Nicotine

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Nicotine
Nicotine.svg
Nicotine-3D-vdW.png
Clinical data
Trade names Nicorette, Nicotrol
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
    Dependence
    liability
    Physical: low–moderate
    Psychological: moderate–high [1] [2]
    Addiction
    liability
    High [3]
    Routes of
    administration
    Inhalation; insufflation; oral – buccal, sublingual, and ingestion; transdermal; rectal
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding <5%
    Metabolism Primarily hepatic: CYP2A6, CYP2B6, FMO3, others
    Metabolites Cotinine
    Elimination half-life 1-2 hours; 20 hours active metabolite
    Excretion Renal, urine pH-dependent; [5]
    10–20% (gum), 30% (inhaled); 10–30% (intranasal)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    PDB ligand
    CompTox Dashboard (EPA)
    ECHA InfoCard 100.000.177 OOjs UI icon edit-ltr-progressive.svg
    Chemical and physical data
    Formula C10H14N2
    Molar mass 162.23 g/mol g·mol−1
    3D model (JSmol)
    Chirality Chiral
    Density 1.01 g/cm3
    Melting point −79 °C (−110 °F)
    Boiling point 247 °C (477 °F)

    Nicotine is a stimulant and potent parasympathomimetic alkaloid that is naturally produced in the nightshade family of plants. It is used for the treatment of tobacco use disorders as a smoking cessation aid and nicotine dependence for the relief of withdrawal symptoms. [4] [6] [7] Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), [8] [9] [10] except at two nicotinic receptor subunits (nAChRα9 and nAChRα10) where it acts as a receptor antagonist. [8]

    Stimulant type of psychoactive drug

    Stimulants is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects. Stimulants are widely used throughout the world as prescription medicines as well as without a prescription as performance-enhancing or recreational drugs. The most frequently prescribed stimulants as of 2013 were lisdexamfetamine, methylphenidate, and amphetamine. It is estimated that the percentage of the population that has abused amphetamine-type stimulants and cocaine combined is between 0.8% and 2.1%.

    Potency (pharmacology) measure of drug activity

    In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a given response at low concentrations, while a drug of lower potency evokes the same response only at higher concentrations. Higher potency does not necessarily mean more side effects.

    Alkaloid class of naturally occurring chemical compounds

    Alkaloids are a class of naturally occurring organic compounds that mostly contain basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar structure may also be termed alkaloids. In addition to carbon, hydrogen and nitrogen, alkaloids may also contain oxygen, sulfur and, more rarely, other elements such as chlorine, bromine, and phosphorus.

    Contents

    Nicotine constitutes approximately 0.6–3.0% of the dry weight of tobacco. [11] Usually consistent concentrations of nicotine varying from 2–7  µg/kg (20–70 millionths of a percent wet weight) are found in the edible family Solanaceae, such as potatoes, tomatoes, and eggplant. [12] Some research indicates that the contribution of nicotine obtained from food is substantial in comparison to inhalation of second-hand smoke. [12] Others consider nicotine obtained from food to be trivial unless exceedingly high amounts of certain vegetables are eaten. [12] It functions as an antiherbivore chemical; consequently, nicotine was widely used as an insecticide in the past, [13] [14] and neonicotinoids, such as imidacloprid, are widely used.

    Percentage Number or ratio as a fraction of 100

    In mathematics, a percentage is a number or ratio expressed as a fraction of 100. It is often denoted using the percent sign, "%", or the abbreviations "pct.", "pct"; sometimes the abbreviation "pc" is also used. A percentage is a dimensionless number.

    In the metric system, a microgram or microgramme is a unit of mass equal to one millionth of a gram. The unit symbol is μg according to the International System of Units; the recommended symbol in the United States when communicating medical information is mcg. In μg the prefix symbol for micro- is the Greek letter μ (Mu).

    Kilogram SI unit of mass

    The kilogram is the base unit of mass in the metric system, formally the International System of Units (SI), having the unit symbol kg. It is a widely used measure in science, engineering, and commerce worldwide, and is often called a kilo. The kilogram is very close to the mass of one litre of water.

    Nicotine is highly addictive. [15] [16] [17] It is one of the most commonly abused drugs. [18] An average cigarette yields about 2 mg of absorbed nicotine; high amounts can be more harmful. [19] Nicotine addiction involves drug-reinforced behavior, compulsive use, and relapse following abstinence. [20] Nicotine dependence involves tolerance, sensitization, [21] physical dependence, and psychological dependence. [22] Nicotine dependence causes distress. [23] [24] Nicotine withdrawal symptoms include depressed mood, stress, anxiety, irritability, difficulty concentrating, and sleep disturbances. [1] Mild nicotine withdrawal symptoms are measurable in unrestricted smokers, who experience normal moods only as their blood nicotine levels peak, with each cigarette. [25] On quitting, withdrawal symptoms worsen sharply, then gradually improve to a normal state. [25]

