Metyrapone

(BAN, USAN, rINN)
Synonyms: Metirapon; Metirapona; Metyrapon; Métyrapone; Metyraponi; Metyraponum; Su-4885 (metyrapone tartrate). 2-Methyl-1,2di(3-pyridyl)propan-1-one.
Cyrillic synonym: Метирапон.

💊 Chemical information

Chemical formula: C14H14N2O = 226.3.
CAS — 54-36-4.
ATC — V04CD01.
ATC Vet — QV04C D01.

Pharmacopoeias.

In Br., Jpn, and US.

BP 2008

(Metyrapone). A white to light amber crystalline powder with a characteristic odour. M.p. 50° to 53°. Sparingly soluble in water; freely soluble in alcohol and in chloroform; it dissolves in dilute mineral acids. Protect from light.

USP 31

(Metyrapone). A white to light amber, fine, crystalline powder, having a characteristic odour. It darkens on exposure to light. Sparingly soluble in water; soluble in chloroform and in methyl alcohol; forms water-soluble salts with acids. Store in airtight containers. Protect from heat and light.

💊 Adverse Effects

Metyrapone may give rise to nausea and vomiting, abdominal pain, headache, sedation, dizziness, hypotension, and hypersensitivity rashes. Hypoadrenalism, hirsutism, and bone marrow depression may occur rarely. Long-term use of metyrapone can cause hypertension.

Alopecia.

Reports of alopecia1,2 associated with administration of metyrapone for Cushing’s syndrome.
1. Harris PL. Alopecia associated with long-term metyrapone use. Clin Pharm 1986; 5: 66–8
2. Harries-Jones R, Overstall P. Metyrapone-induced alopecia. Postgrad Med J 1990; 66: 584.

💊 Precautions

Metyrapone should be used with extreme caution, if at all, in patients with gross hypopituitarism or with reduced adrenal secretory activity because of the risk of precipitating acute adrenal failure. Thyroid dysfunction or liver cirrhosis may alter the response to metyrapone. Dizziness and sedation may affect the performance of skilled tasks such as driving.

Porphyria.

Metyrapone is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in in-vitro systems.

💊 Interactions

Phenytoin is reported to increase the metabolism of metyrapone; doubling the dose of metyrapone may counteract the interaction. However, as many other drugs may interfere with steroid assessment, medication is best avoided where possible during the metyrapone test. Drugs reported to interfere with the metyrapone test include antidepressants such as amitriptyline, antithyroid drugs, antipsychotics such as chlorpromazine, barbiturates, corticosteroids, cyproheptadine, and hormones that affect the hypothalamic-pituitary axis such as oestrogens and progestogens.

💊 Pharmacokinetics

Metyrapone is rapidly absorbed from the gastrointestinal tract. It is metabolised by rapid reduction to metyrapol and excreted in the urine as glucuronide conjugates of metyrapone and metyrapol.

💊 Uses and Administration

Metyrapone inhibits the enzyme 11β-hydroxylase responsible for the synthesis of the glucocorticoids cortisone and hydrocortisone (cortisol) as well as aldosterone from their precursors. The consequent fall in the plasma concentrations of circulating glucocorticoids stimulates the anterior pituitary gland to produce more corticotropin. This, in turn, stimulates the production of more 11-deoxycortisol and other precursors which are metabolised in the liver and excreted in the urine where they can be measured. Metyrapone is therefore used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of Cushing’s syndrome, although the dexamethasone suppression test may be preferred. After demonstration of the responsiveness of the adrenal cortex, metyrapone is given orally, usually in a dose of 750 mg every 4 hours for 6 doses. Taking doses with milk or after a meal may minimise the gastrointestinal adverse effects of metyrapone. A suggested oral dose for children is 15 mg/kg, with a minimum dose of 250 mg, every 4 hours for 6 doses. In patients with a normally functioning pituitary gland excretion of 17-hydroxycorticosteroids is increased two- to fourfold and that of 17-ketosteroids about twofold. Metyrapone is also used in the management of Cushing’s syndrome (below) when doses may range from 250 mg to 6 g daily. Since metyrapone inhibits the synthesis of aldosterone it has been used to treat some cases of resistant oedema; it is given with a glucocorticoid to suppress the normal corticotropin response to low plasma concentrations of glucocorticoids. The suggested usual dosage of metyrapone in resistant oedema is 3 g daily in divided doses. Metyrapone tartrate has also been used.

Cushing’s syndrome.

