New therapies for postural hypotension.
New therapies for postural hypotension.
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体位性低血压的新疗法。
DOI：
10.1161/hypertensionaha.111.187278
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Milic,Milos
中科院分区：
文献类型：
--
作者：
Ziegler,MichaelG;Milic,Milos
自主神经系统恶化的患者对常见的心血管药物可能会产生意想不到的甚至矛盾的反应。例如，周围自主神经系统严重神经病变的患者可能对苯肾上腺素滴眼液有升压反应，而抗高血压的可乐定却自相矛盾地使血压升高。目前，美国唯一批准的体位性低血压治疗药物是米多胺，一种α1激动剂。最常见的治疗方法是氟化可的松，它会导致钠潴留，并使血管对升压药物敏感。这两种疗法都能提高血压，与姿势无关，因此它们会导致卧位高血压。米多定的升压作用是短暂的，通常在晚上停止使用。氟化可的松的加压作用是持久的。即使联合治疗也常常使患者出现体位性头晕的症状。动脉血压受负反馈回路控制，尤其是压反射（图）。压力感受器的伸展刺激传入神经并引发自主心血管反射。压力反射因衰老和高血压而受损，因为越来越僵硬的血管伸展不良。当压力感受器不再被高血压拉伸时，它不能向脑干输入神经信号，因此既不能激活迷走心压神经，也不能将流出物撤回到交感血管收缩纤维。由于不常见原因（如颈部放射治疗）或常见原因（如动脉粥样硬化）导致压力感受器僵硬的患者，血压波动较大，对压力的压力反应也较大。一些人在高碳水化合物餐后会出现症状性低血压。老年性高血压患者的大范围血压波动是压力感受器无法激活通过自主神经系统缓冲血压的压力反射回路的表现。压力反射回路也会因脑干疾病（如多系统萎缩）或周围自主神经疾病而中断。自主神经衰竭的两种原因都会导致低血压引起的体位症状。改变血压的药物通常会影响血压反射设定点或敏感性。例如育亨宾通过降低心血管压力反射来提高心率。2去甲肾上腺素（NE）再摄取转运体（NET）或单胺氧化酶抑制剂可能通过增加突触内NE而升高血压。它们反而降低了站立者的血压。这是因为长时间的NE刺激α2受体抑制交感神经的流出。NE和可乐定刺激α2受体，育亨宾阻断α2受体。育亨宾使正常人血浆NE和血压升高，对一些周围自主神经病变患者有更大的降压作用。育亨宾还与几种阻断NET的三环抗抑郁药相互作用。氯丙帕明、去甲替林、地西帕明与育亨宾合用可有明显的升压作用。育亨宾还能抵消三环抗抑郁药引起的体位性低血压。6在Okamoto等人的报道之前，还没有研究α2阻滞剂联合NET抑制剂在自主神经疾病引起的体位性低血压患者中的降压效果。7周围自主神经的神经病变可导致棘手的体位性低血压，可能是常见疾病的后果，如糖尿病或帕金森病。周围神经病变消耗神经元NE的储存。最大限度地通过前体释放NE，如羟西多巴，或通过抑制腺苷A1受体来最大限度地抑制NE的释放……
Patients with deterioration of the autonomic nervous sys-tem can have unexpected or even paradoxical reactions to common cardiovascular drugs. For example, patients with severe neuropathy of the peripheral autonomic system can have a pressor response to phenylephrine eye drops and a paradoxical increase in blood pressure (BP) from the antihypertensive clonidine. 1 Currently, the only approved therapy for postural hypotension in the United States is midodrine, an α1 agonist. The most common therapy is fludrocortisone, which causes sodium retention and sensitizes blood vessels to pressors. Both of these therapies raise BP irrespective of posture, so they can lead to recumbent hypertension. The pressor effect of midodrine is short lived, and it is customarily withheld in the evening. The pressor effect of fludrocortisone is long lived. Even combined therapy often leaves patients with symptomatic postural lightheadedness. Arterial BP is controlled by negative feedback loops, especially the baroreflex (Figure). Stretch of the baroreceptor fires afferent nerves and initiates autonomic cardiovascular reflexes. The baroreflex is impaired by aging and hypertension as increasingly rigid blood vessels stretch poorly. When the baroreceptor is no longer stretched by high BP, it fails to input nerve signals to the brain stem, thus failing to either activate vagal cardiodepressor nerves or to withdraw outflow to sympathetic vasoconstrictor fibers. Patients with stiff baroreceptors from uncommon causes, such as neck radiotherapy, or common causes, such as atherosclerosis, have wide BP swings with exaggerated pressor responses to stress. Some will have symptomatic hypotension after a high carbohydrate meal. The wide BP swings characteristic of aging hypertensives are a manifestation of failure of the baroreceptor to activate the baroreflex loop to buffer BP through the autonomic nervous system. The baroreflex loop is also interrupted by diseases of the brain stem, such as multisystem atrophy, or by diseases of peripheral autonomic nerves. Both causes of autonomic failure lead to postural symptoms from low BP. Drugs that alter BP usually affect the baroreflex set point or sensitivity. For example yohimbine increases heart rate by decreasing the cardiovagal baroreflex. 2 Inhibitors of either the norepinephrine (NE) reuptake transporter (NET) or monoamine oxidase might be expected to raise BP by increasing intrasynaptic NE. They instead lower the BP of standing persons. This is because prolonged NE stimulation of α2 receptors inhibits sympathetic nervous outflow. The α2 receptors are stimulated by NE and clonidine and are blocked by yohimbine. Yohimbine increases plasma NE and BP in normal subjects and has a greater pressor effect in some patients with peripheral autonomic neuropathy. Yohimbine also interacts with several tricyclic antidepressants that block NET. The combination of clomipramine, 3 nortriptyline, 4 or desipramine5 with yohimbine can have a marked pressor effect. Yohimbine also counteracts the postural hypotension induced by tricyclic antidepressants. 6 The therapeutic pressor effect of an α2 blocker combined with a NET inhibitor had not been studied in patients with postural hypotension because of autonomic disease before the report of Okamoto et al. 7Neuropathy of the peripheral autonomic nerves can lead to troublesome postural hypotension and may be the consequence of common illnesses, such as diabetes mellitus or parkinsonism. Peripheral neuropathy depletes stores of neuronal NE. Maximizing release of NE through precursors, such as droxidopa, or minimizing inhibition of NE release by inhibiting adenosine A1 receptors …