    Cigarette Small roll of cut tobacco designed to be smoked

    A cigarette is a narrow cylinder containing psychoactive material, usually tobacco, that is rolled into thin paper for smoking. Most cigarettes contain a "reconstituted tobacco" product known as "sheet", which consists of "recycled [tobacco] stems, stalks, scraps, collected dust, and floor sweepings", to which are added glue, chemicals and fillers; the product is then sprayed with nicotine that was extracted from the tobacco scraps, and shaped into curls. The cigarette is ignited at one end, causing it to smolder; the resulting smoke is orally inhaled via the opposite end. Most modern cigarettes are filtered, although this does not make them safer. Cigarette manufacturers have described cigarettes as a drug administration system for the delivery of nicotine in acceptable and attractive form. Cigarettes are addictive and cause cancer, chronic obstructive pulmonary disease, heart disease, and other health problems.

    Addiction state characterized by compulsive engagement in rewarding stimuli despite adverse consequences

    Addiction is a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences. Despite the involvement of a number of psychosocial factors, a biological process – one which is induced by repeated exposure to an addictive stimulus – is the core pathology that drives the development and maintenance of an addiction. The two properties that characterize all addictive stimuli are that they are reinforcing and intrinsically rewarding.

    Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, antiepileptics and antidepressants, as well as the recreational misuse of drugs such as alcohol, opioids, amphetamines and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes. Acute withdrawal syndromes can last days, weeks or months. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or "PAWS", is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines. To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.

    Nicotine use as a tool for quitting smoking has a good safety history. [26] Nicotine itself is associated with some health harms. [27] Youth are especially sensitive to the effects of nicotine. [28] Nicotine is potentially harmful to non-users. [28] At low amounts, it has a mild analgesic effect. [28] The Surgeon General of the United States indicates that nicotine does not cause cancer. [29] Nicotine has been shown to produce birth defects in some animal species, but not others. [30] It is considered a teratogen in humans. [31] Nicotine can harm adolescent brain development. [32] The median lethal dose of nicotine in humans is unknown, [33] but high doses are known to cause nicotine poisoning. [29]

    Analgesic pharmaceutical drug

    An analgesic or painkiller is any member of the group of drugs used to achieve analgesia, relief from pain.

    Surgeon General of the United States Head of the U.S. Public Health Service Commissioned Corps

    The surgeon general of the United States is the operational head of the U.S. Public Health Service Commissioned Corps (PHSCC) and thus the leading spokesperson on matters of public health in the federal government of the United States. The surgeon general's office and staff are known as the Office of the Surgeon General (OSG) which is housed within the Office of the Assistant Secretary for Health.

    Effects of electronic cigarettes on human brain development Effects of electronic cigarettes on the developing human brain

    Exposure to nicotine-containing 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.

    Uses

    Medical

    A 21 mg patch applied to the left arm. The Cochrane Collaboration finds that nicotine replacement therapy increases a quitter's chance of success by 50-60%, regardless of setting. Nicoderm.JPG
    A 21 mg patch applied to the left arm. The Cochrane Collaboration finds that nicotine replacement therapy increases a quitter's chance of success by 50–60%, regardless of setting.

    The primary therapeutic use of nicotine is treating nicotine dependence to eliminate smoking and the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, inhalers, electronic/substitute cigarettes or nasal sprays to wean them off their dependence. A 2018 Cochrane Collaboration review found high quality evidence that all current forms of nicotine replacement therapy (gum, patch, lozenges, inhaler, and nasal spray) therapies increase the chances of successfully quitting smoking by 50–60%, regardless of setting. [34]

    Pharmacotherapy is therapy using pharmaceutical drugs, as distinguished from therapy using surgery, radiation, movement, or other modes. Among physicians, sometimes the term medical therapy refers specifically to pharmacotherapy as opposed to surgical or other therapy; for example, in oncology, medical oncology is thus distinguished from surgical oncology. Pharmacists are experts in pharmacotherapy and are responsible for ensuring the safe, appropriate, and economical use of pharmaceutical drugs. The skills required to function as a pharmacist require knowledge, training and experience in biomedical, pharmaceutical and clinical sciences. Pharmacology is the science that aims to continually improve pharmacotherapy. The pharmaceutical industry and academia use basic science, applied science, and translational science to create new pharmaceutical drugs.

