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Nicotine acts on the [[nicotinic acetylcholine receptor]]s, specifically the [[ganglion type nicotinic receptor]] and one [[CNS type nicotinic receptor]]. The former is present e.g. in the [[adrenal medulla]] and the latter in the CNS. In small concentrations it increases the activity of these receptors.
Nicotine acts on the [[nicotinic acetylcholine receptor]]s, specifically the [[ganglion type nicotinic receptor]] and one [[CNS type nicotinic receptor]]. The former is present e.g. in the [[adrenal medulla]] and the latter in the CNS. In small concentrations it increases the activity of these receptors.


====In adrenal medulla====
By binding to [[ganglion type nicotinic receptor]]s the adrenal medulla nicotine increases flow of [[adrenaline]] (epinephrine), a stimulating [[hormone]]. 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 adrenaline causes an increase in [[heart rate]], [[blood pressure]] and [[respiration]], as well as higher [[blood glucose]] levels <ref> Human Anatomy and Physiology. Elaine N Marieb & Katja Hoehn. 2007, Pearson Education. </ref>

[[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|blocking]] of the nicotinic acetylcholine receptor, which is the reason for its [[Nicotine Poisoning|toxicity]] and its effectiveness as an [[insecticide]].{{Fact|date=February 2007}}


====In CNS====
====In CNS====

Revision as of 13:57, 18 May 2008

This article is about the chemical compound. For other uses, see Nicotine (disambiguation).
Nicotine
Clinical data
Dependence
liability		Medium to high
Routes of
administration		Smoked (as tobacco), Insufflated (as snuff), Chewed
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life2 hours
Identifiers
  • (S)-3-(1-Methyl-2-pyrroli- dinyl)pyridine
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard100.000.177 Edit this at Wikidata
Chemical and physical data
FormulaC10H14N2
Molar mass162.26 g/mole g·mol−1
3D model (JSmol)
Density1.01 g/cm3
Melting point−79 °C (−110 °F)
Boiling point247 °C (477 °F)
  • C1=CC=NC=C1[C@@H]2CCCN2C

Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae), predominantly in tobacco and coca, and in lower quantities in tomato, potato, eggplant (aubergine), and green pepper. Nicotine has been found to constitute approximately 0.6 - 3.0% of dry weight of tobacco,[2] with biosynthesis taking place in the roots, and accumulating in the leaves. It functions as an antiherbivore chemical, 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 pharmacological and behavioral characteristics that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine.[3]

History and name

Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after Jean Nicot, French ambassador in Portugal, who sent tobacco and seeds from Brazil to Paris in 1560 and promoted their medicinal use. Nicotine was first isolated from the tobacco plant in 1828 by German chemists Posselt & Reimann.[citation needed] Its chemical empirical formula was described by Melsens in 1843,[4] and it was first synthesized by A. Pictet and Crepieux in 1893.[citation needed]

­For thousands of years, people have smoked or chewed the leaves of the tobacco plant, Nicotiana tabacum. Tobacco was first found and cultivated in the Americas, perhaps as early as 6000 B.C. Following the discovery and colonization of North and South America, the tobacco plant was exported widely, to continental Europe and the rest of the civilized world. Even in its early days, tobacco use was controversial. Some hailed its medicinal properties. For example, tobacco was supposed to be protective against the ravages of the Plague. As early as the 1600s, people speculated that there might be a link between diseases, like cancer, and tobacco use.[citation needed] Since then, modern research methods have provided evidence of this link, and public service announcements that warn of tobacco's health risks and addictive nature are seen regularly on several media.

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 308K (35°C or 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 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[5]. 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, 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, specifically the ganglion type nicotinic receptor and one CNS type nicotinic receptor. The former is present e.g. in the adrenal medulla and the latter in the CNS. In small concentrations it increases the activity of these receptors.

In adrenal medulla

By binding to ganglion type nicotinic receptors the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a stimulating hormone. 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 granules and thus the release of epinephrine (and norepinephrine) into the bloodstream.

