Pharmacodynamics of acute tolerance to multiple nicotinic effects in humans

Tolerance is an important determinant of addiction as well as therapeutic and/or toxic effects of drugs. The development of acute tolerance to various effects of nicotine was studied in nine healthy smokers who were abstaining from tobacco. Nicotine was infused rapidly to reach a concentration of about 25 ng/ml, followed by a computer-controlled infusion to maintain that concentration. A novel semiparametric model of nicotine effects and tolerance was developed. Tolerance to various effects of nicotine (increases in heart rate, blood pressure, plasma epinephrine and energy expenditure) occurred within the range of nicotine levels found in smokers. However, the rate of tolerance development varied considerably. The half-lives of tolerance ranged from 3.5 min for the increase in energy expenditure to 70 min for systolic blood pressure. There was no apparent tolerance to the effects on free fatty acid concentrations, which reflects lipolysis. Differences in the pharmacodynamics of tolerance may reflect differences in rate of desensitization of various subtypes of nicotinic receptors and/or differences in mechanisms of tolerance for various nicotinic effects.