    Smoking Practice in which a substance is burned and the resulting smoke breathed in to be tasted and absorbed into the bloodstream

    Smoking is a practice in which a substance is burned and the resulting smoke breathed in to be tasted and absorbed into the bloodstream. Most commonly, the substance used is the dried leaves of the tobacco plant, which have been rolled into a small square of rice paper to create a small, round cylinder called a "cigarette". Smoking is primarily practiced as a route of administration for recreational drug use because the combustion of the dried plant leaves vaporizes and delivers active substances into the lungs where they are rapidly absorbed into the bloodstream and reach bodily tissue. In the case of cigarette smoking these substances are contained in a mixture of aerosol particles and gasses and include the pharmacologically active alkaloid nicotine; the vaporization creates heated aerosol and gas into a form that allows inhalation and deep penetration into the lungs where absorption into the bloodstream of the active substances occurs. In some cultures, smoking is also carried out as a part of various rituals, where participants use it to help induce trance-like states that, they believe, can lead them to spiritual enlightenment.

    Nicotine gum is a type of chewing gum that delivers nicotine to the body. It is used as an aid in nicotine replacement therapy (NRT), a process for smoking cessation and quitting smokeless tobacco. The nicotine is delivered to the bloodstream via absorption by the tissues of the mouth.

    Combining nicotine patch use with a faster acting nicotine replacement, like gum or spray, improves the odds of treatment success. [35] 4 mg versus 2 mg nicotine gum also increase the chances of success. [35]

    Nicotine patch

    A nicotine patch is a transdermal patch that releases nicotine into the body through the skin. It is used in nicotine replacement therapy (NRT), a process for smoking cessation. Endorsed and approved by the Food and Drug Administration (FDA), it is considered one of the safer NRTs available.

    In contrast to recreational nicotine products, which have been designed to maximize the likelihood of addiction, nicotine replacement products (NRTs) are designed to minimize addictiveness. [29] :112 The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk. [23]

    Pesticide

    Nicotine has been used as an insecticide since at least the 1690s, in the form of tobacco extracts [36] (although other components of tobacco also seem to have pesticide effects). [37] Nicotine pesticides have not been commercially available in the US since 2014, [38] and homemade pesticides are banned on organic crops [39] and not recommended for small gardeners. [40] Nicotine pesticides have been banned in the EU since 2009. [41] Foods are imported from countries in which nicotine pesticides are allowed, such as China, but foods may not exceed maximum nicotine levels. [41] [42] Neonicotinoids, which are derived from and structurally similar to nicotine, are widely used as agricultural and veterinary pesticides as of 2016. [43] [36]

    In nicotine-producing plants, nicotine functions as an antiherbivory chemical; consequently, nicotine has been widely used as an insecticide, [44] [14] and neonicotinoids, such as imidacloprid, are widely used.

    Performance

    Nicotine-containing products are sometimes used for the performance-enhancing effects of nicotine on cognition.[ citation needed ] A meta-analysis of 41  double-blind, placebo-controlled studies concluded that nicotine or smoking had significant positive effects on aspects of fine motor abilities, alerting and orienting attention, and episodic and working memory. [45] A 2015 review noted that stimulation of the α4β2 nicotinic receptor is responsible for certain improvements in attentional performance; [46] among the nicotinic receptor subtypes, nicotine has the highest binding affinity at the α4β2 receptor (ki=1 nM), which is also the biological target that mediates nicotine's addictive properties. [47] Nicotine has potential beneficial effects, but it also has paradoxical effects, which may be due to the inverted U-shape of the dose-response curve or pharmacokinetic features. [48]

    Recreational

    Nicotine is used as a recreational drug. [49] It is widely used because it is highly addictive and hard to discontinue using it. [50] Nicotine is often used compulsively, [51] and dependence can develop within days. [51] [52] Recreational drug users commonly use nicotine for its mood-altering effects. [23] Other recreational nicotine products include chewing tobacco,[ citation needed ] cigars, [53] cigarettes, [53] e-cigarettes, [54] snuff,[ citation needed ] pipe tobacco, [53] and snus.[ citation needed ]

    Contraindications

    Nicotine use for tobacco cessation has few contraindications. [55]

    It is not known whether nicotine replacement therapy is effective for smoking cessation in adolescents, as of 2014. [56] It is therefore not recommended to adolescents. [57] It is not safe to use nicotine during pregnancy or breastfeeding, although it is safer than smoking; the desirability of NRT use in pregnancy is therefore debated. [58] [59] [60]

    Precautions are needed when using NRT in people who have had a myocardial infarction within two weeks, a serious or worsening angina pectoris, and/or a serious underlying arrhythmia. [57] Using nicotine products during cancer treatment is counterrecommended, as nicotine promotes tumour growth, but temporary use of NRTs to quit smoking may be advised for harm reduction. [61]

    Nicotine gum is contraindicated in individuals with temporomandibular joint disease. [62] People with chronic nasal disorders and severe reactive airway disease require additional precautions when using nicotine nasal sprays. [57] Nicotine in any form is contraindicated in individuals with a known hypersensitivity to nicotine. [62] [57]

