Tobacco Cessation and Substance Abuse Treatment in Women’s Healthcare

2. Physiology of Nicotine

Paul Dietz 


Department of Obstetrics and Gynecology, Charleston Area Women’s Medicine Center, Medical Center, Charleston, WV, USA

Paul Dietz



TobaccoNicotineNicotine physiology and biochemistryNicotinic receptors


Nicotine is a stimulating drug used both medically and recreationally in the United States. It is one of the most addictive agents known to science and a major contributing factor to the addictive properties of tobacco use. The nicotine content of popular American-brand cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.78 % per year between the years of 1998 and 2005 [1].


First introduced to Western culture in Europe in 1559, nicotine is named after the tobacco plant Nicotiana tabacum, which received its name from the French ambassador to Portugal, Jean Nicot de Villemain. In 1560, de Villemain, sent tobacco and seeds to Paris as a gift to French King Henry II, who advocated its medicinal use. Luis de Gois, a Portuguese colonist from Sao Paulo, brought the tobacco and seeds to de Villemain from Brazil. Tobacco use was believed to protect against illness, most notably the plague [2].

After its introduction, tobacco was not only smoked recreationally, but also used as an insecticide. After World War II, over 2500 tons of nicotine insecticide were used around the world, but its use has significantly declined since the 1980s with the availability of other agents being cheaper and less harmful to mammals [3]. The United States currently prohibits the use of nicotine as a pesticide for organic farming [45]. The EPA received a request in 2008 to cancel the registration of the last nicotine pesticide in the United States [6]. This request was formally granted and since January 2014, this pesticide has not been available for sale [7].

Nicotine was first isolated from the tobacco plant in 1828 by physician Wilhelm Heinrich Posselt and chemist Karl Ludwig Reimann in Germany and was considered a poison [89]. The empirical chemical formula was described by Melsens in 1843 and its structure discovered by Adolf Pinner and Richard Wolffenstein in 1893 [910]. It was first synthesized in 1904 by Amé Pictet and A. Rotschy [10].


Nicotine is powerful parasympathomimetic alkaloid found in the nightshade family of plants (Solanaceae) and considered a stimulant drug [11]. It is produced in the roots of and accumulates in the leaves of the nightshade family of plants. Specifically, nicotine is found in the leaves of Nicotiana tabacum and Nicotiana rustica in amounts near 15 %, as well as in Duboisia hopwoodii and Asclepias syriaca[12].

Nicotine is a hygroscopic, colorless oily liquid that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its base form between 60 and 210 °C. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Its flash point is 95 °C and its auto-ignition temperature is 244 °C [13].

Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of [α]D = −166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (−)-nicotine. (−)-nicotine is more toxic than (+)-nicotine [14]. The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride and sulphate salts become optically inactive if heated in a closed vessel above 180 °C. On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3), and methylamine [15].

As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 s after inhalation [16]. The elimination half-life of nicotine in the body is around 2 h [17].

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 [18], 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 acts on nicotinic acetylcholine receptors, specifically the α3β4 ganglion type nicotinic receptor, present in the autonomic ganglia and adrenal medulla, and a central nervous system (CNS) α4β2 nicotinic receptor. In small concentrations, nicotine increases the activity of these cholinergic receptors and indirectly on a variety of other neurotransmitters such as dopamine.

Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine. Other primary metabolites include nicotine N′-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine, and nicotine glucuronide [19]. Under some conditions, other substances may be formed such as myosmine [20]. 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 [21].

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 [2223]. Nicotine use is not regulated in competitive sports programs [24].

Physical and Chemical Properties

Nicotine is a hygroscopic, colorless oily liquid that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its base form between 60 and 210 °C. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Its flash point is 95 °C and its auto-ignition temperature is 244 °C [13]. Nicotine is readily volatile (vapor pressure 5.5 Pa at 25 °C) and dibasic (Kb1 = 1 × 10−6Kb2 = 1 × 10−11) [12].

Nicotine is a natural product of tobacco, occurring in the leaves in a range of 0.5–7.5 % depending on variety [25]. Nicotine also naturally occurs in smaller amounts in plants from the family Solanaceae(such as potatoes, tomatoes, and eggplant) [26]. The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ1-pyrrollidium cation [2728]. Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ1-pyrrollidium cation.

The NAD pathway in the genus nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase. This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase to give quinolinic acid. Quinolinic acid then reacts with phosphoribosyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase to form niacin mononucleotide. The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.

The N-methyl-Δ1-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase. N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.

The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ1-pyrrollidium cation to form enantiomerically pure (−)-nicotine [29].


While acute/initial nicotine intake causes activation of nicotine receptors, chronic low doses of nicotine use leads to desensitization of nicotine receptors (due to the development of tolerance) and results in an antidepressant effect, with research showing low-dose nicotine patches being an effective treatment of major depressive disorder in non-smokers [30]. However, the original research concluded that: “Nicotine patches produced short-term improvement of depression with minor side effects. Because of nicotine’s high risk to health, nicotine patches are not recommended for clinical use in depression” [31].

Though tobacco smoking is associated with an increased risk of Alzheimer’s disease [32], there is evidence that nicotine itself has the potential to prevent and treat Alzheimer’s disease [33].

Research into nicotine’s most predominant metabolite, cotinine, suggests that some, if not most, of nicotine’s psychoactive effects may actually be mediated by complex interactions with cotinine, or perhaps even by cotinine alone rather than strictly by nicotine as conventionally thought [3435].

Little research is available in humans but animal research suggests there is potential benefit from nicotine in Parkinson’s disease [36]. There is tentative evidence that nicotinamides may improve depression [37].



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