Article: Dantrolene

Dantrolene
Systematic (IUPAC) name
1-(((5-(4-nitrophenyl)-2-furanyl) methylene)amino)-2,4-imidazolidinedione
Identifiers
CAS number	7261-97-4
ATC code	M03CA01
PubChem	2952
DrugBank	APRD00901
Chemical data
Formula	C14H10N4O5
Mol. weight	314.253 g/mol
Pharmacokinetic data
Bioavailability	70%
Metabolism	Liver
Half life	?
Excretion	Bile, urine
Therapeutic considerations
Pregnancy cat.	C (USA)
Legal status
Routes	oral capsules, intravenous

Dantrolene sodium is a muscle relaxant that is currently the only specific and effective treatment for malignant hyperthermia. It is also used in the management of neuroleptic malignant syndrome, muscle spasticity (e.g. after strokes, in paraplegia, cerebral palsy, or patients with multiple sclerosis) and ecstasy intoxication.

Chemistry

Chemically it is a hydantoin derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as phenytoin.

The related substance azumolene is under development for similar indications. It has a bromine residue instead of the nitrite group, and is 30 times more water-soluble.

Mode of action

Dantrolene depresses excitation-contraction coupling in skeletal muscle by binding to the ryanodine receptor, and decreasing intracellular calcium concentration.

Contraindications

• preexisting liver disease
• compromised lung function
• severe cardiovascular impairment
• known hypersensitivity to dantrolene
• pediatric patients under 5 years of age
• whenever good muscular balance/strength is needed to maintain an upright position, motoric function, or proper neuromuscular balance

If the indication is a medical emergency such as malignant hyperthermia, the only significant contraindication is hypersensitivity.

Pregnancy and Lactation

• Pregnancy: Adequate human studies are lacking, therefore the drug should be given in pregnant women only if clearly indicated.

• Lactation: Dantrolene should not be given to breastfeeding mothers. If a treatment is necessary, breastfeeding should be terminated.

Side-effects

CNS side effects are quite frequently noted and encompass speech and visual disturbances, mental depression and confusion, hallucinations, headache, insomnia and exacerbation or precipitation of seizures, and increased nervousness. Infrequent cases of respiratory depression or a feeling of suffocation have been observed. Dantrolene often causes sedation severe enough to incapacitate the patient to drive or operate machinery.

Gastrointestinal effects include bad taste, anorexia, nausea, vomiting, abdominal cramps, and diarrhea.

Hepatic side effects may be seen either as asymptomatic elevation of liver enzymes and/or bilirubin or, most severe, as fatal and nonfatal hepatitis. The risk of hepatitis is associated with the duration of treatment and the daily dose. In patients treated for hyperthermia, no liver toxicity has been observed so far.

Pleural effusion with pericarditis (oral treatment only), rare cases of bone marrow damage, diffuse myalgias, backache, dermatologic reactions, transient cardiovascular reactions, and crystalluria have additionally been seen. Muscle weakness may persist for several days following treatment.

Mutagenicity and Carcinogenity

Dantrolene gave positive results in animal high dose studies (with and without enzymatic activation) regarding mutagenicity and carcinogenity. No evidence for human mutagenicity and carcinogenity has been found during the long years of clinical experience.

Drug Interactions

• Calcium channel blockers of the Diltiazem/Verapamil type: Intravenous treatment with dantrolene and concomitant calcium channel blocker treatment may lead to severe cardiovascular collapse, arrhythmias, myocardial depressions, and hyperkalemia.
• Vecuronium bromide: Neuromuscular blockade is potentiated.
• CNS depressants: Sedative action is potentiated. Benzodiazepines may also cause additive muscle weakness.
• Estrogens: May enhance liver toxicity of dantrolene in women over 35 years of age.

Dosage

The starting dose in oral treatment is 25 mg once daily, slowly increased to the optimal daily dose for the patient. Doses of up to 400 mg may be used, but not for more than 2 months.

The dosage in hyperthermia and other cases of emergency is strictly individual.