Cushing’s syndrome is the result of a chronic excess of glucocorticoids.1,2 It may be independent of the secretion of adrenocorticotrophic hormone (ACTH; corticotropin), either due to an adrenal tumour secreting cortisol, or to exogenous corticosteroids, or it may be ACTH-dependent, such as Cushing’s disease proper, which is caused by excessive ACTH secretion from a pituitary adenoma; other ACTH-dependent forms may be due to pituitary hyperplasia, or an ectopic ACTHsecreting tumour elsewhere—usually bronchus or lung cancer. About two-thirds of all cases are due to Cushing’s disease, which is 8 times more common in women than men. Symptoms may develop insidiously over several years and include obesity, particularly of the trunk, rounding of the face, atrophy of the skin leading to striae, poor wound healing, muscle weakness, osteoporosis, hypertension, diabetes mellitus, and depression and other psychological disturbances. Hypokalaemia is rare in Cushing’s disease but common in other forms of the syndrome. Women may have hirsutism due to adrenal androgen secretion, and both sexes may develop hypogonadism and loss of libido. Diagnosis of Cushing’s syndrome can be problematic because no test is wholly reliable.1,3-6 Where there is suspicion, options for initial screening include measurement of urinary cortisol, late-night salivary cortisol, midnight plasma-cortisol, and overnight low-dose dexamethasone suppression testing. A dexamethasone-corticorelin test may be used to identify pseudo-Cushing’s conditions such as depression or alcoholism. Once a diagnosis of Cushing’s syndrome has been made, plasma-ACTH measurements are used to distinguish between ACTH-dependent and ACTH-independent forms. High-dose dexamethasone suppression testing and corticorelin stimulation testing have been used to differentiate between pituitary and ectopic ACTHdependent Cushing’s syndrome, but they both have disadvantages and their usefulness has been debated. For further discussion of dexamethasone suppression testing, and for corticorelin stimulation testing. Imaging techniques and sampling of central (petrosal) venous blood are additional procedures that may be used for localising tumours. Appropriate treatment depends on accurate identification of the cause of the syndrome.1 The usual treatment in Cushing’s disease is transsphenoidal resection of the tumour, which when carried out by an experienced surgeon produces a successful response in the majority of patients. Pituitary radiotherapy is slower than surgery to take effect, produces a lower remission rate, and is more likely to produce hypopituitarism. It is therefore usually used as second-line therapy when initial surgery has not been curative and a second operation is considered unsuitable. If pituitary surgery or radiotherapy fails, bilateral adrenalectomy may be considered (although this has some risks including that of Nelson’s syndrome due to hyperactivity of residual pituitary tumour). Patients who undergo such surgery require glucocorticoid and mineralocorticoid replacement therapy for life. Surgery is also the treatment of choice for a resectable adrenal tumour or ectopic ACTH-secreting tumour; even where there is metastasis it may be useful in moderating symptoms. A number of drugs have been used in patients with Cushing’s disease, but their role appears to be mainly adjuvant.1,7 Drugs acting at the hypothalamic-pituitary level, aimed at reducing ACTH secretion, do not seem to be of much value; there have been occasional reports of benefit with bromocriptine, cyproheptadine, and sodium valproate. Drugs that inhibit steroid synthesis in the adrenal gland are more effective, and include mitotane, metyrapone, and ketoconazole. These may be used to control severe complications quickly, prepare patients for surgery, or provide cover while radiotherapy takes effect. Mifepristone acts as a glucocorticoid receptor antagonist, and has been used successfully in a few patients with

Cushing’s syndrome.

Etomidate can be useful for acute control of hypercortisolaemia if the oral route is not available. In patients with the ectopic ACTH syndrome in whom surgery is unsuitable or ineffective, chemotherapy aimed at the primary tumour is the treatment of choice but is likely to be only palliative. Inhibitors of steroid synthesis can be used to control symptoms, and somatostatin analogues such as octreotide may decrease ACTH secretion by ectopic tumours that have somatostatin receptors.1 Surgery is the preferred treatment for an adrenal tumour but, although this is usually curative for adrenal adenoma, it is less successful for adrenal carcinoma.1 In patients who are successfully treated for Cushing’s syndrome adrenocortical replacement therapy is usually required until the hypothalamic-pituitary-adrenal axis recovers normal function, a process which may take many months.
1. Newell-Price J, et al. Cushing’s syndrome. Lancet 2006; 367: 1605–17
2. Newell-Price J, et al. Cushing’s syndrome. Lancet 2006; 367: 1605–17
3. Raff H, Findling JW. A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med 2003; 138: 980–91
4. Arnaldi G, et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2003; 88: 5593–5602
5. Findling JW, Raff H. Cushing’s syndrome: important issues in diagnosis and management. J Clin Endocrinol Metab 2006; 91: 3746–53
6. Nieman LK, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 1526–40. Also available at: http://www.endo-society.org/ guidelines/final/upload/Cushings_Guideline.pdf (accessed 06/08/08
7. Nieman LK. Medical therapy of Cushing’s disease. Pituitary 2002; 5: 77–82.

💊 Preparations

BP 2008: Metyrapone Capsules; USP 31: Metyrapone Tablets.

Proprietary Preparations

Austral.: Metopirone; Cz.: Metopirone†; Fr.: Metopirone; Gr.: Metopirone; Irl.: Metopirone; Israel: Metopirone; Neth.: Metopiron; NZ: Metopirone; Swed.: Metopiron; Switz.: Metopirone; UK: Metopirone; USA: Metopirone.
Published May 08, 2019.