Cotinine

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Cotinine
Cotinine2DACS.svg
Clinical data
Routes of
administration 		Oral, Smoked, Insufflation
ATC code
  • none
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life 20 hours
Identifiers
  • (5S)-1-methyl-5-(3-pyridyl)pyrrolidin-2-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.006.941 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H12N2O
Molar mass 176.219 g·mol−1
3D model (JSmol)
  • O=C2N(C)[C@H](c1cnccc1)CC2
  • InChI=1S/C10H12N2O/c1-12-9(4-5-10(12)13)8-3-2-6-11-7-8/h2-3,6-7,9H,4-5H2,1H3/t9-/m0/s1 Yes check.svgY
  • Key:UIKROCXWUNQSPJ-VIFPVBQESA-N Yes check.svgY
   (verify)

Cotinine is an alkaloid found in tobacco and is also the predominant metabolite of nicotine, [1] [2] typically used as a biomarker for exposure to tobacco smoke. Cotinine is currently being studied as a treatment for depression, post-traumatic stress disorder (PTSD), schizophrenia, Alzheimer's disease and Parkinson's disease. Cotinine was developed as an antidepressant as a fumaric acid salt, cotinine fumarate, to be sold under the brand name Scotine but it was never marketed. [1]

Contents

Similarly to nicotine, cotinine binds to, activates, and desensitizes neuronal nicotinic acetylcholine receptors, though at much lower potency in comparison. [2] [3] [4] [5] It has demonstrated nootropic and antipsychotic-like effects in animal models. [6] [7] Cotinine treatment has also been shown to reduce depression, anxiety, and fear-related behavior as well as memory impairment in animal models of depression, post-traumatic stress disorder, and Alzheimer's disease. [8] Nonetheless, treatment with cotinine in humans was reported to have no significant physiologic, subjective, or performance effects in one study, [9] though others suggest that this may not be the case. [10]

Because cotinine is the main metabolite to nicotine and has been shown to be pharmacologically active, it has been suggested that some of nicotine's effects in the nervous system may be mediated by cotinine and/or complex interactions with nicotine itself. [8] [11]

Pharmacology

A few studies indicate that the affinity for cotinine to the nicotinic acetylcholine receptors (nAChRs) is about 100 times lower than nicotine's. [10] Some work suggests that cotinine may be a positive allosteric modulator of α7 nAChRs. [12] [10] If this is true, cotinine would facilitate endogenous neurotransmission without directly stimulating nAChRs.

Pharmacokinetics

Cotinine has an in vivo half-life of approximately 20 hours, and is typically detectable for several days (up to one week) after the use of tobacco. The level of cotinine in the blood, saliva, and urine is proportionate to the amount of exposure to tobacco smoke, so it is a valuable indicator of tobacco smoke exposure, including secondary (passive) smoke. [13] People who smoke menthol cigarettes may retain cotinine in the blood for a longer period because menthol can compete with enzymatic metabolism of cotinine. [14] African American smokers generally have higher plasma cotinine levels than Caucasian smokers. [15] Males generally have higher plasma cotinine levels than females. [16] These systematic differences in cotinine levels were attributed to variation in CYP2A6 activity. [17] At steady state, plasma cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6. [17] Since CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genetic variation, cotinine accumulates in individuals with slower CYP2A6 activity, resulting in substantial differences in cotinine levels for a given tobacco exposure. [17]

Detection in body fluids

Drug tests can detect cotinine in the blood, urine, or saliva. Salivary cotinine concentrations are highly correlated to blood cotinine concentrations, and can detect cotinine in a low range, making it the preferable option for a less invasive method of tobacco exposure testing. Urine cotinine concentrations average four to six times higher than those in blood or saliva, making urine a more sensitive matrix to detect low-concentration exposure. [18]

