From Wikipedia, the free encyclopedia
Nicotine is a
potent parasympathomimetic stimulant and an
alkaloid found in the
nightshade family of plants. Nicotine acts as an
agonist at most
nicotinic acetylcholine receptors (nAChRs),
[4][5] except at two
nicotinic receptor subunits (
nAChRα9 and
nAChRα10) where it acts as a
receptor antagonist.
[4] Nicotine is found in the leaves of
Nicotiana rustica, in amounts of 2–14%; in the
tobacco plant,
Nicotiana tabacum; in
Duboisia hopwoodii; and in
Asclepias syriaca.
[6]
Nicotine constitutes approximately 0.6–3.0
% of the dry weight of tobacco.
[7] It also occurs in edible plants, such
Solanaceae, which include
eggplants,
potatoes, and
tomatoes, but at trace levels generally under 200
nanograms per gram, dry weight (less than .00002%).
[8][9][10] Nicotine functions as an
antiherbivore chemical; consequently, nicotine was widely used as an
insecticide in the past,
[11][12] and
neonicotinoids, such as
imidacloprid, are widely used.
Nicotine is highly
addictive.
[13][14] An average
cigarette yields about 2 mg of absorbed nicotine; in lesser doses of that order, the substance acts as a
stimulant in
mammals, while high amounts (50–100 mg) can be harmful.
[15][16][17] This stimulant effect is a contributing factor to the addictive properties of
tobacco smoking.
Nicotine's addictive nature includes psychoactive effects,
drug-reinforced behavior, compulsive use, relapse after abstinence,
physical dependence and tolerance.
[18]
Beyond addiction, both short and long-term nicotine exposure have not been established as dangerous to adults,
[19] except among certain vulnerable groups.
[20] At high-enough doses, nicotine is associated with
poisonings and is potentially lethal.
[17][21] Nicotine as a tool for
quitting smoking has a good safety history.
[22] There is inadequate research to show that nicotine itself is associated with cancer in humans.
[21] Nicotine in the form of
nicotine replacement products is less of a cancer risk than
smoking.
[21] Nicotine is linked to possible birth defects.
[23]
During pregnancy, there are risks to the child later in life for type 2
diabetes, obesity, hypertension, neurobehavioral defects, respiratory
dysfunction, and infertility.
[22] The use of
electronic cigarettes, which are designed to be refilled with nicotine-containing
e-liquid,
has raised concerns over nicotine overdoses, especially with regard to
the possibility of young children ingesting the liquids.
[24]
Psychoactive effects
Nicotine's
mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.
[25] 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.
[26]
When a
cigarette is smoked, nicotine-rich blood passes from the
lungs to the
brain within seven seconds and immediately stimulates
nicotinic acetylcholine receptors; this indirectly promotes the release of many chemical messengers such as
acetylcholine,
norepinephrine,
epinephrine,
arginine vasopressin,
serotonin,
dopamine, and
beta-endorphin in parts of the brain.
[27][28] Nicotine also extends the duration of positive effects of dopamine and increases the sensitivity of the brain's
reward system to
rewarding stimuli.
[29][30] Most cigarettes contain 1–3 milligrams of inhalable nicotine.
[31][unreliable source?]
Studies suggest that when smokers wish to achieve a stimulating effect,
they take short quick puffs, which produce a low level of blood
nicotine.
[32][needs update]
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.
[33][34] At very high doses it dampens
neuronal activity.
[35]
Uses
Medical
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. Studies have found that these
therapies increase the chance of success of quitting by 50 to 70%,
[36] though reductions in the population as a whole have not been demonstrated.
[37]
Enhancing performance
Nicotine is frequently used for its performance-enhancing effects on cognition, alertness, and focus.
[38] 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.
[39] A 2015 review noted that stimulation of the
α4β2 nicotinic receptor is responsible for certain improvements in attentional performance;
[40] among the
nicotinic receptor subtypes, nicotine has the highest
binding affinity at the α4β2 receptor (k
i=1
nM), which is also the biological target that mediates nicotine's
addictive properties.
