Metyrapone inhibits the synthesis of cortisol by inhibiting the enzyme 11-Beta hydroxylase. It is primarily used to evaluate the hypothalamic-pituitary ACTH function. It is rarely used nowadays to treat patients with Cushing's syndrome.

Metyrapone Uses:

• ACTH function testing:

  • It is recommended as a diagnostic test of the hypothalamic-pituitary ACTH system.

• Off Label Use of Metyrapone in Adults:

  • Cushing syndrome

Metyrapone Dose in Adults:

Metyrapone Dose in the ACTH function testing: Oral:

• Multiple-dose test:

  • 6 dosages of 750 mg every four hours.

• Single-dose/overnight test:

  • At midnight, 30 mg/kg (maximum: 3 g)

Metyrapone Dose in the treatment of Cushing syndrome (off-label): Oral:

Metyrapone can be used as monotherapy or occasionally in combination with other agents (eg, ketoconazole and/or mitotane).

• Initial: 500 mg/day to 1 g/day in 2 - 4 divided doses; higher initial doses (eg, 1.5 g/day) can be given if patients have ectopic ACTH syndrome or adrenocortical carcinoma
• Titration: Dose can be adjusted with increments of 250 - 500 mg based on cortisol response. Usual dosage range: 500 mg/day - 4.5 g/day.
• Maximum: 6 g/day.

Metyrapone Dose in Children:

Metyrapone Dose as a diagnostic test to evaluate ACTH function:

• Single-dose/overnight test:

Note: Metyrapone has the potential to cause acute adrenal insufficiency, It should be used in inpatient settings, if its to be used in the outpatient setting, use it with extreme caution Children and Adolescents: Oral: 30 mg/kg as a single dose given at midnight the night before the test; maximum dose: 3,000 mg/dose

• Multiple-dose test:

  • Children and Adolescents: Oral: 15 mg/kg/dose every 4 hours for 6 doses;
    • Maximum dose: 750 mg/dose
    • Minimum dose: 250 mg/dose

Pregnancy Risk Factor C

• To date, there are no studies on animal reproduction.
• Medical therapy during pregnancy should be started in the second or third trimester. 
• Cushing syndrome, if left untreated can cause adverse effects in both the mother and the fetus.
• The enzymatic block was used to diagnose the fetal pituitary when it was used during the second and three-quarters of the pregnancy.
• Pregnant women may experience a subnormal response to testing.

Use during breastfeeding:

• Metyrapone excretes breastmilk.
• One case study determined that the infant's relative dosage of metyrapone or metyrapol was 0.1% of the mother's weight-adjusted dose.
• It is recommended that it be used with caution by breastfeeding mothers.

Dose in Kidney Disease:

The manufacturer has not provided any dose adjustment in labeling.

Dose in Liver disease:

The manufacturer has not provided any dose adjustment in labeling.

Side effects of Metyrapone:

• Cardiovascular:

  • Hypotension

• Central nervous system:

  • Dizziness
  • Headache
  • Sedated state

• Dermatologic:

  • Allergic skin rash

• Gastrointestinal:

  • Abdominal discomfort
  • Abdominal pain
  • Nausea
  • Vomiting

• Hematologic & oncologic:

  • Bone marrow depression
  • Decreased white blood cell count

Contraindications to Metyrapone:

• Hypersensitivity to any ingredient of the formulation
• Insufficiency of the adrenal cortex

Warnings and precautions

• CNS depression:

  • Use of it can cause CNS depression and could result in impaired physical or mental capabilities.
  • Patients should be cautious about driving or operating machinery after use.

• Reduction in adrenal secretory ability

  • Acute adrenal insufficiency can occur if the patient has a reduced adrenal secretory ability.

• Thyroid disease:

  • Patients with hypo- and hyperthyroidism may have a subnormal response.

Metyrapone: Drug Interaction

Monitoring parameters:

ACTH function testing:

• Single-dose test: 11-deoxycortisol concentrations <200 nmol/L are diagnostic for adrenal insufficiency.

Multiple-dose test: A 2- to 4-fold rise in urine 17-OHCS excretion or a doubling of 17-KGS excretion is considered a normal response to the test. Cushing syndrome:

• Cortisol (either serum cortisol or 24-hour urinary free cortisol baseline)
  • On day 3 
  • Weekly then periodically thereafter
• Serum potassium
• Blood pressure
• Edema
• Hirsutism

How to administer Metyrapone?

Oral:

• ACTH function testing:
  • Single-dose test: Use it in patients with adequate waking cortisol concentrations (>200 nmol/L).
  • Administer the dose at midnight with yogurt or milk. Blood samples are taken the following morning (7:30-8:00 am).
  • Use a prophylactic dose of cortisone acetate 50 mg once the sample is collected.
• Multiple-dose test:
  • Use it with milk/yogurt for 3 days following the ACTH test. Collect 24 hours of Urine after the last day of administration.
• Cushing syndrome:
  • It may cause GI disturbance, take it with food or milk

Mechanism of action of Metyrapone:

• It blocks the synthesis of cortisol through the following mechanism:
• Metyrapone inhibits 11 Beta-hydroxylase. This prevents the conversion from 11-deoxycortisol into cortisol.
• The urinary rise of the cortisol precursor metabolites in the urine serves as a marker for this blockage (17-hydroxycorticosteroids [17-OHCS] and 17-ketogenic steroids [17-KGS]).

Absorption:

• Oral: Well absorbed; rapid

Metabolism:

• Reduced to metyrapol (active metabolite); parent drug and metabolite also undergo glucuronide conjugation

Onset:

• Peak steroid excretion: Within 24 hours of administration

Half-life elimination:

• Metyrapol (active metabolite): Takes twice as long as metyrapone to be eliminated
•  Metyrapone: 1.9 ± 0.7 hours

Time to peak:

• 1 hour

Excretion:

• Urine; ~5% as metyrapone (primarily as glucuronide conjugate)
• ~38% as metyrapol (primarily as glucuronide conjugate)

International Brand Names of Metyrapone:

• Metopirone
• Metopiron
• Metycor

Metyrapone Brand Names in Pakistan:

No Brands Available in Pakistan.