A Textbook of Clinical Pharmacology and Therapeutics

and metabolic control pathways, as well as its exact effects on
body weight and energy expenditure. In the future, modula-
tion of leptin activity may provide a target for treating obesity.
One hypothesis is that lean people do not become obese
when they overeat because their tissues preferentially liberate
heat (particularly from brown fat). Despite this uncertainty,
there is no doubt that starvation leads to weight loss.
Therefore, research into drugs for the treatment of obesity has
concentrated on finding substances that inhibit appetite.
Learned behaviour is probably important in determining
the frequency of eating and whether food is taken between
major meals. Stretch receptors in the stomach are stimulated
by distention, but the main factors that terminate eating are
humoral. Bombesin and somatostatin are two candidates for
humoral satiety factors released by the stomach. The most
important satiety factor released from the gastro-intestinal
tract beyond the stomach is cholecystokinin (CCK). A small
peptide fragment of this (CCK-8) has been synthesized and
has been found to cause humans to reduce their food intake,
possibly by acting on the appetite/satiety centre in the hypo-
thalamus, but this agent is not in clinical use.
Amphetaminesand related drugs suppress appetite but are
toxic and have considerable abuse potential. The site of action of
amphetamines appears to be in the hypothalamus, where they
increase noradrenaline and dopamine concentrations by caus-
ing transmitter release and blocking re-uptake. Cardiovascular
effects are frequently observed with amphetamines, a dose-
related increase in heart rate and blood pressure being the most

common effect. Dexfenfluramine,fenfluramineandphenter-

minewere associated with less abuse potential, but have been

withdrawn from use in the UK, because they were associated

with valvular heart disease and rarely pulmonary hypertension.

Sibutramineinhibits the re-uptake of noradrenaline and

serotonin. It reduces appetite and is used as an adjunct to diet for

up to one year. Blood pressure and pulse should be monitored.

Contraindications include major psychiatric illness, ischaemic

heart disease, dysrrythmias, hyperthyroidism and pregnancy.

Side effects include dry mouth, nausea, abnormal taste, consti-

pation, myalgia, palpitations, alopecia, seizures and bleeding

disorders.

In 2006, rimonabantwas approved in Europe. It is an oral

selective cannabinoid CB1 receptor antagonist which is used as

an adjunct to diet to achieve weight loss. Rimonabantis con-

traindicated in (and may cause) depression. Adverse effects

include nausea, vomiting, diarrhoea, mood changes, anxiety,

impaired memory, dizziness and sleep disorders. It is highly

protein bound and metabolized by hepatic CYP3A4. The half-

life is six to nine days in those with normal BMI, but approxi-

mately 16 days in obese patients.

Orlistat, is an inhibitor of gastro-intestinal lipases, reduces

fat absorption and is licensed for use to treat obesity in combin-

ation with a weight management programme, including a

mildly hypocaloric diet. NICE has recommended that if

weight reduction is less than 10% after six months, treatment

should be stopped. Systemic absorption is minimal. The main

adverse effects are oily spotting from the rectum, flatus with

DRUGSTHATMODIFYAPPETITE 263

Table 34.7:Dose-independent hepatotoxicity

Drug Mechanism Comment/predisposing factors

Captopril Cholestatic jaundice

Chlorpromazine Cholestatic hepatitis Estimated incidence 0.5% associated with fever, abdominal

pain, pruritus; subclinical hepatic dysfunction is more

common

Flucloxacillin Cholestatic jaundice and hepatitis Very rare, may occur up to several weeks after treatment.

Elderly are at particular risk

Tolbutamide Cholestatic jaundice

Telithromycin Hepatocellular damage

Isoniazid Hepatitis Mild and self-limiting in 20% and severe hepatitis in 0.1%

of cases. Possibly more common in rapid acetylators

Pyrazinamide Hepatitis Similar to isoniazid, but more clearly related to dose

Methyldopa Hepatitis About 5% of cases have subclinical, raised transaminases;

clinical hepatitis is rare

Phenytoin Hypersensitivity reaction Resembles infectious mononucleosis; pharmacogenetic

predisposition; cross-reaction with carbamazepine

Isoniazid Chronic active hepatitis Associated with prolonged treatment, usually regresses

when drug is discontinued

Nitrofurantoin

Dantrolene

Halothane Hepatitis/hepatic necrosis See Chapter 24

Ketoconazole

}