Large doses.16 Nicotine is an agonist to receptors at the ends of peripheral cholinergic nerves whose cell bodies lie in the central nervous system, i.e. it acts at autonomic ganglia and at the voluntary neuromuscular junction (see Fig. 21.1). This is what is meant by the term 'nicotine-like' or 'nicotinic' effect. Higher doses paralyse at the same points. The central nervous system is stimulated, including the vomiting centre, both directly and via chemore-ceptors in the carotid body; tremors and convulsions may occur. As with the peripheral actions, depression follows stimulation.

Doses from/with smoking. Nicotine causes release of catecholamines in the CNS, also serotonin, and antidiuretic hormone, corticotrophin and growth hormone. The effects of nicotine on viscera are probably largely reflex, from stimulation of sensory receptors (chemoreceptors) in the carotid and aortic bodies, pulmonary circulation and left ventricle. Some of the results are mutually antagonistic.

The following account tells what generally happens after one cigarette, from which about 1 mg nicotine is absorbed, although much depends on the amount and depth of inhalation and on the duration of end-inspiratory breath-holding.

On the cardiovascular system the effects are those of sympathetic autonomic stimulation. There is vasoconstriction in the skin and vasodilatation in

16 Fatal nicotine poisoning has been reported from smoking, from swallowing tobacco, from tobacco enemas, from topical application to the skin and from accidental drinking of nicotine insecticide preparations. In 1932 a florist sat down on a chair, on the seat of which a 40% free nicotine insecticide solution had been spilled. Fifteen minutes later he felt ill (vomiting, sweating, faintness, and respiratory difficulty, followed by loss of consciousness and cardiac irregularity). He recovered in hospital over about 24 h. On the fourth day he was deemed well enough to leave hospital and was given his clothes which had been kept in a paper bag. He noticed the trousers were still damp. Within one hour of leaving hospital he had to be readmitted suffering again from poisoning due to nicotine absorbed transdermally from his still contaminated trousers. He recovered over three weeks, apart from persistent ventricular extrasystoles [Faulkner J M 1933 JAMA 100: 1663], the muscles, tachycardia and a rise in blood pressure of about 15 mmHg systolic and 10 mmHg diastolic, and increased plasma noradrenaline (norepinephrine). Ventricular extrasystoles may occur. Cardiac output, work and oxygen consumption rise. Increased demand for blood flow that is not met because coronary vessels are narrowed by atherosclerosis may be a mechanism of tobacco-induced angina pectoris. Nicotine increases platelet adhesiveness, an effect that may be clinically significant in atheroma and thrombosis.

Metabolic rate. Nicotine increases the metabolic rate, only slightly at rest,17 but approximately doubles it during light exercise (occupational tasks, housework). This may be due to increase in autonomic sympathetic activity. The effect declines over 24 h on stopping smoking and accounts for the characteristic weight gain that is so disliked and which is sometimes given as a reason for continuing or resuming smoking. Smokers weigh 2-4 kg less than nonsmokers (not enough to be a health issue).

Tolerance develops to some of the effects of nicotine, taken repeatedly over a few hours; a first experience commonly causes nausea and vomiting, which quickly ceases with repetition of smoking. Tolerance is usually rapidly lost; the first cigarette of the day has a greater effect on the cardiovascular system than do subsequent cigarettes.

Conclusion: the pleasurable effects of smoking are derived from a complex mixture of multiple pharmacological and nonpharmacological factors.

In this account nicotine is represented as being the major (but not the sole) determinant of tobacco dependence after the smoker has adapted to the usual initial unpleasant effects. But there remains some uncertainty as to its role, e.g. nicotine i.v. fails adequately to substitute the effects of smoking. An understanding of the full function of nicotine is important if less harmful alternatives to smoking, such as nicotine chewing gum, are to be exploited.

17 The metabolic rate at rest accounts for about 70% of daily energy expenditure.

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