Abstract
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.
Footnotes
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Send reprint requests to: Neal L. Benowitz, MD, Chief, Division of Clinical Pharmacology and Experimental Therapeutics, University of California San Francisco, Box 1220, San Francisco, CA 94143-1220.
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↵1 This study was supported by National Institutes of Health Grants DA02277, DA01696 and GM26691. Clinical studies were carried out in part in the General Clinical Research Center at San Francisco General Hospital Medical Center with support of the Division of Research Resources, National Institutes of Health (RR-00083). K.F. was a Fellow of the Swiss National Science Foundation.
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↵2 Current address: Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital, CH-8091 Zurich, Switzerland.
- Abbreviations:
- V1
- volume of distribution of central compartment
- V2
- volume of distribution of peripheral compartment
- Vss
- steady-state volume of distribution
- CL
- total plasma clearance
- t½α
- distribution half-life
- t½β
- elimination half-life
- K12 andk21
- intercompartmental transfer rate constants
- Ce
- concentration at the hypothetical effect site
- Keo
- rate constant of exit from the effect site
- Cm
- concentration of the hypothetical antagonist metabolite
- Kmo
- exit constant from the metabolite compartment
- E
- effect compartment
- ACTH
- corticotropin
- Received September 9, 1996.
- Accepted February 10, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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Pharmacodynamics of Acute Tolerance to Multiple Nicotinic Effects in Humans
