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METYRAPONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Metyrapone inhibits 11-beta-hydroxylase, the enzyme responsible for the synthesis of cortisone, hydrocortisone, and aldosterone from their precursors, and is used in the management of Cushing's syndrome and as a test of the feedback hypothalamic-pituitary mechanism.

Specific Substances

    1) 2-methyl-1,2-di-3-pyridyl-1-propanone
    2) Methapyrapone
    3) Mepyrapone
    4) Metopyrone
    5) Methibipyranone
    6) SU-4885
    7) Molecular Formula: C14-H14-N2-O
    8) CAS 54-36-4

Available Forms Sources

    A) USES
    1) Metyrapone has been used, in conjunction with other biochemical and laboratory evaluations, in the diagnostic evaluation of hypothalamic-pituitary ACTH function (Prod Info Metopirone(R), metyrapone, 1987; Hartzband et al, 1988).
    2) Metyrapone was also used in treatment of Cushing's Syndrome, and experimentally as a steroid suppressant in major depression resistant to antidepressant therapy (Murphy et al, 1991)

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS have included hypertension, hyponatremia, hypochloremia, hyperkalemia, and various rashes. Gastrointestinal upset, dizziness, sedation, anxiety, and bone marrow depression may occur.
    B) WITH POISONING/EXPOSURE
    1) OVERDOSE has been associated with dysrhythmias, hypotension, nausea, vomiting, diarrhea and anxiety.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Excessive secretion of desoxycorticosterone can cause hypertension in patients receiving long-term metyrapone therapy.
    B) WITH POISONING/EXPOSURE
    1) Hypotension and dysrhythmias may be seen in overdose.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Dizziness, headache, confusion, and weakness may occur with therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Anxiety may occur with overdose.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Vomiting, diarrhea, epigastric pain, and nausea have been reported with metyrapone overdose.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH POISONING/EXPOSURE
    1) Dehydration may be seen in overdose. Hyponatremia, hypochloremia, and hyperkalemia may be noted.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Bone marrow depression and decreased white blood cell count have been reported infrequently.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Metyrapone may cause a drug-induced allergic rash.
    2) Alopecia was associated with long-term metyrapone use in a 68-year-old female with Cushing's disease. Hirsutism has been reported in women receiving metyrapone for long-term treatment of Cushing's disease.
    0.2.16) ENDOCRINE
    A) WITH THERAPEUTIC USE
    1) Adrenal insufficiency may be induced acutely by metyrapone in patients with reduced adrenal secretory capacity.
    2) A mild mineralocorticoid effect was reported in a pediatric patient during a metyrapone study.
    3) LH, FSH, and TSH concentrations showed lack of responsiveness to administration of a single dose of metyrapone 40 mg/kg given orally to healthy volunteers. ACTH, TSH, and prolactin concentrations were altered in the early phase after oral administration of metyrapone 40 mg/kg in healthy male volunteers.
    B) WITH POISONING/EXPOSURE
    1) Adrenal insufficiency is seen in overdose cases.
    0.2.20) REPRODUCTIVE
    A) Metyrapone is classified as FDA Pregnancy Category C. Animal reproduction studies have not been conducted with metyrapone.
    B) A subnormal response to the metyrapone test may occur in pregnant women.
    C) The fetal pituitary responded to the enzymatic block when metyrapone test was administered to 20 pregnant women in their second and third trimester of pregnancy. The manufacturer recommends that metyrapone should be given to a pregnant woman only if clearly needed.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Adrenal function should be monitored during testing with metyrapone.
    B) Hyperkalemia, hypochloremia, or hyponatremia may be noted following metyrapone poisoning.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) Administer a large dose of hydrocortisone as soon as possible after an overdose.
    C) Administer saline and glucose solutions as appropriate.
    D) Blood pressure and fluid and electrolytes should be monitored for a few days postexposure.
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.