[41] Nicotine has potential beneficial effects, but it also has
paradoxical effects, which may be due to its inverted U-shape or
pharmacokinetic features.
[42]
Recreational
Nicotine is commonly consumed as a recreational drug for its stimulant effects.
[43] Recreational nicotine products include
chewing tobacco,
cigars,
cigarettes,
e-cigarettes,
snuff,
pipe tobacco, and
snus.
Adverse effects
Limited data exists on the health effects of long-term use of pure nicotine, because nicotine is usually consumed via
tobacco products.
[44] The long-term use of nicotine in the form of snus incurs a slight risk of cardiovascular disease compared to tobacco smoking
[44] and is not associated with cancer.
[45][not in citation given] Nicotine is one of the most rigorously studied drugs.
[46] The complex effects of nicotine are not entirely understood.
[23] Studies of continued use of
nicotine replacement products in those who have stopped smoking found no
adverse effects from months to several years, and that people with
cardiovascular disease were able to tolerate them for 12 weeks.
[44] The general medical position is that nicotine itself,
in small doses[failed verification], poses few health risks, except among certain vulnerable groups.
[20] A 2016
Royal College of Physicians report found "nicotine alone in the doses used by smokers represents little if any hazard to the user".
[47] A 2014
American Heart Association policy statement found that some health concerns relate to nicotine.
[44] Experimental research suggests that adolescent nicotine use may harm
brain development.
[21] Children exposed to nicotine may have a number of lifelong health issues.
[14] Administration of nicotine to guinea pigs has been shown to cause harm to cells of the inner ear.
[48][unreliable medical source?] As medicine, nicotine is used to help with
quitting smoking and has good safety in this form.
[22]
Metabolism and body weight
By reducing the
appetite and raising the
metabolism, some smokers may
lose weight as a consequence.
[49][50]
By increasing metabolic rate and inhibiting the usual compensatory
increase in appetite, the body weight of smokers is lower on average
than that of non-smokers. When smokers quit, they gain on average 5–6 kg
weight, returning to the average weight of non-smokers.
[51]
Vascular system
Human epidemiology studies show that nicotine use is not a significant cause of cardiovascular disease.
[52] A 2015 review found that nicotine is associated with cardiovascular disease.
[23]
A 2016 review suggests that "the risks of nicotine without tobacco
combustion products (cigarette smoke) are low compared to cigarette
smoking, but are still of concern in people with cardiovascular
disease."
[53]
Some studies in people show the possibility that nicotine contributes
to acute cardiovascular events in smokers with established
cardiovascular disease, and induces pharmacologic effects that might
contribute to increased
atherosclerosis.
[53] Prolonged nicotine use seems not to increase atherosclerosis.
[53]
Brief nicotine use, such as nicotine medicine, seems to incur a slight
cardiovascular risk, even to people with established cardiovascular
disease.
[53] A 2015 review found "Nicotine
in vitro and in animal models can inhibit
apoptosis and enhance
angiogenesis, effects that raise concerns about the role of nicotine in promoting the acceleration of atherosclerotic disease."
[54] A 2012
Cochrane review found no evidence of an increased risk of cardiovascular disease with nicotine replacement products.
[55] A 1996
randomized controlled trial using
nicotine patches found that
serious adverse events were not more frequent among smokers with cardiovascular disease.
[55] A
meta-analysis shows that
snus consumption, which delivers nicotine at a dose equivalent to that of cigarettes, is not associated with
heart attacks.
[56] Hence, it is not nicotine, but tobacco smoke's other components which seem to be implicated in
ischemic heart disease.
[56] Nicotine increases heart rate and blood pressure
[57] and induces abnormal heart rhythms.
[58] Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells.
[59] Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs).
[60] Nicotine does not adversely affect serum cholesterol levels,
[52] but a 2015 review found it may elevate serum cholesterol levels.
[23] Many quitting smoking studies using nicotine medicines report lowered
dyslipidemia with considerable benefit in HDL/LDL ratios.
[53] Nicotine supports clot formation and aids in plaque formation by enhancing
vascular smooth muscle.