The release of adrenaline causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels [6]

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 blocking of the nicotinic acetylcholine receptor, which is the reason for its toxicity and its effectiveness as an insecticide.[citation needed]

In CNS

By binding to CNS type nicotinic receptors, nicotine increases dopamine levels in the reward circuits of the brain. In this way, it activates the reward system and generates feelings of pleasure.

Furthermore, nicotine activates the sympathetic nervous system[citation needed], 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.

Studies have shown that other ingredients in inhaled tobacco smoke (as opposed to pure nicotine) inhibit the production of monoamine oxidase (MAO)[7], an enzyme responsible for breaking down monoaminergic neurotransmitters, such as dopamine, in the brain.


Dependence

See also: Smoking cessation

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. [8]

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)[citation needed]. 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.[citation needed] 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.[9]

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.[10]

There is significant anecdotal evidence from pharmacist vendors, via their customers, about addiction to nicotine gum or nicotine patches.

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.[11] [12] This makes it an extremely deadly poison. It is more toxic than many other alkaloids such as cocaine, which has an LD50 of 95.1 mg/kg when administered to mice. Spilling liquid nicotine on human skin could result in death.[13]

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. Its teratogenic 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 cholinergic activity it causes have been shown to impede apoptosis[citation needed], 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.

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).[14]

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-medicate with nicotine. [15] [16] More recent research has found the reverse, that it is a risk factor without long-term benefit, used only for its short term effects.[17] However, research on nicotine as administered through a patch or gum is ongoing.

Nicotine and oxidative stress

Nicotine is detoxified by the cytochrome p450 in liver. Recently it has been published that it produces free radicals in this reaction. Study on bidi workers carried out in Solapur district of Maharashtra state of India revealed that nicotine may be the potent free radical generetor. Sanjay Swami et. al. also suggested the carcinogenic effect of nicotine may be due to its free radical generating potential.[18]

Link to circulatory disease

Nicotine has very powerful[specify] effects on arteries throughout the body. Nicotine is a stimulant, speeding up the heart by about 20 beats per minute with every cigarette; it raises blood pressure, and is a vasoconstrictor, making it harder for the heart to pump through the constricted arteries. It causes the body to release its stores of fat and cholesterol into the blood.

Nicotine increases the risk of blood clots significantly. [citation needed] If blood clots in an artery, blood flow is reduced or halted, and tissue loses its source of oxygen and nutrients and dies in minutes.

Peripheral circulation, arteries going to the extremities, are also highly susceptible to the vasoconstrictor effects of nicotine as well as the increased risk of clots and clogging.[citation needed]

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"[19]. 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).[19] 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.[20][21] Smoking also appears to interfere with development of Kaposi's sarcoma,[22] breast cancer among women carrying the very high risk BRCA gene,[23] preeclampsia,[24] and atopic disorders such as allergic asthma.[25] 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.[26]

With regard to neurological diseases, 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.[27] Many such papers regarding Alzheimer's disease[28] and Parkinson's Disease[29] have been published.

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.[30]

Nicotine and its metabolites are being researched for the treatment of a number of disorders, including ADHD, Schizophrenia and Parkinson's Disease. [31]

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 [32] 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. [33]