Cotinine levels <10 ng/mL are considered to be consistent with no active smoking. Values of 10 ng/mL to 100 ng/mL are associated with light smoking or moderate passive exposure, and levels above 300 ng/mL are seen in heavy smokers — more than 20 cigarettes a day. In urine, values between 11 ng/mL and 30 ng/mL may be associated with light smoking or passive exposure, and levels in active smokers typically reach 500 ng/mL or more. In saliva, values between 1 ng/mL and 30 ng/mL may be associated with light smoking or passive exposure, and levels in active smokers typically reach 100 ng/mL or more. [19] Cotinine assays provide an objective quantitative measure that is more reliable than smoking histories or counting the number of cigarettes smoked per day. Cotinine also permits the measurement of exposure to second-hand smoke (passive smoking).

However, tobacco users attempting to quit with the help of nicotine replacement therapies (i.e., gum, lozenge, patch, inhaler, and nasal spray) will also test positive for cotinine, since all common NRT therapies contain nicotine that is metabolized in the same way. Therefore, the presence of cotinine is not a conclusive indication of tobacco use. [20] Cotinine levels can be used in research to explore the question of the amount of nicotine delivered to the user of e-cigarettes, where laboratory smoking machines have many problems replicating real-life conditions. [21]

Serum cotinine concentration has been used for decades in US population surveys of the Centers for Disease Control and Prevention to monitor tobacco use, to monitor levels and trends in exposure to environmental tobacco smoke, and to study the relationship between tobacco smoke and chronic health conditions. [22] An estimated one in four nonsmokers (approximately 58 million persons) were exposed to secondhand smoke during 2013-2014. Nearly 40% of children aged 3–11 years were exposed as were 50% of non-Hispanic blacks.

Related Research Articles

<span class="mw-page-title-main">Nicotine</span> Chemical stimulant produced by some plants

Nicotine is a naturally produced alkaloid in the nightshade family of plants and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is used for smoking cessation to relieve withdrawal symptoms. Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), except at two nicotinic receptor subunits where it acts as a receptor antagonist.

<span class="mw-page-title-main">Tobacco smoking</span> Practice of burning tobacco and breathing the resulting smoke

Tobacco smoking is the practice of burning tobacco and ingesting the resulting smoke. The smoke may be inhaled, as is done with cigarettes, or simply released from the mouth, as is generally done with pipes and cigars. The practice is believed to have begun as early as 5000–3000 BC in Mesoamerica and South America. Tobacco was introduced to Eurasia in the late 17th century by European colonists, where it followed common trade routes. The practice encountered criticism from its first import into the Western world onwards but embedded itself in certain strata of a number of societies before becoming widespread upon the introduction of automated cigarette-rolling apparatus.

<span class="mw-page-title-main">Smoking cessation</span> Process of discontinuing tobacco smoking

Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is addictive and can cause dependence. As a result, nicotine withdrawal often makes the process of quitting difficult.

<span class="mw-page-title-main">Passive smoking</span> Inhalation of tobacco smoke by persons other than the intended active smoker

Passive smoking is the inhalation of tobacco smoke, called passive smoke, secondhand smoke (SHS) or environmental tobacco smoke (ETS), by individuals other than the active smoker. It occurs when tobacco smoke diffuses into the surrounding atmosphere as an aerosol pollutant, which leads to its inhalation by nearby bystanders within the same environment. Exposure to secondhand tobacco smoke causes many of the same diseases caused by active tobacco smoking, although to a lower prevalence due to the reduced concentration of smoke that enters the airway. The health risks of secondhand smoke are a matter of scientific consensus, and have been a major motivation for anti-smoking laws in workplaces and indoor venues, including smoke-free restaurants, bars and night clubs, as well as some open public spaces.

