Nicotin is a pyridine alkaloid in plants of the family of solanaceous ( Solanaceae ), mainly in the leaves and stalks of tobacco (dry concentration from 0.3 to 5% by weight), shag (2-14%), in smaller quantities - in tomatoes , potatoes , eggplant , green pepper . Nicotine alkaloids ( anabasin and others) are also present in coca leaves . The biosynthesis of nicotine occurs in the roots, and the accumulation of nicotine in the leaves. Nicotine is poisonous to some insects ; as a result, nicotine used to be widely used as an insecticide , and now nicotine derivatives continue to be used in the same capacity, such as, for example, imidacloprid .
|(-) - Nicotine  |
|( S ) -3- (1-methyl-2-pyrrolidinyl) pyridine|
|Chem. formula||C 10 H 14 N 2|
|Molar mass||162.23 g / mol|
|Density||1.01 g / cm³|
|T. melt.||−79 ° C|
|T. Kip.||247 ° C|
|T. v.||101 ° C|
|T. sspl.||244 ° C|
|Education enthalpy||39.3 kJ / mol|
|Vapor pressure||5.1 Pa|
|Water solubility||mixed up|
|Solubility in ethanol||5 g / 100 ml|
|Reg. CAS number||54-11-5|
|Reg. EINECS number|
|Reg. EC number||200-193-3|
|LD 50||50 mg / kg (rats, orally);|
0.33 mg / kg (mouse orally);
0.3 mg / kg (mouse, intramuscularly)
highly toxic, is ganglionic poison, affects the central nervous system ; extremely toxic to cold-blooded animals and insects
|H-phrases||H301 , H310 , H400 , H411|
|P-phrases||P273 , P280 , P301 + P310 , P302 + P350 , P310|
The physiology and biomechanism of nicotine exposure on the body is associated with its interaction with the H-cholinergic receptors of cholinergic nerve synapses containing them and, as a result, the initiation of some parts of the parasympathetic nervous system (effects depend on dose: in small doses, it stimulates synapse receptors, linking to them, for example , in smokers, a decrease in the frequency and strength of heart contractions (palpitations), increased salivation and peristalsis of the intestines, etc., in large doses, on the contrary, competitively blocks the airborne receptors Corollary acetylcholine)  . A lethal single dose for acute poisoning for a person is 0.5-1 g (in one cigarette , depending on the brand and type, usually 0.1-1.0 mg of nicotine is contained without taking into account its loss during combustion during smoking)  [ 5]  .
For 2014, there is data on the promotion of nicotine to the risk of certain types of malignant tumors, which, as of 2015, were detected only in in vitro experiments and were not confirmed by clinical studies on living organisms   .
Intake of nicotine, smoking is associated with cardiovascular diseases, the occurrence of birth defects and poisoning  .
When smoking tobacco by women during pregnancy, there is a risk for the unborn child in his later life to become ill with type 2 diabetes , obesity , hypertension , various neurobehavioral defects, respiratory dysfunction and infertility    .
History and Title
The name “nicotine” comes from the Latin name for tobacco, Nicotiana tabacum , which, in turn, was coined in honor of Jean Nico , the French ambassador to the Portuguese court, who sent some tobacco to Queen Catherine de Medici in 1560, recommending it as a means of migraine   .
Nicotine has long been known in its crude form. The first mention of the “tobacco oil” belongs to the French alchemist , a follower of Paracelsus , who diligently sought the opportunity to study plants brought from America. In his work Instruction sur l'herbe petum (1572) there is a first description of the distillation of tobacco leaves. "Tobacco oil", mentioned in the sources of the XVII and XVIII centuries as an external remedy for the treatment of skin diseases, was obtained in this way at that time. A detailed description of the production of nicotine from tobacco leaves is found in the book Traité de la chymie (1660) by another French chemist, Nicolas Lefebvre . As an illustration of the principle of separation of substances and due to its medical significance, he describes in detail the process, which is essentially steam distillation . As a result of this process, evaporating water carries off nicotine with steam, and two layers, aqueous and organic, are formed in the receiver flask. The organic layer was separated, purified and used to combat asthma , spleen inflammation and epilepsy  .
In 1809, French chemist-analyst Louis Nicolas Vauclin published a paper on a thorough analysis of virgin tobacco. As part of this work, Voklen was able to isolate a fairly clean sample of nicotine, and also isolated malic acid , with which nicotine is associated in tobacco. Despite the excellent analytical work, Voklena is not considered the pioneer of nicotine, because he did not recognize the alkaloid in nicotine, but believed that the basic properties of the substance are associated with an admixture of ammonia, while the alkaloids themselves are bases  .
Nicotine was discovered by German chemists and . In 1828 they presented a paper on the active beginning of tobacco, and won the annual prize of the University of Heidelberg for the best work. The study by Posselt and Rymann was criticized, since many chemists refused to believe that the alkaloid could be a liquid , but a specially created commission rechecked and confirmed the results  .
