Nicotine Pharmacology

Description: Nicotine is a naturally occurring alkaloid, long used by pharmacologists to investigate the autonomic nervous system. It is now used clinically as a drug to help smokers quit smoking. Nicotine by itself is not considered a health threat. The benefit of nicotine patches in helping smokers quit smoking has been demonstrated in a meta-analysis of 17 double-blind, placebo-controlled studies.[270] Scientific observations have noted that nicotine, when administered in sustained low doses, desensitizes the nicotine receptors and acts like a nicotine-receptor antagonist. The administration of nicotine in low doses via transdermal patches to patients with nicotine-responsive disorders such as drug-addictions or Tourette's syndrome has been found to subjectively improve disease symptoms. More study on the mechanism of nicotine in psychiatric disorders is needed. Less potent analogs of nicotine, like lobeline sulfate, are under investigation in various disorders (see Lobeline monograph). Commercially, nicotine is available in a multitude of dosage formulations. Nicotine chewing gum was approved by the FDA in January 1984 and transdermal patches were approved in November 1991; the transdermal patches may be used in a step-down regimen using sequentially lower nicotine replacement dosages. The patent for Nicorette® gum expired in 1994. The FDA approved the nonprescription sale of nicotine gum and transdermal patches in February 1996 and July 1996, respectively. The first inhaled dosage form of nicotine, Nicotrol NS®, designed to be used as a nasal inhaler, was launched in September 1996. On May 5, 1997, the FDA approved a prescription-only oral inhalation system (Nicotrol® Inhaler) for nicotine replacement therapy. Nicotine transdermal systems (NTS) may be combined with the use of bupropion (Zyban®) for treating the symptoms of smoking cessation, and the combined therapy received FDA approval in 1999. A nicotine lozenge (Commit®) was approved October 31, 2002 for smoking cessation. In April 2004, Pfizer announced that certain packagings of the Nicotrol® Inhaler and Nicotrol® NS (nasal spray) products would be discontinued from manufacture as of April 12, 2004.

Mechanism of Action: Nicotine's pharmacological actions are complex and include effects on both the central and peripheral nervous systems. Nicotine is classified as a stimulant of autonomic ganglia, although it possesses both stimulant and depressant actions. The end result of stimulation at what are now referred to as nicotinic receptors is a variety of cholinergic and adrenergic effects. These include: tachycardia or bradycardia mediated by either stimulation or interference with sympathetic or parasympathetic pathways, stimulation of receptors in the carotic and aortic bodies, release of epinephrine from the adrenal medulla, and stimulation of the chemoreceptor-trigger zone. At the neuromuscular junction, nicotine is an agonist, but paralysis ensues due to receptor desensitization. The effects on the GI tract are secondary to parasympathetic stimulation.

Pharmacokinetics: Nicotine is administered through several dosage forms which include chewing gum, oral lozenge, inhaler, nasal spray, and transdermal patch. After administration of the gum or lozenge, the absorption of nicotine through the buccal mucosa occurs readily but systemic absorption is slower than that from cigarette smoke or with inhaled or nasal administration. Pharmacokinetic data for the nicotine lozenge are not available in the published literature. However, one study reports that nicotine lozenges deliver 25-27% more nicotine than nicotine gum because the lozenges completely dissolve and deliver their full dose whereas the gum retains some of the nicotine.[3938] The rate and extent of absorption during 20-30 minutes of rhythmic chewing vary from 50-90% of the content of the gum; the amount absorbed depends on the time the saliva is held in the mouth as opposed to being swallowed or expectorated. Buffering the gum product to a pH of 8.5 enhances absorption. Very little nicotine is absorbed from the GI tract due to extensive first-pass metabolism through the liver. After inhaled or nasal administration, nicotine is rapidly absorbed through the mucous membranes and respiratory tract; buccal absorption also occurs slowly with inhaled nicotine. Less than 5% of an inhaled dose reaches the lower respiratory tract. With intranasal administration, approximately 53% of a dosage (i.e., two nasal sprays, one in each nostril) reaches the systemic circulation. After application of a transdermal patch, nicotine is well absorbed through the skin; the extent of absorption is not known.

Peak nicotine plasma concentrations occur within 15-30 minutes after the start of chewing the gum; 15 minutes after inhalation; 4-15 minutes after nasal administration; and 4-12 hours after application of a patch. Time to peak plasma concentrations from some of the various transdermal preparations are as follows: Habitrol®: 5-6 hours; Nicoderm®: 4 hours; and ProStep®: 9 hours after application. Three brands of patches (e.g., Habitrol®, Nicoderm®, ProStep®) are designed to be worn for 24 hours and then removed. Nicotrol® is to be applied upon waking and removed at bedtime.

