Autonomic effects of selegiline: possible cardiovascular toxicity in Parkinson's disease

Abstract

Objectives-The United Kingdom Parkinson's Disease Research Group (UKP-DRG) trial found an increased mortality in patients with Parkinson's disease randomised to receive selegiline (10 mg/day) and levodopa compared with those taking levodopa alone. Unwanted eVects of selegiline on cardiovascular regulation have been investigated as a potential cause for the unexpected mortality finding of the UKPDRG trial. Methods-The cardiovascular responses to a range of physiological stimuli, including standing and head up tilt, were studied in patients with Parkinson's disease receiving levodopa alone and a matched group on levodopa and selegiline. Results-Head up tilt caused selective and often severe orthostatic hypotension in nine of 16 patients taking selegiline and levodopa, but was without eVect on nine patients receiving levodopa alone. Two patients taking selegiline lost consciousness with unrecordable blood pressures and a further four had severe symptomatic hypotension. The normal protective rises in heart rate and plasma noradrenaline were impaired. The abnormal response to head up tilt was reversed by discontinuation of selegiline. Drug withdrawal caused a pronounced deterioration in motor function in 13 of the 16 patients taking selegiline. Conclusion-Therapy with selegiline and levodopa in combination may be associated with severe orthostatic hypotension not attributable to levodopa alone. Selegiline also has pronounced symptomatic motor eVects in advanced Parkinson's disease. The possibilities that these cardiovascular and motor findings might be due either to non-selective inhibition of monoamine oxidase or to amphetamine and met-amphetamine are discussed.

Selegiline-induced postural hypotension in Parkinson's disease: A longitudinal study on the effects of drug withdrawal

“…Blood pressure (BP) and heart rate (HR) were measured when supine for 20 minutes, during head-up tilt to 45°at 2 and 10 minutes, and on standing at 2 minutes as previously described. 3,5 Cardiovascular responses to other physiological challenges were not examined because no patient had autonomic failure. Patients were continuously monitored with a three-lead electrocardiogram.…”

“…In a previous series of Parkinson's disease (PD) patients without underlying autonomic failure, we found that selegiline in combination with L-dopa caused selective and predominantly systolic orthostatic hypotension which was abolished by withdrawal of the drug. 3 The mechanism(s) by which selegiline might cause orthostatic hypotension is unknown. Although not formally examined because of the study design, motor function deteriorated within a week of stopping selegiline in most patients in our first study.…”

“…Although not formally examined because of the study design, motor function deteriorated within a week of stopping selegiline in most patients in our first study. 3 This study was undertaken to determine the time course of the cardiovascular and motor effects of stopping selegiline in the expectation that this might shed light on the mechanisms by which the drug causes orthostatic hypotension.…”

Double‐blind, randomized, controlled trial of rasagiline as monotherapy in early Parkinson's disease patients

“…6,13 In addition, a potential disadvantage of selegiline is its metabolism to (-)-amphetamine and (-)-methamphetamine, which may be related to its adverse effects. 14,15 In contrast, rasagiline has no amphetamine metabolites, 7 and its major metabolite, 1(R)-aminoindan, is devoid of amphetamine-like properties or other toxicity.…”

Disease progress and response to treatment as predictors of survival, disability, cognitive impairment and depression in Parkinson's disease

“…These studies noted that patients taking selegiline long term had a higher risk of orthostatic hypotension [36][37][38][39]. However, no studies have yet shown a causal relationship between selegiline and cardiotoxicity that may explain the increased death rate.…”