Clinical Pharmacology and Therapeutics
A Textbook of Clinical Pharmacology and ... - clinicalevidence
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CENTRAL DEPRESSANTS 439<br />
Peak plasma levels after smoking cigarettes can be matched<br />
by nicotine gum or patches but the rate of increase is much<br />
slower after chewing gum or applying transdermal patches.<br />
Effect of smoking on drug disposition<br />
<strong>and</strong> effects<br />
The most common effect of tobacco smoking on drug disposition<br />
is an increase in elimination consistent with induction of<br />
drug-metabolizing enzymes. Nicotine itself is metabolized<br />
more extensively by smokers than by non-smokers. Substrates<br />
for cytochrome P450 1A2 (e.g. theophylline, caffeine,<br />
imipramine) are metabolized more rapidly in smokers than in<br />
non-smokers.<br />
Drug treatment for nicotine dependence<br />
Nicotine is a potent drug of dependence. Withdrawal can lead<br />
to an abstinence syndrome consisting of craving, irritability <strong>and</strong><br />
sometimes physical features (e.g. alimentary disturbances).<br />
Substitution of nicotine via skin patches or nicotine gum as<br />
part of a smoking cessation programme significantly increases<br />
success rates. The antidepressant bupropion appears to reduce<br />
the desire to smoke <strong>and</strong> is licensed as an adjunct to motivational<br />
support in smoking cessation. It is contraindicated in patients<br />
with a history of seizures or of eating disorders, or who are<br />
experiencing acute alcohol or benzodiazepine withdrawal.<br />
Varenicline, a selective nicotinic receptor partial agonist, is<br />
an oral adjunct to smoking cessation. It is started 1–2 weeks<br />
before stopping smoking. It is contraindicated in pregnancy.<br />
Side effects include gastro-intestinal disturbances, headache,<br />
dizziness <strong>and</strong> sleep disorders.<br />
XANTHINES<br />
This group of compounds includes caffeine (present in tea<br />
<strong>and</strong> colas, as well as coffee), theobromine (present in chocolate)<br />
<strong>and</strong> theophylline (Chapter 33). Caffeine is included in a<br />
number of proprietary <strong>and</strong> prescription medicines, particularly<br />
in analgesic combinations. The major effects of these compounds<br />
are mediated by inhibition of phosphodiesterase,<br />
resulting in a raised intracellular cyclic adenosine monophosphate<br />
(AMP) concentration.<br />
Adverse effects<br />
In large doses, caffeine exerts an excitatory effect on the CNS<br />
that is manifested by tremor, anxiety, irritability <strong>and</strong> restlessness,<br />
<strong>and</strong> interference with sleep. Its use does not lead to<br />
improved intellectual performance except perhaps when<br />
normal performance has been impaired by fatigue.<br />
Circulatory effects include direct myocardial stimulation<br />
producing tachycardia, increased cardiac output, ectopic beats<br />
<strong>and</strong> palpitations. Caffeine use should be curtailed in patients<br />
who suffer paroxysmal dysrhythmias. Its effect on blood pressure<br />
is unpredictable. Cerebral vasoconstriction provides some<br />
rationale for use of caffeine in migraine. Bronchial smooth<br />
muscle relaxes <strong>and</strong> respiration is stimulated centrally. Mild<br />
diuresis occurs due to an increased glomerular filtration rate<br />
subsequent to dilatation of the afferent arterioles. Caffeine<br />
increases gastric acid secretion via its action on cyclic AMP.<br />
Pharmacokinetics<br />
Caffeine is rapidly <strong>and</strong> completely absorbed after oral administration<br />
<strong>and</strong> undergoes hepatic metabolism. The plasma t 1/2<br />
of caffeine is 2.5–12 hours.<br />
Caffeine dependence<br />
Tolerance is low grade <strong>and</strong> dependence is not clinically<br />
important.<br />
CENTRAL DEPRESSANTS<br />
ALCOHOL<br />
Ethyl alcohol (alcohol) has few clinical uses when given systemically,<br />
but is of great medical importance because of its<br />
pathological <strong>and</strong> psychological effects when used as a beverage.<br />
Alcohol is the most important drug of dependence, <strong>and</strong><br />
in Western Europe <strong>and</strong> North America the incidence of alcoholism<br />
is about 5% among the adult population.<br />
Pharmacokinetics<br />
Ethyl alcohol is absorbed from the buccal, oesophageal, gastric<br />
<strong>and</strong> intestinal mucosae – approximately 80% is absorbed from<br />
the small intestine. Alcohol delays gastric emptying <strong>and</strong> in<br />
high doses delays its own absorption. Following oral administration,<br />
alcohol can usually be detected in the blood within five<br />
minutes. Peak concentrations occur between 30 minutes <strong>and</strong><br />
two hours. Fats <strong>and</strong> carbohydrates delay absorption.<br />
Alcohol is distributed throughout the body water. About<br />
95% is metabolized (mainly in the liver) <strong>and</strong> the remainder is<br />
excreted unchanged in the breath, urine <strong>and</strong> sweat. Hepatic<br />
oxidation to acetaldehyde is catalysed by three parallel<br />
processes. The major pathway (Figure 53.1) is rate limited by<br />
cytoplasmic alcohol dehydrogenase using nicotinamide<br />
adenine dinucleotide (NAD) as coenzyme.<br />
Alcohol elimination follows Michaelis–Menten kinetics,<br />
with saturation occurring in the concentration range encountered<br />
during social drinking. A small additional ‘dose’ can<br />
thus have a disproportionate effect on the concentration of<br />
alcohol in the plasma.<br />
Effects of alcohol<br />
Nervous system: Alcohol decreases concentration, judgement,<br />
discrimination, <strong>and</strong> reasoning <strong>and</strong> increases self-confidence.<br />
Progressively increasing plasma concentrations are associated<br />
with sensations of relaxation followed by mild euphoria,<br />
incoordination, ataxia <strong>and</strong> loss of consciousness. At high blood<br />
concentrations, the gag reflex is impaired, vomiting may occur<br />
<strong>and</strong> death may result from aspiration of gastric contents. The<br />
importance of alcohol as a factor in road traffic accidents is<br />
well known (see Figure 53.2). The central depressant actions of<br />
alcohol greatly enhance the effects of other central depressant<br />
drugs. In patients with organic brain damage, alcohol may<br />
induce unusual aggression <strong>and</strong> destructiveness, known as<br />
pathological intoxication. Death may also result from direct