Editing Nicotine (section)

==Pharmacology==
===Pharmacodynamics===
Nicotine acts as a [[receptor agonist]] at most [[nicotinic acetylcholine receptor]]s (nAChRs),<ref name="IUPHAR"/><ref name=MalenkaNicotine>{{cite book|vauthors=Malenka RC, Nestler EJ, Hyman SE|veditors=Sydor A, Brown RY|title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience|year=2009|publisher=McGraw-Hill Medical|location=New York|isbn=978-0-07-148127-4|page=234|edition=2nd|chapter=Chapter 9: Autonomic Nervous System|quote=Nicotine&nbsp;... is a natural alkaloid of the tobacco plant. Lobeline is a natural alkaloid of Indian tobacco. Both drugs are agonists are nicotinic cholinergic receptors&nbsp;...}}</ref> except at two [[nicotinic receptor subunits]] ([[nAChRα9]] and [[nAChRα10]]) where it acts as a [[receptor antagonist]].<ref name=IUPHAR>{{cite web|title=Nicotinic acetylcholine receptors: Introduction|url=http://www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=76&familyType=IC|website=IUPHAR Database|publisher=International Union of Basic and Clinical Pharmacology|access-date=1 September 2014|archive-date=29 June 2017|archive-url=https://web.archive.org/web/20170629235725/http://www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=76&familyType=IC}}</ref> Such antagonism results in mild [[analgesic|analgesia]].

====Central nervous system====
[[File:NicotineDopaminergic WP1602.png|thumb|right|class=skin-invert-image|Effect of nicotine on dopaminergic neurons]]
By binding to [[nicotinic acetylcholine receptor]]s in the brain, nicotine elicits its psychoactive effects and increases the levels of several [[neurotransmitter]]s in various brain structures&nbsp;– acting as a sort of "volume control".<ref name=Pomerleau1984>{{cite journal | vauthors = Pomerleau OF, Pomerleau CS | title = Neuroregulators and the reinforcement of smoking: towards a biobehavioral explanation | journal = Neuroscience and Biobehavioral Reviews | volume = 8 | issue = 4 | pages = 503–13 | year = 1984 | pmid = 6151160 | doi = 10.1016/0149-7634(84)90007-1 | s2cid = 23847303 }}</ref><ref>{{cite journal | vauthors = Pomerleau OF, Rosecrans J | title = Neuroregulatory effects of nicotine | journal = Psychoneuroendocrinology | volume = 14 | issue = 6 | pages = 407–23 | year = 1989 | pmid = 2560221 | doi = 10.1016/0306-4530(89)90040-1 | hdl = 2027.42/28190 | s2cid = 12080532 | hdl-access = free }}</ref> Nicotine has a higher affinity for nicotinic receptors in the brain than those in [[skeletal muscle]], though at toxic doses it can induce contractions and respiratory paralysis.<ref>{{cite book | vauthors = Katzung BG |title=Basic and Clinical Pharmacology |publisher=McGraw-Hill Medical |location=New York |year=2006 |pages=99–105 }}</ref> Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.<ref name="pmid19252481">{{cite journal | vauthors = Xiu X, Puskar NL, Shanata JA, Lester HA, Dougherty DA | title = Nicotine binding to brain receptors requires a strong cation-pi interaction | journal = Nature | volume = 458 | issue = 7237 | pages = 534–7 | date = March 2009 | pmid = 19252481 | pmc = 2755585 | doi = 10.1038/nature07768 | bibcode = 2009Natur.458..534X }}</ref> Nicotine is unusual in comparison to most drugs, as its profile changes from [[stimulant]] to [[sedative]] with increasing [[dose (biochemistry)|dosages]], a phenomenon known as "Nesbitt's paradox" after the doctor who first described it in 1969.<ref>Nesbitt P <!-- note: not [[Paul Nesbitt]] -->(1969). Smoking, physiological arousal, and emotional response. Unpublished doctoral dissertation, Columbia University.</ref><ref name=Parrott1998>{{cite journal | vauthors = Parrott AC | title = Nesbitt's Paradox resolved? Stress and arousal modulation during cigarette smoking | journal = Addiction | volume = 93 | issue = 1 | pages = 27–39 | date = January 1998 | pmid = 9624709 | doi = 10.1046/j.1360-0443.1998.931274.x | citeseerx = 10.1.1.465.2496 }}</ref> At very high doses it dampens [[neuronal activity]].<ref name=Wadgave2016>{{cite journal | vauthors = Wadgave U, Nagesh L | title = Nicotine Replacement Therapy: An Overview | journal = International Journal of Health Sciences | volume = 10 | issue = 3 | pages = 425–35 | date = July 2016 | pmid = 27610066 | pmc = 5003586 | doi=10.12816/0048737}}</ref> Nicotine induces both behavioral stimulation and anxiety in animals.<ref name="inchem" /> Research into nicotine's most predominant metabolite, [[cotinine]], suggests that some of nicotine's psychoactive effects are mediated by cotinine.<ref>{{cite journal | vauthors = Grizzell JA, Echeverria V | title = New Insights into the Mechanisms of Action of Cotinine and its Distinctive Effects from Nicotine | journal = Neurochemical Research | volume = 40 | issue = 10 | pages = 2032–46 | date = October 2015 | pmid = 24970109 | doi = 10.1007/s11064-014-1359-2 | s2cid = 9393548 }}</ref>

