Dantrolene

Dantrolene

Systematic (IUPAC) name
1-{[5-(4-nitrophenyl)-2-furyl]methylideneamino} imidazolidine-2,4-dione
Clinical data
Trade names	Dantrium
AHFS/Drugs.com	monograph
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Oral, intravenous
Pharmacokinetic data
Bioavailability	70%
Metabolism	Liver
Excretion	Biliary, renal
Identifiers
CAS Number	7261-97-4 Y
ATC code	M03CA01 (WHO)
PubChem	CID: 2952
IUPHAR/BPS	4172
DrugBank	DB01219 Y
ChemSpider	2847 Y
UNII	F64QU97QCR Y
KEGG	D02347 N
ChEBI	CHEBI:4317 Y
ChEMBL	CHEMBL1201288 N
Chemical data
Formula	C14H10N4O5
Molecular mass	314.253 g/mol
SMILES [O-][N+](=O)c3ccc(c2oc(C=NN1C(=O)NC(=O)C1)cc2)cc3
InChI InChI=1S/C14H10N4O5/c19-13-8-17(14(20)16-13)15-7-11-5-6-12(23-11)9-1-3-10(4-2-9)18(21)22/h1-7H,8H2,(H,16,19,20) Y Key:OZOMQRBLCMDCEG-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

The sodium salt of dantrolene (shown) is an orange crystalline solid.

Dantrolene sodium is a postsynaptic muscle relaxant that lessens excitation-contraction coupling in muscle cells. It achieves this by inhibiting Ca²⁺ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors. It is the primary drug used for the treatment and prevention of malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia. 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 2,4-dinitrophenol poisoning. It is marketed by JHP Pharmaceuticals LLC as Dantrium (in North America) and by Norgine BV as Dantrium, Dantamacrin, or Dantrolen (in Europe). A hospital is recommended to keep a minimum stock of 36 dantrolene vials (720 mg) sufficient for a 70-kg person.

History

Dantrolene was first described in the scientific literature in 1967, as one of several hydantoin derivatives proposed as a new class of muscle relaxant. Dantrolene underwent extensive further development, and its action on skeletal muscle was described in detail in 1973.

Dantrolene was widely used in the management of spasticity before its efficacy in treating malignant hyperthermia was discovered by South African anesthesiologist Gaisford Harrison and reported in a landmark 1975 article published in the British Journal of Anaesthesia. Harrison experimentally induced malignant hyperthermia with halothane anesthesia in genetically susceptible pigs, and obtained an 87.5% survival rate, where seven of his eight experiments survived after intravenous administration of dantrolene. The efficacy of dantrolene in humans was later confirmed in a large, multicenter study published in 1982, and confirmed epidemiologically in 1993. Before dantrolene, the only available treatment for malignant hyperthermia was procaine, which was associated with a 60% mortality rate in animal models.

Contraindications

Oral dantrolene cannot be used by:

• people with a pre-existing liver disease
• people with compromised lung function
• people with severe cardiovascular impairment
• people with a known hypersensitivity to dantrolene
• pediatric patients under five years of age
• people who need good muscular balance or strength 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 breastfeeding

If needed in pregnancy, adequate human studies are lacking, therefore the drug should be given in pregnant women only if clearly indicated. It may cause hypotonia in the newborn if given closely before delivery.

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

Adverse effects

Central nervous system 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, decreased appetite, nausea, vomiting, abdominal cramps, and diarrhea.

Liver side effects may be seen either as asymptomatic elevation of liver enzymes and/or bilirubin or, most severe, as fatal and nonfatal liver inflammation. The risk of liver inflammation 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 inflammation of the fibrous sac around the heart (oral treatment only), rare cases of bone marrow damage, diffuse muscle pains, backache, dermatologic reactions, transient cardiovascular reactions, and crystals in the urine 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.

Mechanism of action

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

Chemistry

Skeletal formula of azumolene. The bromine atom replacing the nitro group found in dantrolene may be seen at left.

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

The poor water solubility of dantrolene leads to certain difficulties in its use. A more water-soluble analog of dantrolene, azumolene, is under development for similar indications. Azumolene has a bromine residue instead of the nitro group found in dantrolene, and is 30 times more water-soluble.

Drug interactions

Dantrolene may interact with the following drugs:

• Calcium channel blockers of the diltiazem/verapamil type: Intravenous treatment with dantrolene and concomitant calcium channel blocker treatment may lead to severe cardiovascular collapse, abnormal heart rhythms, myocardial depressions, and high blood potassium.
• Nondepolarizing neuromuscular blocking agents, such as vecuronium bromide: Neuromuscular blockade is potentiated.
• CNS depressants: Sedative action is potentiated. Benzodiazepines may also cause additive muscle weakness.
• Combined oral contraceptives and hormone replacement therapy with estrogens may enhance liver toxicity of dantrolene, particularly in women over 35 years of age.

Synthesis

The original patent synthesis started with para-nitroaniline which undergoes diazoniation followed by a copper(II) chloride catalysed arylation with furfural (essentially a modified Meerwein arylation). This then reacts with 1-aminohydantoin to form the final product.

Dantrolene synthesis: Davis and Snyder; U.S. Patent 3,415,821 (1968 to Norwich Pharma Co).

External links

• http://www.kompendium.ch/MonographieTxt.aspx?lang=de&MonType=fi Swiss Drug Compendium on oral Dantrolene (German)