Dantrolene

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. Patients on chronic dantrolene therapy should routinely have LFTs monitored.

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.

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.

Dantrolene may interact with the following drugs:[11]

• 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.

Dantrolene depresses excitation-contraction coupling in skeletal muscle by acting as a receptor antagonist to the ryanodine receptor, and decreasing free intracellular calcium concentration.[9]

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.[9]

The poor water solubility of dantrolene leads to certain difficulties in its use.[9][12] A more water-soluble analog of dantrolene, azumolene, is under development for similar indications.[12] Azumolene has a bromine residue instead of the nitro group found in dantrolene, and is 30 times more water-soluble.[9]

Synthesis

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

Dantrolene synthesis:[13] Davis and Snyder; U.S. Patent 3,415,821 (1968 to Norwich Pharma Co).

Dantrolene was first described in the scientific literature in 1967, as one of several hydantoin derivatives proposed as a new class of muscle relaxant.[14] Dantrolene underwent extensive further development, and its action on skeletal muscle was described in detail in 1973.[15]

Dantrolene was widely used in the management of spasticity[16] 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.[17] 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,[18] and confirmed epidemiologically in 1993.[19] Before dantrolene, the only available treatment for malignant hyperthermia was procaine, which was associated with a 60% mortality rate in animal models.[17]

• "Dantrolene". Drug Information Portal. U.S. National Library of Medicine.
• "Dantrolene sodium". Drug Information Portal. U.S. National Library of Medicine.