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112 Nicotine

Actions of Nicotine

Acetylcholine (ACh) is a mediator in the ganglia of the sympathetic and parasympathetic divisions of the autonomic nervous system. Here, ACh receptors are considered that are activated by nicotine (nicotinic receptors; NAChR, p.102) and that play a leading part in fast ganglionic neurotransmission. These receptors represent ligand-gated ion channels with a structure and mode of operation as described on p.64. Opening of the ion pore induces Na+ influx followed by membrane depolarization and excitation of the cell. NAChR tend to desensitize rapidly; that is, during prolonged occupation by an agonist the ion pore closes spontaneously and cannot reopen until the agonist detaches itself.

enjoyment of its central stimulant action. Nicotine activates the brain’s reward system, thereby promoting dependence. Regular intake leads to habituation, which is advantageous in some respects (e.g., stimulation of the area postrema, p.342). In habituated subjects, cessation of nicotine intake results in mainly psychological withdrawal symptoms (increased nervousness, lack of concentration). Prevention of these is an additional important incentive for continuing nicotine intake. Peripheral effects caused by stimulation of autonomic ganglia may be perceived as useful (“laxative” effect of the first morning cigarette). Sympathoactivation without corresponding physical exertion (“silent stress”) may in the long term lead to grave cardiovascular damage (p.114).

Localization of Nicotinic ACh Receptors

Autonomic nervous system (A, middle). In analogy to autonomic ganglia, NAChR are found also on epinephrine-releasing cells of the adrenal medulla, which are innervated by spinal first neurons. At all these synapses, thereceptorislocatedpostsynapticallyinthe somatodendritic region of the gangliocyte.

Motor end plate. Here the ACh receptors are of the motor type (p.182).

Central nervous system (CNS; A, top). NAChR are involved in various functions. They have a predominantly presynaptic location and promote transmitter release from innervated axon terminals by means of depolarization. Together with ganglionic NAChR they belong to the neuronal type, which differs from the motor type in terms of the composition of its five subunits.

Effects of Nicotine on Body Function

Nicotine served as an experimental tool for the classification of acetylcholine receptors. As a tobacco alkaloid, nicotine is employed daily by a vast part of the human race for the

Aids for Smoking Cessation

Administration of nicotine by means of skin patch, chewing gum, or nasal spray is intended to eliminate craving for cigarette smoking. Breaking of the habit is to be achieved by stepwise reduction of the nicotine dose. Initially this may happen; however, the long-term relapse rate is disappointingly high.

Bupropion (amfebutamon) shows structural similarity with amphetamine (p.329) and inhibits neuronal reuptake of dopamine and norepinephrine. It is supposed to aid smokers in “kicking the habit,” possibly because it evokes CNS effects resembling those of nicotine. The high relapse rate after termination of the drug and substantial side effects put its therapeutic value in doubt.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Actions of Nicotine

113

A. Effects of nicotine in body

 

 

 

 

 

 

Attentiveness

Stimulation

 

 

 

Avoidance of withdrawal

of reward system

 

 

 

 

symptoms:

Vigilance

 

 

 

 

 

 

 

 

 

 

Irritability, impatience

Ability to concentrate

 

 

 

 

 

 

 

 

 

 

Difficulty concentrating

 

 

 

 

 

 

 

Dependence

 

 

 

Dysphoria

 

 

 

 

 

Excitation of

Release of

 

 

 

Release of vasopressin

area postrema

transmitters

 

 

 

 

Nausea, vomiting

 

 

 

 

 

 

 

Mainly presynaptic

 

Postsynaptic

 

receptors

 

 

 

receptors of

 

 

 

 

 

 

motor end plate

Sensitization of

 

 

 

 

 

 

receptors for pressure,

 

N

 

 

 

temperature and

 

 

 

 

 

 

 

 

 

 

pain sensation

 

 

CH

 

 

 

 

N

Nicotine

3

 

 

 

 

 

 

 

 

 

 

 

 

 

Postsynaptic

 

 

 

 

 

 

receptors of

 

 

 

 

 

 

autonomic

 

 

Adrenal

 

 

 

gangliocytes and

 

 

medulla

 

 

 

adrenal medullary

 