In 1843, found the empirical formula of nicotine. The structure of nicotine was widely discussed during the 80s - early 90s of the XIX century, and in 1893 it was installed by the German chemist Adolf Pinner . Synthesis of this substance was required to confirm the structure: it was implemented by in 1904. In a series of articles, Pictet published not only a method for producing synthetic nicotine identical to natural, but also two products of its oxidation — nicotine and dihydronicotyrin. Unfortunately, some stages of the synthesis proceeded under very harsh conditions, which could give reason to doubt the value of Picte's synthesis as a method for confirming the structure. However, a later synthesis (1928), carried out under mild conditions, confirmed the correctness of the established formula  .
The first synthesis of optically active ( S ) -nicotine was conducted in 1982. The optically active substituted pyrrolidine served as the starting material, and the pyridine cycle was created during the synthesis  .
Nicotine in the Bokarma Case
Nicotine is associated with a sensational case of poisoning in Belgium in 1850, when was accused of poisoning his wife's brother. The consultant was a Belgian chemist Jean Serva Stas , who, during a difficult analysis, not only found that nicotine was poisoned, but also developed an alkaloid detection method, which is used in analytical chemistry with minor modifications  .
The French chemist Mathieu Orfil was also involved in the investigation, who, hearing about the case and conducting toxicological experiments on animals, came to the method of determining alkaloids, similar to the method of Stas. Moreover, between the end of the investigation and the court, Orfila published his findings, while Stas, being an expert in the case, was forced to remain silent. The Belgian press accused Orfil of fraud, but Stas still commended Orfile in his publications, nevertheless indicating that he himself was a pioneer  .
Physical and chemical properties
Nicotine is a hygroscopic oily liquid with a bitter taste, easily mixed with water (at temperatures below 60 ° C and above 210 ° C) in its basic form. The density of nicotine is almost equal to the density of water (1.01 g / cm 3 ).
The nicotine molecule consists of pyridine and pyrrolidine cycles. The pyrrolidine cycle adopts the envelope conformation with the trans -position of the pyridine cycle and the N - methyl group  .
Being a base (p K b ( pyrrolidine ) = 8.02, p K b ( pyridine ) = 3.12), nicotine forms salts (usually solid and water soluble) by reaction with acids . Nicotine sorption through biological membranes depends on pH and for mucous membranes is accelerated at high pH values when the nicotine molecule has no charge. At physiological pH values, nicotine is protonated at 69%. Nicotine is low polar and well soluble in low polarity media, so it is well absorbed through the skin and penetrates the brain tissue through the hemato-encephalic barrier  .
Nicotine is easily oxidized to non-toxic and physiologically important nicotinic acid , vitamin PP , in the body of warm-blooded animals, with the pyrrolidine cycle being replaced by a carboxyl group . Also, under the action of various oxidants and ultraviolet radiation, nicotine is oxidized to methylamine and nicotine oxide  .
Once nicotine enters the body, it quickly spreads through the bloodstream and can cross the blood-brain barrier . On average, 7 seconds are enough after inhaling tobacco smoke, so that nicotine reaches the brain . The half-life of nicotine from the body is about two hours  . Nicotine, inhaled with tobacco smoke while smoking, accounts for a small proportion of the nicotine contained in tobacco leaves (most of the substance burns out). The amount of nicotine absorbed by the body during smoking depends on many factors, including the type of tobacco, whether all the smoke is inhaled and whether a filter is used. In the case of chewing and snuff tobacco , which are placed in the mouth and chewed or inhaled through the nose, the amount of nicotine entering the body is much greater than when smoking tobacco. Nicotine is metabolized in the liver by the enzyme cytochrome P450 (mainly , as well as ). The main metabolite is cotinine .
Nicotine acts on nicotinic acetylcholine receptors : the protonated nitrogen atom of the pyrrolidine cycle in nicotine mimics the quaternary nitrogen atom in acetylcholine, and the nitrogen atom of pyridine has the character of a Lewis base , as well as the oxygen of the keto group of acetylcholine  . In low concentrations, it increases the activity of these receptors, which, among other things, leads to an increase in the amount of the stimulating hormone adrenaline (epinephrine). An adrenaline rush leads to an acceleration of the heartbeat, an increase in blood pressure and increased respiration, as well as a higher level of glucose in the blood.
The sympathetic nervous system , acting through the celiac nerves on the medulla of the adrenal gland , stimulates the release of adrenaline. Acetylcholine , produced by these nerves, acts on nicotinic acetylcholine receptors, causing cell depolarization and calcium influx through voltage-dependent calcium channels . Calcium triggers the exocytosis of chromaffin granules , thereby contributing to the release of adrenaline (and norepinephrine ) into the blood .
Cotinine is a byproduct of the absorption of nicotine, which remains in the blood for up to 48 hours and can be used as an indicator of whether a person is exposed to smoking. At high doses, nicotine results in blocking the nicotine acetylcholine receptor, which is the cause of nicotine toxicity and its efficacy as an insecticide .
