|Natural substance nicotine|
|Molecular formula||C 10 H 14 N 2|
colorless to brownish oily liquid with a tobacco ( pyridine ) like odor
|External identifiers / databases|
Means of smoking cessation
|Molar mass||162.23 g mol −1|
1.01 g cm −3
−79 ° C
246 ° C
5.6 Pa (20 ° C)
|pK s value||
easily in water , ethanol , diethyl ether and chloroform , miscible with many organic solvents
1.5282 (20 ° C)
Switzerland: 0.07 ml m −3 or 0.5 mg m −3
|As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . Refractive index: Na-D line , 20 ° C|
Nicotine , also known as nicotine , is an alkaloid naturally occurring in the leaves of the tobacco plant and, in lower concentrations, in other nightshade plants , which has stimulating or paralyzing effects on ganglia of the autonomic nervous system . Nicotine derivatives are rarely referred to as nicotinoids ; usually the synthetic neonicotinoids used as insecticides are meant.
The tobacco plant was ritually consumed in America by the Maya since the 10th century at the latest. In 1492, Christopher Columbus was presented with dried tobacco on his arrival in the New World . The ambassador of France to Portugal, Jean Nicot de Villemain, sent seeds of Nicotiana tabacum to the French king in 1560 , promoting their medicinal use. Nicotine was first isolated under the name Nicotianine in 1828 by the chemist Karl Ludwig Reimann and the physician Christian Wilhelm Posselt as part of a competition at the University of Heidelberg ; they chose the name after Jean Nicot. The chemical structure was clarified by Adolf Pinner and Richard Wolffenstein . In 1851, the Belgian chemist Jean Servais Stas proved that Hippolyte Visart de Bocarmé had poisoned his victim Gustave Fougnies with nicotine.
Nicotine is mainly produced as a secondary metabolite in significant quantities by various species of the genus Nicotiana (especially Nicotiana tabacum and Nicotiana rustica ) and other genera of the nightshade family (for example Duboisia hopwoodii and Asclepias syriaca ) . Nicotine is also found in very low concentrations in some other species of the family and the closely related bindweed family . Outside of these families, the substance occurs sporadically in lower concentrations, for example in the genus Erythroxylum from the redwood family . Nicotine is also found in smaller quantities in various nightshade plants such as potatoes , tomatoes and eggplant . Since nicotine is formed almost exclusively in the roots of the tobacco plant, nicotine-free tobacco can be made from tobacco plants that have been grafted onto the roots of tomato plants .
Nicotine content of tobacco products and substitutes
The nicotine content of the smoke of a cigarette is measured in a standardized smoking machine about 0.6 to 2.4 milligrams , of which 0.9 to 1.2 mg are ingested by the smoker . The nicotine content in dried tobacco is 0.6 to 2.9 percent of the dry matter . It should be noted, however, that the indication of the amount of nicotine per cigarette has only an extremely limited information quality, since the content of nicotine ingested varies depending on the type of inhalation and the construction of the cigarette. Furthermore, it is essential that a smoker does not necessarily consume less nicotine per day by switching to nicotine-reduced cigarettes, as many smokers pull on these more and longer. The cigarette itself contains significantly more nicotine (approx. 12 mg, see section on toxic effects ), which when smoked, however, simply burns for the most part before it is inhaled.
A typical nicotine patch releases about one milligram of nicotine per hour over 16 or 24 hours.
The snuff can be a daily Nicotinaufnahmemenge similar to that of a heavy smoker result (20 to 60 mg).
Nicotiana , the Latin name for the genus of tobacco plants , produce nicotine in their roots. When the plant ripens, the substance migrates into the leaves, where it reaches a mass fraction of 0.5 to 7.5 percent. The nicotine serves in the plant parts, especially in the leaves, to ward off predators of the plant , provided that the predator has a nervous system with nicotinic acetylcholine receptor . Nicotine and nicotinoids are powerful insecticides .
Pure nicotine is a colorless, oily liquid at room temperature that quickly turns brown when exposed to air. It is a water-soluble base and volatile in water vapor.
|Enantiomers of nicotine|
|Surname||( S ) nicotine||( R ) nicotine|
(-) - nicotine
(+) - nicotine
|22083-74-5 (mixture of isomers)|
|623-834-2 (mixture of isomers)|
|ECHA info card||100.211.968|
|100.152.478 (mixture of isomers)|
|942 (mixture of isomers)|
|Q12144 (mixture of isomers)|
The chemical structure of nicotine, which is based on two connected rings made of pyridine and pyrrolidine , was elucidated by Adolf Pinner and Richard Wolffenstein . Nicotine has a stereogenic center , it is chiral . Only ( S ) -nicotine occurs in nature . Natural nicotine is in the same configuration as L- proline at the center of chirality . The enantiomer ( R ) -nicotine has no pathophysiological significance. Whenever the term 'nicotine' is used in this article, it always means ( S ) -nicotine.
