now been established, albeit in few laboratories. These encompass sensitive and specific methodologies, such as tandem mass spectrometry (Byrd et al., 1994). These tools will afford a more comprehensive approach to investigating genetic (e.g., nAchR or CYP2A6 polymorphisms; McKinney et al., 2000; Nakajima et al., 1996) and environmental factors (e.g., CYP2A6 induction or repression by alcohol or other drugs; Niemela et al., 2000), which might contribute to interindividual variability in nicotine pharmacokinetics. For example, they will include the integration of assessment of nitrosamines formed from nicotine into long-term studies of the safety of NRT.

Excretion

Nicotine is excreted by both glomerular filtration and tubular secretion. Acidification of urine greatly increases its renal clearance, which impedes tubular reabsorption by ionizing the nicotine (Benowitz and Jacob, 1999). Urinary excretion of cotinine is less influenced by pH since it is more basic. However, renal clearance of both compounds is influenced highly by urinary flow rates (Benowitz and Jacob, 1999).

PHARMACODYNAMICS

Cardiovascular Effects

The factors that mediate the effects of nicotine are complex, confounded as they are in the cardiovascular system by direct and reflex effects, acute effects and long-term desensitization, and secondary effects due to sympathoadrenal activation. Acute delivery of nicotine in a cigarette results in a transient tachycardia, cutaneous vasoconstriction, and a rise in blood pressure (Cryer et al, 1976). By contrast, desensitization of vascular or central receptors by nicotine may contribute to the lower blood pressure observed in chronic smokers (Charlton and While, 1995).

The mechanisms involved in mediating the adverse effects of cigarette smoking and of smokeless tobacco on the cardiovascular system are poorly understood, but are thought to include induction of an adverse lipoprotein profile (Allen et al., 1994), induction of a chronic inflammatory response (Strandberg and Tilvis, 2000) including oxidative tissue injury (Morrow et al., 1995; Patrignani et al., 2000; Reilly et al., 1996; Traber et al., 2000), activation of platelets and other hemostatic variables (Benowitz et al., 1993; Ludviksdottir et al., 1999; Whiss et al., 2000), and impairment of endothelial function (Raitakari et al., 2000). Following the introduction of NRT, there was considerable concern about the cardiovascular safety of this intervention, especially in patients with preexisting cardiovascular disease. However, NRT has been shown to be effective, without an apparent cardiovascular hazard, not only in the general



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