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Nicotine
Nicotine
3-[(2S)-1-methylpyrrolidin-2-yl]pyridine
Identifiers
PubChem [4]
CID 942
DrugBank [5]
DB00184
ChemSpider [6]
80863
UNII [7]
6M3C89ZY6R
Chemical data
Formula C H N
10 14 2
Mol. mass 162.26 g/mol
Physical data
Density 1.01 g/cm³
Pharmacokinetic data
Metabolism hepatic
Half-life 2 hours
Therapeutic considerations
Routes smoked (as smoking tobacco, mapacho, etc.), insufflated (as tobacco snuff or nicotine nasal spray), chewed (as
nicotine gum, tobacco gum or chewing tobacco), transdermal (as nicotine patch, nicogel or topical tobacco
paste), intrabuccal (as dipping tobacco, snuffs, dissolvable tobacco or creamy snuff), vaporized (as electronic
cigarette, etc.), directly inhaled (as nicotine inhaler), oral (as nicotini)
[10]
(what is this?) (verify)
Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae) that constitutes approximately
0.6–3.0% of the dry weight of tobacco,[11] [12] with biosynthesis taking place in the roots and accumulation
occurring in the leaves. It functions as an antiherbivore chemical with particular specificity to insects; therefore
nicotine was widely used as an insecticide in the past,[13] [14] and currently nicotine analogs such as imidacloprid
continue to be widely used. Nicotine is also found in several other members of the Solanaceae family, with small
amounts being present in species such as the Eggplant and Tomato.
In low concentrations (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant
in mammals and is the main factor 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, while the pharmacological and behavioral characteristics that determine tobacco addiction are similar to
those that determine addiction to drugs such as heroin and cocaine.[15] Nicotine content in cigarettes has slowly
increased over the years, and one study found that there was an average increase of 1.6% per year between the years
of 1998 and 2005. This was found for all major market categories of cigarettes.[16]
Chemistry
Nicotine is a hygroscopic, oily liquid that is miscible with water in its base 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, free base nicotine will burn at a temperature below its boiling point, and its vapors will combust at
308 K (35 °C; 95 °F) 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 cause pharmacological effects.
Nicotine 3
Optical activity
Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory,
with [α]D = –166.4°. The dextrorotatory form, (+)-nicotine, has only one-half the physiological activity of
(–)-nicotine. It is therefore weaker in the sense that a higher dose is required to attain the same effects.[20] The salts
of (+)-nicotine are usually dextrorotatory.
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.[22]
metabolite is cotinine.
Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and
nicotine glucuronide.[23]
Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive to
mentholated cigarettes, thus increasing the half-life of nicotine in vivo.[24]
Detection of use
Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a
medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the
purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is
important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by
the appearance of its metabolites in various body fluids.[25] [26] Interestingly, nicotine use is not regulated in
competitive sports programs, yet the drug has been shown to have a significant beneficial effect on athletic
performance.[27]
Nicotine 4
Pharmacodynamics
Nicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNS
nicotinic receptor. The former is present in the adrenal medulla and elsewhere, while the latter is present in the
central nervous system (CNS). In small concentrations, nicotine increases the activity of these receptors. Nicotine
also has effects on a variety of other neurotransmitters through less direct mechanisms.
In CNS
In SNS
Nicotine also activates the sympathetic nervous system,[36] 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 the release of epinephrine (and norepinephrine) into the bloodstream.
Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or its
irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence
and lower smoking cessation rates in darker pigmented individuals.[37]
In adrenal medulla
Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. In the other hand, cotinine is the
metabolite of nicotine which remains in the blood for 18 to 20 hours, making it a more stable compound, which
Nicotine 5
results more desirable and easier to analyze due to its longer half-life.[39]
Psychoactive effects
Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.[40] First
causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes
stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness.[41] Like any stimulant, it may
very rarely cause the often catastrophically uncomfortable neuropsychiatric effect of akathisia. By reducing the
appetite and raising the metabolism, some smokers may lose weight as a consequence.[42] [43]
Smokers often report that cigarettes help relieve feelings of stress. However, the stress levels of adult smokers are
slightly higher than those of nonsmokers, adolescent smokers report increasing levels of stress as they develop
regular patterns of smoking, and smoking cessation leads to reduced stress . Far from acting as an aid for mood
control, nicotine dependency seems to exacerbate stress. This is confirmed in the daily mood patterns described by
smokers, with normal moods during smoking and worsening moods between cigarettes. Thus, the apparent relaxant
effect of smoking only reflects the reversal of the tension and irritability that develop during nicotine depletion.