Nicotine activates nicotinic receptors (particularly [[α4β2 nicotinic receptor]]s, but also [[Alpha5 Nicotinic Acetylcholine Receptor|α5 nAChRs]]) on neurons that innervate the [[ventral tegmental area]] and within the [[mesolimbic pathway]] where it appears to cause the release of [[dopamine]].<ref name="Nicotine reinforcement and euphoria">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |year=2009 |publisher=McGraw-Hill Medical |location=New York |isbn=978-0-07-148127-4 |pages=369, 372–373 |edition=2nd }}</ref><ref name="Cholinergic-dopaminergic reward link" /> This nicotine-induced dopamine release occurs at least partially through activation of the [[cholinergic–dopaminergic reward link]] in the [[ventral tegmental area]].<ref name="Cholinergic-dopaminergic reward link">{{cite journal | vauthors = Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E | title = The role of the central ghrelin system in reward from food and chemical drugs | journal = Molecular and Cellular Endocrinology | volume = 340 | issue = 1 | pages = 80–7 | date = June 2011 | pmid = 21354264 | doi = 10.1016/j.mce.2011.02.017 | url = https://gupea.ub.gu.se/bitstream/2077/26318/1/gupea_2077_26318_1.pdf | quote = This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. | hdl = 2077/26318 | s2cid = 206815322 | access-date = 23 September 2019 | archive-date = 4 August 2020 | archive-url = https://web.archive.org/web/20200804221721/https://gupea.ub.gu.se/bitstream/2077/26318/1/gupea_2077_26318_1.pdf }}</ref><ref name="Picciotto2014">{{cite journal | vauthors = Picciotto MR, Mineur YS | title = Molecules and circuits involved in nicotine addiction: The many faces of smoking | journal = Neuropharmacology | volume = 76 | issue = Pt B | pages = 545–53 | date = January 2014 | pmid = 23632083 | pmc = 3772953 | doi = 10.1016/j.neuropharm.2013.04.028 | quote = Rat studies have shown that nicotine administration can decrease food intake and body weight, with greater effects in female animals (Grunberg et al., 1987). A similar nicotine regimen also decreases body weight and fat mass in mice as a result of β4* nAChR-mediated activation of POMC neurons and subsequent activation of MC4 receptors on second order neurons in the paraventricular nucleus of the hypothalamus (Mineur et al., 2011). | type = Review }}</ref> Nicotine can modulate the firing rate of the ventral tegmental area neurons.<ref name="Picciotto2014"/> These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of [[euphoria]];<ref name="Nicotine reinforcement and euphoria" /> however, mild euphoria from nicotine use can occur in some individuals.<ref name="Nicotine reinforcement and euphoria" /> Chronic nicotine use inhibits class I and II [[histone deacetylases]] in the [[striatum]], where this effect plays a role in nicotine addiction.<ref>{{cite journal | vauthors = Levine A, Huang Y, Drisaldi B, Griffin EA, Pollak DD, Xu S, Yin D, Schaffran C, Kandel DB, Kandel ER | title = Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine | journal = Science Translational Medicine | volume = 3 | issue = 107 | pages = 107ra109 | date = November 2011 | pmid = 22049069 | pmc = 4042673 | doi = 10.1126/scitranslmed.3003062 }}</ref><ref>{{cite journal | vauthors = Volkow ND | title = Epigenetics of nicotine: another nail in the coughing | journal = Science Translational Medicine | volume = 3 | issue = 107 | pages = 107ps43 | date = November 2011 | pmid = 22049068 | pmc = 3492949 | doi = 10.1126/scitranslmed.3003278 }}</ref>

====Sympathetic nervous system====
[[File:NicotineChromaffinCells WP1603.png|thumb|right|300px|class=skin-invert-image|Effect of nicotine on chromaffin cells]]
Nicotine also activates the [[sympathetic nervous system]],<ref>{{cite journal | vauthors = Yoshida T, Sakane N, Umekawa T, Kondo M | title = Effect of nicotine on sympathetic nervous system activity of mice subjected to immobilization stress | journal = Physiology & Behavior | volume = 55 | issue = 1 | pages = 53–7 | date = January 1994 | pmid = 8140174 | doi = 10.1016/0031-9384(94)90009-4 | s2cid = 37754794 }}</ref> acting via [[splanchnic nerves]] to the adrenal medulla, stimulating 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]].

