Nicotine

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{{Drugbox||IUPAC_name = (S)-3-(1-Methyl-2-pyrroli-dinyl)pyridine| image=Nicotine-2D-skeletal.png| image2=Nicotine.qutemol.png| CAS_number=54-11-5| ATC_prefix=N07| ATC_suffix=BA01| ATC_supplemental=| PubChem=942| DrugBank=| C=10 | H=14 | N=2 || molecular_weight = 162.23| density= 1.01| boiling_point= 247| melting_point= -79| bioavailability=| metabolism =| elimination_half-life= 2 hours| excretion =| pregnancy_US = Category X| legal_AU = Unscheduled| legal_CA =| legal_UK = Unscheduled| legal_US =| legal_status =| routes_of_administration= Tobacco smoking, Insufflated (as snuff), Nicotine gum| dependency_liability = Medium to high-->

Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae), predominantly in tobacco, and in lower quantities in tomato, potato, eggplant (aubergine), and Bell pepper. Nicotine alkaloids are also found in the leaves of the coca plant. Nicotine constitutes 0.3 to 5% of the tobacco plant by dry weight, with biosynthesis taking place in the roots, and accumulating in the leaves. It functions as an Plant defense against herbivory, being a potent neurotoxin with particular specificity to insects; therefore nicotine was widely used as an insecticide in the past, and currently nicotine derivatives such as imidacloprid continue to be widely used.

In low concentrations (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals and is one of the main factors responsible for the dependence-forming properties of tobacco smoking. According to the American Heart Association, "Nicotine addiction has historically been one of the hardest addictions to break." The pharmacologic and behavioral characteristics that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. American Heart Association and Nicotine addiction.

History and name Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after Jean Nicot, a France ambassador, who sent tobacco and seeds from Brazil to Paris in 1550 and promoted their medicinal use. Nicotine was first isolated from the tobacco plant in 1828 by Germany chemists Posselt & Reimann. Its chemical empirical formula was described by Melsens in 1843, and it was first synthesized by A. Pictet and Crepieux in 1893.

Chemistry Nicotine is a hygroscopy, oily liquid that is miscible with water (molecule) in its base (chemistry) form. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Nicotine easily penetrates the skin. As shown by the physical data, freebase nicotine will burn at a temperature below its boiling point, and its vapors will combust at 95 °C in air despite a low vapor pressure. Because of this, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to provide the desired effects.

Pharmacology Pharmacokinetics As nicotine enters the body, it is distributed quickly through the bloodstream and can cross the blood-brain barrier. On average it takes about seven seconds for the substance to reach the brain when inhaled. The half life of nicotine in the body is around two hours. The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves. The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, dipping tobacco and Snuff (tobacco), which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body tends to be much greater than smoked tobacco. Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine.

Pharmacodynamics Nicotine acts on the nicotinic acetylcholine receptors. In small concentrations it increases the activity of these receptors, among other things leading to an increased flow of adrenaline (epinephrine), a stimulating hormone. The release of adrenaline causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels.

The sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream.

Cotinine is a byproduct of the metabolism of nicotine which remains in the blood for up to 48 hours and can be used as an indicator of a person's exposure to smoke. In high doses, nicotine will cause a Neuromuscular-blocking drugs of the nicotinic acetylcholine receptor, which is the reason for its Nicotine Poisoning and its effectiveness as an insecticide.

In addition, nicotine increases dopamine levels in the reward circuits of the brain. Studies have shown that smoking tobacco inhibits monoamine oxidase (MAO), an enzyme responsible for breaking down monoamine such as dopamine, in the brain. It is currently believed that nicotine by itself does not inhibit the production of monoamine oxidase (MAO), but that other ingredients in inhaled tobacco smoke are believed to be responsible for this activity. In this way, it generates feelings of pleasure, similar to that caused by cocaine and other stimulants.

Psychoactive effects Nicotine's Mood (psychology)-altering effects are different by report. First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Subjectively, users report feelings of relaxation, calmness, and alertness. It is even reported to produce a mildly Euphoria (emotion) state. By reducing the appetite and raising the metabolism, some smokers may weight loss as a consequence. It also allows the mouth to be stimulated without food and the taste of tobacco smoke may curb the appetite.

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers including acetylcholine, norepinephrine, epinephrine, vasopressin, arginine, dopamine, and beta-endorphin. This results in enhanced pleasure, decreased anxiety, and a state of alert relaxation. Nicotine enhances attention, learning, and memory due to the increase of acetylcholine. It also enhances alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. The effects of nicotine last from five minutes to two hours. Most cigarettes (in the smoke inhaled) contain 0.1 to 2.8 milligrams of nicotine.