    Adverse effects

    Nicotine may not be harmless, [63] but it is safer than inhaled tobacco smoke. [64] As medicine, nicotine is used to help with quitting smoking and has good safety in this form. [26] Nicotine itself poses health risks to certain vulnerable groups [65] such as youth, [28] but the ideal course of action for smokers is to quit all nicotine use. [66] Nicotine can harm adolescent brain development, which continues into the early to mid-20s. [32]

    The common side effects from nicotine exposure are listed in the table below. Serious adverse events due to the use of nicotine replacement therapy are extremely rare. [34] At low amounts, it has a mild analgesic effect. [28] At sufficiently high doses, nicotine may result in nausea, vomiting, diarrhea, salivation, bradyarrhythmia, and possibly seizures and hypoventilation. [67]

    Common side effects of nicotine use according to route of administration and dosage form
    Route of administration Dosage form Associated side effects of nicotineSources
    Buccal Nicotine gum Indigestion, nausea, hiccups, traumatic injury to oral mucosa or teeth, irritation or tingling of the mouth and throat, oral mucosal ulceration, jaw-muscle ache, burping, gum sticking to teeth, unpleasant taste, dizziness, lightheadedness, headache, and insomnia. [34] [62]
    Buccal Lozenge Nausea, dyspepsia, flatulence, headache, upper respiratory tract infections, irritation (i.e., a burning sensation), hiccups, sore throat, coughing, dry lips, and oral mucosal ulceration. [34] [62]
    Transdermal Transdermal
    patch
    Application site reactions (i.e., pruritus, burning, or erythema), diarrhea, dyspepsia, abdominal pain, dry mouth, nausea, dizziness, nervousness or restlessness, headache, vivid dreams or other sleep disturbances, and irritability. [34] [62] [68]
    Intranasal Nasal spray Runny nose, nasopharyngeal and ocular irritation, watery eyes, sneezing, and coughing. [34] [62] [69]
    Oral inhalation Inhaler Dyspepsia, oropharyngeal irritation (e.g., coughing, irritation of the mouth and throat), rhinitis, and headache. [34] [62] [70]
    All (nonspecific)Peripheral vasoconstriction, tachycardia (i.e., fast heart rate), elevated blood pressure, and increased alertness and cognitive performance. [62] [69]

    Sleep

    Possible side effects of nicotine. Side effects of nicotine.png
    Possible side effects of nicotine.

    Nicotine reduces the amount of rapid eye movement (REM) sleep, slow-wave sleep (SWS), and total sleep time in healthy nonsmokers given nicotine via a transdermal patch, and the reduction is dose-dependent. [72] Acute nicotine intoxication has been found to significantly reduce total sleep time and increase REM latency, sleep onset latency, and non-rapid eye movement (NREM) stage 2 sleep time. [72] [73]

    Cardiovascular system

    A 2018 Cochrane review found that, in rare cases, nicotine replacement therapy can cause non-ischemic chest pain (i.e., chest pain that is unrelated to a myocardial infarction) and heart palpitations. [34] The same review indicated that nicotine replacement therapy does not increase the incidence of serious cardiac adverse events (i.e., myocardial infarction, stroke, and cardiac death) relative to controls. [34]

    Reinforcement disorders

    ΔFosB accumulation from excessive drug use
    DFosB accumulation.svg
    Top: this depicts the initial effects of high dose exposure to an addictive drug on gene expression in the nucleus accumbens for various Fos family proteins (i.e., c-Fos, FosB, ΔFosB, Fra1, and Fra2).
    Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these phosphorylated (35–37  kilodalton) ΔFosB isoforms persist in the D1-type medium spiny neurons of the nucleus accumbens for up to 2 months. [74] [75]

    Nicotine is highly addictive. [15] [16] [17] Nicotine dependence involves aspects of both psychological dependence and physical dependence, since discontinuation of extended use has been shown to produce both affective (e.g., anxiety, irritability, craving, anhedonia) and somatic (mild motor dysfunctions such as tremor) withdrawal symptoms. [1] Withdrawal symptoms peak in one to three days [76] and can persist for several weeks. [77] Some people experience symptoms for 6 months or longer. [78]

    Normal between-cigarettes discontinuation, in unrestricted smokers, causes mild but measurable nicotine withdrawal symptoms. [79] These include mildly worse mood, stress, anxiety, cognition, and sleep, all of which briefly return to normal with the next cigarette. [79] Smokers have worse mood than they would have if they were not nicotine-dependent; they experience normal moods only immediately after smoking. [25] Nicotine dependence is associated with poor sleep quality and shorter sleep duration among smokers. [80] [81]

    In dependent smokers, withdrawal causes impairments in memory and attention, and smoking during withdrawal returns these cognitive abilities to pre-withdrawal levels. [82] The temporarily increased cognitive levels of smokers after inhaling smoke are offset by periods of cognitive decline during nicotine withdrawal. [79] Therefore, the overall daily cognitive levels of smokers and non-smokers are roughly similar. [79]

