Peak plasma levels after smoking cigarettes can be matched
bynicotinegum or patches but the rate of increase is much
slower after chewing gum or applying transdermal patches.
Effect of smoking on drug disposition
and effects
The most common effect of tobacco smoking on drug dispos-
ition is an increase in elimination consistent with induction of
drug-metabolizing enzymes. Nicotineitself is metabolized
more extensively by smokers than by non-smokers. Substrates
for cytochrome P450 1A2 (e.g. theophylline, caffeine,
imipramine) are metabolized more rapidly in smokers than in
non-smokers.
Drug treatment for nicotine dependence
Nicotineis a potent drug of dependence. Withdrawal can lead
to an abstinence syndrome consisting of craving, irritability and
sometimes physical features (e.g. alimentary disturbances).
Substitution of nicotinevia skin patches or nicotinegum as
part of a smoking cessation programme significantly increases
success rates. The antidepressant bupropionappears to reduce
the desire to smoke and is licensed as an adjunct to motivational
support in smoking cessation. It is contraindicated in patients
with a history of seizures or of eating disorders, or who are
experiencing acute alcohol or benzodiazepine withdrawal.
Varenicline, a selective nicotinic receptor partial agonist, is
an oral adjunct to smoking cessation. It is started 1–2 weeks
before stopping smoking. It is contraindicated in pregnancy.
Side effects include gastro-intestinal disturbances, headache,
dizziness and sleep disorders.
XANTHINES
This group of compounds includes caffeine(present in tea
and colas, as well as coffee), theobromine(present in choco-
late) and theophylline(Chapter 33). Caffeineis included in a
number of proprietary and prescription medicines, particularly
in analgesic combinations. The major effects of these com-
pounds are mediated by inhibition of phosphodiesterase,
resulting in a raised intracellular cyclic adenosine monophos-
phate (AMP) concentration.
Adverse effects
In large doses, caffeineexerts an excitatory effect on the CNS
that is manifested by tremor, anxiety, irritability and restless-
ness, and interference with sleep. Its use does not lead to
improved intellectual performance except perhaps when
normal performance has been impaired by fatigue.
Circulatory effects include direct myocardial stimulation
producing tachycardia, increased cardiac output, ectopic beats
and palpitations. Caffeineuse should be curtailed in patients
who suffer paroxysmal dysrhythmias. Its effect on blood pres-
sure is unpredictable. Cerebral vasoconstriction provides some
rationale for use of caffeinein migraine. Bronchial smooth
muscle relaxes and respiration is stimulated centrally. Mild
diuresis occurs due to an increased glomerular filtration rate
subsequent to dilatation of the afferent arterioles. Caffeine
increases gastric acid secretion via its action on cyclic AMP.
Pharmacokinetics
Caffeineis rapidly and completely absorbed after oral admin-
istration and undergoes hepatic metabolism. The plasma t1/2
of caffeine is 2.5–12 hours.Caffeine dependence
Tolerance is low grade and dependence is not clinically
important.CENTRAL DEPRESSANTS
ALCOHOL
Ethyl alcohol(alcohol) has few clinical uses when given sys-
temically, but is of great medical importance because of its
pathological and psychological effects when used as a bever-
age.Alcoholis the most important drug of dependence, and
in Western Europe and North America the incidence of alco-
holism is about 5% among the adult population.Pharmacokinetics
Ethyl alcoholis absorbed from the buccal, oesophageal, gastric
and intestinal mucosae – approximately 80% is absorbed from
the small intestine. Alcoholdelays gastric emptying and in
high doses delays its own absorption. Following oral adminis-
tration,alcoholcan usually be detected in the blood within five
minutes. Peak concentrations occur between 30 minutes and
two hours. Fats and carbohydrates delay absorption.
Alcoholis distributed throughout the body water. About
95% is metabolized (mainly in the liver) and the remainder is
excreted unchanged in the breath, urine and sweat. Hepatic
oxidation to acetaldehyde is catalysed by three parallel
processes. The major pathway (Figure 53.1) is rate limited by
cytoplasmic alcohol dehydrogenase using nicotinamide
adenine dinucleotide (NAD) as coenzyme.
Alcohol elimination follows Michaelis–Menten kinetics,
with saturation occurring in the concentration range encoun-
tered during social drinking. A small additional ‘dose’ can
thus have a disproportionate effect on the concentration of
alcoholin the plasma.Effects of alcohol
Nervous system:Alcoholdecreases concentration, judgement,
discrimination, and reasoning and increases self-confidence.
Progressively increasing plasma concentrations are associated
with sensations of relaxation followed by mild euphoria,
incoordination, ataxia and loss of consciousness. At high blood
concentrations, the gag reflex is impaired, vomiting may occur
and death may result from aspiration of gastric contents. The
importance of alcoholas a factor in road traffic accidents is
well known (see Figure 53.2). The central depressant actions of
alcoholgreatly enhance the effects of other central depressant
drugs. In patients with organic brain damage, alcoholmay
induce unusual aggression and destructiveness, known as
pathological intoxication. Death may also result from directCENTRALDEPRESSANTS 439