Nicotine is widely distributed in the body tissues, particularly the CNS. After a single puff on a cigarette, nicotine reaches the brain within 7 seconds. Nicotine crosses the placenta and is excreted in breast milk (average milk to plasma ratio is 2.9:1). The concentrations of nicotine in amniotic fluid and fetal serum exceed those in maternal serum. Detectable amounts also appear in the serum and urine of infants of lactating mothers who smoke. Plasma concentrations of nicotine decline in a biphasic manner. Most of the drug is metabolized in the liver by oxidation to cotinine and nicotine-1'-oxide. The initial half-life of nicotine is 2-3 minutes and the terminal half-life is 30-120 minutes, with considerable variation among individuals. However, with the transdermal patch, the elimination half-life is 3-4 hours due to continued absorption from skin depot. Cotinine has a plasma half-life of about 10-40 hours. Nicotine and its metabolites are excreted by the kidneys; roughly 10-20% of nicotine is eliminated unchanged in the urine.

Adverse Reactions

Concern has been expressed regarding the potential cardiovascular toxicity of nicotine patches in subjects with cardiovascular disease. To assess this, Joseph et al. evaluated VA subjects, 45 years or older, with documented cardiac disease and found that, while study end points including both serious and minor events were slightly more frequent in the group receiving and using nicotine patches compared to the placebo group, this difference was not statistically significant.[1326] Since nicotine patches generally produce lower nicotine blood concentrations than tobacco smoking and since the nicotine dose-response curve from patches is much flatter than for smoking, it should not be expected that use of nicotine patches would pose a greater cardiovascular risk than smoking itself. Pharmacologically, the effects of nicotine on the cardiovascular system mimick those of sympathetic stimulation; agonism of nicotinic receptors on adrenal medullary cells causes the release of epinephrine and norepinephrine. Nicotine raises systolic and diastolic blood pressure and can increase the inotropic and chronotropic actions of the heart. The degree to which these reactions occur is a function of the nicotine blood concentration. Hypertension has been reported with nicotine patches. New onset or worsening of existing hypertension occurs in a higher percentage of patients (i.e., 6.1%) taking bupropion concurrently with nicotine trandermal systems (NTS) for smoking cessation. However, the product literature for nicotine patches does not describe other cardiovascular reactions such as atrial fibrillation, ventricular tachycardia, premature ventricular contractions (PVCs), myocardial ischemia, or myocardial infarction as adverse reactions. The absence of these findings is consistent with the kinetics of nicotine patches and the Joseph study. Since nicotine blood levels from patches can be additive to nicotine from tobacco smoking, patients should be warned against smoking while wearing the patches. The use of patches in a subject with preexisting cardiovascular disease does not appear to pose a greater risk than smoking itself, as long as the subject refrains from smoking while wearing the patch.

Nicotine patches may cause localized erythema, pruritus, rash, or urticaria.

Symptoms of nicotine overdose include nausea/vomiting, severe abdominal pain, diarrhea, severe headache, and/or severe weakness. More severe symptoms of overdose include fainting or syncope, hypotension, weak pulse, and seizures.

Minor side effects that occur during use of nicotine products include mild headache, appetite stimulation, constipation, diarrhea, dizziness, dysmenorrhea, flushing, insomnia, and irritability. Other reported side effects include hiccups, jaw ache, and sore throat.

Nicotine chewing gum is stickier and heavier than regular gum and can affect artificial teeth or other dental work.

Contraindications/Precautions

Nicotine from drug products can be additive to the nicotine from tobacco; patients should be warned against continued tobacco smoking while using nicotine replacement products. Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes and thus tobacco smoking can increase the metabolism of many therapeutic drugs. Conversely, sudden smoking cessation may cause increased serum levels or effects of concomitant drug therapies (despite the use of a nicotine replacement product). Examples of drugs that may be affected include: caffeine, clozapine, oxazepam, olanzapine, pentazocine, phenothiazines, propoxyphene, propranolol (and possibly other beta-adrenergic blockers), theophylline, tricyclic antidepressants (e.g., imipramine), and warfarin. A decreased dosage of these drugs may be required at the cessation of smoking.

Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes and thus tobacco smoke can increase the metabolism of many therapeutic drugs. Because the process of smoking cessation may result in decreased clearance of medications used to treat asthma or depression, patients with these conditions are encouraged to check with their health care provider before pursuing nicotine therapy for smoking cessation.

For any smoker, with or without concomitant disease, the risk of nicotine replacement therapy in a smoking cessation program should be weighed against the hazard of continued smoking, and the likelihood of achieving cessation of smoking without nicotine replacement.

