Nicotine

Pharmacokinetics

When smoked in cigarettes and inhaled, nicotine is quickly absorbed in the lungs, with the freebase largely suspended on tiny tar particles. Inhaled nicotine reaches the brain within eight seconds, almost as quickly as an intravenous injection (Figure 7.6). Tobacco in oral products is more basic (has a high pH) and is better absorbed via the mouth than cigarette smoke, which is more acidic. Cigarettes contain 1–2% nicotine or approximately 10–20 mg of nicotine each. Most of the nicotine in inhaled smoke is absorbed in the lungs; much less is absorbed through the mouth. Dependent cigarette smokers tend to titrate their intake over time within the confines of the rapid rise and fall associated with each cigarette, but they average approximately 1 mg of delivered nicotine per cigarette (Figure 7.7). Dependent smokers will maintain relatively stable blood nicotine levels over the course of their waking hours (Figure 7.8). Plasma nicotine levels range from 4–6 ng/ml for pipe smoking to 20–50 ng/ml for cigarette smoking. Tobacco smokers can accumulate substantial levels of carboxyhemoglobin (7–10%) produced by 12 h of tobacco exposure (Figure 7.8). These carboxyhemoglobin levels produced by exposure to carbon monoxide are sufficient to meet and exceed the Environmental Protection Agency occupational threshold limit of 50 ppm of carbon monoxide (which produces 5% carboxyhemoglobin). For example, in both males and females with an average cigarette consumption of 36 and 32 cigarettes per day, respectively, who had smoked 21 and 18 cigarettes, respectively, by the time of sampling, venous blood nicotine levels were approximately 32 ng/ml, and average carboxyhemoglobin levels were 8% (Table 7.2). Nicotine can also be passively absorbed, and non-smokers who live with a 40-cigarette-per-day smoker will achieve levels of urinary cotinine (a nicotine metabolite) that are equivalent to smoking approximately three cigarettes. The minimal acute fatal dose of oral nicotine appears to be about 65 mg, but some individuals have ingested much larger quantities and recovered.

Figure 7.6 Blood concentrations of nicotine in subjects who smoked cigarettes for 9 min (1.33 cigarettes), used oral snuff (2.5 g), used chewing tobacco (mean 7.0 g), or chewed nicotine gum (two 2 mg pieces). Shaded bars indicate the period of exposure to tobacco or nicotine gum. These data show that smoking cigarettes produces the most rapid rise in blood nicotine levels. Notice also, however, that oral snuff, chewing tobacco, and nicotine gum also have relatively rapid absorption, more than one sees with the oral administration of other drugs. This is attributable to the more basic pH in these preparations. [Taken with permission from Benowitz NL. Drug therapy: pharmacologic aspects of cigarette smoking and nicotine addiction. New England Journal of Medicine, 1988, (319), 1318–1330.]

About 80–90% of nicotine is metabolized in the liver, and nicotine and its metabolites, mainly cotinine and nicotine-1’-N-oxide, are excreted in the urine. Approximately 4% of nicotine is converted to nicotine N-oxide, which is largely excreted in urine without further metabolism. Approximately 70% of nicotine is metabolized to cotinine, which is then further metabolized (Figure 7.9). The half-life of nicotine is about 2 h after inhalation or parenteral administration, and the half-life of cotinine is 19 h. The metabolite cotinine has been shown to have psychoactive effects. Intravenously administered cotinine (30 mg) produced blood cotinine levels similar to those of smoking (378 mg/ml) and significantly decreased tobacco withdrawal symptoms in abstinent cigarette smokers.

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