Nicotine is an alkaloid Alkaloids are a group of naturally occurring chemical compounds which mostly contain basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids. Beside carbon, hydrogen and nitrogen, molecules of alkaloids may found in the nightshade Solanum, the nightshades, horsenettles and relatives, is a large and diverse genus of annual and perennial plants. They grow as forbs, vines, subshrubs, shrubs, and small trees, and often have attractive fruit and flowers. Many formerly independent genera like Lycopersicon or Cyphomandra are included in Solanum as subgenera or sections today. Thus, family of plants (Solanaceae Solanaceae is a family of flowering plants that contains a number of important agricultural crops as well as many toxic plants. The name of the family comes from the Latin Solanum "the nightshade plant", but the further etymology of that word is unclear. Most likely, the name comes from the perceived resemblance that some of the flowers) that constitutes approximately 0.6–3.0% of dry weight of tobacco Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as an organic pesticide and, in the form of nicotine tartrate, it is used in some medicines. It is most commonly used as a recreational drug, and is a valuable cash crop for countries such as Cuba, China and United States,^[1][2] with biosynthesis Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step. Examples for such multi-step biosynthetic pathways are those for the taking place in the roots and accumulation occurring in the leaves. It functions as an antiherbivore chemical Plant defense against herbivory or host-plant resistance describes a range of adaptations evolved by plants which improve their survival and reproduction by reducing the impact of herbivores. Plants use several strategies to defend against damage caused by herbivores. Many plants produce secondary metabolites, known as allelochemicals, that with particular specificity to insects; therefore nicotine was widely used as an insecticide An insecticide is a pesticide used against insects. They include ovicides and larvicides used against the eggs and larvae of insects respectively. Insecticides are used in agriculture, medicine, industry and the household. The use of insecticides is believed to be one of the major factors behind the increase in agricultural productivity in the 20 in the past,^[3][4] and currently nicotine analogs such as imidacloprid Imidacloprid is a neonicotinoid, which is a class of neuro-active insecticides modeled after nicotine. A patented chemical, imidacloprid is manufactured by Bayer Cropscience and sold under trade names Kohinor, Admire, Advantage(Advocate), Gaucho, Merit, Confidor, Hachikusan, Premise, Prothor, Provado and Winner. It is marketed as pest control, continue to be widely used. Nicotine is also found in several other members of the Solanaceae family, with small amounts being present in species such as the Egg plant and Tomato The tomato is a savory, typically red, edible fruit, as well as the plant which bears it. Originating in South America, the tomato was spread around the world following the Spanish colonization of the Americas, and its many varieties are now widely grown, often in greenhouses in cooler climates.

In low concentrations (an average cigarette A cigarette is a small roll of finely-cut tobacco leaves wrapped in a cylinder of thin paper for smoking. The cigarette is ignited at one end and allowed to smoulder; its smoke is inhaled from the other end, which is held in or to the mouth. Most modern manufactured cigarettes are filtered and include reconstituted tobacco and other additives yields about 1 mg of absorbed nicotine), the substance acts as a stimulant Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others. Due to their effects typically having an "up" quality to them, stimulants are also occasionally referred to as & in mammals Mammals are a class of vertebrate, air-breathing animals whose females are characterized by the possession of mammary glands while both males and females are characterized by hair and/or fur, three middle ear bones used in hearing, and a neocortex region in the brain. Some mammals have sweat glands, but most do not and is the main factor responsible for the dependence-forming properties of tobacco smoking Tobacco smoking is the practice where tobacco is burned and the vapors either tasted or inhaled. The practice began as early as 5000–3000 BC. Many civilizations burnt incense during religious rituals, which was later adopted for pleasure or as a social tool. Tobacco was introduced to the Old World in the late 1500s where it followed common trade. According to the American Heart Association The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas. The American Heart Association is a national voluntary health agency whose mission is: "Building, nicotine addiction Substance use disorders include substance abuse and substance dependence. In DSM-IV, the conditions are formally diagnosed as one or the other, but it has been proposed that DSM-5 combine the two into a single condition called "Substance-use disorder" has historically been one of the hardest addictions to break, while the pharmacological and behavioral characteristics that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin Heroin, or diacetylmorphine , also known as diamorphine (BAN), is a semi-synthetic opioid drug synthesized from morphine, a derivative of the opium poppy. It is the 3,6-diacetyl ester of morphine (di (two)-acetyl-morphine). The white crystalline form is commonly the hydrochloride salt diacetylmorphine hydrochloride, though often adulterated thus and cocaine Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic. Specifically, it is a serotonin-norepinephrine-dopamine.^[5] Nicotine content in cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.6% per year between the years of 1998 and 2005. This was found for all major market categories of cigarettes.^[6]

