PHARMACODYNAMICS OF ACUTE TOLERANCE TO MULTIPLE NICOTINIC EFFECTS IN HUMANS

Tolerance is an important determinant of addiction as well as therapeu tic and for toxic effects of drugs. The development of acute tolerance to various effects of nicotine was studied in nine healthy smokers wh o were abstaining from tobacco. Nicotine was infused rapidly to reach a concentration of about 25 ng/ml, followed by a computer-controlled i nfusion to maintain that concentration. A novel semiparametric model o f nicotine effects and tolerance was developed. Tolerance to various e ffects of nicotine (increases in heart rate, blood pressure, plasma ep inephrine and energy expenditure) occurred within the range of nicotin e levels found in smokers. However, the rate of tolerance development varied considerably. The half-lives of tolerance ranged from 3.5 min f or the increase in energy expenditure to 70 min for systolic blood pre ssure. There was no apparent tolerance to the effects on free fatty ac id concentrations, which reflects lipolysis. Differences in the pharma codynamics of tolerance may reflect differences in rate of desensitiza tion of various subtypes of nicotinic receptors and/or differences in mechanisms of tolerance for various nicotinic effects.