Nicotine is a tertiary amine composed of a pyridine and a pyrolidine ring (DHHS, 1988). Absorption of nicotine across biological membranes depends on pH. Modern cigarettes produce smoke that is suitably flavored and suffi ciently nonirritating to be inhaled deeply into lung alveoli (Jones, 1987). When tobacco smoke reaches the small airways and alveoli of the lung, the nicotine is readily absorbed. The rapid absorption of nicotine from cigarette smoke in the lung occurs because of the huge surface area of the alveoli and small airways, and because of the dissolution of nicotine at physiological pH, which facilitates transfer across cell membranes. Concentrations of nicotine in blood rise quickly during cigarette smoking and peak at its completion (U.S. Department of Health and Human Services, 1988).

Chewing tobacco, snuff, and nicotine polacrilex gum have an alkaline pH as a result of tobacco selection and/or buffering with additives by the manufacturer. The alkaline pH facilitates absorption of nicotine through mucous membranes. The rate of nicotine absorption from smokeless tobacco depends on the product and the route of administration. With fine-ground nasal snuff, blood levels of nicotine rise almost as fast as after cigarette smoking. The rate of nicotine absorption with the use of oral snuff, chewing tobacco, and nicotine polacrilex gum is more gradual (U.S. Department of Health and Human Services, 1988). Transdermal nicotine provides a stable source of nicotine, while new products, such as the nicotine nasal spray and inhaler, deliver a quicker bolus of nicotine to the brain that more closely matches what happens when a cigarette is inhaled. Swallowed nicotine is poorly absorbed because of the high acidity of the gut.

Nicotine inhaled in tobacco smoke enters the blood very rapidly, with uptake into the brain occurring within 1-2 minutes. After smoking, the action of nicotine on the brain occurs very quickly. The rapid onset of effects after a puff is believed to provide optimal reinforcement for the development of drug dependence (U.S. Department of Health and Human Services, 1988). The effects of nicotine decline after it is distributed to other tissues. The distribution half-life, which describes the movement of nicotine from the blood and rapidly perfused tissues to other body tissues, is approximately 9 minutes (U.S. Department of Health and Human Services, 1988).

After absorption into the blood, which is at pH 7.4, about 69% of the nicotine is ionized and 31% is nonionized. Binding to plasma protein is less than 5%. The drug is distributed to body tissues with a steady-state volume of distribution averaging 180 liters. Spleen, liver, lungs, and brain have a high affinity for nicotine, whereas the affinity of adipose tissue is very low (U.S. Department of Health and Human Services, 1988). Nicotine-binding sites or receptors in the brain have been identified and differentiated as very-high-affinity, high-affinity, and low-affinity types (U.S. Department of Health and Human Services, 1988). The most intense localization of labeled nicotine has been found in the interpeduncular nucleus and medial habenula.

Nicotine is extensively metabolized, primarily in the liver, but also to a small extent in the lung. Renal excretion of unchanged nicotine depends on urinary pH and urine flow, and may range from 2 to 35% but typically accounts for 5-10% of elimination (U.S. Department of Health and Human Services, 1988).

The relationship between the dose of nicotine and the resulting response (dose-response relationship) is complex and varies with the specific response that is measured. Nicotine is commonly thought of as an example of a drug that in low doses causes ganglionic stimulation and in high doses causes ganglionic blockade (U.S. Department of Health and Human Services, 1988). At very low doses, similar to those seen during cigarette smoking, cardiovascular effects appear to be mediated by the central nervous system, either through activation of chemoreceptor afferent pathways or by direct effects on the brainstem. The net result is sympathetic neural discharge, with an increase in blood pressure and heart rate. At higher doses, nicotine may act directly on the peripheral nervous system, producing ganglionic stimulation and the release of adrenal catecholamine. With high doses or rapid administration, nicotine produces hypotension and slowing of heart rate, mediated by either peripheral vagal activation or direct central depressor effects (U.S. Department of Health and Human Services, 1988).

Humans and other species readily develop tolerance of the effects of nicotine. Studies of tolerance to nicotine on in vitro tissue preparations may be summarized as follows: (1) With repeated dosing, responses diminish to nearly negligible levels; (2) after tolerance occurs, responsiveness can be restored by increasing the size of the dose; and (3) after a few hours without nicotine, responsiveness is partially or fully restored (U.S. Department of Health and Human Services, 1988). It is apparent that cigarette smokers reveal evidence for both acute tolerance (tachyphylaxis) and chronic tolerance to nicotine. This is consistent with the fact that smokers increase their tobacco consumption and intake of nicotine with experience (chronic tolerance). When smokers abstain for a while, the first few cigarettes they smoke produce a variety of bodily symptoms. Thereafter, they quickly become less sensitive (acute tolerance). Tolerance may be related to an increase in central nicotine-binding sites or to a decrease in the sensitivity of the sites (U.S. Department of Health and Human Services, 1988).

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