====Adrenal medulla====
By binding to [[ganglion type nicotinic receptor]]s in the adrenal medulla, nicotine increases flow of [[adrenaline]] (epinephrine), a stimulating [[hormone]] and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of [[calcium]] through voltage-gated calcium channels. Calcium triggers the [[exocytosis]] of [[Chromaffin cell|chromaffin granules]] and thus the release of [[epinephrine]] (and norepinephrine) into the [[bloodstream]]. The release of [[epinephrine]] (adrenaline) causes an increase in [[heart rate]], [[blood pressure]] and [[breathing|respiration]], as well as higher [[blood glucose]] levels.<ref name="Marieb" >{{cite book  | vauthors = Marieb EN, Hoehn K |title=Human Anatomy & Physiology (7th Ed.) | url = https://archive.org/details/humananatomyphys00mari_4 | url-access = registration |publisher=Pearson |pages=? |year=2007 |isbn=978-0-8053-5909-1}}{{page needed|date=December 2013}}</ref>

===Pharmacokinetics===
[[File:Nicotine metabolism.png|thumb|upright=1.5|600px|class=skin-invert-image|Urinary metabolites of nicotine, quantified as average percentage of total urinary nicotine<ref>{{cite book| vauthors = Henningfield JE, Calvento E, Pogun S  |title=Nicotine Psychopharmacology |series=Handbook of Experimental Pharmacology |date=2009 |volume=192 |publisher=Springer|isbn=978-3-540-69248-5|pages=35, 37 |doi=10.1007/978-3-540-69248-5 }}</ref>]]
<!--Summarize this: "Nicotine undergoes first-pass metabolism in the liver, reducing the overall bioavailability of swallowed nicotine pills. A pill that could reliably produce high enough nicotine levels in the central nervous system would risk causing adverse gastrointestinal effects. To avoid this problem, nicotine replacement products are formulated for absorption through the oral or nasal mucosa (chewing gum, lozenges, sublingual tablets, inhalator, spray) or through the skin (transdermal patches)."<ref name="Cochrane NRT 2018" /> -->
As nicotine enters the body, it is distributed quickly through the [[blood]]stream and crosses the [[blood–brain barrier]] reaching the [[human brain|brain]] within 10–20 seconds after inhalation.<ref name="pmid12971663">{{cite journal | vauthors = Le Houezec J | title = Role of nicotine pharmacokinetics in nicotine addiction and nicotine replacement therapy: a review | journal = The International Journal of Tuberculosis and Lung Disease | volume = 7 | issue = 9 | pages = 811–9 | date = September 2003 | pmid = 12971663 }}</ref> The [[elimination half-life]] of nicotine in the body is around two hours.<ref>{{cite journal | vauthors = Kolli AR, Calvino-Martin F, Kuczaj AK, Wong ET, Titz B, Xiang Y, Lebrun S, Schlage WK, Vanscheeuwijck P, Hoeng J | title = Deconvolution of Systemic Pharmacokinetics Predicts Inhaled Aerosol Dosimetry of Nicotine | journal = European Journal of Pharmaceutical Sciences | volume = 180 | pages = 106321 | date = January 2023 | pmid = 36336278 | doi = 10.1016/j.ejps.2022.106321 | doi-access = free }}</ref><ref name="pmid7077531">{{cite journal | vauthors = Benowitz NL, Jacob P, Jones RT, Rosenberg J | title = Interindividual variability in the metabolism and cardiovascular effects of nicotine in man | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 221 | issue = 2 | pages = 368–72 | date = May 1982 | doi = 10.1016/S0022-3565(25)33068-5 | pmid = 7077531 }}</ref> Nicotine is primarily [[Excretion|excreted]] in [[urine]] and urinary concentrations vary depending upon [[urine flow rate]] and [[urine pH]].<ref name="inchem" />

The amount of nicotine absorbed by the body from smoking can depend on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. However, it has been found that the nicotine yield of individual products has only a small effect (4.4%) on the blood concentration of nicotine,<ref name="Russell_1980">{{cite journal | vauthors = Russell MA, Jarvis M, Iyer R, Feyerabend C | title = Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers | journal = British Medical Journal | volume = 280 | issue = 6219 | pages = 972–976 | date = April 1980 | pmid = 7417765 | pmc = 1601132 | doi = 10.1136/bmj.280.6219.972 }}</ref> suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".