[23]
Cancer
Although there is insufficient evidence to classify nicotine as a
carcinogen, there is an ongoing debate about whether it functions as a
tumor promoter.
[62] In vitro studies have associated it with cancer, but carcinogenicity has not been demonstrated
in vivo.
[23]
There is inadequate research to demonstrate that nicotine is associated
with cancer in humans, but there is evidence indicating possible oral,
esophageal, or pancreatic cancer risks.
[21] Nicotine in the form of nicotine replacement products is less of a cancer risk than
smoking.
[21] Nicotine replacement products have not been shown to be associated with cancer in the real world.
[23]
While no epidemiological evidence directly supports the notion that
nicotine acts as a carcinogen in the formation of human cancer, research
has identified nicotine's indirect involvement in cancer formation in
animal models and
cell cultures.
[63][64][65] Nicotine increases
cholinergic signalling and
adrenergic signalling in the case of colon cancer,
[66] 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.
[67][68] In one study, nicotine administered to mice with tumors caused increases in tumor size (twofold increase),
metastasis (nine-fold increase), and tumor recurrence (threefold increase).
[69] N-Nitrosonornicotine (NNN), classified by the
International Agency for Research on Cancer (IARC) as a
Group 1 carcinogen, has been shown to form
in vitro from
nornicotine in human saliva, indicating nornicotine is a carcinogen precursor.
[70] The IARC has not evaluated pure nicotine or assigned it to an official carcinogenic classification.
In cancer cells, nicotine promotes the
epithelial–mesenchymal transition which makes the cancer cells more resistant to drugs that treat cancer.
[71]
Fetal development
In
pregnancy, a 2013 review noted that "nicotine is only 1 of more than
4000 compounds to which the fetus is exposed through maternal smoking.
Of these, ∼30 compounds have been associated with adverse health
outcomes. Although the exact mechanisms by which nicotine produces
adverse fetal effects are unknown, it is likely that hypoxia,
undernourishment of the fetus, and direct vasoconstrictor effects on the
placental and umbilical vessels all play a role. Nicotine also has been
shown to have significant deleterious effects on brain development,
including alterations in brain metabolism and neurotransmitter systems
and abnormal brain development." It also notes that "abnormalities of
newborn neurobehavior, including impaired orientation and autonomic
regulation and abnormalities of muscle tone, have been identified in a
number of prenatal nicotine exposure studies" and that there is weak
data associating fetal nicotine exposure with newborn
facial clefts, and that there is no good evidence for newborns suffering
nicotine withdrawal from fetal exposure to nicotine.
[72]
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 cause developmental toxicity.
[73]
Nicotine is not safe to use in any amount during pregnancy.
[74] Questions exist regarding nicotine use during pregnancy and their potential consequences on fetal growth and mortality.
[47] Nicotine negatively affects pregnancy outcomes and fetal brain development.
[21]
Risks to the child later in life via nicotine exposure during pregnancy
include type 2 diabetes, obesity, hypertension, neurobehavioral
defects, respiratory dysfunction, and infertility.
[22] Nicotine crosses the
placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale
passive smoke.
[75]
Reinforcement disorders
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 the first day or two
[76] and can persist for several weeks.
[77] Nicotine has
clinically significant
cognitive-enhancing effects at low doses, particularly in fine motor
skills, attention, and memory. These beneficial cognitive effects may
play a role in the maintenance of tobacco dependence.
[77]
Nicotine is highly
addictive,
[13][14][78] comparable to heroin or cocaine.
[20] Nicotine activates the
mesolimbic pathway and induces long-term
ΔFosB expression in the
nucleus accumbens when inhaled or injected at sufficiently high doses, but not necessarily when ingested.
[79][80][81] Consequently, repeated daily exposure (possibly excluding
oral route) to nicotine can result in accumbal ΔFosB overexpression, in turn causing nicotine addiction.
[79][80]
In dependent smokers, smoking during withdrawal returns cognitive
abilities to pre-withdrawal levels, but chronic use may not offer
cognitive benefits over not smoking.