 

 

 

 

 

cells

Norepinephrine

Epinephrine

 

 

Acetylcholine

 

 

 

 

 

Vasoconstriction

Glycogenolysis

 

 

Bowel peristalsis

Heart rate

Lipolysis

 

 

 

Defecation

Blood pressure

“Silent stress”

 

 

Diarrhea

 

 

Neuro-

 

 

 

Presynaptic receptors

 

transmitters

Postsynaptic receptors

Nicotine

 

 

 

 

 

 

 

 

 

 

 

 

Nicotine

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

114 Nicotine

Consequences of Tobacco Smoking

The dried and cured leaves of the nightshade plant Nicotianatabacumare known as tobacco. Tobacco is mostly smoked, less frequently chewed or taken as dry snuff. Combustion of tobacco generates ~ 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. The amount of nicotine absorbed during smoking depends on the nicotine content, the size of membrane area exposed to tobacco smoke (N.B.: inhalation), and the pH of the absorbing surface. It is rapidly absorbed through bronchi and lung alveoli when present in free base form. However, protonation of the pyrrolidine nitrogen renders the corresponding part of the molecule hydrophilic and absorption is impeded. To maximize the yield of nicotine, tobaccos of some manufacturers are made alkaline. Smoking of a single cigarette produces peak plasma levels in the range of 25–50 ng/ml. The effects described on p.113 become evident. When intake stops, nicotine concentration in plasma shows an initial rapid fall, due to distribution into tissues, and a terminal elimination phase with a half-life of 2 hours. 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. At the least, nicotine is under discussion as a factor favoring the progression of atherosclerosis. 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. Further-

more, 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 these promote formation of thrombogenic plaques; others possess demonstrable carcinogenic properties (e.g., the tobacco-specific nitrosoketone).

Dust particles inhaled in tobacco smoke, together with bronchial mucus, must be removed by the ciliated epithelium from the airways. However, ciliary activity is depressed by tobacco smoke and mucociliary transport is impaired. This favors bacterial infection and contributes to the chronic bronchitis associated with regular smoking (smoker’s cough). 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 numbers of cigarettes smoked per day and the risk of death from coronary disease or lung cancer. On the other hand, 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 nonsmokers. Similarly, the risk of developing bronchial carcinoma is reduced.

An association with tobacco use has also been established for cancers of the larynx, pharynx, esophagus, stomach, pancreas, kidney, and bladder.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Consequences of Tobacco Smoking

115

A. Sequelae of tobacco smoking

 

 

 

 

 

 

 

 

 

+

 

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

H

CH3

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

-H+

+H+

 

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

N

CH3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nicotine free base

 

 

 

 

Nicotiana

 

 

 

 

 

 

 

 

tabacum

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

“Tar”

 

 

 

 

 

 

 

Nitrosamines,

 

 

 

 

 

 

 

acrolein,

 

 

 

 

 

 

 

 

polycyclic

 

 

 

 

 

 

 

hydrocarbons, e.g.,

 

 

 

 

 

 

 

benzopyrene

 

 

 

 

 

 

 

heavy metals

 

 

 

 

 

 

 

Sum of noxious

 

 

 

 

 

 

 

stimuli

 

 

Platelet

 

 

Damage to

 

Damage to

 

Inhibition of

aggregation

 

vascular

 

bronchial

 

mucociliary

 

 

 

endothelium

 

epithelium

 

transport

Fibrinolytic

 

Epinephrine

 

Years

Duration

Months

 

 

of

activity

 

 

 

 

 

 

 

 

 

 

 

 

 

exposure

 

 

 

 

 

 

 

 

 

Free

 

 

 

 

 

Chronic

 

Bronchitis

fatty acids

 

 

 

 

bronchitis

 

 

 

Coronary disease

 

 

Bronchial carcinoma

 

Annual deaths/1000 people

 

 

Annual cases/1000 people

5

 

 

 

 

 

 

 

 

4

 

 

 

 

 

 

 

 

3

 

 

 

 

 

 

 

Ex-smoker

2

 

 

 

 

 

 

 

1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

0

–10

–20

–40

>40

0

–15

–40

>40

 

 

 

Number of cigarettes per day

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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