Among other things, nicotine increases the level of dopamine in the ways of pleasure centers in the brain . It has been found that smoking tobacco inhibits monoamine oxidase , the enzyme responsible for the breakdown of monoamine neurotransmitters (for example, dopamine) in the brain. It is believed that nicotine itself does not suppress the production of monoamine oxidase; other components of tobacco smoke are responsible for this. The increased dopamine content excites the pleasure centers of the brain, these same brain centers are responsible for the “ pain threshold of the body” therefore, the question of whether a smoker gets pleasure is still open.
Despite its strong toxicity, when consumed in small doses (eg when smoking ), nicotine acts as a psychostimulant . Nicotine effect on mood is different. By causing the release of glucose from the liver and adrenaline (epinephrine) from the adrenal medulla , it causes arousal. From a subjective point of view, this is manifested by feelings of relaxation, calmness and liveliness, as well as a moderately euphoric state.
The use of nicotine leads to a decrease in body weight, reducing appetite as a result of stimulation of POMC neurons  and an increase in blood glucose (glucose, affecting the saturation and hunger centers in the hypothalamus of the brain, dulls the feeling of hunger ).
Nicotine is mainly metabolized in the liver by oxidation and N-demethylation. In this case, the pyrrolidine cycle breaks down and N-methylation of the pyridine cycle, while nicotine oxidation leads to cotinine. These metabolites are excreted in the urine.
Historically, nicotine has often been used for medical purposes. The use of nicotine for the treatment of various diseases is also being developed. The most common direction is the delivery of nicotine into the body in alternative ways for the treatment of nicotine addiction . The possibility of using nicotine in other areas is being investigated, for example, as a painkiller , a means of attention deficit disorder , Alzheimer's disease , Parkinson's disease , colitis , herpes , tuberculosis  and schizophrenia  .
Use as an insecticide
At the beginning of the 20th century, nicotine was the main insecticide used to protect plants. For these purposes, nicotine was used in the form of a pure substance, its sulfate , tobacco dust, with the pure substance having the greatest activity, which is also toxic to mammals . The cause of the insecticidal action of nicotine is the same as the cause of toxicity: at high doses, it blocks the nicotinic acetylcholine receptors . Later, nicotine was replaced by its synthetic analogues: imidacloprid , acetamiprid, and others  .
Nicotine is extremely toxic to cold-blooded animals . Acts as a neurotoxin , causing paralysis of the nervous system (respiratory arrest, cessation of cardiac activity, death ).
Toxic in high doses and to warm-blooded animals . The average lethal dose for humans is 0.5–1 mg / kg  , for rats — 140 mg / kg through the skin, for mice — 0.8 mg / kg intravenously and 5.9 mg / kg when administered intraperitoneally [24 ] .
Repeated nicotine use causes physical and mental dependence  .
Длительное употребление может вызвать такие заболевания и дисфункции, как гипергликемия , артериальная гипертония , атеросклероз , тахикардия , аритмия , стенокардия , ишемическая болезнь сердца , сердечная недостаточность и инфаркт миокарда  . В сочетании со смолами никотин способствует развитию онкологических заболеваний, в том числе рака лёгких   , языка, гортани. Способствует развитию гингивита и стоматита .
Никотин и психические расстройства
У пациентов с психическими расстройствами отмечается повышенное пристрастие к курению. Большое количество исследований по всему миру утверждает, что больные шизофренией более склонны к курению (20 разных стран исследовали в общей сложности 7593 пациентов с шизофренией, из них 62 % были курильщиками)  . На 2006 год в США 80 % или более людей с шизофренией курят, по сравнению с 20 % общего населения некурящих (по данным NCI )  . Существует ряд гипотез относительно причин этого пристрастия, объясняющих его как стремлением противостоять симптомам расстройства, так и стремлением противостоять негативному действию антипсихотиков . По одной из гипотез никотин сам нарушает психику  .
According to one study, injections of nicotine into mice reduce the concentration of DNA , the methylating enzyme DNMT1, and increase the expression of GABA- producing GAD67 enzyme in the rodent prefrontal cortex  . It suggests that patient addiction to cigarettes can be partly explained by the ability of nicotine to eliminate the negative epigenetic effects of elevated levels of DNMT1. However, it is not clear whether mental disorders lead to an imbalance of DNMT1 and GAD67, requiring correction, and the antipsychotics they take change many of the indicators, including GABAergic  .
According to a study in 2017, nicotine eliminates hypofrontality - insufficient cerebral blood flow in the prefrontal cortex , characteristic of schizophrenia, thereby, according to the researchers, in theory, nicotine can have a favorable therapeutic effect on patients with schizophrenia  . A new drug, a partial α7- nicotinic acetylcholine receptor agonist , GTS-21 (DMBX-A), is under study  .
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