Anti-androgens

Anti-androgens

Examples include onadorelin, leuprolide (both agonists of gonadotropin releasing hormone), cyproterone acetate, and flutamide (both specific androgen receptor antagonists). Other non-specific anti-androgens include the antifungal drugs ketoconazole and liarozole, the aldosterone antagonist spirono-lactone and 5a-reductase inhibitors such as finasteride.

Cyproterone is a synthetic progestogen which competes with dihydrotestosterone for binding to the androgen receptor, and has been used in the treatment of acne, hirsutism, male pattern baldness, virilising syndromes, and prostate cancer. There are indications that cyproterone is hepatotoxic, and may even cause hepatocellular carcinoma.

Flutamide (niftolide) is a non-steroidal anti-androgen which is sometimes used in the treatment of prostatic cancer. It has been demonstrated to block the action of dihydrotestos-terone (DHT) on prostatic tissue androgen receptors resulting in involution of the prostate gland. It does not possess andro-genic, adrenocortical, antiestrogenic, oestrogenic, proges-tational, antilibido, antifertility, or gonadotropin-inhibiting actions. Flutamide is used in the treatment of metastatic pros-tatic adenocarcinoma as a single drug therapy, or in combi-nation with either a luteinising hormone-releasing hormone analogue or orchidectomy. Flutamide, in combination with oral contraceptives, has also been used for the treatment of hirsutism and benign prostatic hyperplasia.

Adverse effects of flutamide include breast tenderness, gynaecomastia, and possible hepatotoxicity. Other effects include hypertension, drowsiness, confusion, depression, anorexia, nausea, vomiting, and diarrhoea/constipation. Anaemia, leukopenia, and thrombocytopenia have also been reported following therapeutic doses of flutamide in humans. Teratogenic data is lacking for humans, but animal data indicate that a decreased survival time for offspring, feminisation of male foetuses, cryptorchidism, and a slight increase in minor skeletal malformations occur when high doses are given.

Primary signs of overdose may include hypoactivity, decreased respirations, ataxia, lacrimation, somnolence, emesis, and methaemoglobinaemia. It is logical to conclude that an overdose may also result in hypertension, as this is reported in approximately 1% of patients following therapeutic doses of flutamide. Hepatotoxicity is also likely.

Treatment

·              Flutamide blood levels are not clinically useful.

·              Monitor liver and renal function tests and ECG in overdose.

·              In acute single overdosage, toxicity is unlikely and supportive treatment to ease gastrointestinal irritation and CNS depression may be all that is required.

·              Consider pre-hospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion.

·              Consider gastric lavage with a large-bore orogastric tube after a substantial ingestion if it can be performed soon after ingestion (generally within 60 minutes).

·              Determine the methaemoglobin concentration and evaluate the patient for clinical effects of methaemoglobinaemia (dyspnoea, headache, fatigue, CNS depression, tachycardia, acidosis, etc.). Treat patients with symptomatic methae- moglobinaemia with methylene blue (1 to 2 mg/kg/dose, i.e. 0.1 to 0.2 ml/kg/dose, intravenously over 5 minutes as needed every 4 hours). Administer oxygen while preparing for methylene blue therapy.

·     Because flutamide is so highly protein-bound, it is unlikely that haemodialysis would be of any clinical benefit in removal of drug in overdose cases.

·     In chronic toxicity, patients should be monitored for the development of gynaecomastia and galactorrhoea.