<span class="mw-page-title-main">Nicotine replacement therapy</span> Treatment for tobacco use disorder

Nicotine replacement therapy (NRT) is a medically approved way to treat people with tobacco use disorder by taking nicotine through means other than tobacco. It is used to help with quitting smoking or stopping chewing tobacco. It increases the chance of quitting tobacco smoking by about 55%. Often it is used along with other behavioral techniques. NRT has also been used to treat ulcerative colitis. Types of NRT include the adhesive patch, chewing gum, lozenges, nose spray, and inhaler. The use of multiple types of NRT at a time may increase effectiveness.

<span class="mw-page-title-main">Chain smoking</span> Practice of smoking several cigarettes/cigars in succession

Chain smoking is the practice of smoking several cigarettes in succession, sometimes using the ember of a finishing cigarette to light the next. The term chain smoker often also refers to a person who smokes relatively constantly, though not necessarily chaining each cigarette. The term applies primarily to cigarettes, although it can be used to describe incessant cigar and pipe smoking as well as vaping. It is a common indicator of addiction.

<span class="mw-page-title-main">Nicotine poisoning</span> Medical condition

Nicotine poisoning describes the symptoms of the toxic effects of nicotine following ingestion, inhalation, or skin contact. Nicotine poisoning can potentially be deadly, though serious or fatal overdoses are rare. Historically, most cases of nicotine poisoning have been the result of use of nicotine as an insecticide. More recent cases of poisoning typically appear to be in the form of Green Tobacco Sickness, or due to unintended ingestion of tobacco or tobacco products or consumption of nicotine-containing plants.

<span class="mw-page-title-main">Health effects of tobacco</span> Circumstances, mechanisms, and factors of tobacco consumption on human health

Tobacco products, especially when smoked or used orally, have negative effects on human health, and concerns about these effects have existed for a long time. Research has focused primarily on cigarette smoking.

NicVAX is an experimental conjugate vaccine intended to reduce or eliminate physical dependence to nicotine. According to the U.S. National Institute of Drug Abuse, NicVAX can potentially be used to inoculate against nicotine addiction. This proprietary vaccine is being developed by Nabi Biopharmaceuticals of Rockville, MD. with the support from the U.S. National Institute on Drug Abuse. NicVAX consists of the hapten 3'-aminomethylnicotine which has been conjugated (attached) to Pseudomonas aeruginosa exotoxin A.

<span class="mw-page-title-main">Sidestream smoke</span> Smoke directly released into the air from a burning cigarette, cigar, or smoking pipe

Sidestream smoke is smoke which goes into the air directly from a burning cigarette, cigar, or smoking pipe. Sidestream smoke is the main component of second-hand smoke (SHS), also known as Environmental Tobacco Smoke (ETS) or passive smoking. The relative quantity of chemical constituents of sidestream smoke are different from those of directly inhaled ("mainstream") smoke, although their chemical composition is similar. Sidestream smoke has been classified as a Class A carcinogen by the U.S. Environmental Protection Agency.


Tobacco harm reduction (THR) is a public health strategy to lower the health risks to individuals and wider society associated with using tobacco products. It is an example of the concept of harm reduction, a strategy for dealing with the use of drugs. Tobacco smoking is widely acknowledged as a leading cause of illness and death, and reducing smoking is vital to public health.

<span class="mw-page-title-main">Electronic cigarette</span> Device that vaporizes a liquid nicotine solution for inhalation

An electronic cigarette (e-cigarette) or vape is a device that simulates tobacco smoking. It consists of an atomizer, a power source such as a battery, and a container such as a cartridge or tank filled with liquid. Instead of smoke, the user inhales vapor. As such, using an e-cigarette is often called "vaping". The atomizer is a heating element that vaporizes a liquid solution called e-liquid, which quickly cools into an aerosol of tiny droplets, vapor and air. E-cigarettes are activated by taking a puff or pressing a button. Some look like traditional cigarettes, and most kinds are reusable. The vapor mainly comprises propylene glycol and/or glycerin, usually with nicotine and flavoring. Its exact composition varies, and depends on several things including user behavior.