[21][82]
Use of other drugs
In animals it is relatively simple to determine if consumption of a
certain drug increases the later attraction of another drug. In humans,
where such direct experiments are not possible,
longitudinal studies can show if the probability of a substance use is related to earlier use of other substances.
[83]
In mice nicotine increased the probability of later consumption of
cocaine and the experiments permitted concrete conclusions on the underlying
molecular biological alteration in the brain.
[84] The biological changes in mice correspond to the
epidemiological observations in humans that nicotine consumption is coupled to an increased probability of later use of
cannabis and cocaine.
[85]
In rats cannabis consumption – earlier in life – increased the later self-administration of nicotine.
[86]
A study of drug use of 14,577 US 12th graders showed that alcohol
consumption was associated with an increased probability of later use of
tobacco, cannabis, and other illegal drugs.
[87]
Overdose
Nicotine is regarded as a potentially
lethal poison.
[88] The
LD50 of nicotine is 50 mg/kg for
rats and 3 mg/kg for
mice. 30–60 mg (0.5–1.0 mg/kg) can be a lethal dosage for adult humans.
[15][89] However, the widely used human LD
50
estimate of 0.5–1.0 mg/kg was questioned in a 2013 review, in light of
several documented cases of humans surviving much higher doses; the 2013
review suggests that the lower limit causing fatal outcomes is
500–1000 mg of ingested nicotine, corresponding to 6.5–13 mg/kg orally.
[17] Nevertheless, nicotine has a relatively high
toxicity in comparison to many other alkaloids such as
caffeine, which has an LD
50 of 127 mg/kg when administered to mice.
[90]
At high-enough doses, it is associated with nicotine poisoning.
[21] 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 or due to accidental ingestion of
tobacco or tobacco products or ingestion of nicotine-containing plants.
[91][92][93]
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.
[91][94] 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/m
3 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/m
3 skin exposure over an 8-hour workday. At environmental levels of 5 mg/m
3, nicotine is
immediately dangerous to life and health.
[95]
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 using more than one
OTC NRT at the same time, or using an OTC NRT at the same time as another nicotine-containing product—including a cigarette."
[96]
The rise in the use of
electronic cigarettes, many forms of which are designed to be refilled with nicotine-containing
e-liquid
supplied in small plastic bottles, has raised concerns over nicotine
overdoses, especially in the possibility of young children ingesting the
liquids.
[24] A 2015
Public Health England
report noted an "unconfirmed newspaper report of a fatal poisoning of a
two-year old child" and two published case reports of children of
similar age who had recovered after ingesting e-liquid and vomiting.
[24] They also noted case reports of suicides by nicotine.
[24]
Where adults drank liquid containing up to 1,500 mg of nicotine they
recovered (helped by vomiting), but an ingestion apparently of about
10,000 mg was fatal, as was an injection.
[24]
They commented that "Serious nicotine poisoning seems normally
prevented by the fact that relatively low doses of nicotine cause nausea
and vomiting, which stops users from further intake."
[24]
Pharmacology
Pharmacodynamics
Nicotine acts as a
receptor agonist at most
nicotinic acetylcholine receptors (nAChRs),
[4][5] except at two
nicotinic receptor subunits (
nAChRα9 and
nAChRα10) where it acts as a
receptor antagonist.
[4]
Central nervous system
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."
[medical citation needed] 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.
[97] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.
[98]
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.
[99][100] This nicotine-induced dopamine release occurs at least partially through activation of the
cholinergic–dopaminergic reward link in the
ventral tegmental area.
[100] 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.
[99] These actions are largely responsible for the strongly reinforcing effects of nicotine, which often occur in the absence of
euphoria;
[99] however, mild euphoria from nicotine use can occur in some individuals.
[99] Chronic nicotine use inhibits class I and II
histone deacetylases in the
striatum, where this effect plays a role in nicotine addiction.
[101][102]
Sympathetic nervous system
Effect of nicotine on chromaffin cells.
Nicotine also activates the
sympathetic nervous system,
[103] 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.
[104]
Pharmacokinetics
Urinary metabolites of nicotine, quantified as average percentage of total urinary nicotine.
