Clinical Pharmacology and Therapeutics

DRUGS THAT MODIFY APPETITE 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
and metabolic control pathways, as well as its exact effects on
body weight and energy expenditure. In the future, modulation
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 hypothalamus,
but this agent is not in clinical use.
Amphetamines and 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 causing
transmitter release and blocking re-uptake. Cardiovascular
effects are frequently observed with amphetamines, a doserelated
increase in heart rate and blood pressure being the most
common effect. Dexfenfluramine, fenfluramine and phentermine
were 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.
Sibutramine inhibits 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, constipation,
myalgia, palpitations, alopecia, seizures and bleeding
disorders.
In 2006, rimonabant was approved in Europe. It is an oral
selective cannabinoid CB1 receptor antagonist which is used as
an adjunct to diet to achieve weight loss. Rimonabant is contraindicated
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 halflife
is six to nine days in those with normal BMI, but approximately
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 combination
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