See also

External links

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ "Smoking and Tobacco Control Monograph No. 9" (PDF).
  3. ^ American Heart Association and Nicotine addiction.
  4. ^ Melsens (1844). "Ueber das Nicotin". Journal für Praktische Chemie. 32 (1): 372–377. doi:10.1002/prac.18440320155.
  5. ^ "Interindividual variability in the metabolism and cardiovascular effects of nicotine in man".
  6. ^ Human Anatomy and Physiology. Elaine N Marieb & Katja Hoehn. 2007, Pearson Education.
  7. ^ Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, MacGregor R, Alexoff D, Wolf AP, Warner D, Cilento R, Zezulkova I (1998). "Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition". Journal of addictive diseases. PMID 9549600.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ NIDA - Research Report Series - Tobacco Addiction - Extent, Impact, Delivery, and Addictiveness
  9. ^ NIDA - Publications - NIDA Notes - Vol. 19, No. 2 - Research Findings
  10. ^ Nolley E.P. & Kelley B.M. "Adolescent reward system perseveration due to nicotine: Studies with methylphenidate.," Neurotoxicol Teratol., 2006 Oct 4
  11. ^ Okamoto M., Kita T., Okuda H., Tanaka T., Nakashima T. (1994). "Effects of aging on acute toxicity of nicotine in rats". Pharmacol Toxicol. 75 (1): 1–6.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ IPCS INCHEM
  13. ^ [1] "Interview with Prof Thoedore Slotkin"
  14. ^ Machaalani et al. (2005) "Effects of postnatal nicotine exposure on apoptotic markers in the developing piglet brain"
  15. ^ Schizophr. Res. 2002
  16. ^ Am. J. Psychiatry 1995
  17. ^ Br. J. Psychiatry 2005
  18. ^ [2]
  19. ^ a b Cohen, David J. (2001). "Impact of Smoking on Clinical and Angiographic Restenosis After Percutaneous Coronary Intervention". Circulation. 104: 773. Retrieved 2006-11-06. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  20. ^ Longmore, M., Wilkinson, I., Torok, E. Oxford Handbook of Clinical Medicine (Fifth Edition) p. 232
  21. ^ Green, JT (November, 2000). "Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis". Aliment Pharmacol Ther. 14 (11): 1429–1434. PMID: 11069313. Retrieved 2006-11-06. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  22. ^ "Smoking Cuts Risk of Rare Cancer". UPI. March 29, 2001. Retrieved 2006-11-06. {{cite news}}: Cite has empty unknown parameter: |coauthors= (help)
  23. ^ Recer, Paul (May 19, 1998). "Cigarettes May Have an Up Side". AP. Retrieved 2006-11-06. {{cite news}}: Cite has empty unknown parameter: |coauthors= (help)
  24. ^ Lain, Kristine Y. (November 1991). "Urinary cotinine concentration confirms the reduced risk of preeclampsia with tobacco exposure". American Journal of Obstetrics and Gynecology. 181 (5): 908–14. PMID: 11422156. Retrieved 2006-11-06. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); line feed character in |coauthors= at position 79 (help)
  25. ^ Hjern, A (June 2001). "Does tobacco smoke prevent atopic disorders? A study of two generations of Swedish residents". Clin Exp Allergy. 31 (6): 908–914. PMID: 11422156. Retrieved 2006-11-06. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  26. ^ Lisa Melton (June 2006). "Body Blazes". Scientific American: p.24. {{cite journal}}: |pages= has extra text (help)
  27. ^ Fratiglioni, L (August 2000). "Smoking and Parkinson's and Alzheimer's disease: review of the epidemiological studies". Behav Brain Res. 113 (1–2): 117–120. PMID: 10942038. Retrieved 2006-11-06. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  28. ^ Thompson, Carol. "Alzheimer's disease is associated with non-smoking". Retrieved 2006-11-06. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  29. ^ Thompson, Carol. "Parkinson's disease is associated with non-smoking". Retrieved 2006-11-06. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  30. ^ "Nicotine as an antiepileptic agent in ADNFLE: An n-of-one study".
  31. ^ "Attention-Deficit Hyperactivity Disorder". Reuters Health. Reuters. 2001. Archived from the original on 2006-04-26. Nicotine improves ADHD symptoms. Although such findings should certainly not encourage anyone to smoke, some studies are focusing on benefits of nicotine therapy in adults with ADHD. {{cite web}}: Unknown parameter |month= ignored (help)
  32. ^ NIH, online at [3]
  33. ^ Cigarette Smoking and Weight Loss in Nursing Home Residents [4]

Further reading

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