Peripheral Nervous System. The major action of nicotine consists initially of transient stimulation and subsequently of a more persistent depression of all autonomic ganglia. Small doses of nicotine stimulate the ganglion cells directly and may facilitate impulse transmission. Following larger doses, the initial stimulation is followed very quickly by a blockade of transmission. Whereas stimulation of the ganglion cells coincides with their depolarization, depression of transmission by adequate doses of nicotine occurs both during the depolarization and after it has subsided. Nicotine also possesses a biphasic action on the adrenal medulla: small doses evoke the discharge of catecholamines; larger doses prevent their release in response to splanchnic nerve stimulation.
The effects of high doses of nicotine on the neuromuscular junction are similar to those on ganglia. However, with the exception of avian and denervated mammalian muscle, the stimulant phase is obscured largely by the rapidly developing paralysis. In the latter stage, nicotine also produces neuromuscular blockade by receptor desensitization. At lower concentrations, such as those typically achieved by recreational tobacco use (~200 nM), nicotine's effects reflect its higher affinity for a neuronal nicotinic receptor (α4β2) than for the neuromuscular junction receptor (α1β1γδ), as explained in molecular detail by Xiu and associates (2009). This high affinity, coupled with the ability of nicotine to cross the blood-brain barrier, allows nicotine to selectively activate neuronal receptors without causing intolerable contractions or paralysis of skeletal muscle.
Nicotine, like ACh, stimulates a number of sensory receptors. These include mechanoreceptors 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.
Central Nervous System. 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 the diaphragm and intercostal muscles that facilitate respiration.
Nicotine induces vomiting by both central and peripheral actions. The central component of the vomiting response is due to stimulation of the emetic chemoreceptor trigger zone in the area postrema of the medulla oblongata. In addition, nicotine activates vagal and spinal afferent nerves that form the sensory input of the reflex pathways involved in the act of vomiting. Studies in isolated higher centers of the brain and spinal cord reveal that 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, dopamine, and other biogenic amines from various CNS centers (MacDermott et al., 1999). Release of excitatory amino acids may account for much of nicotine's stimulatory action.
Chronic exposure to nicotine in several systems causes a marked increase in the density or number of nicotinic receptors, possibly contributing to tolerance and dependence. Nicotine acts as an intracellular molecular chaperone to promote the assembly of receptor subunits by inducing an active conformation in the nascent subunits that assemble more efficiently. Chronic low dose exposure to nicotine also significantly increases the t1/2 of receptors on the cell surface (Kuryatov et al., 2005; Lester et al., 2009).
Cardiovascular System. When administered intravenously to dogs, nicotine characteristically produces an increase in heart rate and blood pressure. The latter is usually more sustained. In general, the cardiovascular responses to nicotine are due to stimulation of sympathetic ganglia and the adrenal medulla, together with the discharge of catecholamines from sympathetic nerve endings. Contributing to the sympathomimetic response to nicotine is the activation of chemoreceptors of the aortic and carotid bodies, which reflexly results in vasoconstriction, tachycardia, and elevated blood pressure.
GI Tract. The combined activation of parasympathetic ganglia and cholinergic nerve endings by nicotine results in increased tone and motor activity of the bowel. Nausea, vomiting, and occasionally diarrhea are observed following systemic absorption of nicotine in an individual who has not been exposed to nicotine previously.
Exocrine Glands. Nicotine causes an initial stimulation of salivary and bronchial secretions that is followed by inhibition.
Absorption, Distribution, and Elimination. Nicotine is readily absorbed from the respiratory tract, buccal membranes, and skin. Severe poisoning has resulted from percutaneous absorption. As a relatively strong base, nicotine has limited absorption from the stomach. Intestinal absorption is far more efficient. Nicotine in chewing tobacco, because it is absorbed more slowly than inhaled nicotine, has a longer duration of effect. The average cigarette contains 6-11 mg nicotine and delivers ~1-3 mg nicotine systemically to the smoker; bioavailability can increase as much as 3-fold with the intensity of puffing and technique of the smoker (Benowitz, 1998).
