Pharmacodynamics of acute tolerance to multiple nicotinic effects in humans.
Level 4 - case-series / case-control
Uncontrolled experimental pharmacodynamic study in a single small human cohort
What was done
Nine healthy smokers abstaining from tobacco received a rapid intravenous nicotine infusion to reach a target plasma concentration of approximately 25 ng/ml, maintained via computer-controlled infusion. Researchers tracked multiple physiological and biochemical responses—including heart rate, blood pressure, plasma epinephrine, energy expenditure, and free fatty acid levels—and applied a semiparametric pharmacodynamic model to evaluate the development of acute tolerance.
What was found
Acute tolerance developed for heart rate, blood pressure, plasma epinephrine, and energy expenditure within nicotine levels typical of smokers. The rate of tolerance development varied widely across endpoints: tolerance half-lives ranged from 3.5 minutes for energy expenditure to 70 minutes for systolic blood pressure. No apparent tolerance occurred for free fatty acid concentrations (lipolysis).
Why it matters
This study demonstrates that human tolerance to nicotine is effect-specific rather than uniform, pointing to different desensitization kinetics or distinct mechanisms across nicotinic receptor subtypes.
Limits
The sample size was very small (n = 9) and restricted to healthy smokers, without a placebo control group. The abstract does not provide numerical values or variance for heart rate or epinephrine tolerance rates.
Cited by
- context Every dose of nicotine raises heart rate by 10 to 15 beats per minute and blood pressure by 5 to 10 mmHg.