Range Of Toxicity

    A) A 6-year-old child died after receiving a total of 4 grams in two divided doses.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS have included hypertension, hyponatremia, hypochloremia, hyperkalemia, and various rashes. Gastrointestinal upset, dizziness, sedation, anxiety, and bone marrow depression may occur.
    B) WITH POISONING/EXPOSURE
    1) OVERDOSE has been associated with dysrhythmias, hypotension, nausea, vomiting, diarrhea and anxiety.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Excessive secretion of desoxycorticosterone can cause hypertension in patients receiving long-term metyrapone therapy.
    B) WITH POISONING/EXPOSURE
    1) Hypotension and dysrhythmias may be seen in overdose.
    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Excessive secretion of desoxycorticosterone can cause hypertension in patients receiving long-term metyrapone therapy (Schimmer & Parker, 1996). Sonino et al (1981) found no significant change in blood pressure with metyrapone administration (400 mg/m(2) every 4 hours for 5 to 9 days) in either normotensive or hypertensive children.
    b) CASE REPORT - A 20-year-old pregnant female at 23 weeks gestation, presented with hypertension (160/110 mmHg) and glycosuria. Further testing revealed that the patient had Cushing's syndrome, which was complicating the pregnancy. Metyrapone was administered whereupon the patient's blood pressure increased to 210/130 mmHg. It is not clear if the hypertension was related to metyrapone or the natural progression of preeclampsia (Connell et al, 1985).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension may be seen in overdose (Prod Info Metopirone(R), metyrapone, 1991).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) dysrhythmias may occur in overdose (Prod Info Metopirone(R), metyrapone, 1991).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dizziness, headache, confusion, and weakness may occur with therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Anxiety may occur with overdose.
    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness may occur with therapeutic use of metyrapone (Prod Info Metopirone(R), metyrapone, 1987).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache may occur with therapeutic use of metyrapone (Prod Info Metopirone(R), metyrapone, 1987).
    C) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) Weakness and confusion may occur with metyrapone use (Prod Info Metopirone(R), metyrapone, 1991).
    D) ANXIETY
    1) WITH POISONING/EXPOSURE
    a) Anxiety may be seen in overdose (Prod Info Metopirone(R), metyrapone, 1991).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Vomiting, diarrhea, epigastric pain, and nausea have been reported with metyrapone overdose.
    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) WITH POISONING/EXPOSURE
    a) Abdominal discomfort including vomiting, epigastric pain, and nausea have been reported with metyrapone overdose (Prod Info Metopirone(R), metyrapone, 1991).
    B) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Diarrhea may be seen after overdoses of metyrapone (Prod Info Metopirone(R), metyrapone, 1991).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Bone marrow depression and decreased white blood cell count have been reported infrequently.
    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Bone marrow depression and decreased white blood cell count have been reported infrequently with therapeutic use (Prod Info Metopirone(R), metyrapone, 1987).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Metyrapone may cause a drug-induced allergic rash.
    2) Alopecia was associated with long-term metyrapone use in a 68-year-old female with Cushing's disease. Hirsutism has been reported in women receiving metyrapone for long-term treatment of Cushing's disease.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Metyrapone may cause a drug-induced allergic rash (Prod Info Metopirone(R), metyrapone, 1987).
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Alopecia was associated with long-term metyrapone use in a 68-year-old female with Cushing's disease (Harris, 1986).
    C) EXCESSIVE HAIR GROWTH
    1) WITH THERAPEUTIC USE
    a) Hirsutism has been reported in women receiving metyrapone for long-term treatment of Cushing's disease (Orth, 1978).

Endocrine

    3.16.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Adrenal insufficiency may be induced acutely by metyrapone in patients with reduced adrenal secretory capacity.
    2) A mild mineralocorticoid effect was reported in a pediatric patient during a metyrapone study.
    3) LH, FSH, and TSH concentrations showed lack of responsiveness to administration of a single dose of metyrapone 40 mg/kg given orally to healthy volunteers. ACTH, TSH, and prolactin concentrations were altered in the early phase after oral administration of metyrapone 40 mg/kg in healthy male volunteers.
    B) WITH POISONING/EXPOSURE
    1) Adrenal insufficiency is seen in overdose cases.
    3.16.2) CLINICAL EFFECTS
    A) ADRENAL CORTICAL HYPOFUNCTION
    1) WITH THERAPEUTIC USE
    a) Adrenal insufficiency may be induced acutely by metyrapone in patients with reduced adrenal secretory capacity (JEF Reynolds , 1998).
    2) WITH POISONING/EXPOSURE
    a) It is seen in overdose cases (Prod Info Metopirone(R), metyrapone, 1991).
    B) DISORDER OF ENDOCRINE SYSTEM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A mild mineralocorticoid effect was noted in one pediatric normotensive subject administered metyrapone 400 mg/m(2) every 4 hours for 5 to 9 days (Sonino et al, 1981).
    C) HORMONE ABNORMALITY
    1) WITH THERAPEUTIC USE
    a) LH, FSH, and TSH concentrations showed lack of responsiveness to administration of a single dose of metyrapone 40 mg/kg given orally to healthy volunteers (Schoneshofer & Fenner, 1981).
    b) ACTH, TSH, and prolactin concentrations were altered in the early phase after oral administration of metyrapone 40 mg/kg in healthy male volunteers (Schoneshofer & Fenner, 1981).
    c) Metyrapone inhibits the enzymatic step of cholesterol cleavage (to a lesser degree than on 11-hydroxylase) that may be overcome competitively by increasing amounts of ACTH (Maxeiner et al, 1980).