History and name

Nicotine is named after the tobacco plant Nicotiana tabacum Nicotiana tabacum, or cultivated tobacco, is a perennial herbaceous plant. It is found only in cultivation, where it is the most commonly grown of all plants in the Nicotiana genus, and its leaves are commercially grown in many countries to be processed into tobacco. It grows to heights between 1 to 2 metres. Research is ongoing into its ancestry which in turn is named after Jean Nicot de Villemain Born in Nîmes, in the south of France, he was French ambassador in Lisbon, Portugal from 1559 to 1561, French France (pronounced /ˈfrænts/ frantss or /ˈfrɑːnts/ frahnts; French pronunciation (help·info): [fʁɑ̃s]), officially the French Republic (French: République française, pronounced: [ʁepyblik fʁɑ̃sɛz]), is a state in Western Europe with several of its overseas territories and islands located on other continents and in the Indian, ambassador in Portugal Portugal /ˈpɔɹtʃʉɡəl/ (Portuguese: Portugal, Mirandese: Pertual), officially the Portuguese Republic (Portuguese: República Portuguesa; Mirandese: República Pertuesa), is a country located in southwestern Europe on the Iberian Peninsula. Portugal is the westernmost country of Europe and is bordered by the Atlantic Ocean to the west and, who sent tobacco and seeds from Brazil Brazil (pronounced /brəˈzɪl/ ; Portuguese: Brasil, IPA: [bɾaˈziw]), officially the Federative Republic of Brazil (Portuguese: República Federativa do Brasil, listen (help·info)), is the largest country in South America and the only Portuguese-speaking country in the Americas. It is the world's fifth largest country, both by geographical to Paris Paris ([paʁi] in French, pronounced /ˈpærɪs/ in English) is the capital and largest city of France. It is situated on the river Seine, in northern France, at the heart of the Île-de-France region (or Paris Region, French: Région parisienne). The city of Paris, within its administrative limits largely unchanged since 1860, has an estimated in 1560 and promoted their medicinal use. Nicotine was first isolated from the tobacco plant in 1828 by German A region named Germania, inhabited by several Germanic peoples, has been known and documented before AD 100. Beginning in the 10th century, German territories formed a central part of the Holy Roman Empire, which lasted until 1806. During the 16th century, northern Germany became the centre of the Protestant Reformation. As a modern nation-state, chemists Posselt & Reimann, who considered it a poison.^[7] Its chemical empirical formula In chemistry, the empirical formula of a chemical compound is the simplest whole number ratio of atoms of each element present in a compound. An empirical formula makes no reference to isomerism, structure, or absolute number of atoms. The empirical formula is used as standard for most ionic compounds, such as CaCl2, and for macromolecules, such was described by Melsens in 1843,^[8] its structure was discovered by Garry Pinner in 1893, and it was first synthesized by A. Pictet and Crepieux in 1904.^[9]