In tobacco plants, nicotine is synthesized from nicotinic acid and L- ornithine in the following steps:
- 1,4-Reduction of the pyridine ring of nicotinic acid to 1,4-dihydronicotinic acid , using NADPH as a reducing agent.
- Decarboxylation of 1,4-dihydronicotinic acid to 1,2-dihydropyridine .
- Formation of putrescine from L- ornithine.
- Synthesis of an N -methylpyrrolinium cation from putrescine.
Reaction to finished nicotine:
1,4-Dihydronicotinic acid (an enamine) reacts with the N -methylpyrrolinium cation (an iminium ion) via an intermediate and subsequent reoxidation of the dihydropyridine ring with NADP + to give nicotine.
The reliable qualitative and quantitative determination of nicotine in the various test materials is possible after appropriate sample preparation by coupling gas chromatography or HPLC with mass spectrometry . The headspace technique is also used in special cases.
Biochemical meaning and effect
The absorption of nicotine takes place differently depending on the pH value. Cigar tobacco is made from leaves that are harvested when they are not fully ripe. As a result, the carbohydrates in the leaf are largely broken down during drying and fermentation, so that mainly basic protein breakdown products are present in the smoke. The smoke from cigars therefore usually has a pH value of 8.0–8.6. In cigarette tobacco, on the other hand, nicotine is partly present in a protonated form in salt-bound form, with a smoke pH range of 6.3 to 5.6. The absorption of free nicotine from alkaline smoke occurs well through the mucous membranes. About 2 - 5% of the nicotine contained in tobacco is absorbed. For the physiological effect of the nicotine from acid cigarette smoke intended by the smoker, however, inhalation is necessary, with about 10-20% of the nicotine contained in the mainstream smoke remaining in the body. It arrives in the brain at a comparatively high influx speed of 10 to 20 seconds after inhalation. There the nicotine has a stimulating effect on the nicotinic acetylcholine receptors. This type of receptor is found in parasympathetic ganglia , sympathetic ganglia, in the adrenal medulla , central nervous system, and on the motor endplates . Nicotine activates parasympathetic nerves and inhibits sympathetic nerves in their activity. Nicotine also promotes the release of the hormone adrenaline and the neurotransmitters dopamine and serotonin . In small amounts, nicotine has a stimulating effect. Nicotine briefly and reversibly accelerates the heartbeat and causes a narrowing of the v. a. the peripheral blood vessels; this leads to an increase in blood pressure , slight sweating (decrease in skin resistance ) and, as a result of the narrowing of the peripheral blood vessels, a decrease in skin temperature. The central effects include, above all, an increase in psychomotor performance as well as attention and memory skills and relaxation in some negative affective states. However, this increase is only during the duration of action. Nicotine intake reduces appetite. There is an increase in gastric juice production due to the release of histamine and increased bowel activity. In addition, nicotine is also known to have an anti- diuretic effect. On the effects of nicotine and the release of dopamine, a will gain in consumer behavior triggered, which can result in nicotine dependence. Withdrawal symptoms such as irritability or dysphoric moods can last up to 72 hours. In healthy cells, nicotine activates protein kinase B , which controls the metabolism , growth and death of cells. This increases the survivability of the cells.
Nicotine is not on the doping list , although it increases stamina.
According to the criteria of a longitudinal study, studies related to the tobacco industry came to the conclusion that nicotine has a beneficial and protective influence on Alzheimer's disease , whereas the other publications do not and identify it as a risk factor . In further studies, however, a positive effect of nicotine in relation to the development and therapy of the disease is documented. The consumption of nicotine is associated with a lower likelihood of developing Parkinson's disease. In albino laboratory rats, a harmful effect on embryos during pregnancy was demonstrated by a nicotine salt (nicotine bi-tartrate), which epigenetically manifested itself as asthma in the next generation and the next but one . It is not known whether such an effect exists in humans. Nicotine and some metabolites are being studied in the treatment of Parkinson's disease and depression in nonsmokers.
