Nicotine

Ganglionic Transmission
Whether sympathetic or parasympathetic,
all efferent visceromotor nerves
are made up of two serially connected
neurons. The point of contact (synapse)
between the first and second neurons
occurs mainly in ganglia; therefore, the
first neuron is referred to as preganglionic
and efferents of the second as
postganglionic.
Electrical excitation (action potential)
of the first neuron causes the release
of acetylcholine (ACh) within the
ganglia. ACh stimulates receptors located
on the subsynaptic membrane of the
second neuron. Activation of these receptors
causes the nonspecific cation
channel to open. The resulting influx of
Na+ leads to a membrane depolarization.
If a sufficient number of receptors
is activated simultaneously, a threshold
potential is reached at which the membrane
undergoes rapid depolarization in
the form of a propagated action potential.
Normally, not all preganglionic impulses
elicit a propagated response in
the second neuron. The ganglionic synapse
acts like a frequency filter (A). The
effect of ACh elicited at receptors on the
ganglionic neuronal membrane can be
imitated by nicotine; i.e., it involves nicotinic
cholinoceptors.
Ganglionic action of nicotine. If a
small dose of nicotine is given, the ganglionic
cholinoceptors are activated. The
membrane depolarizes partially, but
fails to reach the firing threshold. However,
at this point an amount of released
ACh smaller than that normally
required will be sufficient to elicit a
propagated action potential. At a low
concentration, nicotine acts as a ganglionic
stimulant; it alters the filter
function of the ganglionic synapse, allowing
action potential frequency in the
second neuron to approach that of the
first (B). At higher concentrations, nicotine
acts to block ganglionic transmission.
Simultaneous activation of many
nicotinic cholinoceptors depolarizes the
ganglionic cell membrane to such an extent
that generation of action potentials
is no longer possible, even in the face of
an intensive and synchronized release
of ACh (C).
Although nicotine mimics the action
of ACh at the receptors, it cannot
duplicate the time course of intrasynaptic
agonist concentration required for
appropriate high-frequency ganglionic
activation. The concentration of nicotine
in the synaptic cleft can neither
build up as rapidly as that of ACh released
from nerve terminals nor can
nicotine be eliminated from the synaptic
cleft as quickly as ACh.
The ganglionic effects of ACh can be
blocked by tetraethylammonium, hexamethonium,
and other substances (ganglionic
blockers). None of these has intrinsic
activity, that is, they fail to stimulate
ganglia even at low concentration;
some of them (e.g., hexamethonium)
actually block the cholinoceptor-linked
ion channel, but others (mecamylamine,
trimethaphan) are typical receptor
antagonists.
Certain sympathetic preganglionic
neurons project without interruption to
the chromaffin cells of the adrenal medulla.
The latter are embryologic homologues
of ganglionic sympathocytes. Excitation
of preganglionic fibers leads to
release of ACh in the adrenal medulla,
whose chromaffin cells then respond
with a release of epinephrine into the
blood (D). Small doses of nicotine, by inducing
a partial depolarization of adrenomedullary
cells, are effective in liberating
epinephrine.