Chemistry

Nicotine is a hygroscopic Hygroscopy is the ability of a substance to attract water molecules from the surrounding environment through either absorption or adsorption, oily liquid that is miscible In chemistry, miscibility is the property of liquids to mix in all proportions, forming a homogeneous solution. In principle, the term applies also to other phases , but the main focus is usually on the solubility of one liquid in another. Water and ethanol, for example, are miscible since they mix in all proportions with water Water is the most abundant compound on Earth's surface, constituting about 70% of the planet's surface. In nature it exists in liquid, solid, and gaseous states. It is in dynamic equilibrium between the liquid and gas states at standard temperature and pressure. At room temperature, it is a nearly colorless with a hint of blue, tasteless, and in its base In chemistry, a base is most commonly thought of as an aqueous substance that can accept hydrogen ions. Bases are also the oxides or hydroxides of metals. A soluble base is also often referred to as an alkali if hydroxide ions are involved. This refers to the Brønsted-Lowry theory of acids and bases. Alternative definitions of bases include form. As a nitrogenous base A nitrogenous base is an organic compound that owes its property as a base to the lone pair of electrons of a nitrogen atom. In biological sciences, nitrogenous bases are typically classified as the derivatives of two parent compounds, pyrimidine and purine. They are non-polar and due to their aromaticity, planar. Both pyrimidines and purines, nicotine forms salts Salt is a mineral that is composed primarily of sodium chloride. It is essential for animal life in small quantities, but is harmful to animals and plants in excess. Salt flavor is one of the basic tastes, making salt one of the oldest, most ubiquitous food seasonings. Salting is an important method of food preservation with acids An acid is any chemical compound that, when dissolved in water, gives a solution with a hydrogen ion activity greater than in pure water, i.e. a pH less than 7.0 in its standard state. That approximates the modern definition of Johannes Nicolaus Brønsted and Martin Lowry, who independently defined an acid as a compound which donates a hydrogen that are usually solid and water soluble. Nicotine easily penetrates the skin The skin is a soft outer covering of an animal, in particular a vertebrate. Other animal coverings such the arthropod exoskeleton or the seashell have different developmental origin, structure and chemical composition. The adjective cutaneous literally means "of the skin" . In mammals, the skin is the largest organ of the integumentary. As shown by the physical data, free base Freebase or free base refers to the pure basic form of an amine, as opposed to its salt form. The amine is usually an alkaloid natural product. Free base is commonly used in chemistry and pharmaceuticals to describe the unprotonated amine form of a compound nicotine will burn at a temperature below its boiling point, and its vapors will combust at 308 K (35 °C; 95 °F) in air despite a low vapor pressure Vapor pressure or equilibrium vapor pressure are the pressure of a vapor in thermodynamic equilibrium with its condensed phases in a closed bottle. All liquids and solids have a tendency to evaporate into a gaseous form, and all gases have a tendency to condense back to their liquid or solid form. Because of this, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to provide the desired effects. The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves.^{[citation needed]}

Optical activity

Nicotine is optically active Optical rotation is the turning of the plane of linearly polarized light about the direction of motion as the light travels through certain materials. It occurs in solutions of chiral molecules such as sucrose , solids with rotated crystal planes such as quartz, and spin-polarized gases of atoms or molecules. It is used in the sugar industry to, having two enantiomeric In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are "non-superposable" , much as one's left and right hands are "the same" but opposite. The term, pronounced /ɨˈnæntɪ.ɵmər/, is derived from the Greek ἐνάντιος, opposite, and μέρος, part or portion forms. The naturally occurring form of nicotine is levorotatory, with [α]_D = –166.4°. The dextrorotatory Dextrorotation and levorotation refer, respectively, to the properties of rotating plane polarized light clockwise (for dextrorotation) or counterclockwise (for levorotation), seen by an observer whom the light is approaching. A compound with dextrorotation is called dextrorotatory or dextrorotary, while a compound with levorotation is called form, (+)-nicotine, has only one-half the physiological activity of (–)-nicotine. It is therefore weaker in the sense that a higher dose is required to attain the same effects.^[10] The salts of (+)-nicotine are usually dextrorotatory.