Cardiovascular effects of nicotine typically include peripheral vasoconstriction, tachycardia, and blood pressure elevation. The risks of nicotine replacement therapy in patients with certain cardiovascular and peripheral vascular diseases should be weighed against the benefits of including nicotine replacement in a smoking cessation program. The use of patches in a subject with preexisting cardiovascular disease does not appear to pose a greater risk than smoking itself, as long as the subject refrains from smoking while wearing the patch. Transdermal nicotine has been used safely as an aid to smoking cessation in patients with cardiac disease; however, those with a recent history (within the past 2 weeks) of unstable angina, myocardial infarction, CABG surgery, or cardiac arrhythmia were excluded.[1326] In general, nicotine replacement therapy should not be used in patients with serious cardiac arrhythmias, during the immediate post-myocardial infarction period, or in patients with severe or worsening angina pectoris. Nicotine therapy should be used with caution in patients with hypertension, pheochromocytoma, insulin-dependent diabetes mellitus, vasospastic diseases (e.g., Buerger's disease, Prinzmetal's angina), or thyroid disease resulting in hyperthyroidism or thyrotoxicosis, because increases in blood pressure, heart rate, and plasma glucose can follow the effects of nicotine-induced catecholamine release. In a comparative trial, the combination of nicotine (Habitrol®) and bupropion (Zyban®) for smoking cessation resulted in a higher incidence of treatment-emergent hypertension compared to either agent alone or to placebo. Most patients in the trial had evidence of preexisting hypertension. Monitoring for treatment-emergent hypertension is recommended in patients receiving the combination of nicotine and bupropion as well as for those receiving nicotine alone.

Clinical studies of nicotine dosage forms in elderly patients have not included sufficient numbers of patients > 65 years of age to determine if they respond differently to treatment than younger adults. However, clinical experience has not identified differences between older and younger patients. In general, dosage selection for elderly patients should be cautious, starting at the lower end of the dosage range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and concomitant disease.

Whenever possible, nicotine should be avoided during pregnancy; pregnant patients should seek qualified healthcare professional advice prior to use of non-prescription smoking cessation products. Pregnant smokers should be encouraged to stop smoking through educational and behavioral interventions before using pharmacological agents. Nicotine transdermal systems and inhalers are classified as FDA pregnancy risk category D and nicotine gum is classified as FDA pregnancy category C; however, conflicting information exists in many resources in regard to pregnancy safety ratings of these products. The specific effects of nicotine replacement therapy on fetal development are unknown; nicotine may increase fetal heart rate. Spontaneous abortion has been reported in pregnant women during nicotine replacement therapy; although a causal relationship has not been established, nicotine may have been a contributing factor. Studies of pregnant rhesus monkeys have shown that intravenous nicotine can decrease uterine blood flow and may produce acidosis, hypercarbia, and hypotension in the fetus. Teratogenicity has been noted in mice. The harmful effects of cigarette/tobacco smoking on maternal and fetal health are clearly established; effects include low birth weight, an increased risk of spontaneous abortion, and increased perinatal mortality. Nicotine replacement therapy should be used during pregnancy only if the likelihood of smoking cessation justifies the potential risk of nicotine replacement by the patient or the risk that the patient will continue to smoke.

Nicotine replacement therapy should be used with caution in women who are breast-feeding. Nicotine is distributed into breast milk. However, proper use of nicotine gum or transdermal or intranasal nicotine would be expected to produce lower concentrations of nicotine in milk than would cigarette smoking. Although some clearance of orally absorbed nicotine in infants will occur through first-pass metabolism in the liver, the efficiency of nicotine removal is probably lowest at birth. The safety of nicotine replacement therapy in nursing infants has not been examined. The decision of whether to use nicotine replacement therapy in a woman who is breast-feeding should be evaluated in comparison to the risks associated with exposure of the infant to nicotine and other tobacco contaminants in the breast milk as well as those of passive exposure to tobacco smoke.

Nicotine may delay healing in peptic ulcer disease. Therefore, nicotine should be used with caution in patients with active peptic ulcers. Nicotine replacement in a smoking cessation program should only be used when the benefits outweigh the potential risks.

The effectiveness of nicotine replacement therapy in children who smoke has not been evaluated. The amount of nicotine tolerated by adult smokers could produce toxic symptoms in children. Thus, nicotine gum or transdermal or intranasal nicotine should not be used in children.

Nicotine chewing gum is relatively contraindicated in patients with dental disease and in patients with temporomandibular joint (TMJ) disorder because injury to teeth or aggravation of TMJ can result from chewing.

Nicotine is relatively contraindicated in patients with a history of esophagitis, hiatal hernia, gastroesophageal reflux disease (GERD) because these conditions can be exacerbated by nicotine's pharmacologic effects.

Mouth or throat inflammation may be irritated by the nicotine chewing gum formulation.

Nicotine transdermal systems may be irritating for patients with some types of skin disease such as atopic or eczematous dermatitis.

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