    Nicotine activates the mesolimbic pathway and induces long-term ΔFosB expression (i.e., produces phosphorylated ΔFosB isoforms) in the nucleus accumbens when inhaled or injected frequently or at high doses, but not necessarily when ingested. [83] [84] [85] Consequently, high daily exposure (possibly excluding oral route) to nicotine can cause ΔFosB overexpression in the nucleus accumbens, resulting in nicotine addiction. [83] [84]

    Cancer

    Although nicotine does not cause cancer in humans, [86] it is unclear whether it functions as a tumor promoter as of 2012. [87] A 2018 report by the National Academies of Sciences, Engineering, and Medicine concludes, “[w]hile it is biologically plausible that nicotine can act as a tumor promoter, the existing body of evidence indicates this is unlikely to translate into increased risk of human cancer.” [88]

    Low levels of nicotine stimulate cell proliferation, while high levels are cytotoxic. [89] Nicotine increases cholinergic signaling and adrenergic signaling in colon cancer cells, [90] thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-lipoxygenase (5-LOX), and epidermal growth factor (EGF). Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization. [91] [92] In cancer cells, nicotine promotes the epithelial–mesenchymal transition which makes the cancer cells more resistant to drugs that treat cancer. [93]

    Pregnancy and breastfeeding

    Nicotine has been shown to produce birth defects in some animal species, but not others; [30] consequently, it is considered to be a possible teratogen in humans. [30] In animal studies that resulted in birth defects, researchers found that nicotine negatively affects fetal brain development and pregnancy outcomes; [30] [29] the negative effects on early brain development are associated with abnormalities in brain metabolism and neurotransmitter system function. [94] Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke. [95]

    Some evidence suggests that in utero nicotine exposure influences the occurrence of certain conditions later in life, including type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility. [26]

    Overdose

    It is unlikely that a person would overdose on nicotine through smoking alone. The US Food and Drug Administration (FDA) stated in 2013 that there are no significant safety concerns associated with the use of more than one form of over-the-counter (OTC) nicotine replacement therapy at the same time, or using OTC NRT at the same time as another nicotine-containing product, like cigarettes. [96] The median lethal dose of nicotine in humans is unknown. [33] [19] Nevertheless, nicotine has a relatively high toxicity in comparison to many other alkaloids such as caffeine, which has an LD50 of 127 mg/kg when administered to mice. [97] At sufficiently high doses, it is associated with nicotine poisoning, [29] which, while common in children, rarely results in significant morbidity or death. [30]

    The initial symptoms of a nicotine overdose typically include nausea, vomiting, diarrhea, hypersalivation, abdominal pain, tachycardia (rapid heart rate), hypertension (high blood pressure), tachypnea (rapid breathing), headache, dizziness, pallor (pale skin), auditory or visual disturbances, and perspiration, followed shortly after by marked bradycardia (slow heart rate), bradypnea (slow breathing), and hypotension (low blood pressure). [30] Respiratory stimulation (i.e., tachypnea) is one of the primary signs of nicotine poisoning. [30] At sufficiently high doses, somnolence (sleepiness or drowsiness), confusion, syncope (loss of consciousness from fainting), shortness of breath, marked weakness, seizures, and coma may occur. [5] [30] Lethal nicotine poisoning rapidly produces seizures, and death – which may occur within minutes – is believed to be due to respiratory paralysis. [30]

    Toxicity

    Today nicotine is less commonly used in agricultural insecticides, which was a main source of poisoning. More recent cases of poisoning typically appear to be in the form of Green Tobacco Sickness, [30] accidental ingestion of tobacco or tobacco products, or ingestion of nicotine-containing plants. [98] [99] [100] People who harvest or cultivate tobacco may experience Green Tobacco Sickness (GTS), a type of nicotine poisoning caused by dermal exposure to wet tobacco leaves. This occurs most commonly in young, inexperienced tobacco harvesters who do not consume tobacco. [98] [101] People can be exposed to nicotine in the workplace by breathing it in, skin absorption, swallowing it, or eye contact. The Occupational Safety and Health Administration (OSHA) has set the legal limit (permissible exposure limit) for nicotine exposure in the workplace as 0.5 mg/m3 skin exposure over an 8-hour workday. The US National Institute for Occupational Safety and Health (NIOSH) has set a recommended exposure limit (REL) of 0.5 mg/m3 skin exposure over an 8-hour workday. At environmental levels of 5 mg/m3, nicotine is immediately dangerous to life and health. [102]

    Drug interactions

    Pharmacodynamic

    Pharmacokinetic

    Nicotine and cigarette smoke both induce the expression of liver enzymes (e.g., certain cytochrome P450 proteins) which metabolize drugs, leading to the potential for alterations in drug metabolism. [62]

    Pharmacology

    Pharmacodynamics

    Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), [8] [9] except at two nicotinic receptor subunits (nAChRα9 and nAChRα10) where it acts as a receptor antagonist. [8]

    Central nervous system

    Effect of nicotine on dopaminergic neurons. NicotineDopaminergic WP1602.png
    Effect of nicotine on dopaminergic neurons.

