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
because the pH of the cell membrane is difficult nicotine acid through the cell membrane and the ionization takes place there?
BalasHapus