<span class="mw-page-title-main">Nicotine dependence</span> Chronic disease

Nicotine dependence is a state of dependence upon nicotine. Nicotine dependence is a chronic, relapsing disease defined as a compulsive craving to use the drug, despite social consequences, loss of control over drug intake, and emergence of withdrawal symptoms. Tolerance is another component of drug dependence. Nicotine dependence develops over time as a person continues to use nicotine. The most commonly used tobacco product is cigarettes, but all forms of tobacco use and e-cigarette use can cause dependence. Nicotine dependence is a serious public health problem because it leads to continued tobacco use, which is one of the leading preventable causes of death worldwide, causing more than 8 million deaths per year.

<span class="mw-page-title-main">Ventilated cigarette</span> Cigarette that delivers a lower concentration of chemicals than regular cigarettes

Ventilated cigarettes are considered to have a milder flavor than regular cigarettes. These cigarette brands may be listed as having lower levels of tar ("low-tar"), nicotine, or other chemicals as "inhaled" by a "smoking machine". However, the scientific evidence is that switching from regular to light or low-tar cigarettes does not reduce the health risks of smoking or lower the smoker's exposure to the nicotine, tar, and carcinogens present in cigarette smoke.

Schizophrenia and tobacco smoking have been historically associated. Smoking is known to harm the health of people with schizophrenia, and to negatively affect their cognition.

The use of electronic cigarettes (vaping) carries health risks. The risk depends on the fluid and varies according to design and user behavior. In the United Kingdom, vaping is considered by some to be around 95% less harmful than tobacco after a controversial landmark review by Public Health England.

<span class="mw-page-title-main">Composition of electronic cigarette aerosol</span>

The chemical composition of the electronic cigarette aerosol varies across and within manufacturers. Limited data exists regarding their chemistry. However, researchers at Johns Hopkins University analyzed the vape clouds of popular brands such as Juul and Vuse, and found "nearly 2,000 chemicals, the vast majority of which are unidentified."

Jed Eugene Rose is an American academic professor, inventor and researcher in the field of nicotine and smoking cessation. Rose is presently the President and CEO of the Rose Research Center, LLC in Raleigh, North Carolina. Additionally, he is the Director of the Duke Center for Smoking Cessation at Duke University Medical Center.

Exposure to nicotine, from conventional or electronic cigarettes during adolescence can impair the developing human brain. E-cigarette use is recognized as a substantial threat to adolescent behavioral health. The use of tobacco products, no matter what type, is almost always started and established during adolescence when the developing brain is most vulnerable to nicotine addiction. Young people's brains build synapses faster than adult brains. Because addiction is a form of learning, adolescents can get addicted more easily than adults. The nicotine in e-cigarettes can also prime the adolescent brain for addiction to other drugs such as cocaine. Exposure to nicotine and its great risk of developing an addiction, are areas of significant concern.

<span class="mw-page-title-main">Smoker's macrophages</span>

Smoker’s macrophages are alveolar macrophages whose characteristics, including appearance, cellularity, phenotypes, immune response, and other functions, have been affected upon the exposure to cigarettes. These altered immune cells are derived from several signaling pathways and are able to induce numerous respiratory diseases. They are involved in asthma, chronic obstructive pulmonary diseases (COPD), pulmonary fibrosis, and lung cancer. Smoker’s macrophages are observed in both firsthand and secondhand smokers, so anyone exposed to cigarette contents, or cigarette smoke extract (CSE), would be susceptible to these macrophages, thus in turns leading to future complications.