Research{{cite book]| date = 1989| pages = 101-118| isbn = 0306413787--> suggests that when smokers wish to achieve a stimulating effect, they take short quick puffs, which produces a low level of blood nicotine. This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, Nicotine potently enhances the actions of norepinephrine and dopamine in the brain causing a drug effect typical of pyschostimulants. At higher doses nicotine enhances the effect of serotonin and opiate activity, producing a calming, analgesic effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use.

Nicotine gum and patches are available, usually in 2 mg or 4 mg doses of gum, that do not have all the other ingredients in smoked tobacco. They appear to be not as addictive or as pleasurable, and perhaps have fewer side effects . Whether all the other psychoactive effects also occur has not been well studied.

Dependence Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically, its addictive nature has been found to show that nicotine activates reward pathways—the circuitry within the brain that regulates feelings of pleasure and euphoria. http://www.nida.nih.gov/researchreports/nicotine/nicotine2.html

Dopamine is one of the key neurotransmitters actively involved in the brain. Research shows that by increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a chemical with intense addictive qualities. In many studies it has been shown to be more addictive than cocaine and heroin, though chronic treatment has an opposite effect on reward thresholds. Like other physically addictive drugs, nicotine causes down-regulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. In addition, the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. The net effect is an increase in reward pathway sensitivity, opposite of other drugs of abuse (namely cocaine and heroin, which reduce reward pathway sensitivity). This neuronal brain alteration persists for months after administration ceases. Due to an increase in reward pathway sensitivity, nicotine withdrawal is relatively mild compared to ethanol or heroin withdrawal. Nicotine also has the potential to cause dependence in many animals other than humans. Mice have been administered nicotine and exhibit withdrawal reactions when its administration is stopped. Gorillas have been forced to smoke cigarettes by humans, and have similar difficulty quitting.http://www.nida.nih.gov/NIDA_notes/NNvol19N2/Early.html

A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing the risk of substance abuse during adulthood. Nolley E.P. & Kelley B.M. " Adolescent reward system perseveration due to nicotine: Studies with methylphenidate.," Neurotoxicol Teratol., 2006 Oct 4

There is only anecdotal evidence about abuse or addiction with nicotine gum or nicotine patches.

Due to its stimulation of the nicotinic receptors (mimicking the effects of acetylcholine) it has been reported as a useful tool for the induction of lucid dreams, where a nicotine patch is applied after 4–6 hours of normal sleep and the subject falls back to sleep (into a more Rapid eye movement sleep intense sleep cycle). Non-lucid dreams may become vivid, more memorable and some report a higher frequency of disturbing dreams. However it should be stressed that a consistent use of nicotine will desensitize the nicotinic receptors and therefore addicts are actually far less likely to achieve lucid dreams.

Toxicology The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mouse. 40–60 mg (0.5-1.0 mg/kg) can be a lethal dosage for adult humans. IPCS INCHEM This makes it an extremely deadly poison. It is more toxic than many other alkaloids such as cocaine, which has an LD50]ic properties of nicotine in standalone form, separate from tobacco smoke, have not been evaluated by the International Agency for Research on Cancer, and it has not been assigned to an official carcinogen group. The currently available literature indicates that nicotine, on its own, does not promote the development of cancer in healthy tissue and has no mutagenic properties. Its Teratogenesis properties have not yet been adequately researched, and while the likelihood of birth defects caused by nicotine is believed to be very small or nonexistent, nicotine replacement product manufacturers recommend consultation with a physician before using a nicotine patch or nicotine gum while pregnant or nursing. However, nicotine and the increased Nicotinic acetylcholine receptor activity it causes have been shown to impede apoptosis, which is one of the methods by which the body destroys unwanted cells (programmed cell death). Since apoptosis helps to remove mutated or damaged cells that may eventually become cancerous, the inhibitory actions of nicotine create a more favourable environment for cancer to develop. Thus nicotine plays an indirect role in carcinogenesis. It is also important to note that its addictive properties are often the primary motivating factor for tobacco smoking, contributing to the proliferation of cancer.

At least one study has concluded that exposure to nicotine alone, not simply as a component of cigarette smoke, could be responsible for some of the neuropathological changes observed in infants dying from Sudden Infant Death Syndrome (SIDS). Machaalani et al. (2005) "Effects of postnatal nicotine exposure on apoptotic markers in the developing piglet brain"

It has been noted that the majority of people diagnosed with schizophrenia smoke tobacco. Estimates for the number of schizophrenics that smoke range from 75% to 90%. It was recently argued that the increased level of smoking in schizophrenia may be due to a desire to self-medication with nicotine. Schizophr. Res. 2002 Am. J. Psychiatry 1995 More recent research has found the reverse, that it is a risk factor without long-term benefit, used only for its short term effects. Br. J. Psychiatry 2005 However, research on nicotine as administered through a patch or gum is ongoing.