Dependent smokers need nicotine to remain feeling normal.[44]
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, autocrine agents, and beta-endorphin.[45] This release of
neurotransmitters and hormones is responsible for most of nicotine's effects. Nicotine appears to enhance
concentration[46] and memory due to the increase of acetylcholine. It also appears to enhance 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.
Nicotine also extends the duration of positive effects of dopamine[47] and increases sensitivity in brain reward
systems.[48] Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.[49]
Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which
produce a low level of blood nicotine.[50] 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 those of psychostimulants. At higher doses, nicotine enhances the effect of
serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most
drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use.
Technically, nicotine is not significantly addictive, as nicotine administered alone does not produce significant
reinforcing properties.[51] However, only after coadministration with an MAOI, such as those found in tobacco,
nicotine produces significant behavioral sensitization, a measure of addiction potential. This is similar in effect to
amphetamine.[52]
Nicotine gum, usually in 2-mg or 4-mg doses, and nicotine patches are available, as well as smokeless tobacco and
electronic cigarettes which do not have all the other ingredients in smoked tobacco.
Nicotine 6
A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing
the risk of substance abuse during adolescence.[57]
Immunology prevention
Because of the severe addictions and the harmful effects of smoking, vaccination protocols have been developed.
The principle is under the premise that if an antibody is attached to a nicotine molecule, it will be prevented from
diffusing through the capillaries, thus making it less likely that it ever affects the brain by binding to nicotinic
acetylcholine receptors.
These include attaching the nicotine molecule to a hapten such as Keyhole limpet hemocyanin or a safe modified
bacterial toxin to elicit an active immune response. Often it is added with bovine serum albumin.
Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodies
against endogenous hormones and over the counter drugs, monoclonal antibodies have been developed for short term
passive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on their
ability to resist degradation from pinocytosis by epithelial cells.[58]
Toxicology
The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 40–60 mg (0.5-1.0 mg/kg) can be a lethal dosage for
adult humans.[59] [60] Nicotine therefore has a high toxicity in comparison to many other alkaloids such as cocaine,
which has an LD50 of 95.1 mg/kg when administered to mice. It is unlikely that a person would overdose on nicotine
through smoking alone, although intoxication can occur through the excessive use of nicotine patches, gum, nasal
sprays or oral inhalers intended as smoking cessation aids.[61] [62] Spilling a high concentration of nicotine onto the
skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal
contact.[63]
Nicotine 7
The carcinogenic properties of nicotine in standalone form, separate from tobacco smoke, have not been evaluated
by the IARC, 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. However, nicotine and the increased cholinergic 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
may create a more favourable environment for cancer to develop, though this also remains to be proven.[64]
Though the teratogenic properties of nicotine may or may not yet have been adequately researched, women who use
nicotine gum and patches during the early stages of pregnancy face an increased risk of having babies with birth
defects, according to a study of around 77,000 pregnant women in Denmark. The study found that women who use
nicotine-replacement therapy in the first 12 weeks of pregnancy have a 60 percent greater risk of having babies with
birth defects, compared to women who are non-smokers, the Daily Mail reported. The findings were published in the
journal Obstetrics and Gynaecology.
Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the California
Environmental Protection Agency added nicotine to the list of chemicals known to the state to cause developmental
toxicity, for the purposes of Proposition 65.[65]
Therapeutic uses
The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the
damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges,
electronic/substitute cigarettes 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. These are often
referred to as "Smoker’s Paradoxes".[68] 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).[68] 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.[69] [70] Smoking also appears to
interfere with development of Kaposi's sarcoma in patients with HIV,[71].[72]
Nicotine reduces the chance of Breast cancer among women carrying the very high risk BRCA gene,[73]
preeclampsia,[74] and atopic disorders such as allergic asthma.[75] A plausible mechanism of action in these cases
may be nicotine acting as an anti-inflammatory agent, and interfering with the inflammation-related disease process,
as nicotine has vasoconstrictive effects.[76]
Nicotine 8
Tobacco smoke has been shown to contain compounds capable of inhibiting MAO. Monoamine oxidase is
responsible for the degradation of dopamine in the human brain. When dopamine is broken down by MAO-B,
neurotoxic by-products are formed, possibly contributing to Parkinson's and Alzheimers disease.[77] Many such
papers regarding Alzheimer's disease[78] and Parkinson's Disease[79] have been published. Recent studies find no
beneficial link between smoking and Alzheimer's disease and in some cases, suggest it may actually result in an
earlier onset of the disease.[80] [81] [82] [83] However, nicotine has been shown to delay the onset of Parkinson's
disease in studies involving monkeys and humans.[84] [85] [86]
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 responsible for processing
nicotine in the brain.[87]
Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion of
schizophrenic patients who smoke. Although the nature of this association remains unclear, it was recently argued
that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.[88] [89]
More recent research has found that mildly dependent users got some benefit from nicotine, but not those who were
highly dependent.[90] All of these studies are based only on observation, and no interventional (randomized) studies
have been done. Research on nicotine as administered through a patch or gum is ongoing.
Nicotine appears to improve ADHD symptoms. Some studies are focusing on benefits of nicotine therapy in adults
with ADHD.[91]
Nicotine (in the form of chewing gum or a transdermal patch) is being explored as an experimental treatment for
OCD. Small studies show some success, even in otherwise treatment-refractory cases.[92] [93] [94]
See also
• Nicotiana
• Nicotiana rustica
• Mapacho
• Nicotiana tabacum
• Tobacco
• Tobacco products
• Nicotinic acid (Niacin)
• Drug addiction
Nicotine 9
• Tobacco cessation
• Chantix
• Zyban
• Nicogel
• Nicotini
• NicVAX
• Nicotine gum
• Nicotine patch
• Nicotine inhaler
• Nicotine nasal spray
• Snus
• Electronic Cigarette
• Psychoactive drug
• Drug Discovery and Development: Nicotinic Acetylcholine Receptor Agonists
• Nicotinic receptor
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Further reading
• Bilkei-Gorzo A, Rácz I, Michel K, Darvas M, Rafael Maldonado López, Zimmer A. (2008). "A common genetic
predisposition to stress sensitivity and stress-induced nicotine craving". Biol. Psychiatry 63 (2): 164–71.
doi:10.1016/j.biopsych.2007.02.010. PMID 17570348.
• Willoughby JO, Pope KJ, Eaton V (Sep 2003). "Nicotine as an antiepileptic agent in ADNFLE: an N-of-one
study" (http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&
issn=0013-9580&date=2003&volume=44&issue=9&spage=1238). Epilepsia 44 (9): 1238–40.
doi:10.1046/j.1528-1157.2003.11903.x. PMID 12919397.
• Minna JD (Jan 2003). "Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression
in the pathogenesis of lung cancer" (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&
artid=151841). J Clin Invest. 111 (1): 31–3. doi:10.1172/JCI17492. PMID 12511585. PMC 151841.
• Fallon JH, Keator DB, Mbogori J, Taylor D, Potkin SG (Mar 2005). "Gender: a major determinant of brain
response to nicotine" (http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=282494).
Int J Neuropsychopharmacol. 8 (1): 17–26. doi:10.1017/S1461145704004730. PMID 15579215.
• West KA, Brognard J, Clark AS, et al. (Jan 2003). "Rapid Akt activation by nicotine and a tobacco carcinogen
modulates the phenotype of normal human airway epithelial cells" (http://www.pubmedcentral.nih.gov/
articlerender.fcgi?tool=pmcentrez&artid=151834). J Clin Invest. 111 (1): 81–90. doi:10.1172/JCI16147.
PMID 12511591. PMC 151834.
• National Institute on Drug Abuse (http://www.nida.nih.gov/researchreports/nicotine/nicotine.html)
• Erowid information on tobacco (http://www.erowid.org/plants/tobacco/tobacco.shtml)
Nicotine 13
External links
• Description of nicotine mechanisms (http://www.howstuffworks.com/nicotine.htm)
Article Sources and Contributors 14
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