Effects of Nicotine on Body Functions
At a low concentration, the tobacco alkaloid
nicotine acts as a ganglionic stimulant
by causing a partial depolarization
via activation of ganglionic cholinoceptors.
A similar action is evident
at diverse other neural sites, considered
below in more detail.
Autonomic ganglia. Ganglionic
stimulation occurs in both the sympathetic
and parasympathetic divisions of
the autonomic nervous system. Parasympathetic
activation results in increased
production of gastric juice
(smoking ban in peptic ulcer) and enhanced
bowel motility (“laxative” effect
of the first morning cigarette: defecation;
diarrhea in the novice).
Although stimulation of parasympathetic
cardioinhibitory neurons
would tend to lower heart rate, this response
is overridden by the simultaneous
stimulation of sympathetic cardioaccelerant
neurons and the adrenal medulla.
Stimulation of sympathetic
nerves resulting in release of norepinephrine
gives rise to vasoconstriction;
peripheral resistance rises.
Adrenal medulla. On the one hand,
release of epinephrine elicits cardiovascular
effects, such as increases in heart
rate und peripheral vascular resistance.
On the other, it evokes metabolic responses,
such as glycogenolysis and lipolysis,
that generate energy-rich substrates.
The sensation of hunger is suppressed.
The metabolic state corresponds
to that associated with physical
exercise – “silent stress”.
Baroreceptors. Partial depolarization
of baroreceptors enables activation
of the reflex to occur at a relatively
smaller rise in blood pressure, leading
to decreased sympathetic vasoconstrictor
activity.
Neurohypophysis. Release of vasopressin
(antidiuretic hormone) results
in lowered urinary output.
Levels of vasopressin necessary for vasoconstriction
will rarely be produced
by nicotine.
Carotid body. Sensitivity to arterial
pCO2 increases; increased afferent input
augments respiratory rate and depth.
Receptors for pressure, temperature,
and pain. Sensitivity to the corresponding
stimuli is enhanced.
Area postrema. Sensitization of
chemoceptors leads to excitation of the
medullary emetic center.
At low concentration, nicotine is also
able to augment the excitability of
the motor endplate. This effect can be
manifested in heavy smokers in the
form of muscle cramps (calf musculature)
and soreness.
The central nervous actions of nicotine
are thought to be mediated largely
by presynaptic receptors that facilitate
transmitter release from excitatory
aminoacidergic (glutamatergic) nerve
terminals in the cerebral cortex. Nicotine
increases vigilance and the ability
to concentrate. The effect reflects an enhanced
readiness to perceive external
stimuli (attentiveness) and to respond
to them.
The multiplicity of its effects makes
nicotine ill-suited for therapeutic use.


Consequences of Tobacco Smoking
The dried and cured leaves of the nightshade
plant Nicotiana tabacum are
known as tobacco. Tobacco is mostly
smoked, less frequently chewed or taken
as dry snuff. Combustion of tobacco
generates approx. 4000 chemical compounds
in detectable quantities. The
xenobiotic burden on the smoker depends
on a range of parameters, including
tobacco quality, presence of a filter,
rate and temperature of combustion,
depth of inhalation, and duration of
breath holding.
Tobacco contains 0.2–5 % nicotine.
In tobacco smoke, nicotine is present as
a constituent of small tar particles. It is
rapidly absorbed through bronchi and
lung alveoli, and is detectable in the
brain only 8 s after the first inhalation.
Smoking of a single cigarette yields peak
plasma levels in the range of 25–50
ng/mL. The effects described on p. 110
become evident. When intake stops,
nicotine concentration in plasma shows
an initial rapid fall, reflecting distribution
into tissues, and a terminal elimination
phase with a half-life of 2 h. Nicotine
is degraded by oxidation.
The enhanced risk of vascular disease
(coronary stenosis, myocardial infarction,
and central and peripheral ischemic
disorders, such as stroke and
intermittent claudication) is likely to be
a consequence of chronic exposure to
nicotine. Endothelial impairment and
hence dysfunction has been proven to
result from smoking, and nicotine is
under discussion as a factor favoring
the progression of arteriosclerosis. By
releasing epinephrine, it elevates plasma
levels of glucose and free fatty acids
in the absence of an immediate physiological
need for these energy-rich metabolites.
Furthermore, it promotes
platelet aggregability, lowers fibrinolytic
activity of blood, and enhances coagulability.
The health risks of tobacco smoking
are, however, attributable not only to
nicotine, but also to various other ingredients
of tobacco smoke, some of which
possess demonstrable carcinogenic
properties.
Dust particles inhaled in tobacco
smoke, together with bronchial mucus,
must be removed from the airways by
the ciliated epithelium. Ciliary activity,
however, is depressed by tobacco
smoke; mucociliary transport is impaired.
This depression favors bacterial infection
and contributes to the chronic
bronchitis associated with regular
smoking. Chronic injury to the bronchial
mucosa could be an important causative
factor in increasing the risk in
smokers of death from bronchial carcinoma.
Statistical surveys provide an impressive
correlation between the number
of cigarettes smoked a day and the
risk of death from coronary disease or
lung cancer. Statistics also show that, on
cessation of smoking, the increased risk
of death from coronary infarction or
other cardiovascular disease declines
over 5–10 years almost to the level of
non-smokers. Similarly, the risk of developing
bronchial carcinoma is reduced.
Abrupt cessation of regular smoking
is not associated with severe physical
withdrawal symptoms. In general,
subjects complain of increased nervousness,
lack of concentration, and weight
gain.