[105]
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.
[106] The
elimination half-life of nicotine in the body is around two hours.
[107]
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,
[108]
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.
[109]
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.
[110] Under some conditions, other substances may be formed such as
myosmine.
[111]
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.
[112]
Chemistry
NFPA 704
fire diamond
|
|
|
| The fire diamond hazard sign for nicotine.[113] |
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.
[114]
Nicotine is readily volatile (
vapor pressure 5.5 ㎩ at 25 ℃) and dibasic (K
b1 = 1×10⁻⁶, K
b2 = 1×10⁻¹¹).
[6]
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.
[115]
The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride
and sulphate salts become optically inactive if heated in a closed
vessel above 180 °C.
[116]
On exposure to ultraviolet light or various oxidizing agents,
nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3),
and methylamine.
[116]
Occurrence and biosynthesis
Nicotine is a natural product of tobacco, occurring in the leaves in a range of 0.5 to 7.5% depending on variety.
[117] Nicotine also naturally occurs in smaller amounts in plants from the family
Solanaceae (such as
potatoes,
tomatoes, and
eggplant).
[9]
The biosynthetic pathway of nicotine involves a coupling reaction
between the two cyclic structures that compose nicotine. Metabolic
studies show that the
pyridine ring of nicotine is derived from
niacin (nicotinic acid) while the pyrrolidone is derived from
N-methyl-Δ
1-pyrrollidium cation.
[118][119]
Biosynthesis of the two component structures proceeds via two
independent syntheses, the NAD pathway for niacin and the tropane
pathway for
N-methyl-Δ
1-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-Δ
1-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-Δ
1-pyrrollidium cation.
[citation needed]
The final step in the synthesis of nicotine is the coupling between
N-methyl-Δ
1-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-Δ
1-pyrrollidium cation to form
enantiomerically pure (−)-nicotine.
[120]
Detection in body fluids
Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a forensic
autopsy.
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.
[121][122] Nicotine use is not regulated in competitive sports programs.
[123]
History
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,
[124] and who promoted their medicinal use. Smoking was believed to protect against illness, particularly the plague.
[124]
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.
[12]
Currently, nicotine, even in the form of tobacco dust, is prohibited as a
pesticide for
organic farming in the United States.
[125][126]
In 2008, the
EPA
received a request, from the registrant, to cancel the registration of
the last nicotine pesticide registered in the United States.
[127] This request was granted, and since 1 January 2014, this pesticide has not been available for sale.
[128]
Chemical identification
Nicotine
was first isolated from the tobacco plant in 1828 by physician Wilhelm
Heinrich Posselt and chemist Karl Ludwig Reimann of
Germany, who considered it a poison.
[129][130] Its chemical
empirical formula was described by
Melsens in 1843,
[131] its structure was discovered by
Adolf Pinner and
Richard Wolffenstein in 1893,
[132][133][134][clarification needed] and it was first synthesized by Amé Pictet and A. Rotschy in 1904.
[135]
Society and culture
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.
[136]
Research
While
acute/initial nicotine intake causes activation of nicotine receptors,
chronic low doses of nicotine use leads to desensitisation of nicotine
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.
[137]
However, the original research concluded that: "Nicotine patches
produced short-term improvement of depression with minor side effects.
Because of nicotine's high risk to health, nicotine patches are not
recommended for clinical use in depression."
[138]
Though tobacco smoking is associated with an increased risk of
Alzheimer's disease,
[139] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.
[140]
Research into nicotine's most predominant metabolite,
cotinine, suggests that some of nicotine's psychoactive effects are mediated by cotinine.
[141][142]
Little research is available in humans but animal research suggests there is potential benefit from nicotine in
Parkinson's disease.
[143]
NGC 891, a very thin disk galaxy
An image of Messier 101, a prototypical spiral galaxy seen face-on
A spiral galaxy, ESO 510-G13, was warped as a result of colliding with another galaxy. After the other galaxy is completely absorbed, the distortion will disappear. The process typically takes millions if not billions of years.