Pharmacokinetics and pharmacokinetic interactions
The plasma half-life of nicotine is 1–2 hours. 10% of nicotine is excreted unchanged through the kidneys. The rest is mainly metabolized by CYP2A6 to cotinine, which is partly excreted and partly further metabolized with a significantly longer plasma half-life.
Polycyclic aromatic carbohydrates in cigarette smoke and tobacco tar induce the activity of the cytochrome CYP1A2 and CYP2B6, which accelerates the breakdown of CYP1A2 substrates. CYP1A2 is involved in the oxidative metabolism of a number of drugs and environmental toxins and accelerates their breakdown, so that as a result, therapeutically desired plasma levels of pharmaceuticals cannot be reached or maintained. Among other things, this applies to some psychotropic drugs and antidepressants. Since this effect is not due to nicotine, it is not influenced by nicotine replacement treatment. Nicotine is broken down in the body into cotinine , nicotine- N ' -oxide , nornicotine , hydroxynicotine and being tainted .
Other toxins that act on acetylcholine receptors are anatoxin-a some cyanobacteria , conine the spotted hemlock , arecoline of betel nuts , cytisine of laburnum and Epibatidin of poison dart frog .
Nicotine is primarily a stimulant in low doses . In a medium dose, on the other hand, it has a relaxing effect. The phenomenon of the dose-dependent change in effect has been described as the Nesbitt paradox . Nicotine is only very toxic to higher animals in high concentrations , since in high doses it blocks the ganglia of the autonomic nervous system . Nicotine is the active ingredient in tobacco that is mainly responsible for the addictive potential of tobacco consumption. Acute overdoses are associated with nausea and vomiting.
In the kidneys, blood pressure rises under the action of nicotine, accompanied by a reduced glomerular filtration rate and reduced local flow of blood plasma. In adolescents, nicotine can lead to changes in the development of the nucleus accumbens , the middle prefrontal cortex , the basolateral amygdala , the bed nucleus of the stria terminalis and the dentate gyrus .
The rate of nicotine absorption through human skin is generally slow and depends on the solvent. The pure base (100% nicotine) is taken up extremely slowly at a rate of 82 µg / cm² per hour; H. if you apply pure nicotine to 10 cm² of skin, you ingest 0.8 mg per hour (which is roughly equivalent to smoking half a cigarette). When applying a 20 percent solution of nicotine in an alcoholic solution to 10 cm², the absorption is 0.1 mg nicotine per hour. In a dilute aqueous solution (20 percent) nicotine uptake is significantly faster at 8.8 mg per hour.
For a long time it was assumed that even if 60 mg of nicotine were swallowed, an adult was in danger of death. This assumption was based on the research results of the toxicologist and pharmacologist Rudolf Kobert. In 1906 he published the Textbook of Intoxications , in which he relied on experimental results of 2 to 4 mg and deduced from them that the maximum lethal oral dose of nicotine could not be higher than 60 mg. Kobert traced his surveys back to self-experiments by the Austrian doctor Karl Damian von Schroff in 1856. In 2014, the pharmacologist Bernd Mayer from the Karl-Franzens University in Graz corrected the value to over 500 mg.
In the case of cigarettes swallowed by children, an American 4-year study with 700 analyzed cases showed that the course of the disease was always easy when up to two cigarettes were swallowed. The Swiss Toxicological Information Center therefore recommends that children only consult a doctor if more than two cigarettes have been swallowed or symptoms of intoxication (such as vomiting, reddened skin, paleness, restlessness) occur. In some cases, however, a medical consultation is seen as mandatory even for smaller quantities.
Information on nicotine and tar content may no longer be given on the packaging of a cigarette packet, as this information has turned out to be misleading. The consumer could come to the assumption that the choice he has made is healthier in comparison. The packs are to be provided with warning notices according to strict specifications. The upper limits for the amount of nicotine supplied through the smoke is limited to 1 milligram, the amount of tar to 10 milligrams and the amount of CO to 10 milligrams per cigarette by EU Directive 2014/40. The tobacco in a cigarette contains on average around 12 milligrams of nicotine.
At the suggestion of the Dutch chemicals authority, the chemical classification of nicotine was reviewed in 2015. The Committee for Risk Assessment (RAC) of the European Chemicals Agency (ECHA) changed the classification for nicotine on September 10, 2015 as follows: The classification is in the acute toxicity category 2, both orally, dermally and by inhalation, the warnings are extended to H300 , H310 and H330 (fatal if swallowed, skin contact and inhalation) and H411 (Aquatic Chronic 2). This classification of the RAC was then implemented by the EU Commission into applicable law, which has to be taken into account by companies and authorities since May 1, 2020.
