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Journal of Pharmacology and Experimental Therapeutics

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OtherBEHAVIORAL PHARMACOLOGY

Pharmacodynamics of Acute Tolerance to Multiple Nicotinic Effects in Humans

Karin Fattinger, Davide Verotta and Neal L. Benowitz
Journal of Pharmacology and Experimental Therapeutics June 1997, 281 (3) 1238-1246;
Karin Fattinger
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Davide Verotta
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Neal L. Benowitz
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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

  • 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.

  • ↵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.

  • ↵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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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 3
1 Jun 1997
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OtherBEHAVIORAL PHARMACOLOGY

Pharmacodynamics of Acute Tolerance to Multiple Nicotinic Effects in Humans

Karin Fattinger, Davide Verotta and Neal L. Benowitz
Journal of Pharmacology and Experimental Therapeutics June 1, 1997, 281 (3) 1238-1246;

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OtherBEHAVIORAL PHARMACOLOGY

Pharmacodynamics of Acute Tolerance to Multiple Nicotinic Effects in Humans

Karin Fattinger, Davide Verotta and Neal L. Benowitz
Journal of Pharmacology and Experimental Therapeutics June 1, 1997, 281 (3) 1238-1246;
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