Reproductive

    3.20.1) SUMMARY
    A) Metyrapone is classified as FDA Pregnancy Category C. Animal reproduction studies have not been conducted with metyrapone.
    B) A subnormal response to the metyrapone test may occur in pregnant women.
    C) The fetal pituitary responded to the enzymatic block when metyrapone test was administered to 20 pregnant women in their second and third trimester of pregnancy. The manufacturer recommends that metyrapone should be given to a pregnant woman only if clearly needed.
    3.20.2) TERATOGENICITY
    A) PREGNANCY CATEGORY
    1) Metyrapone is classified as FDA Pregnancy Category C (Prod Info Metopirone(R), metyrapone, 1987).
    B) ANIMAL STUDIES
    1) Animal reproduction studies have not been conducted with metyrapone (Prod Info Metopirone(R), metyrapone, 1987).
    3.20.3) EFFECTS IN PREGNANCY
    A) HUMANS
    1) A subnormal response to the metyrapone test may occur in pregnant women (Prod Info Metopirone(R), metyrapone, 1987).
    2) The fetal pituitary responded to the enzymatic block when metyrapone test was administered to 20 pregnant women in their second and third trimester of pregnancy. The manufacturer recommends that metyrapone should be given to a pregnant woman only if clearly needed (Prod Info Metopirone(R), metyrapone, 1987).
    3) When used in pregnancy for Cushing's syndrome, metyrapone lowered plasma cortisol and urinary cortisol excretion. The placental steroid synthesis was also inhibited, but this was not thought to be clinically significant (Connell et al, 1985).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Adrenal function should be monitored during testing with metyrapone.
    B) Hyperkalemia, hypochloremia, or hyponatremia may be noted following metyrapone poisoning.
    4.1.2) SERUM/BLOOD
    A) ENDOCRINE
    1) Adrenal function should be monitored during testing with Metyrapone (Prod Info Metopirone(R), metyrapone, 1987).
    B) BLOOD/SERUM CHEMISTRY
    1) Hyperkalemia, hypochloremia, or hyponatremia may be noted following metyrapone poisoning (Prod Info Metopirone(R), metyrapone, 1987), therefore fluid and electrolyte levels should be monitored.

Methods

    A) CHROMATOGRAPHY
    1) A coupled achiral-chiral liquid chromatographic method was used to determine the concentrations of metyrapone and its metabolite, metyrapol, in human plasma and urine. The limits of detection, in plasma and urine, for metyrapone and metyrapol were 0.03 mcg/mL. The limits of quantification for metyrapone and metyrapol were 0.10 mcg/mL and 0.05 mcg/mL, respectively (Chiarotto & Wainer, 1995).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Adrenal function should be monitored during testing with metyrapone.
    B) Hyperkalemia, hypochloremia, or hyponatremia may be noted following metyrapone poisoning.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital 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. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no specific antidote. Treatment, after decontamination, is basically symptomatic and supportive.
    B) CORTICOSTEROID
    1) Administer a large dose of hydrocortisone as soon as possible after an overdose (Prod Info Metopirone(R), metyrapone, 1991).
    C) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Administer saline and glucose solutions as appropriate (Prod Info Metopirone(R), metyrapone, 1991).
    D) MONITORING OF PATIENT
    1) Blood pressure and fluid and electrolytes should be monitored for a few days postexposure (Prod Info Metopirone(R), metyrapone, 1991).
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Range Of Toxicity

