Nicotine is an alkaloid found in the nightshade
family of plants (Solanaceae) that acts as a nicotinic acetylcholine agonist
and a monoamine oxidase inhibitor[citation needed]. The biosynthesis takes
place in the roots and accumulation occurs in the leaves of the Solanaceae. It
constitutes approximately 0.6–3.0% of the dry weight of tobacco and is present
in the range of 2–7 µg/kg of various edible plants. It functions as an
antiherbivore chemical; therefore, nicotine was widely used as an insecticide
in the past and nicotine analogs such as imidacloprid are currently widely
used.
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 cause pharmacological effects.
Optical activity
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.[17] The
salts of (+)-nicotine are usually dextrorotatory.
Biosynthesis
Pharmacokinetics
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. The elimination half-life of nicotine in the body is around two
hours.
The amount of
nicotine absorbed by the body from smoking depends on many factors, including
the types 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.[clarification
needed][citation needed] 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. Under some conditions, other
substances may be formed such as myosmine.
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.
In the central
nervous system
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 apparent euphoria and relaxation, and 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.[30] Nicotine's selectivity
is thought to be due to a particular amino acid difference on these receptor
subtypes.
Tobacco smoke
contains anabasine, anatabine, and nornicotine.[citation needed] It also
contains the monoamine oxidase inhibitors harman and norharman.These
beta-carboline compounds significantly decrease MAO activity in smokers.MAO
enzymes break down monoaminergic neurotransmitters such as dopamine,
norepinephrine, and serotonin. It is thought that the powerful interaction
between the MAOI's and the nicotine is responsible for most of the addictive properties
of tobacco smoking.The addition of five minor tobacco alkaloids increases
nicotine-induced hyperactivity, sensitization and intravenous self-administration
in rats.
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 the sympathetic nervous system
Nicotine also
activates the sympathetic nervous system,[40] 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 due to the 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. However, further research is
warranted before a definite conclusive link can be inferred.
Effect of nicotine on chromaffin cells.
In adrenal medulla
By binding to
ganglion type nicotinic receptors in the adrenal medulla nicotine increases
flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter.
By binding to the receptors, it causes cell depolarization and an influx of
calcium through voltage-gated calcium channels. Calcium triggers the exocytosis
of chromaffin granules and thus the release of epinephrine (and norepinephrine)
into the bloodstream. The release of epinephrine (adrenaline) causes an
increase in heart rate, blood pressure and respiration, as well as higher blood
glucose levels.
Nicotine is the
natural product of tobacco, having a half-life of 1 to 2 hours. Cotinine is an
active metabolite of nicotine that remains in the blood for 18 to 20 hours,
making it easier to analyze due to its longer half-life.
Sumber: en.wikipedia.org
The Metabolism of Nicotine
1 - Absorption of nicotine
Absorption of
nicotine through cellular membranes depends on the pH. If the pH is acidic,
nicotine is ionized and does not easily pass through membranes. At physiologic
pH (pH = 7.4), 31% of nicotine is not ionized and easily passes through
membranes.
The tobacco smoke
pH is acidic, and this acidity only allows a little absorption in the mouth.
Inhalation is therefore necessary to allow nicotine to be absorbed by the huge
area of alveolar epithelium. In the lungs, nicotine is quicklyt absorbed by the
systemic circulation. This absorption is easy because the blood flow is high in
the lung capillaries : a volume equal to the blood volume of the body passes
each minute. So, the rate of nicotine qickly rises when a cigarette is smoked.
Absorbed nicotine is rapidly distributed among all the organs, and it reaches
the brain within only ten seconds.
2 - Action on nicotinic receptors
The active form
of nicotine is a cation whose charge is located on the nitrogen of the pyrrole
cycle. This active form is very close to acetylcholine. It has been
demonstrated that nicotine interferes with acetylcholine, which is the major
neurotransmitter of the brain. Acetylcholine can bind to two different kinds of
receptors: nicotinic receptors, which are activated by nicotine, and muscarinic
receptors, which are activated by muscarine. Nicotine and muscarine are thus
specific agonists of one kind of cholinergic receptors (an agonist is a
molecule that activates a receptor by reproducing the effect of the
neurotransmitter.)
