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Nicotine
Nicotine molecule
History: Nicotine is named after the tobacco plant Nicotiana tabacum which in
turn is named after Jean Nicot de Villemain, French ambassador in Portugal, who
sent tobacco and seeds from Brazil to Paris in 1560 and promoted their medicinal
use. Nicotine was first isolated from the tobacco plant in 1828 by German chemists
Posselt & Reimann, who considered it a poison. Its chemical empirical formula
was described by Melsens in 1843, its structure was discovered by Garry Pinner in
1893, and it was first synthesized by A. Pictet and Crepieux in 1904.
Chemistry: Nicotine is a hygroscopic, oily liquid that is miscible with water in its
base form. As a nitrogenous base, nicotine forms salts with acids that are usually
solid and water soluble. Nicotine easily penetrates the skin. As shown by the
physical data, free base 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. 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.
Optical activity: Nicotine is optically active, having two enantiomeric forms. The
naturally occurring form of nicotine is levorotatory,
with [α]D = –166.4°. The
dextrorotatory 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. The salts of nicotine are usually dextrorotatory.
Pharmacology-Pharmacokinetics: As nicotine enters the body, it is distributed
quickly through the bloodstream and can cross the blood-brain barrier. On average
it takes about seven seconds for the substance to reach the brain when inhaled. The
half life of nicotine in the body is around two hour.
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, dipping tobacco, snus and snuff, 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 in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also
by CYP2B6). A major metabolite is cotinine.
Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine
isomethonium ion, 2-hydroxynicotine and nicotine glucuronide. 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.
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. Nicotine's selectivity is thought to be due to a particular
amino acid difference on these receptor subtypes. Tobacco smoke contains the
monoamine oxidase inhibitors harman, norharman, anabasine, anatabine, and
nornicotine. These compounds significantly decrease MAO activity in smokers.
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 but not habenulopeduncular structures.
Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play
a crucial role in mediating the reinforcement effects of nicotine.
In SNS
Nicotine also activates the sympathetic nervous system, 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.
In adrenal medulla
By binding to ganglion type nicotinic receptors in the adrenal medulla nicotine
increases flow of adrenaline (epinephrine), a stimulating hormone. 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 nor epinephrine) 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
Cotinine is a byproduct of the metabolism of nicotine which remains in the blood
for up to 48 hours. It can therefore be used as an indicator of a person's exposure to
nicotine.
Psychoactive effects: Nicotine’s mood-altering effects are different by report: in
particular it is both a stimulant and a relaxant. 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.
By reducing the appetite and raising the metabolism, some smokers may lose
weight as a consequence.
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, nor epinephrine, epinephrine, vasopressin,
arginine, dopamine, autocrine
agents, and beta-endorphin. This release of
neurotransmitters and hormones is responsible for most of nicotine's effects.
Nicotine appears to enhance concentration and memory due to the increase of
acetylcholine. It also appears to enhance alertness due to the increases of
acetylcholine and nor epinephrine. 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 and increases sensitivity in brain reward
systems. Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of
nicotine.
Research suggests that, when smokers wish to achieve a stimulating effect, they
take short quick puffs, which produce a low level of blood nicotine. 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 nor epinephrine and dopamine in the brain, causing a drug effect typical
of those of psycho stimulants. 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. (Another drug that behaves
similarly is ethanol).