Summary

    A) A 6-year-old child died after receiving a total of 4 grams in two divided doses.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) ORAL
    a) The usual diagnostic adult dose of metyrapone is 750 mg (15 mg/kg) orally every 4 hours for 6 doses on day 5 of hypothalamic-pituitary ACTH function testing (Prod Info Metopirone(R) oral capsules, 2013).
    7.2.2) PEDIATRIC
    A) ROUTE OF ADMINISTRATION
    1) ORAL
    a) The usual diagnostic pediatric dose of metyrapone is 15 mg/kg orally every 4 hours for 6 doses on day 5 of hypothalamic-pituitary ACTH function testing. A minimum single dose of 250 mg is recommended (Prod Info Metopirone(R) oral capsules, 2013).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) PEDIATRIC
    a) A 6-year-old child died after receiving a total of 4 grams in two divided doses (Prod Info Metopirone(R), metyrapone, 1991).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) THERAPEUTIC DRUG CONCENTRATION LEVELS -
    1) During treatment with metyrapone, plasma concentrations range from 0.5 to 1 microgram per milliliter (Prod Info Metopirone(R), metyrapone, 1987).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 521 mg/kg (Prod Info Metopirone(R), metyrapone, 1991)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Metyrapone inhibits 11-beta-hydroxylation, and 18-hydroxylation and side chain cleavage is inhibited to some degree, resulting in reduced production of cortisol (Schimmer & Parker, 1996).
    B) The adrenal cortex must have the ability to respond to ACTH before metyrapone is employed to test the capacity of the pituitary to respond to a decreased concentration of plasma cortisol (Schimmer & Parker, 1996).
    C) Cushing's syndrome of pituitary origin will result in a pituitary response that is greater than normal when metyrapone test is employed. Cushing's syndrome caused by ectopic production of ACTH will result in no response to metyrapone (Schimmer & Parker, 1996).
    D) Aldosterone synthesis is also inhibited by metyrapone. Mineralocorticoid deficiency does not usually occur with long-term metyrapone therapy because inhibition of the 11-beta-hydroxylation reaction results in an increase production of 11-desoxycorticosterone, a mineralocorticoid. Excessive secretion of desoxycorticosterone can cause hypertension in patients receiving long-term metyrapone therapy (Schimmer & Parker, 1996).
    E) Plasma glucocorticoids have been suggested to play a role in the regulation of ocular pressure. Levi & Schwartz (1987) demonstrated that administration of metyrapone significantly decreased ocular pressure in 14 subjects with elevated ocular pressure.
    F) Metyrapone appears to have a dual effect on plasma ACTH. Schoneshofer et al (1983) demonstrated metyrapone has a suppressive effect on plasma ACTH as well as the previously described stimulatory effect on plasma ACTH.
    G) Metyrapone decreased the total overnight basal insulin requirement but not the early morning rise in insulin required to maintain euglycemia in 5 insulin-dependent diabetic subjects (Bright et al, 1980).
    H) Sonino et al (1981a) reported mineralocorticoid and glucocorticoid pathways are equally affected by metyrapone.

Physicochemical

Physical Characteristics

    A) The USP product is light amber to white in color.

Molecular Weight

    A) 226.28

Animal Toxicology

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) DOG
    1) The maximum tolerated IV dose in one dog was 300 mg/kg (Prod Info Metopirone(R), metyrapone, 1991).

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Bright GM, Melton TW, & Rogol AD: Failure of cortisol blockade to inhibit early morning increases in basal insulin requirements in fasting insulin-dependent diabetics. Diabetes 1980; 29:662-664.
    3) Chiarotto JA & Wainer IW: Determination of metyrapone and the enantiomers of its chiral metabolite metyrapol in human plasma and urine using coupled achiral-chiral liquid chromatography. J Chromatogr B 1995; 665:147-154.
    4) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    5) Connell JMC, Cordiner J, & Davies DL: Pregnancy complicated by Cushing's syndrome: potential hazard of metyrapone therapy. Case report. Br J Obstet Gynaecol 1985; 92:1192-1195.
    6) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    7) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    8) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    9) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    10) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    11) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    12) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
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