Reserpine: A New Consideration of and Old Drug for Refractory Hypertension.
Reserpine: A New Consideration of and Old Drug for Refractory Hypertension.
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利血平：治疗难治性高血压的新药和旧药。
DOI：
10.1093/ajh/hpaa069
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发表时间：
2020
影响因子：
3.2
通讯作者：
Weir,MatthewR
中科院分区：
文献类型：
--
作者：
Weir,MatthewR
难治性高血压是抗高血压治疗失败的一种表型，其中所有形式的适当药物和剂量都未能将血压控制在理想水平。其定义为使用5种或5种以上不同类别的最高耐受剂量的抗高血压药物（包括长效噻嗪类利尿剂和盐皮质激素受体拮抗剂）控制血压失败。1不应与顽固性高血压混淆，顽固性高血压定义为使用三种或三种以上适当剂量的药物（包括利尿剂）控制血压不充分，或需要四种或四种以上适当剂量药物的血压控制。2大多数先前估计的顽固性高血压包括难治性高血压。Buhnerkempe et al. 3发表了唯一一份关于顽固性和难治性高血压的国家概率样本人群估计值（超过8个国家健康和检查调查周期），并指出6.2%的顽固性高血压患者实际上患有难治性高血压。有趣的是，与临床研究不同，这些患者没有更高的心率。虽然难治性高血压是罕见的，它是一个令人不安的临床表型，困扰临床医生谁欣赏需要更好地控制血压，以避免心血管事件。用于控制顽固性和难治性高血压的新药的管道是有限的，并且尽管引入了内皮素受体拮抗剂、中性内肽酶-血管紧张素转换酶（ACE）抑制剂和肾脏去神经支配，但是没有发生重大突破。一些作者认为，顽固性高血压与容量过多有关，2而难治性高血压可能代表交感神经系统活动控制不充分的疾病。1，4，5无论理论如何，Siddiqui等人6在本期杂志中的概念验证研究不仅提供了关于难治性高血压发病机制的重要新认识，而且还可能提供一些希望，即旧药物可以重新用于治疗这种难治性血压表型。利血平是一种多年来用于治疗高血压的药物，通常与噻嗪类利尿剂或血管扩张剂联合使用。7大型临床试验表明，利血平加噻嗪类利尿剂联合治疗可降低高血压患者的死亡率。8-10它于1955年首次获得FDA批准。对于一线治疗（噻嗪类利尿剂）未能充分控制血压的患者，建议与噻嗪类利尿剂或血管扩张剂联合使用。有趣的是，利血平-氢氯噻嗪是2012年使用的第17种最常用处方的联合降压治疗。[11]该药物的主要作用是消耗外周交感神经末梢的儿茶酚胺。12.儿茶酚胺通常参与调节心率、心肌收缩力和外周血管阻力。常用剂量为每天0.05-0.2 mg。它被描述为耐受性良好，最常见的不良反应是鼻塞。它也被用来治疗精神病症状。其他副作用包括心动过缓和哮喘恶化，剂量为0.5 mg或更高，并有嗜睡，噩梦和疲劳的报告。利血平被JNC 8委员会推荐为治疗高血压的替代药物，14和2016年的科克伦综述发现利血平与其他一线降压药物一样有效。
Refractory hypertension is a phenotype of antihypertensive treatment failure whereby all forms of appropriate medications and doses fail to control blood pressure to a desirable level. It has been defined by the failure to control blood pressure with five or more different classes of antihypertensive medication in their highest tolerated doses, which would include a long acting thiazide diuretic and a mineralocorticoid receptor antagonist. 1 It should not be confused with resistant hypertension which is defined as inadequately controlled blood pressure with three or more appropriately dosed medications, including a diuretic, or blood pressure control which requires four or more appropriately dosed medications. 2 Most prior estimates of resistant hypertension included refractory hypertension. Buhnerkempe et al. 3 published the only national probability sample population estimates of resistant and refractory hypertension (over 8 National Health and Examination Survey cycles), and noted that 6.2% of patients with resistant hypertension actually had refractory hypertension instead. Interestingly, unlike clinical studies, these patients did not have higher heart rate. Although refractory hypertension is infrequent, it is a disturbing clinical phenotype that vexes clinicians who appreciate the need to better control the blood pressure to avoid cardiovascular events. The pipeline of new drugs to control both resistant and refractory hypertension are limited, and no major breakthroughs have occurred despite the introduction of endothelin receptor antagonists, neutral endopeptidase–angiotensin converting enzyme (ACE) inhibitors, and renal denervation. Some authors have suggested that resistant hypertension is related to volume excess, 2 whereas refractory hypertension may represent a disorder of inadequately controlled sympathetic nervous system activity. 1, 4, 5 Regardless of the theories, the proof of concept study in this edition of the journal by Siddiqui et al. 6 provides important new understanding as to not only the pathogenesis of refractory hypertension, but may also provide some hope that an old drug could be repurposed for the treatment of this refractory blood pressure phenotype. Reserpine is a drug that was used for many years in the treatment of hypertension, usually in combination with a thiazide diuretic or a vasodilator. 7 Large clinical trials have demonstrated that combined treatment with reserpine plus a thiazide diuretic reduces mortality in people with hypertension. 8–10 It was first approved by the FDA in 1955. It was recommended to be used with a thiazide diuretic or vasodilator in patients who did not achieve adequate blood pressure control with a first line treatment (thiazide diuretic). Interestingly, reserpine-hydrochlorothiazide was the seventeenth most commonly prescribed combination antihypertensive therapy utilized in 2012. 11 The main effect of the drug is to deplete catecholamines from peripheral sympathetic nerve endings. 12 Catecholamines are normally involved in regulating heart rate, as well as myocardial inotropy and peripheral vascular resistance. The usual doses were 0.05–0.2 mg per day. It was described as being well tolerated with the most common adverse effects being nasal stuffiness. 13 It was also used to treat psychotic symptoms. Other side effects include bradycardia and worsening of asthma with higher doses of 0.5 mg or greater and there are reports of drowsiness, nightmares, and fatigue. Reserpine was recommended as an alternate drug for treating hypertension by the JNC 8 Committee, 14 and a 2016 Cochrane review found reserpine to be as effective as other first line antihypertensive drugs for lowering blood pressure …