    By binding to nicotinic acetylcholine receptors in the brain, nicotine elicits its psychoactive effects and increases the levels of several neurotransmitters in various brain structures – acting as a sort of "volume control." [103] [104] Nicotine has a higher affinity for nicotinic receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis. [105] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes. [106] Nicotine is unusual in comparison to most drugs, as its profile changes from stimulant to sedative with increasing dosages, a phenomenon known as "Nesbitt's paradox" after the doctor who first described it in 1969. [107] [108] At very high doses it dampens neuronal activity. [109] Nicotine induces both behavioral stimulation and anxiety in animals. [5] Research into nicotine's most predominant metabolite, cotinine, suggests that some of nicotine's psychoactive effects are mediated by cotinine. [110]

    Nicotine activates nicotinic receptors (particularly α4β2 nicotinic receptors) on neurons that innervate the ventral tegmental area and within the mesolimbic pathway where it appears to cause the release of dopamine. [111] [112] This nicotine-induced dopamine release occurs at least partially through activation of the cholinergic–dopaminergic reward link in the ventral tegmental area. [112] Nicotine also appears to induce the release of endogenous opioids that activate opioid pathways in the reward system, since naltrexone  – an opioid receptor antagonist  – blocks nicotine self-administration. [111] These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of euphoria; [111] however, mild euphoria from nicotine use can occur in some individuals. [111] Chronic nicotine use inhibits class I and II histone deacetylases in the striatum, where this effect plays a role in nicotine addiction. [113] [114]

    Sympathetic nervous system

    Effect of nicotine on chromaffin cells NicotineChromaffinCells WP1603.png
    Effect of nicotine on chromaffin cells

    Nicotine also activates the sympathetic nervous system, [115] acting via splanchnic nerves to the adrenal medulla, stimulating 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.

    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. [116]

    Pharmacokinetics

    Urinary metabolites of nicotine, quantified as average percentage of total urinary nicotine. Nicotine metabolism.png
    Urinary metabolites of nicotine, quantified as average percentage of total urinary nicotine.

    As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation. [118] The elimination half-life of nicotine in the body is around two hours. [119] Nicotine is primarily excreted in urine and urinary concentrations vary depending upon urine flow rate and urine pH. [5]

    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, [120] 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 has a half-life of 1–2 hours. Cotinine is an active metabolite of nicotine that remains in the blood with a half-life of 18–20 hours, making it easier to analyze. [121]

    Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6) and FMO3, which selectively metabolizes (S)-nicotine. A major metabolite is cotinine. Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide. [122] Under some conditions, other substances may be formed such as myosmine. [123]

    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. [124]

    Chemistry

    NFPA 704
    fire diamond
    Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilHealth code 4: Very short exposure could cause death or major residual injury. E.g. VX gasReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no codeNicotine
    1
    4
    0
    The fire diamond hazard sign for nicotine. [125]

    Nicotine is a hygroscopic, colorless to yellow-brown, oily liquid, that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its base form between 60 °C 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. [126] Nicotine is readily volatile (vapor pressure 5.5 ㎩ at 25 ℃) and dibasic (Kb1=1×10⁻⁶, Kb2=1×10⁻¹¹). [127] On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3), and methylamine. [128]

    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. [129] The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride and sulphate salts become optically inactive if heated in a closed vessel above 180 °C. [128] Anabasine is a structural isomer of nicotine, as both compounds have the molecular formula C 10 H 14 N 2. Pod mod electronic cigarettes use nicotine in the form of a protonated nicotine, rather than free-base nicotine found in earlier generations. [130]

    Occurrence

    Nicotine is a natural product of tobacco, occurring in the leaves of Nicotiana tabacum in a range of 0.5 to 7.5% depending on variety. [131] Nicotine is also found in the leaves of Nicotiana rustica , in amounts of 2–14%; in Duboisia hopwoodii ; and in Asclepias syriaca . [127]

    Nicotine also naturally occurs in smaller amounts (varying from 2–7  µg/kg, or 20–70 millionths of a percent wet weight [12] ) in Solanaceaein plants from the family Solanaceae (such as potatoes, tomatoes, eggplant, and peppers [12] ). [132]