Therapeutic uses The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with its risks to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, or nasal sprays in an effort to wean them off their dependence.

However, in a few situations, smoking has been observed to apparently be of therapeutic value to patients.These are often referred to as "Smoker’s Paradoxes" . Although in most cases the actual mechanism is understood only poorly or not at all, it is generally believed that the principal beneficial action is due to the nicotine administered, and that administration of nicotine without smoking may be as beneficial as smoking, without the higher risk to health due to tar and other ingredients found in tobacco.

For instance, recent studies suggest that smokers require less frequent repeated revascularization after percutaneous coronary intervention (PCI). Risk of ulcerative colitis has been frequently shown to be reduced by smokers on a dose-dependent basis; the effect is eliminated if the individual stops smoking.Longmore, M., Wilkinson, I., Torok, E. Oxford Handbook of Clinical Medicine (Fifth Edition) p. 232 Smoking also appears to interfere with development of Kaposi's sarcoma,{{cite news | last = | first = | coauthors = | title = Smoking Cuts Risk of Rare Cancer | work = | pages = | language = English | publisher = UPI | date = March 29, 2001 | url = http://www.data-yard.net/10b/kaposi.htm | accessdate = 2006-11-06--> breast cancer among women carrying the very high risk BRCA gene,{{cite news | last = Recer | first = Paul | coauthors = | title = Cigarettes May Have an Up Side | work = | pages = | language = English | publisher = AP | date = May 19, 1998 | url = http://www.forces.org/evidence/files/brea.htm | accessdate = 2006-11-06--> preeclampsia, and atopys such as allergic asthma. A plausible mechanism of action in these cases may be nicotine acting as an Inflammation, and interfering with the inflammation-related disease process, as nicotine has vasoconstrictive effects.

With regard to neurology, a large body of evidence suggests that the risks of Parkinson's disease or Alzheimer's disease might be twice as high for non-smokers than for smokers. Many such papers regarding Alzheimer's disease{{cite web | last = Thompson | first = Carol | authorlink = | coauthors = | title = Alzheimer's disease is associated with non-smoking | work = | date = | url = http://www.forces.org/evidence/carol/carol16.htm | format = | doi = | accessdate =2006-11-06--> and Parkinson's Disease{{cite web | last = Thompson | first = Carol | authorlink = | coauthors = | title = Parkinson's disease is associated with non-smoking | work = | date = | url = http://www.forces.org/evidence/carol/carol36.htm | format = | doi = | accessdate =2006-11-06--> have been published. A plausible mechanism of action in these cases may be the effect of nicotine, a cholinergic receptor agonist, in decreasing the levels of acetylcholine in the smoker's brain; Parkinson's disease occurs when the effect of dopamine is less than that of acetylcholine.

Recent studies have indicated that nicotine can be used to help adults suffering from Autosomal dominant nocturnal frontal lobe epilepsy. The same areas that cause seizures in that form of epilepsy are also responsible for processing nicotine in the brain.

Nicotine and its metabolites are being researched for the treatment of a number of disorders, including ADHD and Parkinson's Disease.

The therapeutic use of nicotine as a means of appetite-control and to promote weight loss is anecdotally supported by many ex-smokers who claim to put on weight after quitting. However studies of nicotine in mice NIH, online at suggests it may play a role in weight-loss that is independent of appetite. And studies involving the elderly suggest that nicotine affects not only weight loss, but also prevents some weight gain. Cigarette Smoking and Weight Loss in Nursing Home Residents

See also

References Further reading

Guardian article: "Nicotine could soon be rehabilitated as a treatment for schizophrenia, Alzheimer's and Parkinson's diseases, as well as hyperactivity disorders."
Nicotine Therapy for ADNFLE: "Nicotine as an antiepileptic agent in ADNFLE: An n-of-one study"
Minna, John D.: "Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression in the pathogenesis of lung cancer"
James Fallon, et al. (2005) Gender: A major determinant of brain response to nicotine. International Journal of Neuropharmacology. 8:1-10.
West, Kip A., et al.: "Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells"
National Institute on Drug Abuse
Powledge TM (2004) Nicotine as therapy. PLoS Biol 2(11): e404.:
Erowid information on tobacco

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