APPETITE-SUPPRESSING (ANORECTIC) DRUGS The most common form of malnutrition in the UK is obesity.
Obesity is a major risk factor for cardiovascular disease, stroke and type 2 diabetes mellitus. It is preventable, since obese patients are fat because they eat too many calories for their energy needs. Naturally, a calorie-controlled diet and adequate but sensible amounts of exercise are the essentials of treatment.
Unfortunately, the results of treating patients at weight-reduc- tion clinics are disappointing and only a few individuals achieve permanent weight loss. There has accordingly been a great deal of interest in the possibility of altering appetite phar- macologically in order to help the patient to reduce his or her calorie intake. Unfortunately, the causes of obesity are only currently being more comprehensively studied.
In 1994, the gene for obesity (OB) in the mouse was identi- fied. The OB gene encodes the protein leptin, which is pro- duced only in fat cells and is secreted into the blood. The human homologue of the OB gene has now been identified.
Leptin is thought to be a blood-borne signal from the adipose tissue that informs the brain about the size of an individual’s fat mass. Much more research is required to determine its exact role in neuroendocrine, reproductive, haematopoietic 262 ALIMENTARY SYSTEM AND LIVER
Table 34.6:Dose-dependent hepatotoxicity
Drug Mechanism Comment/predisposing factors
Paracetamol Hepatitis See Chapter 54
Salicylates Focal hepatocellular necrosis Autoimmune disease (especially systemic lupus erythematosus)
Reye’s sydrome In children with viral infection (contraindicated in
children16 years) Tetracycline Central and mid-zonal necrosis with fat droplets –
Azathioprine Cholestasis and hepatitis Underlying liver disease
Methotrexate Hepatic fibrosis –
Fusidic acid Cholestasis, conjugated hyperbilirubinaemia Rare Rifampicin Cholestasis, conjugated and unconjugated Transient
hyperbilirubinaemia
Synthetic oestrogens Cholestasis, may precipitate gallstone disease Underlying liver disease, rare now that low-dose oestrogens are generally given
HMG CoA reductase Unknown Usually mild and asymptomatic (statins)
inhibitors
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.
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, 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 }
APPETITE STIMULATION
This is often difficult, as patients with a poor appetite may have a debilitating systemic illness or an underlying psychi- atric disorder. Drugs that inhibit serotonin (5HT) receptors, (e.g.cyproheptadine, pizotifen) increase appetite and cause weight gain. Weight gain occurs during treatment with various other drugs, including atypical neuroleptics, e.g. risperidone, amitriptyline, lithium, glucocorticosteroids and ACTH, as well as the oral contraceptive pill. Glucocorticosteroids may help to improve appetite in terminally ill patients.
FURTHER READING
Bateson MC. Advances in gastroenterology and hepatology.
Postgraduate Medical Journal2000;76: 328–32.
Reidenburg M. Drugs and the liver. British Journal of Clinical Pharmacology1998;46: 351–9.
Zaman A, Chalasani N. Bleeding caused by portal hypertension.
Gastroenterology Clinics of North America2005;34: 623–42.
264 ALIMENTARY SYSTEM AND LIVER
discharge, faecal urgency and oily faeces. Although there is less absorption of the fat-soluble vitamins (vitamins A, D, E and K) and of β-carotene, this does not appear to cause patho- logical vitamin deficiency, and vitamin supplementation is not routinely indicated.
BULK AGENTS
Substances such as methylcellulose and guar gum act as bulk- ing agents in the diet and are ineffective at producing weight loss. A high-fibre diet may help weight loss, provided that total caloric intake is reduced, and is desirable for other rea- sons as well.
MISCELLANEOUS
Diuretics cause a transient loss of weight through fluid loss, and their use for such an effect is to be deplored. Myxoedema is associated with weight gain. Thyroxine has been used to increase the basal metabolic rate and reduce weight in euthy- roid obese patients. This is both dangerous and irrational.
●Introduction 265
●General physiology of vitamins 265
●Vitamin A (retinoic acid) and its derivatives 265
●Vitamin B1(thiamine) 266
●Vitamin B3(niacin and nicotinic acid) 266
●Vitamin B6(pyridoxine) 267
●Vitamin C (ascorbic acid) 267
●Vitamin E (tocopherol) 268
●Essential fatty acids 268
●Trace elements 268
CHAPTER 35