    The amounts of nicotine of tomato varieties lowered substantially as the fruits ripened. [12] Nicotine content in tea leaves is greatly inconsistent and in some cases considerably greater than in the Solanaceae fruits. [12] A 1999 report found "In some papers it is suggested that the contribution of dietary nicotine intake is significant when compared with exposure to ETS [environmental tobacco smoke] or by active smoking of small numbers of cigarettes. Others consider the dietary intake to be negligible unless inordinately large amounts of specific vegetables are consumed." [12] The amount of nicotine eaten per day is roughly around 1.4 and 2.25  µg/day at the 95th percentile. [12] These numbers may be low due to insufficient food intake data. [12] Since the amounts of nicotine from the Solanum family including potato, tomato, eggplant, and from the Capsicum family vary in the parts per billion, they are tough to measure. [133]

    Biosynthesis

    Nicotine biosynthesis Nicotine biosynthesis june 2012.png
    Nicotine biosynthesis

    The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that comprise nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidine is derived from N-methyl-Δ1-pyrrollidium cation. [134] [135] 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 (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.[ citation needed ]

    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 (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.[ citation needed ]

    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. [136]

    Detection in body fluids

    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. [137] [138] Nicotine use is not regulated in competitive sports programs. [139]

    History, society, and culture

    Nicotine was originally isolated from the tobacco plant in 1828 by chemists Wilhelm Heinrich Posselt and Karl Ludwig Reimann from Germany, who believed it was a poison. [140] [141] Its chemical empirical formula was described by Melsens in 1843, [142] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893, [143] [144] [145] [ clarification needed ] and it was first synthesized by Amé Pictet and A. Rotschy in 1904. [146]

    Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, presented to the French King, [147] and who promoted their medicinal use. Smoking was believed to protect against illness, particularly the plague. [147]

    Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals. [14]

    The nicotine content of popular American-brand cigarettes has increased over time, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005. [148]

    In the United States, nicotine products and Nicotine Replacement Therapy products like Nicotrol are only available to persons 18 and above; proof of age is required; not for sale in vending machine or from any source where proof of age cannot be verified. In some states[ where? ], these products are only available to persons over the age of 21.[ medical citation needed ][ where? ] Many states in the US have implemented a Tobacco 21 law for tobacco products, raising the minimum age from 18 to 21. [149]

    In the European Union, the minimum age to purchase nicotine products is 18. However, there is no minimum age requirement to use tobacco or nicotine products. [150]

    In media

    External image
    Searchtool.svg An image showing Nick O'Teen fleeing from Superman, Comic Vine

    In some anti-smoking literature, the harm that tobacco smoking and nicotine addiction does is personified as Nick O'Teen, represented as a humanoid with some aspect of a cigarette or cigarette butt about him or his clothes and hat. [151] Nick O'Teen was a villain that was created for the Health Education Council. [151]

    Research

    Central nervous system

    While acute/initial nicotine intake causes activation of neuronal nicotine receptors, chronic low doses of nicotine use leads to desensitisation of those receptors (due to the development of tolerance) and results in an antidepressant effect, with early research showing low dose nicotine patches could be an effective treatment of major depressive disorder in non-smokers. [152]

    Though tobacco smoking is associated with an increased risk of Alzheimer's disease, [153] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease. [154]

    Smoking is associated with a decreased risk of Parkinson's Disease; however, it is unknown whether this is due to people with healthier brain dopaminergic reward centers (the area of the brain affected by Parkinson's) being more likely to enjoy smoking and thus pick up the habit, nicotine directly acting as a neuroprotective agent, or other compounds in cigarette smoke acting as neuroprotective agents. [155]

    Immune system

    Immune cells of both the Innate immune system and adaptive immune systems frequently express the α2, α5, α6, α7, α9, and α10 subunits of nicotinic acetylcholine receptors. [156] Evidence suggests that nicotinic receptors which contain these subunits are involved in the regulation of immune function. [156]

    Optopharmacology

    A photoactivatable form of nicotine, which releases nicotine when exposed to ultraviolet light with certain conditions, has been developed for studying nicotinic acetylcholine receptors in brain tissue. [157]

    Oral Health

    Several in vitro studies have investigated the potential effects of nicotine on a range of oral cells. A recent systematic review concluded that nicotine was unlikely to be cytotoxic to oral cells in vitro in most physiological conditions but further research is needed. [158] Understanding the potential role of nicotine in oral health has become increasingly important given the recent introduction of novel nicotine products and their potential role in helping smokers quit. [159]

    See also

    Related Research Articles

    Smoking cessation Process of discontinuing tobacco smoking

    Smoking cessation is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is addictive and can cause dependence. Nicotine withdrawal often makes the process of quitting difficult.

    Drug withdrawal is the group of symptoms that occur upon the abrupt discontinuation or decrease in intake of medications or recreational drugs.

    Cotinine chemical compound

    Cotinine is an alkaloid found in tobacco and is also the predominant metabolite of nicotine. Cotinine is used as a biomarker for exposure to tobacco smoke. Cotinine is currently being studied as a treatment for depression, 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.

