassium is likely to be used in patients who are intolerant of ACE inhibitors, but its future in the management of hypertension will depend on long term tolerability studies and data on its effects beyond simple blood pressure control.
氯沙坦钾是一类新型口服活性抗高血压药物中的首个药物，它可在AT1受体亚型处拮抗血管紧张素（AT）II的作用。氯沙坦钾经肝脏转化为活性代谢物E-3174，后者是一种对AT1受体更具活性的拮抗剂。E-3174介导了氯沙坦钾的大部分药理作用，其长半衰期导致该药作用持续时间延长。氯沙坦钾作为每日一次的抗高血压药物有效。在轻度至中度高血压患者中，氯沙坦钾与依那普利、阿替洛尔和缓释非洛地平疗效相似。氯沙坦钾与氢氯噻嗪联用时，血压可进一步降低。氯沙坦钾在轻度、中度和重度原发性高血压患者中耐受性良好，唯一报道的与药物相关的不良反应为头晕。因氯沙坦钾不良反应而停药的患者总体比例（2.3%）低于安慰剂组（3.7%）。首剂低血压不常见，可能是由于该药起效较慢，且咳嗽似乎不是一个严重问题。关于氯沙坦钾安全性和有效性的若干方面仍有待阐明。特别是，需要进行长期耐受性研究；咳嗽作为ACE抑制剂的一种不良反应，在使用3至4年后才显现出来。上市后监测表明，血管性水肿这种ACE抑制剂罕见但危及生命的不良反应，氯沙坦钾也会出现。在接受无需调整剂量的建议之前，需要进一步获取氯沙坦钾在肾功能损害患者中应用的数据。氯沙坦钾在肝病患者中的药代动力学和药效学也需要进一步研究。氯沙坦钾可增加尿酸分泌并降低血浆尿酸水平，当氯沙坦钾与噻嗪类利尿剂联用时可能有益，但否则可能导致尿酸结石形成并可能引发肾病。单纯控制血压已不再是高血压管理的充分目标。任何新型抗高血压药物还应减少心血管事件，预防或促使诸如左心室肥厚、动脉粥样硬化和肾衰竭等靶器官损害消退，且不应损害生活质量。目前尚无关于氯沙坦钾的此类数据。氯沙坦钾可能用于不耐受ACE抑制剂的患者，但其在高血压管理中的未来将取决于长期耐受性研究以及其在单纯控制血压之外的效应数据。
