Comparative efficacy of yohimbine against pyridostigmine for the treatment of orthostatic hypotension in autonomic failure

Abstract

Orthostatic hypotension affects patients with autonomic failure producing considerable disability because of presyncopal symptoms. Severely affected patients may have residual sympathetic tone that can be engaged to increase blood pressure (BP) with the α-2 adrenergic antagonist yohimbine. This medication activates sympathetic outflow centrally and unrestrains norepinephrine release from noradrenergic neurons. Alternatively, the acetylcholinesterase inhibitor, pyridostigmine, can increase sympathetic tone by improving ganglionic cholinergic neurotransmission. Our purpose was to compare these complementary approaches and to explore whether the combination would lead to synergistic increases in BP. We compared the effects of 60 mg of pyridostigmine and 5.4 mg of yohimbine in a single-blind, randomized, placebo-controlled, crossover fashion. In a subset of patients we tested the combination of pyridostigmine and yohimbine. Our primary outcome was the change in standing diastolic BP 60 minutes after drug administration from baseline. We studied a total of 31 patients with severe autonomic failure. Yohimbine significantly improved standing diastolic BP as compared with placebo (11±3 mm Hg [95% CI: 6 to 16 mm Hg]; P<0.001). On the contrary, pyridostigmine did not increase the standing diastolic BP (0.6±3 mm Hg [95% CI: -5 to 5 mm Hg]; P=0.823). Only yohimbine showed a significant improvement in presyncopal symptoms. Sixteen patients received the combination of pyridostigmine and yohimbine, but no evidence of synergistic pressor effect was found. Engaging residual sympathetic tone with yohimbine is a more effective approach to improve orthostatic hypotension as compared with pyridostigmine in patients with severe orthostatic hypotension.

Trial registration: ClinicalTrials.gov NCT00223691.

Figure 1

Changes in standing diastolic blood pressure 60 minutes after drug administration, there was a statistical significant difference between yohimbine versus placebo and yohimbine versus pyridostigmine (P<0.001 and P=0.001, respectively). No significant difference was found between pyridostigmine versus placebo.

Figure 2

Changes in standing diastolic blood pressure 60 minutes after drug administration from baseline in sixteen patients in whom we tried the combination yohimbine and pyridostigmine, there was a significant difference between the combination versus placebo (P=0.006) and the combination versus pyridostigmine alone (P=0.003). There was no statistical significant difference between the combination and yohimbine alone.

Figure 3

Orthostatic symptoms score at baseline and 1 hour post-drug administration. There was a significant decrease in pre-syncopal symptoms only after yohimbine administration.

Figure 4

Panel A showed the treatment effect of yohimbine in patients with central autonomic failure (multiple system atrophy) versus those with peripheral autonomic failure (Parkinson's Disease and Pure Autonomic Failure). Panel B showed the treatment effect of pyridostigmine between patients with central versus peripheral autonomic failure