    Nicotine replacement therapy stop-smoking treatment

    Nicotine replacement therapy (NRT) is a medically-approved way to take nicotine by means other than tobacco. It is used to help with quitting smoking or stopping chewing tobacco. It increases the chance of quitting 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 more than one type of NRT at a time may increase effectiveness.

    Substance dependence, also known as drug dependence, is an adaptive state that develops from repeated drug administration, and which results in withdrawal upon cessation of drug use. A drug addiction, a distinct concept from substance dependence, is defined as compulsive, out-of-control drug use, despite negative consequences. An addictive drug is a drug which is both rewarding and reinforcing. ΔFosB, a gene transcription factor, is now known to be a critical component and common factor in the development of virtually all forms of behavioral and drug addictions, but not dependence.

    Health effects of tobacco circumstances, mechanisms, and factors of tobacco consumption on human health

    Tobacco use has predominantly negative effects on human health and concern about health effects of tobacco has a long history. Research has focused primarily on cigarette tobacco smoking.

    Varenicline pharmaceutical drug

    Varenicline is a prescription medication used to treat nicotine addiction. It reduces both craving for and decreases the pleasurable effects of cigarettes and other tobacco products.

    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 exoprotein A.

    Nicotine withdrawal Process of withdrawing from nicotine addiction

    Nicotine withdrawal is a group of symptoms that occur in the first few weeks upon the abrupt discontinuation or decrease in intake of nicotine. Symptoms include intense cravings for nicotine, anger/irritability, anxiety, depression, impatience, trouble sleeping, restlessness, hunger or weight gain, and difficulty concentrating. A smoking cessation program may improve one’s chance for success in quitting nicotine. Nicotine withdrawal is recognized in both the American Psychiatric Association Diagnostic and Statistical Manual and the WHO International Classification of Diseases.

    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 abuse of other drugs. Tobacco smoking is widely acknowledged as a leading cause of illness and death, and reducing smoking is vital to public health.

    Electronic cigarette electronic cigarette

    An electronic cigarette or e-cigarette is a handheld battery-powered vaporizer that simulates smoking and provides some of the behavioral aspects of smoking, including the hand-to-mouth action of smoking, but without burning tobacco. Using an e-cigarette is known as "vaping" and the user is referred to as a "vaper." Instead of cigarette smoke, the user inhales an aerosol, commonly called vapor. E-cigarettes typically have a heating element that atomizes a liquid solution called e-liquid. E-cigarettes are automatically activated by taking a puff; others turn on manually by pressing a button. Some e-cigarettes look like traditional cigarettes, but they come in many variations. Most versions are reusable, though some are disposable. There are first-generation, second-generation, third-generation, and fourth-generation devices. There is also pod mod devices that use nicotine in the form of a protonated nicotine, rather than free-base nicotine found in earlier generations. E-liquids usually contain propylene glycol, glycerin, nicotine, flavorings, additives, and differing amounts of contaminants. E-liquids are also sold without propylene glycol, nicotine, or flavors.

    Nicotine dependence state of dependence upon nicotine

    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 harmful social consequences. Tolerance is another component of drug dependence. Nicotine dependence develops over time as a person continues to use nicotine. Nicotine dependence is a serious public health concern due to it being one of the leading causes of avoidable deaths worldwide.

    Psychological dependence is a state that involves emotional–motivational withdrawal symptoms, e.g. anxiety and anhedonia, upon cessation of drug use or certain behaviours. It develops through frequent exposure to a psychoactive substance or behaviour, though behavioural dependence is less talked about. The specific mechanism involves a neuronal counter-adaption, which could be mediated through changes in neurotransmittor activity or altered receptor expression. Withdrawal symptoms can be attenuated by environmental enrichment and physical activity. Psychological dependence is not to be confused with physical dependence, which induces physical withdrawal symptoms upon discontinuation of use. However they are not mutually exclusive.

    Studies across 20 countries show a strong association between schizophrenia and tobacco smoking, whereby people with schizophrenia are much more likely to smoke than those without the disease. For example, in the United States, 80% or more of people with schizophrenia smoke, compared to 20% of the general population in 2006.

    The scientific community in United States and Europe are primarily concerned with the possible effect of electronic cigarette use on public health. There is concern among public health experts that e-cigarettes could renormalize smoking, weaken measures to control tobacco, and serve as a gateway for smoking among youth. The public health community is divided over whether to support e-cigarettes, because their safety and efficacy for quitting smoking is unclear. Many in the public health community acknowledge the potential for their quitting smoking and decreasing harm benefits, but there remains a concern over their long-term safety and potential for a new era of users to get addicted to nicotine and then tobacco. There is concern among tobacco control academics and advocates that prevalent universal vaping "will bring its own distinct but as yet unknown health risks in the same way tobacco smoking did, as a result of chronic exposure", among other things.

    Jed Eugene Rose, Ph.D. 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.

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      Conclusions
      ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a ‘‘molecular switch’’ (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124).
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