The complex and often unpredictable changes that occur in the body after administration of nicotine are due not only to its actions on a variety of neuroeffector and chemosensitive sites but also to the fact that the alkaloid can stimulate and desensitize receptors. The ultimate response of any one system represents the summation of stimulatory and inhibitory effects of nicotine. For example, the drug can increase heart rate by excitation of sympathetic or paralysis of parasympathetic cardiac ganglia, or it can slow heart rate by paralysis of sympathetic or stimulation of parasympathetic cardiac ganglia. In addition, the effects of the drug on the chemoreceptors of the carotid and aortic bodies and on brain centers influence heart rate, as do the cardiovascular compensatory reflexes resulting from changes in blood pressure caused by nicotine. Finally, nicotine elicits a discharge of epinephrine from the adrenal medulla, which accelerates heart rate and raises blood pressure.
The major action of nicotine consists initially of transient stimulation followed by a more persistent depression of all autonomic ganglia. Small doses of nicotine stimulate the ganglion cells directly and may facilitate impulse transmission. When larger doses of the drug are applied, the initial stimulation is followed very quickly by a blockade of transmission. Nicotine also possesses a biphasic action on the adrenal medulla; small doses evoke the discharge of catecholamines, and larger doses prevent their release in response to splanchnic nerve stimulation.
The effects of nicotine on the neuromuscular junction are similar to those on ganglia. However, the stimulant phase is obscured largely by the rapidly developing paralysis. In the latter stage, nicotine also produces neuromuscular blockade by receptor desensitization.
Nicotine, like ACh, will stimulate a number of sensory receptors. These include mechanore-ceptors that respond to stretch or pressure of the skin, mesentery, tongue, lung, and stomach; chemoreceptors of the carotid body; thermal receptors of the skin and tongue; and pain receptors. Prior administration of hexamethonium prevents stimulation of the sensory receptors by nicotine but has little, if any, effect on the activation of sensory receptors by physiological stimuli.
Nicotine markedly stimulates the CNS. Low doses produce weak analgesia; with higher doses, tremors leading to convulsions at toxic doses are evident. The excitation of respiration is a prominent action of nicotine; although large doses act directly on the medulla oblongata, smaller doses augment respiration reflexly by excitation of the chemoreceptors of the carotid and aortic bodies.
Stimulation of the CNS with large doses is followed by depression, and death results from failure of respiration owing to both central paralysis and peripheral blockade of muscles of respiration.
Nicotine induces vomiting by both central and peripheral actions. The primary sites of action of nicotine in the CNS are prejunctional, causing the release of other transmitters. Accordingly, the stimulatory and pleasure—reward actions of nicotine appear to result from release of excitatory amino acids, DA, and other biogenic amines from various CNS centers. Release of excitatory amino acids may account for much of nicotine's stimulatory action. Chronic exposure to nicotine increases the density or number of nicotinic receptors.
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