Pharmacology

Pharmacokinetics

As nicotine enters the body, it is distributed quickly through the bloodstream Blood is a specialized bodily fluid that delivers necessary substances to the body's cells – such as nutrients and oxygen – and transports waste products away from those same cells and can cross the blood-brain barrier The blood-brain barrier is a separation of circulating blood and cerebrospinal fluid (CSF) in the central nervous system (CNS). It occurs along all capillaries and consists of tight junctions around the capillaries that don't exist in normal circulation. Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria) and large or. On average it takes about seven seconds for the substance to reach the brain The brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all. In vertebrates, the brain is located in the head, protected by the skull and close to the primary when inhaled.^{[citation needed]} The half life Half-life is the period of time it takes for a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but may apply to any quantity which follows a set-rate decay of nicotine in the body is around two hours.^[11]

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 Chewing tobacco refers to a form of smokeless tobacco furnished as long strands of whole leaves and consumed by placing a portion of the tobacco between the cheek and gum or teeth and chewing. Unlike dipping tobacco, it isn't ground and must be mechanically crushed with the teeth to release flavour and nicotine. Unwanted juices are then, dipping tobacco Dipping tobacco, also known as moist snuff or spit tobacco, is a form of smokeless tobacco. It is commonly referred to as dip. The act of using it is called dipping. Dip is colloquially called "chew"; because of this, it is commonly confused with chewing tobacco. It is a version of the Swedish "snus" that was brought to America, snus Snus is a moist powder tobacco product originated from a variant of dry snuff, in the early 19th century in Sweden, consumed by placing it under the lip for extended periods of time. However, the precursor of snus, the dry form of snuff inhaled through the nose, was introduced in Europe much earlier. Snus is a form of snuff that is used in a and snuff Snuff is ground or pulverized tobacco, which is generally inhaled or "snuffed" through the nose. It is a type of smokeless tobacco. There are several types, but traditionally it means Dry/European nasal snuff. In the United States, "snuff" can also refer to dipping tobacco, which is applied to the gums rather than inhaled, 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 Metabolism is the set of chemical reactions that happen in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism breaks down organic matter, for example to harvest energy in cellular in the liver The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion. The liver is necessary for survival; there is currently no way to compensate for the absence of liver function by cytochrome P450 The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances such as drugs and other toxic chemicals enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine Cotinine is an alkaloid found in tobacco and is also a metabolite of nicotine. The word "cotinine" is an anagram of "nicotine". Cotinine is used as a biomarker for exposure to tobacco smoke and has also been sold as an antidepressant under the brand name Scotine.

Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.^[12]

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.^[13]

Detection of use

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.^[14][15] Interestingly, nicotine use is not regulated in competitive sports programs, yet the drug has been shown to have a significant beneficial effect on athletic performance.^[16]

Pharmacodynamics

Nicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNS nicotinic receptor. The former is present in the adrenal medulla and elsewhere, while the latter is present in the central nervous system (CNS). In small concentrations, nicotine increases the activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters through less direct mechanisms.

In CNS

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters - acting as a sort of "volume control". It is thought that increased levels of dopamine in the reward circuits of the brain are responsible for the euphoria and relaxation and eventual addiction caused by nicotine consumption. Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis.^[19] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.^[20]

Tobacco smoke contains the monoamine oxidase inhibitors harman, norharman,^[21] anabasine, anatabine, and nornicotine. These compounds significantly decrease MAO activity in smokers.^[21][22] MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin.

Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and brainstem regions^[23][24] but not habenulopeduncular structures.^[25] Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.^[26]

In SNS

Nicotine also activates the sympathetic nervous system,^[27] 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. Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or its irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals.^[28]

In adrenal medulla

By binding to ganglion type nicotinic receptors in the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. 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 epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels.^[29]

Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. In the other hand, cotinine is the metabolite of nicotine which remains in the blood for 18 to 20 hours, making it a more stable compound, which results more desirable and easier to analize due to its longer half-life.^[31]

Psychoactive effects

Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.^[32] First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness.^[33] By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.^[34][35]

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers including acetylcholine, norepinephrine, epinephrine, vasopressin, arginine, dopamine, autocrine agents, and beta-endorphin.^[36] This release of neurotransmitters and hormones is responsible for most of nicotine's effects. Nicotine appears to enhance concentration^[37] and memory due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. Nicotine also extends the duration of positive effects of dopamine^[38] and increases sensitivity in brain reward systems.^[39] Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.^[40]

Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.^[41] This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use.