Nicotine has a half-life of 1–2&nbsp;hours. [[Cotinine]] is an active metabolite of nicotine that remains in the blood with a half-life of 18–20&nbsp;hours, making it easier to analyze.<ref>{{cite journal| vauthors = Bhalala O |title=Detection of Cotinine in Blood Plasma by HPLC MS/MS |journal=MIT Undergraduate Research Journal |volume=8 |date=Spring 2003 |pages=45–50 |url=http://www.docstoc.com/docs/89426297/Detection-of-Cotinine-in-Blood-Plasma-by-HPLC-MS-MS |archive-url=https://web.archive.org/web/20131224105112/http://www.docstoc.com/docs/89426297/Detection-of-Cotinine-in-Blood-Plasma-by-HPLC-MS-MS |archive-date=24 December 2013 }}</ref>

Nicotine is [[metabolized]] in the [[liver]] by [[cytochrome P450]] enzymes (mostly [[CYP2A6]], and also by [[CYP2B6]]) and [[FMO3]], which selectively metabolizes (''S'')-nicotine. A major metabolite is [[cotinine]]. Other primary metabolites include nicotine ''N''-oxide, [[nornicotine]], nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.<ref name="pmid15734728">{{cite journal | vauthors = Hukkanen J, Jacob P, Benowitz NL | title = Metabolism and disposition kinetics of nicotine | journal = Pharmacological Reviews | volume = 57 | issue = 1 | pages = 79–115 | date = March 2005 | pmid = 15734728 | doi = 10.1124/pr.57.1.3 | s2cid = 14374018 }}</ref> Under some conditions, other substances may be formed such as [[myosmine]].<ref name="Petrick_2011">{{cite journal | vauthors = Petrick LM, Svidovsky A, Dubowski Y | title = Thirdhand smoke: heterogeneous oxidation of nicotine and secondary aerosol formation in the indoor environment | journal = Environmental Science & Technology | volume = 45 | issue = 1 | pages = 328–33 | date = January 2011 | pmid = 21141815 | doi = 10.1021/es102060v | bibcode = 2011EnST...45..328P | s2cid = 206939025 }}</ref><ref>{{cite news |title=''The danger of third-hand smoke: Plain language summary'' – Petrick et al., "Thirdhand smoke: heterogeneous oxidation of nicotine and secondary aerosol formation in the indoor environment" in ''Environmental Science & Technology'' |url=http://www.chromatographyonline.com/danger-third-hand-smoke |work=The Column |issue=3 |publisher=Chromatography Online |date=22 February 2011 |volume=7 |language=en}}</ref>

[[Glucuronidation]] and oxidative metabolism of nicotine to cotinine are both inhibited by [[menthol]], an additive to [[menthol cigarettes|mentholated cigarettes]], thus increasing the half-life of nicotine ''[[in vivo]]''.<ref>{{cite journal | vauthors = Benowitz NL, Herrera B, Jacob P | title = Mentholated cigarette smoking inhibits nicotine metabolism | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 310 | issue = 3 | pages = 1208–15 | date = September 2004 | pmid = 15084646 | doi = 10.1124/jpet.104.066902 | s2cid = 16044557 }}</ref>

===Metabolism===
Nicotine decreases hunger and as a consequence food consumption, alongside increasing [[energy expenditure]].<ref>{{cite journal |title=Nicotine' actions on energy balance: Friend or foe? |journal=[[Pharmacology & Therapeutics]] |date=March 2021 |volume=219}}</ref><ref name=HuYang2018>{{cite journal | vauthors = Hu T, Yang Z, Li MD | title = Pharmacological Effects and Regulatory Mechanisms of Tobacco Smoking Effects on Food Intake and Weight Control | journal = Journal of Neuroimmune Pharmacology | volume = 13 | issue = 4 | pages = 453–466 | date = December 2018 | pmid = 30054897 | doi = 10.1007/s11481-018-9800-y | s2cid = 51727199 |quote=Nicotine's weight effects appear to result especially from the drug's stimulation of α3β4 nicotine acetylcholine receptors (nAChRs), which are located on pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC), leading to activation of the melanocortin circuit, which is associated with body weight. Further, α7- and α4β2-containing nAChRs have been implicated in weight control by nicotine.}}</ref> The majority of research shows that nicotine reduces body weight, but some researchers have found that nicotine may result in weight gain under specific types of eating habits in animal models.<ref name=HuYang2018 /> Nicotine effect on weight appears to result from nicotine's stimulation of α3β4 nAChR receptors located in the [[Proopiomelanocortin|POMC neurons]] in the arcuate nucleus and subsequently the [[central melanocortin system|melanocortin system]], especially the melanocortin-4 receptors on second-order neurons in the paraventricular nucleus of the hypothalamus, thus modulating feeding inhibition.<ref name="Picciotto2014" /><ref name=HuYang2018/> POMC neurons are a precursor of the melanocortin system, a critical regulator of body weight and peripheral tissue such as skin and hair.<ref name=HuYang2018/>