How Obesity Drugs Affect The Autonomic Nervous System - Brief Article - Statistical Data Included

Nutrition Research Newsletter, July, 2000

It is believed that a variety of afferent stimuli are detected by a central mechanism that changes body fat level by adjusting food intake and caloric expenditure. The effector mechanisms include endocrine alterations and neurological changes, particularly in the autonomic nervous system (ANS). Drugs used for the treatment of obesity often affect on the ANS. Phentermine (PHE), a centrally acting anorectic agent, has sympathomimetic activities similar to but less than amphetamine. Sibutramine (Meridia), a drug recently approved by the US Food and Drug Administration, is both a norepinephrine and a 5-hyrdroxytryptamine reuptake inhibitor in the central nervous system. Increases in pulse and blood pressure in patients receiving sibutramine (SIB) suggest that there are increases in peripheral sympathetic activity. Dexfenfluramine (Redux), a drug formerly used to treat obesity, has been reported to lower blood pressure. It is believed to reduce appetite by inhibiting the reuptake of serotonin and by increasing the release of serotonin. No systematic evaluation has been made of the effect of these drugs on parasympathetic activities.

A recently published study evaluated the effects of dexfenfluramine, PHE, and SIB on the ANS. Studies were conducted on never-obese adult males aged 22 to 38 years while hospitalized in the metabolic ward of the Clinical Research Center at the Rockerfeller University Hospital. Patients were maintained at a constant weight in order to evaluate the effect of each drug on autonomic activity uncontaminated by changes that occur with weight change. All three studies utilized a single-blind, placebo-controlled design. The first eight-day period was the predrug placebo phase, the next five-day period was the drug phase. The dosages and timing of drug administration were as follows: dexfenfluramine, 15 mg twice daily (with breakfast and dinner); PHE, 8 mg three times a day (before each meal); and SIB, 15 mg daily (before breakfast). Resting metabolic rate (RMR) was measured using indirect calorimetry. Twenty-four-hour urine collection was performed on all days of the studies.

Weight change data indicated a high degree of weight stability in all subjects in all three studies. No statistically significant drug effect on resting baseline heart period was found in any of the studies. Significant drug effects on parasympathetic control (PC) of and on sympathetic control (SC) of the heart were found. Both PHE and SIB, drugs known to be sympathetic antagonists, brought about a significant increase in SC, but had no effect on PC or RMR. In contrast, Dexfenfluramine brought about a marked and significant decline in SC, PC, and RMR. The results indicate that three drugs used in the treatment of obesity have measurable, distinctive effects on the ANS. Significant changes in sympathetic activity and parasympathetic activity were found, independent of weight change. Because all of these drugs produce a decline in body weight primarily by their anorexiant action, it would not appear that differences in parasympathetic or sympathetic tone axe predictive of the efficacy of the drug. The large, and unanticipated, response to dexfenfluramine suggests further study to determine whether there could be any relation of these ANS changes to the adverse cardiovascular effects of treatment with dexfenfluramine.

J. Hirsch, R. Mackintosh, L. Aronne, The Effects of Drugs Used to Treat Obesity on the Autonomic Nervous System, Obes Res 8:227-233 (June 2000) [Correspondence: Jules Hirsch, Rockerfeller University, 1230 York Ave., New York, NY 10021-6399. E-mail: hirsch@rockvax.rockerfeller.edu.]