Technically, nicotine is not significantly addictive, as nicotine administered alone does not produce significant reinforcing properties.^[42] However, only after coadministration with an MAOI, such as those found in tobacco, nicotine produces significant behavioral sensitization, a measure of addiction potential. This is similar in effect to amphetamine.^[43]

Nicotine gum, usually in 2-mg or 4-mg doses, and nicotine patches are available, as well as smokeless tobacco which do not have all the other ingredients in smoked tobacco.^{[citation needed]}

Dependence and withdrawal

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.^[44]

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.^{[citation needed]} 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 such as cocaine and heroin, which reduce reward pathway sensitivity.^[39] 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 alcohol 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.^{[citation needed]}

A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing the risk of substance abuse during adolescence.^[45]

Immunology prevention

Because of the severe addictions and the harmful effects of smoking, vaccination protocols have been developed. The principle is under the premise that if an antibody is attached to a nicotine molecule, it will be prevented from diffusing through the capillaries, thus making it less likely that it ever affects the brain by binding to nicotinic acetylcholine receptors.

These include attaching the nicotine molecule to a hapten such as Keyhole limpet hemocyanin or a safe modified bacterial toxin to elicit an active immune response. Often it is added with bovine serum albumin.

Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodies against endogenous hormones and over the counter drugs, monoclonal antibodies have been developed for short term passive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on their ability to resist degradation from pinocytosis by epithelial cells.^[46]

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.^[47][48] Nicotine therefore has a high toxicity in comparison to many other alkaloids such as cocaine, which has an LD₅₀ of 95.1 mg/kg when administered to mice. It is unlikely that a person would overdose on nicotine through smoking alone, although intoxication can occur through the excessive use of nicotine patches, gum, nasal sprays or oral inhalers intended as smoking cessation aids.^[49][50] Spilling a high concentration of nicotine onto the skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal contact.^[51]

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. However, nicotine and the increased cholinergic activity it causes have been shown to impede apoptosis, 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 may create a more favourable environment for cancer to develop, though this also remains to be proven.^[52]

The teratogenic properties of nicotine 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.^[52]

Women who use nicotine gum and patches during the early stages of pregnancy face an increased risk of having babies with birth defects, says a study that looked at about 77,000 pregnant women in Denmark. The study found that women who use nicotine-replacement therapy in the first 12 weeks of pregnancy have a 60 percent greater risk of having babies with birth defects, compared to women who are non-smokers, the Daily Mail reported. The findings were published in the journal Obstetrics and Gynaecology.

Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency added nicotine to the list of chemicals known to the state to cause developmental toxicity, for the purposes of Proposition 65.^[53]

Link to circulatory disease

Nicotine has very powerful effects on arteries throughout the body. Nicotine is a stimulant, 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.^{[citation needed]}

It has been speculated^[who?] that nicotine increases the risk of blood clots by increasing plasminogen activator inhibitor-1, though this has not been proven. Plasma fibrinogen levels are elevated in smokers and are further elevated during acute COPD exacerbation. Also Factor XIII, which stabilizes fibrin clots, is increased in smokers. But neither of these two effects has been shown to be caused by nicotine [1] as of 2009^[update]. 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 in arteries going to the extremities is also highly susceptible to the vasoconstrictor effects of nicotine and 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 the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes 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".^[54] 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).^[54] 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.^[55][56] Smoking also appears to interfere with development of Kaposi's sarcoma,^[57] breast cancer among women carrying the very high risk BRCA gene,^[58] preeclampsia,^[59] and atopic disorders such as allergic asthma.^[60] 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.^[61]

Tobacco smoke has been shown to contain compounds capable of inhibiting MAO. Monoamine oxidase is responsible for the degradation of dopamine in the human brain. When dopamine is broken down by MAO-B, neurotoxic by-products are formed, possibly contributing to Parkinson's and Alzheimers disease.^[62] Many such papers regarding Alzheimer's disease^[63] and Parkinson's Disease^[64] have been published. Recent studies find no beneficial link between smoking and Alzheimer's disease and in some cases, suggest it may actually result in an earlier onset of the disease.^{[65][66][67][68]} However, nicotine has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans.^[69][70][71]

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 responsible for processing nicotine in the brain.^[72]

It has been noted that the majority of people diagnosed with schizophrenia smoke tobacco^{[citation needed]}. Estimates for the proportion of schizophrenics who 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.^[73][74] More recent research has found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent.^[75] All of these studies are based only on observation, and no interventional (randomized) studies have been done. Research on nicotine as administered through a patch or gum is ongoing.

