Nicotine
Nicorette®
Habitrol®
Nicoderm®
Nicotrol®
Nicotrol®
Inhaler
Nicotrol®
NS
Prostep®
Commit™
Nicoderm CQ® Clear
Nicorelief™
Nicorelief™ Mint
Nicorette® DS
Nicotrol® Step 1
Nicotrol® Step 2
Nicotrol® Step 3
Nicotrol®
Transdermal System
Classification:
Autonomic Agents
Toxicology Agents
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. 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. 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. 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.
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