Tobacco and Other Nicotine Products

Chemical Structure and Mechanism of Action of Nicotine

The nicotine molecule is a tertiary amine alkaloid with pyridine and pyrrolidine rings, and it exists in two enantiomeric forms. The S-enantiomer is a more potent agonist at the nicotinic acetylcholine receptor compared to the R-enantiomer. Nicotinic acetylcholine receptors are ionotropic ligand-gated ion channels found throughout the central and peripheral nervous systems. As a nicotinic receptor agonist, nicotine activates the ventral tegmental area dopaminergic neurons in the mesolimbic dopamine system and the glutamatergic neurons that innervate ventral tegmental area dopamine neurons. Nicotine may also indirectly activate endogenous opioid pathways.

Nicotine acts as a stimulant at lower doses and a sedative at higher doses. It causes vasoconstriction, increased blood pressure, increased cerebral blood flow, tachycardia, decreased appetite, and skeletal muscle relaxation. As such, nicotinic agonists have been found to improve performance on attention and memory tasks ( Table 7.1 ). Nicotine has been studied for its effects on cognitive enhancement in patients with some types of dementia, psychoses, and attention deficit disorders.

Nicotine Pharmacology

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  Mucosal nicotine absorption is pH-dependent and is marked by decreased absorption with a more acidic, lower pH.

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  Inhaled nicotine reaches the brain within 20 seconds.

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  Nicotine is metabolized predominantly in the liver through CYP2A6 into cotinine (and to a lesser extent in the lungs and brain).

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  The half-life of nicotine is about 2 hours. In contrast, the metabolite cotinine has a half-life of 16 hours. Because of its longer half-life, cotinine is more useful as a biomarker of nicotine use.

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  Individuals of African and Chinese descents metabolize nicotine at a slower rate than Whites because of an increased prevalence of hypoactive CYP2A6 alleles.

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  Women and persons taking exogenous estrogen are faster metabolizers of nicotine because of higher levels of estrogen, which induce CYP2A6. At the same time, cigarette smoking can reduce the efficacy of estrogen and estrogen’s ability to prevent osteoporosis and cardiovascular disease.

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  CYP2A6 inducers such as estrogen, phenobarbital, and rifampicin increase the rate of nicotine metabolism.

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  Older adults metabolize nicotine more slowly because of reduced CYP2A6 activity.

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  The polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for the induction of the isoenzyme CYP1A2, possibly affecting plasma levels of medications metabolized by this isoenzyme. CYP1A2 activity is higher in heavy smokers than in nonsmokers, and quitting can normalize the CYP1A2 activity. Individuals using nicotine replacement products will not experience alterations in CYP1A2 activity.

Nicotine Product Additives

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  The majority of the adverse medical consequences of nicotine are caused by other additives and compounds. Keep in mind that although nicotine is the addictive component of tobacco, it has not been found to be carcinogenic. A cigarette contains about 1 mg of nicotine as well as 7000 other chemicals, including known carcinogens such as nitrosamines, polycyclic aromatic hydrocarbons, and many others.

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  Beta-carotene, vitamin E, and alpha-tocopherol are added as antioxidants to counteract the carcinogenic effects in some tobacco products.

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  Menthol is added to provide anesthetic activity and to make cigarettes less harsh to smoke, although they are no safer than regular cigarettes and may in fact be more addicting. It may inhibit the CYP2A6, decreasing the metabolism of nicotine. Menthol cigarettes were recently banned by the European Union and the United Kingdom.

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  Eucalyptol is an antimicrobial additive believed to increase the mucociliary clearance of some of the chemicals in cigarettes, protecting the lungs from tobacco exposure.