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
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
Flutamide blood levels are not
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.