Nicotine-mecamylamine interactions

OBJECTIVES: Mecamylamine blocks nicotinic cholinergic receptors and has been proposed, in combination with nicotine, as a novel therapy to aid smoking cessation. The objective of this study was to characterize the pharmacokinetic and pharmacodynamic interactions between transdermal mecamylamine and intravenous nicotine. STUDY DESIGN: Twelve cigarette smokers were studied while receiving transdermal mecamylamine 6 mg/24 h and placebo patches for 7 days each. On the fifth day of patch use, subjects received a combined infusion of deuterium-labeled nicotine and cotinine, with measurement of disposition kinetics of nicotine and cotinine, and cardiovascular and plasma catecholamine responses to nicotine. Half of the subjects were studied under alkaline urine conditions and the other half under acidic urine conditions. RESULTS: Steady-state plasma mecamylamine concentrations were twice as high (mean, 12.2 versus 6.3 ng/mL), consistent with lower renal clearance (2.1 versus 5.8 mL/min/kg) during alkaline compared with acidic urine conditions. Mecamylamine did not significantly affect the clearances of nicotine or cotinine. Mecamylamine significantly reduced the volume of distribution and inhibited the cardioacceleratory and epinephrine-releasing effects of nicotine. CONCLUSIONS: Mecamylamine has little effect on the clearance of nicotine and is not expected to affect steady-state levels during transdermal nicotine dosing. The reduction of the volume of distribution of nicotine by mecamylamine suggests that part of the antagonism of nicotinic central nervous system effects by mecamylamine may be due to a pharmacokinetic interaction-most likely decreased transport of nicotine into the brain or decreased binding to nicotine receptors. Mecamylamine may decrease the potential adverse cardiovascular effects of coadministered nicotine.