A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
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DRUGS THAT MODIFY APPETITE 263<br />
Table 34.7: Dose-independent hepatotoxicity<br />
Drug Mechanism Comment/predisposing factors<br />
Captopril<br />
Cholestatic jaundice<br />
Chlorpromazine Cholestatic hepatitis Estimated incidence 0.5% associated with fever, abdominal<br />
pain, pruritus; subclinical hepatic dysfunction is more<br />
common<br />
Flucloxacillin Cholestatic jaundice <strong>and</strong> hepatitis Very rare, may occur up to several weeks after treatment.<br />
Elderly are at particular risk<br />
Tolbutamide<br />
Cholestatic jaundice<br />
Telithromycin<br />
Hepatocellular damage<br />
Isoniazid Hepatitis Mild <strong>and</strong> self-limiting in 20% <strong>and</strong> severe hepatitis in 0.1%<br />
<strong>of</strong> cases. Possibly more common in rapid acetylators<br />
Pyrazinamide Hepatitis Similar to isoniazid, but more clearly related to dose<br />
Methyldopa Hepatitis About 5% <strong>of</strong> cases have subclinical, raised transaminases;<br />
clinical hepatitis is rare<br />
Phenytoin Hypersensitivity reaction Resembles infectious mononucleosis; pharmacogenetic<br />
predisposition; cross-reaction with carbamazepine<br />
Isoniazid Chronic active hepatitis Associated with prolonged treatment, usually regresses<br />
when drug is discontinued<br />
Nitr<strong>of</strong>urantoin<br />
}<br />
Dantrolene<br />
Halothane Hepatitis/hepatic necrosis See Chapter 24<br />
Ketoconazole<br />
<strong>and</strong> metabolic control pathways, as well as its exact effects on<br />
body weight <strong>and</strong> energy expenditure. In the future, modulation<br />
<strong>of</strong> leptin activity may provide a target for treating obesity.<br />
One hypothesis is that lean people do not become obese<br />
when they overeat because their tissues preferentially liberate<br />
heat (particularly from brown fat). Despite this uncertainty,<br />
there is no doubt that starvation leads to weight loss.<br />
Therefore, research into drugs for the treatment <strong>of</strong> obesity has<br />
concentrated on finding substances that inhibit appetite.<br />
Learned behaviour is probably important in determining<br />
the frequency <strong>of</strong> eating <strong>and</strong> whether food is taken between<br />
major meals. Stretch receptors in the stomach are stimulated<br />
by distention, but the main factors that terminate eating are<br />
humoral. Bombesin <strong>and</strong> somatostatin are two c<strong>and</strong>idates for<br />
humoral satiety factors released by the stomach. The most<br />
important satiety factor released from the gastro-intestinal<br />
tract beyond the stomach is cholecystokinin (CCK). A small<br />
peptide fragment <strong>of</strong> this (CCK-8) has been synthesized <strong>and</strong><br />
has been found to cause humans to reduce their food intake,<br />
possibly by acting on the appetite/satiety centre in the hypothalamus,<br />
but this agent is not in clinical use.<br />
Amphetamines <strong>and</strong> related drugs suppress appetite but are<br />
toxic <strong>and</strong> have considerable abuse potential. The site <strong>of</strong> action <strong>of</strong><br />
amphetamines appears to be in the hypothalamus, where they<br />
increase noradrenaline <strong>and</strong> dopamine concentrations by causing<br />
transmitter release <strong>and</strong> blocking re-uptake. Cardiovascular<br />
effects are frequently observed with amphetamines, a doserelated<br />
increase in heart rate <strong>and</strong> blood pressure being the most<br />
common effect. Dexfenfluramine, fenfluramine <strong>and</strong> phentermine<br />
were associated with less abuse potential, but have been<br />
withdrawn from use in the UK, because they were associated<br />
with valvular heart disease <strong>and</strong> rarely pulmonary hypertension.<br />
Sibutramine inhibits the re-uptake <strong>of</strong> noradrenaline <strong>and</strong><br />
serotonin. It reduces appetite <strong>and</strong> is used as an adjunct to diet for<br />
up to one year. Blood pressure <strong>and</strong> pulse should be monitored.<br />
Contraindications include major psychiatric illness, ischaemic<br />
heart disease, dysrrythmias, hyperthyroidism <strong>and</strong> pregnancy.<br />
Side effects include dry mouth, nausea, abnormal taste, constipation,<br />
myalgia, palpitations, alopecia, seizures <strong>and</strong> bleeding<br />
disorders.<br />
In 2006, rimonabant was approved in Europe. It is an oral<br />
selective cannabinoid CB1 receptor antagonist which is used as<br />
an adjunct to diet to achieve weight loss. Rimonabant is contraindicated<br />
in (<strong>and</strong> may cause) depression. Adverse effects<br />
include nausea, vomiting, diarrhoea, mood changes, anxiety,<br />
impaired memory, dizziness <strong>and</strong> sleep disorders. It is highly<br />
protein bound <strong>and</strong> metabolized by hepatic CYP3A4. The halflife<br />
is six to nine days in those with normal BMI, but approximately<br />
16 days in obese patients.<br />
Orlistat, is an inhibitor <strong>of</strong> gastro-intestinal lipases, reduces<br />
fat absorption <strong>and</strong> is licensed for use to treat obesity in combination<br />
with a weight management programme, including a<br />
mildly hypocaloric diet. NICE has recommended that if<br />
weight reduction is less than 10% after six months, treatment<br />
should be stopped. Systemic absorption is minimal. The main<br />
adverse effects are oily spotting from the rectum, flatus with