DESCRIPTION

Dantrolene is a medication used in the treatment of malignant hyperthermia and proposed for some poisonings complicated by hyperthermia and muscle rigidity.

FORMS AND USES

Dantrolene (Dantrium, Dantamacrin) is available as:

• A suspension of 5 mg/ml
• Capsules containing 25, 50, or 100 mg of dantrolene
• A 70-ml vial of lyophilized powder for reconstitution and intravenous injection (lyophilized dantrolene 20 mg, mannitol 3000 mg, reconstituted with water for injection 60 ml)

MECHANISM OF ACTION

• Dantrolene acts directly on skeletal muscle; it does not affect central or peripheral nerves.
• It decreases calcium release from the sarcoplasmic reticulum, thereby decreasing the strength of skeletal muscle contraction.
• Dantrolene may inhibit the cellular inward calcium activator current, thereby decreasing the amount of calcium available to trigger intracellular calcium release.
• It does not produce complete muscle paralysis therapeutically or in overdose.
• Dantrolene is highly protein bound; elimination occurs via both liver and kidney clearance.

DRUG AND DISEASE INTERACTIONS

Dantrolene may potentiate the effects of CNS depressants and may further impair respiratory or cardiovascular function in patients with respiratory or cardiac muscle weakness.

PREGNANCY AND LACTATION

• US FDA Pregnancy Category C. The drug exhibits animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
• Dantrolene appears safe when administered in the third trimester to women at risk for developing malignant hyperthermia related to anesthetics administered at the time of delivery.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• MECHANISM OF ACTION
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

TOXIC CONDITIONS

Dantrolene may be useful in the treatment of muscle rigidity syndromes associated with the following conditions.

• Malignant hyperthermia
• Prophylaxis for malignant hyperthermia
• Neuroleptic malignant syndrome (NMS)
• Serotonin syndrome
• Amphetamine or cocaine toxicity
• Carbon monoxide poisoning
• Monoamine oxidase (MAO) inhibitor poisoning
• Dantrolene also has been used in the treatment of lethal catatonia or tremors induced by amphotericin refractory to other therapy.

NONTOXIC CONDITIONS

• Multiple sclerosis
• Spasticity
• Muscle cramping and spasm

Section Outline:

• TOXIC CONDITIONS
• NONTOXIC CONDITIONS

CONTRAINDICATIONS

• Chronic use in patients with hepatic insufficiency, especially active hepatitis or cirrhosis
• When spasticity or muscle tone is required for function

ADVERSE EFFECTS

• Most adverse effects occur during chronic therapy.
• Adverse reactions are very uncommon during short-term therapy of a few days for malignant hyperthermia, NMS, or serotonin syndrome.

Pulmonary

Pulmonary edema, possibly related to large crystalloid volume required to administer dantrolene

Cardiovascular

Tachycardia, hypertension, hypotension, and pericarditis

Gastrointestinal

Nausea, vomiting, diarrhea, abdominal pain, gastrointestinal hemorrhage, constipation, and ileus with functional bowel obstruction

Hepatic

• Increased transaminase (aspartate aminotransferase and alanine aminotransferase), bilirubin, and alkaline phosphatase have been reported.
• Incidence of hepatotoxicity is increased with high dose (more than 300 mg), longer duration of therapy (more than 2 months), older age (more than 30 years old), and female gender.

Neurologic

CNS depression, muscle weakness, ataxia, hallucinations, and fatigue

Genitourinary

Increased urinary frequency, crystalluria, hematuria, incontinence, and impotence

Dermatologic

Rash, acne, and photosensitivity

Musculoskeletal

Myalgia and subjective muscle weakness

Section Outline:

• CONTRAINDICATIONS
• ADVERSE EFFECTS
  • Pulmonary
  • Cardiovascular
  • Gastrointestinal
  • Hepatic
  • Neurologic
  • Genitourinary
  • Dermatologic
  • Musculoskeletal

• Malignant hyperthermia, NMS, serotonin syndrome, prophylaxis for malignant hyperthermia, amphetamine toxicity, carbon monoxide poisoning, and MAO inhibitor poisoning
  • The first action should be to discontinue all agents that may cause the syndrome.
  • The preparation should be reconstituted with sterile water because dantrolene may be incompatible with dextrose 5% in water, normal saline, or any acidic solution.
  • The dose for either adult or pediatric patients is a minimum of 1 mg/kg, administered by rapid intravenous injection.
  • After the first dose, the patient should receive repeated 1 mg/kg dosing until symptoms resolve or a cumulative dosage of 10 mg/kg has been administered.
  • Most patients respond to 2 to 5 mg/kg; however, the use of 40 mg/kg has been reported in the control of malignant hyperthermia.
  • Following intravenous treatment, patients should receive 4 to 8 mg/kg per day orally divided four times a day for 1 to 3 days following the acute event to reduce the probability of recurrence.
  • In the treatment of NMS or serotonin syndrome, it is often necessary to administer 5 to 10 mg/kg because the response is often not dramatic.
• Prophylaxis of malignant hyperthermia
  • Adult or pediatric patient should receive dantrolene 4 to 8 mg/kg per day orally, divided four times a day, for 1 to 2 days prior to surgery.
  • The last dose should be administered 3 to 4 hours prior to surgery.
• Syndromes with muscle spasticity
  • Adult patients should receive 25 to 100 mg orally two to four times a day; doses above 400 mg/day are rarely required.
  • Pediatric patients should receive 0.5 mg/kg, up to 3 mg/kg, orally two to four times a day.
  • Treatment may be required for 1 to 2 weeks to produce clinical improvement.

• Dantrolene administration is not a substitute for aggressive supportive care and cooling measures when treating malignant hyperthermia, NMS, or serotonin syndrome.
• Dantrolene is not likely to be effective for treating hyperthermia caused by disorders of impaired heat dissipation (e.g., anticholinergic syndromes), increased metabolic rate (e.g., salicylate toxicity), or environment stress (e.g., heat stroke).
• Liver function tests should be monitored, especially in patients with advanced age, history of hepatic disease, large daily doses, or prolonged therapy.
• Older patients are more prone to develop hepatotoxicity.

Poisoning by agents primarily acting on the smooth and skeletal muscles and respiratory system.

See Also: SECTION II, Hyperthermia and Neuroleptic Malignant Syndrome and Serotonin Syndrome chapters.

RECOMMENDED READING

Granato JE, Stern BJ, Ringel A, et al. Neuroleptic malignant syndrome: successful treatment with dantrolene and bromocriptine. Ann Neurol 1983;14:89-90.

May DC, Morris SW, Stewart RW, et al. Neuroleptic malignant syndrome: response to dantrolene sodium. Ann Intern Med 1983;98:183-184.

Rosebush PI, Stewart T, Mazurek MF. The treatment of neuroleptic malignant syndrome: Are dantrolene and bromocriptine useful adjuncts to supportive care? Br J Psych 1991;159:709-712.

Author: Edwin K. Kuffner

Reviewer: Katherine M. Hurlbut