References

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  3. ↑ Anderson DJ, Arneric SP (March 1994). "Nicotinic receptor binding of [3H]cytisine, [3H]nicotine and [3H]methylcarbamylcholine in rat brain". European Journal of Pharmacology. 253 (3): 261–267. doi:10.1016/0014-2999(94)90200-3. PMID   8200419.
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  9. ↑ Hatsukami DK, Grillo M, Pentel PR, Oncken C, Bliss R (August 1997). "Safety of cotinine in humans: physiologic, subjective, and cognitive effects". Pharmacology, Biochemistry, and Behavior. 57 (4): 643–650. doi:10.1016/s0091-3057(97)80001-9. PMID   9258989. S2CID   13460499.
  10. 1 2 3 Moran VE (October 2012). "Cotinine: Beyond that Expected, More than a Biomarker of Tobacco Consumption". Frontiers in Pharmacology. 3: 173. doi: 10.3389/fphar.2012.00173 . PMC   3467453 . PMID   23087643.
  11. ↑ Crooks PA, Dwoskin LP (October 1997). "Contribution of CNS nicotine metabolites to the neuropharmacological effects of nicotine and tobacco smoking". Biochemical Pharmacology. 54 (7): 743–753. doi:10.1016/s0006-2952(97)00117-2. PMID   9353128.
  12. ↑ Young GT, Zwart R, Walker AS, Sher E, Millar NS (September 2008). "Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site". Proceedings of the National Academy of Sciences of the United States of America. 105 (38): 14686–14691. doi: 10.1073/pnas.0804372105 . PMC   2535569 . PMID   18791069.
  13. ↑ Florescu A, Ferrence R, Einarson T, Selby P, Soldin O, Koren G (February 2009). "Methods for quantification of exposure to cigarette smoking and environmental tobacco smoke: focus on developmental toxicology". Therapeutic Drug Monitoring. 31 (1): 14–30. doi:10.1097/FTD.0b013e3181957a3b. PMC   3644554 . PMID   19125149.
  14. ↑ Ham B (December 2002). "Signs of smoking linger longer in menthol smokers". Center for the Advancement of Health. Science Blog. Archived from the original on 26 June 2010. Retrieved 17 March 2010.
  15. ↑ Wagenknecht LE, Cutter GR, Haley NJ, Sidney S, Manolio TA, Hughes GH, Jacobs DR (September 1990). "Racial differences in serum cotinine levels among smokers in the Coronary Artery Risk Development in (Young) Adults study". American Journal of Public Health. 80 (9): 1053–1056. doi:10.2105/ajph.80.9.1053. PMC   1404871 . PMID   2382740.
  16. ↑ Gan WQ, Cohen SB, Man SF, Sin DD (August 2008). "Sex-related differences in serum cotinine concentrations in daily cigarette smokers". Nicotine & Tobacco Research. 10 (8): 1293–1300. doi:10.1080/14622200802239132. PMID   18686176.
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  18. ↑ Avila-Tang, Erika et al (September 2012). "Assessing secondhand smoke using biological markers" - Nicotine and metabolites . Retrieved 10 June 2013
  19. ↑ Jarvis MJ, Fidler J, Mindell J, Feyerabend C, West R (September 2008). "Assessing smoking status in children, adolescents and adults: cotinine cut-points revisited". Addiction. 103 (9): 1553–1561. doi:10.1111/j.1360-0443.2008.02297.x. PMID   18783507.
  20. ↑ Hewitt D. "Reasons for False Positives for Nicotine on a Blood Test". LiveStrong.com. Retrieved 21 October 2011.
  21. ↑ McNeil A, Brose LS, Calder R, Hitchman SC, Hajek P, McRobbie H (2015). "E-cigarettes: an evidence update. A report commissioned by Public Health England" (PDF). Gov.uk. UK: Public Health England. pp. 70–75. Retrieved 20 August 2015.
  22. ↑ Tsai J, Homa DM, Gentzke AS, Mahoney M, Sharapova SR, Sosnoff CS, et al. (December 2018). "Exposure to Secondhand Smoke Among Nonsmokers - United States, 1988-2014". MMWR. Morbidity and Mortality Weekly Report. 67 (48): 1342–1346. doi: 10.15585/mmwr.mm6748a3 . PMC   6329485 . PMID   30521502.
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