Nicotine appears to improve ADHD symptoms. Some studies are focusing on benefits of nicotine therapy in adults with ADHD.^[76]

Nicotine (in the form of chewing gum or a transdermal patch) is being explored as an experimental treatment for OCD. Small studies show some success, even in otherwise treatment-refractory cases.^[77][78][79]

Research as a potential basis for an antipsychotic agent

When the metabolites of nicotine were isolated and their effect on first the animal brain and then the human brain in people with schizophrenia were studied, it was shown that the effects helped with cognitive and negative symptoms of schizophrenia. Therefore, the nicotinergic agents, as antipsychotics which do not contain nicotine but act on the same receptors in the brain are showing promise as adjunct antipsychotics in early stages of FDA studies on schizophrenia. The prepulse inhibition (PPI) is a phenomenon in which a weak prepulse attenuates the response to a subsequent startling stimulus. Therefore, PPI is believed to have face, construct, and predictive validity for the PPI disruption in schizophrenia, and it is widely used as a model to study the neurobiology of this disorder and for screening antipsychotics.^[80] Additionally, studies have shown that there are genes predisposing people with schizophrenia to nicotine use.^[81]

Therefore with these factors taken together the heavy usage of cigarettes and other nicotine related products among people with schizophrenia may be explained and novel antipsychotic agents developed that have these effects in a manner that is not harmful and controlled and is a promising arena of research for schizophrenia.

See also

• Nicotiana
  • Nicotiana rustica
    • Mapacho
  • Nicotiana tabacum
    • Tobacco
      • Tobacco products
• Nicotinic acid (Niacin)
• Drug addiction
• Tobacco cessation
  • Chantix
  • Zyban
  • Electronic cigarette
  • Nicogel
  • Nicotini
  • NicVAX
  • Nicotine gum
  • Nicotine patch
  • Nicotine inhaler
  • Nicotine nasal spray
  • Snus
• Psychoactive drug
• Drug Discovery and Development: Nicotinic Acetylcholine Receptor Agonists
• Nicotinic receptor

References

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External links

• Description of nicotine addiction
• Description of nicotine mechanisms

Further reading

• Bilkei-Gorzo A, Rácz I, Michel K, Darvas M, Rafael Maldonado López, Zimmer A. (2008). "A common genetic predisposition to stress sensitivity and stress-induced nicotine craving". Biol. Psychiatry 63 (2): 164–71. doi:10.1016/j.biopsych.2007.02.010. PMID 17570348.
• Willoughby JO, Pope KJ, Eaton V (Sep 2003). "Nicotine as an antiepileptic agent in ADNFLE: an N-of-one study". Epilepsia 44 (9): 1238–40. doi:10.1046/j.1528-1157.2003.11903.x. PMID 12919397. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0013-9580&date=2003&volume=44&issue=9&spage=1238.
• Minna JD (Jan 2003). "Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression in the pathogenesis of lung cancer". J Clin Invest. 111 (1): 31–3. doi:10.1172/JCI17492. PMID 12511585.
• Fallon JH, Keator DB, Mbogori J, Taylor D, Potkin SG (Mar 2005). "Gender: a major determinant of brain response to nicotine". Int J Neuropsychopharmacol. 8 (1): 17–26. doi:10.1017/S1461145704004730. PMID 15579215. http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=282494.
• West KA, Brognard J, Clark AS, et al. (Jan 2003). "Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells". J Clin Invest. 111 (1): 81–90. doi:10.1172/JCI16147. PMID 12511591.
• National Institute on Drug Abuse
• Erowid information on tobacco

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