ENZYME INHIBITORS
Ketoconazole 20-Jul-2017
lDRUG ACTIONAn imidazole derivative which acts as a
potent inhibitor of cortisol and aldosterone synthesis by
inhibiting the activity of 17 a-hydroxylase,
11 -hydroxylation steps and at higher doses the cholesterol
side-chain cleavage enzyme. It also inhibits the activity of
adrenal C 17 - 20 lyase enzymes resulting in androgen
synthesis inhibition, and may have a direct effect on
corticotropic tumour cells in patients with Cushing’s
disease.lINDICATIONS AND DOSE
Endogenous Cushing’s syndrome (specialist use only)
▶BY MOUTH
▶Child 12–17 years:Initially 400 – 600 mg daily in
2 – 3 divided doses, increased to 800 – 1200 mg daily;
maintenance 400 – 800 mg daily in 2 – 3 divided doses,
for dose titrations in patients with established dose,
adjustments in adrenal insufficiency, or concomitant
corticosteroid replacement therapy, consult product
literature; maximum 1200 mg per daylCONTRA-INDICATIONSAcquired QTc prolongation.Acute
porphyrias p. 603.avoid concomitant use of hepatotoxic
drugs.congenital QTc prolongation
lCAUTIONSRisk of adrenal insufficiency
lINTERACTIONS→Appendix 1 : antifungals, azoles
lSIDE-EFFECTS
▶Common or very commonAdrenal insufficiency.diarrhoea.
gastrointestinal discomfort.nausea.skin reactions.
vomiting
▶UncommonAllergic conditions.alopecia.angioedema.
asthenia.dizziness.drowsiness.headache.
thrombocytopenia
▶Rare or very rareFever.hepatic disorders.taste altered
▶Frequency not knownAlcohol intolerance.appetite
abnormal.arthralgia.azoospermia.dry mouth.epistaxis.
flatulence.fontanelle bulging.gynaecomastia.hotflush.
insomnia.intracranial pressure increased.malaise.
menstrual disorder.myalgia.nervousness.papilloedema.
paraesthesia.peripheral oedema.photophobia.
photosensitivity reaction.tongue discolouration
SIDE-EFFECTS, FURTHER INFORMATIONPotentially life-
threatening hepatotoxicity reported rarely with oral use.
lCONCEPTION AND CONTRACEPTIONEffective
contraception must be used in women of child-bearing
potential.
lPREGNANCYManufacturer advises avoid—teratogenic in
animalstudies.
lBREAST FEEDINGManufacturer advises avoid—present in
breast milk.
lHEPATIC IMPAIRMENTAvoid in acute or chronic
impairment. Do not initiate treatment if liver enzymes
greater than 2 times the normal upper limit.
lMONITORING REQUIREMENTS
▶Monitor ECG before and one week after initiation, and
then as clinically indicated thereafter.
▶Adrenal insufficiencyMonitor adrenal function within one
week of initiation, then regularly thereafter. When cortisol
levels are normalised or close to target and effective dose
established, monitor every 3 – 6 months as there is a risk of
autoimmune disease development or exacerbation after
normalisation of cortisol levels. If symptoms suggestive of
adrenal insufficiency such as fatigue, anorexia, nausea,
vomiting, hypotension, hyponatraemia, hyperkalaemia,
and/or hypoglycaemia occur, measure cortisol levels and
discontinue treatment temporarily (can be resumedthereafter at lower dose) or reduce dose and if necessary,
initiate corticosteroid substitution.
▶HepatotoxicityMonitor liver function before initiation of
treatment, then weekly for^1 month after initiation, then
monthly for 6 months—more frequently if dose adjusted or
abnormal liver function detected. Reduce dose if liver
enzymes increase less than 3 times the normal upper
limit—consult product literature; if liver enzymes are
raised to 3 times or greater the normal upper limit,
discontinue treatment permanently.
lPATIENT AND CARER ADVICEPatients or their carers should
be told how to recognise signs of liver disorder, and
advised to discontinue treatment and seek prompt medical
attention if symptoms such as anorexia, nausea, vomiting,
fatigue, jaundice, abdominal pain, or dark urine develop.
Patients or their carers should also be told how to
recognise signs of adrenal insufficiency.
Driving and skilled tasksDizziness and somnolence may
affect the performance of skilled tasks (e.g. driving).lMEDICINAL FORMS
There can be variation in the licensing of different medicines
containing the same drug. Forms available from special-order
manufacturers include: oral suspension
Tablet
CAUTIONARY AND ADVISORY LABELS2, 5, 21
▶Ketoconazole (non-proprietary)A
Ketoconazole 200 mgKetoconazole 200 mg tablets|
60 tabletP£ 480. 00Metyrapone
lDRUG ACTIONMetyrapone is a competitive inhibitor of
11 b-hydroxylation in the adrenal cortex; the resulting
inhibition of cortisol (and to a lesser extent aldosterone)
production leads to an increase in ACTH production
which, in turn, leads to increased synthesis and release of
cortisol precursors. Metyrapone may be used as a test of
anterior pituitary function.lINDICATIONS AND DOSE
Differential diagnosis of ACTH-dependent Cushing’s
syndrome (specialist supervision in hospital)
▶BY MOUTH
▶Child: 15 mg/kg every 4 hours for 6 doses, alternatively
300 mg/m^2 every 4 hours for 6 doses; usual dose
250 – 750 mg every 4 hours
Management of Cushing’s syndrome (specialist
supervision in hospital)
▶BY MOUTH
▶Child:Usual dose 0. 25 – 6 g daily, dose to be tailored to
cortisol production, dose is either low, and tailored to
cortisol production, or high, in which case
corticosteroid replacement therapy is also neededlCONTRA-INDICATIONSAdrenocortical insufficiency
lCAUTIONSAvoid in Acute porphyrias p. 603 .gross
hypopituitarism (risk of precipitating acute adrenal failure)
.hypertension on long-term administration.
hypothyroidism (delayed response)
lINTERACTIONS→Appendix 1 : metyrapone
lSIDE-EFFECTS
▶Common or very commonDizziness.headache.
hypotension.nausea.sedation.vomiting
▶Rare or very rareAbdominal pain.adrenal insufficiency.
allergic dermatitis.hirsutism
▶Frequency not knownAlopecia.bone marrow failure.
hypertension
lPREGNANCYAvoid (may impair biosynthesis of fetal-
placental steroids).
lBREAST FEEDINGAvoid—no information available.444 Corticosteroid responsive conditions BNFC 2018 – 2019
Endocrine system6