Nicotine competitively
binds to nicotinic cholinergic receptors. The binding of the agonist to the
nicotinic receptor triggers off a conformation change of the architecture of
the receptor, which opens the ionic channel during a few milliseconds. This
channel is selective for cations (especially sodium). Its opening thus leads to
a brief depolarization. Then, the channel closes and the receptor
transitionally becomes refractory to agonists. This is the state of
desensitization. Then, the receptor usually goes back to a state of rest,
which means that it is closed and sensitive to the agonists. In case of
continuous exposure to agonists (even in small doses), this state of
desensitization will last long (long-term inactivation).
Operating cycle
of a nicotinic receptor:
Physiological normal conditions:
After the opening of the canal by binding to acethylcholine, the receptor
becomes desensitized before it goes back to the state of rest or it is
regenerated.
Continuous exposure to tobacco: Nicotine
substitutes for acetylcholine and over stimulates the nicotinic receptor. Then,
the receptor is long-term inactivated and its regeneration is prevented by
nicotine.
3 - Tolerance and dependence on nicotine
Nicotine rises
the stimulation of nicotinic receptors. The excessive and chronic activation of
these receptors is balanced by a down-regulation in the number of active
receptors. The reduction of the number of active receptors reduces the psychotropic
effect of nicotine. Due to the phenomenon of tolerance, the smoker needs to
smoke more and more cigarettes to keep a constant effect.
Nicotine
activates dopamine systems within the brain. Dopamine is a neurotransmitter
which is directly responsible for mediating the pleasure response. Nicotine
triggers off the production of dopamine in the nucleus accumbens. A prolonged
exposure of these receptors to nicotine reduces the efficiency of dopamine by
cutting down the number of available receptors. Consequently, more and more
nicotine is needed to give the same pleasurable effect.
After a brief
period of abstinence (overnight for instance), the brain concentration of
nicotine lowers and allows a part of the receptors to recover their
sensibility. The return to an active state rises the neurotransmission to an
abnormal rate. The smoker feels uncomfortable, which induces him to smoke
again. The first cigarette of the day is the most pleasant because the
sensibility of the dopamine receptors is maximal. Then, the receptors are soon
desensitized and the pleasure wears off. This is the vicious circle of smoking.
4 - Chemical
transformations undergone by nicotine
Nicotine is
mainly transformed in the liver, but also in the lungs and the kidneys. The
primary metabolites of nicotine are cotinine and nicotine N-oxide, which are some products of
the hepatic oxidation of nicotine by
P-450 cytochrome.
How can nicotine
be dangerous for the body?
Nicotine and its
metabolites may be dangerous for the body. Actually, nicotine is a strong
carcinogen. In fact, nicotine can undergo several kinds of transformation like
a pyrrole cycle opening. The methyl group on this cycle can become a very
powerful alkylating agent when removed from the cycle.
The amine
function of nicotine may react with nitrogen monoxide or with nitrous acid in
order to form a "nitrosonium" type molecule. This compound may then
be transformed by the body, which means oxidized and opened. This opening leads
to two isomers, two "nitrosamino" type molecules (R2N-N=O) where one
of the two R group is a methyl. This reaction occurs as follows:
A = 4
(N-methyl-N-nitrosamino)-1-(3-pyridyl)-butan-1-one B = 4
(N-methyl-N-nitrosamino)-4-(3-pyridyl)-butanal
In acidic
medium, the oxygen of the "nitrosamino" group is protonated and the
double bond moves to the central nitrogen, which becomes positively charged.
This new molecule is a methyl source. The "nitrosamino" group can
then react with another amine, which removes the positive charge from the
nitrogen. If the amine that reacts is a part of the structure of the DNA, an
irreversible alkylation of the DNA occurs:
This alkylation
is really noxious and may help in the
development of cancer as it prevents the normal development of the cell.
Sumber : http://www.chm.bris.ac.uk