Approximately 80-90% of nicotine is altered in the body, mainly in the liver but also in the kidney and lung. Cotinine is the major metabolite, with nicotine-1′-N-oxide and 3-hydroxycotinine and conjugated metabolites found in lesser quantities (Benowitz, 1998). The profile of metabolites and the rate of metabolism appear to be similar in smokers and nonsmokers. The t1/2 of nicotine following inhalation or parenteral administration is ~2 hours. Nicotine and its metabolites are eliminated rapidly by the kidney. The rate of urinary excretion of nicotine diminishes when the urine is alkaline. Nicotine also is excreted in the milk of lactating women who smoke; the milk of heavy smokers may contain 0.5 mg/L.
Acute Nicotine Poisoning. Poisoning from nicotine may occur from accidental ingestion of nicotine-containing insecticide sprays or in children from ingestion of tobacco products. The acutely fatal dose of nicotine for an adult is probably ~ 60 mg. Smoking tobacco usually contains 1-2% nicotine. Apparently, the gastric absorption of nicotine from tobacco taken by mouth is delayed because of slowed gastric emptying, so vomiting caused by the central effect of the initially absorbed fraction may remove much of the tobacco remaining in the GI tract.
The onset of symptoms of acute, severe nicotine poisoning is rapid; they include nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, headache, dizziness, disturbed hearing and vision, mental confusion, and marked weakness. Faintness and prostration ensue; the blood pressure falls; breathing is difficult; the pulse is weak, rapid, and irregular; and collapse may be followed by terminal convulsions. Death may result within a few minutes from respiratory failure.
Therapy. Vomiting may be induced, or gastric lavage should be performed. Alkaline solutions should be avoided. A slurry of activated charcoal is then passed through the tube and left in the stomach. Respiratory assistance and treatment of shock may be necessary.
Smoking Cessation. Two goals of the pharmacotherapy of smoking cessation are the reduction of the craving for nicotine and inhibition of the reinforcing effects of nicotine. Myriad approaches and drug regimens are used, including nicotine replacement, bupropion (Chapter 15), and nicotinic ACh receptor agonists (Chapters 15 and 24 and the review by Frishman, 2009). Nicotine dependence is likely mediated, at least in part, by subtypes of the neuronal nicotinic acetylcholine receptor (Nn). The mesolimbic α4β2 subtype of Nn and α4β2-stimulated release of dopamine seem to play major roles in nicotine dependence. Thus, one aim of drug development in this area is discovery of an agent that will stimulate α4β2-mediated DA release sufficiently to reduce craving during periods of abstinence from smoking yet occupy the α4β2 Nn receptor sufficiently to inhibit nicotine reinforcement during smoking (Rollema et al., 2007).
Varenicline (chantix) has been recently introduced as an aid to smoking cessation. The drug interacts with nicotinic ACh receptors. In model systems, varenicline is a partial agonist at α4β2 receptors and a full agonist at the α7 subtype, with weak activity toward α3β2- and α6-containing receptors (Mihalak et al., 2006). The drug is effective clinically; however, it is not benign: Based on post-marketing studies, the FDA has issued a warning about mood and behavioral changes associated with its use (Frishman, 2009).
Nicotine itself is available in several dosage forms to help achieve abstinence from tobacco use. Efficacy results primarily from preventing a withdrawal or abstinence syndrome. Nicotine is marketed for over-the-counter use as a gum or lozenge (nicotine polacrilex, nicorette, commit, thrive, others), transdermal patch (nicoderm, habitrol, others), a nasal spray (nicotrol), or a vapor inhaler (nicotrol). The gum and transdermal systems are used most widely, and the objective is to obtain a sustained plasma nicotine concentration lower than venous blood concentrations after smoking. Arterial blood concentrations immediately following inhalation can be as much as 10-fold higher than venous concentrations. The efficacy of these dosage forms in producing abstinence from smoking is enhanced when linked to counseling and motivational therapy (Benowitz, 1999; Fant et al., 1999; Frishman, 2009).