Nicotine is not on the list of carcinogenic substances of the International Agency for Research on Cancer of the World Health Organization .
The US Journal of Clinical Investigation reported that nicotine, as part of chemotherapy, blocks the body's ability to destroy cells with damaged genetic material. Such cells, however, have to be broken down by the body as quickly as possible during such a therapy, because otherwise the cancerous tumors already in the body will continue to multiply with less hindrance. In healthy cells, nicotine activates protein kinase B. This increases the survivability of the cells, which is beneficial in principle, but harmful if they later mutate into cancer cells. In addition, it has been reported that nicotine promotes the formation of new blood vessels ( angiogenesis ) and thus any existing cancerous tumors are better supplied with nutrients and can grow faster.
Nicotine is mainly responsible for the dependence on tobacco products . The addictive effect of nicotine is intensified by the monoamine oxidase inhibitors contained in tobacco smoke . Comparisons of animal studies and studies on human drug consumption show that pure nicotine is very addictive, while tobacco cigarette smoke is very addictive. Lewin referred to this fact in Phantastica as early as 1924. Nicotine, in connection with other substances in tobacco smoke, has an extremely high potential for dependence and can very quickly lead to dependent behavior . According to a paper published in 2007 by David Nutt et al. a. the addiction potential of tobacco smoke lies somewhere between alcohol and cocaine. More precisely, the potential for physical dependence is that of alcohol or barbiturates and the potential for psychological dependence is that of cocaine. A comparison with addiction to opiates such as heroin is not indicated because this is much more complicated to treat and the withdrawal symptoms are more severe. A few cigarettes or a few days with small cigarette consumption are enough to become physically dependent. The potential for dependence on orally ingested nicotine is significantly lower, and patches have almost no potential for dependence.
Connection with the use of other substances
In animal experiments it is relatively easy to determine whether the consumption of a substance increases the later attractiveness of another substance. However, in people where such direct experimentation is not possible, longitudinal studies can be used to determine whether the likelihood of using one substance is related to prior use of other substances.
In mice, nicotine increased the likelihood of later use of cocaine , and the experiments led to concrete conclusions about the underlying molecular changes in the brain. The biological imprint in mice thus corresponded to the epidemiological observations that nicotine consumption in humans is linked to a later increased likelihood of cannabis and cocaine use.
In rats, cannabis increased the subsequent self-administration of nicotine in subsequent experiments. A study of the drug use of around 14,500 12th grade students showed that alcohol consumption was associated with an increased likelihood of later use of tobacco, cannabis and other illegal substances.
Nicotine is used in smoking cessation therapy in the form of patches, sprays or chewing gum. The supplied nicotine reduces the withdrawal symptoms when not smoking; many of the risks posed by tobacco smoke are avoided by using pure nicotine.
A meta-analysis of 103 randomized, placebo-controlled studies found that the likelihood of relapse among smokers who quit smoking without aids is 97 percent within six months of quitting. Up until 2012, it was assumed that nicotine replacement preparations with the correct dosage and further professional guidance could increase the chances of success by three percent. A recent study from 2012 found that relapse rates among those who used nicotine replacement supplements to quit were just as high as those who quit without aids.
Nicotine chewing gums usually have a nicotine content of 2 mg for smokers with moderate tobacco consumption or 4 mg for those who are heavily dependent. In Germany they are only available in pharmacies. In Switzerland, all nicotine cessation drugs are in dispensing category D, so they are available in pharmacies and drugstores.
Regarding conjugate vaccines with nicotine to generate anti-nicotine antibodies there are similar studies. Furthermore, antagonists of the nicotinic acetylcholine receptor for weaning are being investigated.
Application in crop protection
Pure nicotine was previously used in crop protection as a pesticide against sucking or biting insects (including aphids ). The substance is well tolerated by plants and also readily biodegradable. However, due to its high toxicity, nicotine has been banned from use since the 1970s. Synthetic insecticides such as E605 were used as replacements. Other natural nicotinoids and synthetic neonicotinoids are being developed as insecticides primarily for commercial use.
Application in the e-cigarette
Nicotine is also used as an optional ingredient in the e-cigarette .
Nicopatch (A), Nicorette (D, A, CH), Nicotinell (D, A, CH), Nicotrol (A), Nikaloz (A), Nikofrenon (D), NiQuitin (D, A)
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