Dantrolene

Dantrolene
Structural formula of dantrolene
Space-filling model of the dantrolene molecule
Systematic (IUPAC) name
1-{[5-(4-nitrophenyl)-2-furyl]methylideneamino}
imidazolidine-2,4-dione
Clinical data
Trade names Dantrium
AHFS/Drugs.com monograph
  • US: C (Risk not ruled out)
Oral, intravenous
Pharmacokinetic data
Bioavailability 70%
Metabolism Liver
Excretion Biliary, renal
Identifiers
7261-97-4 Yes
M03CA01
PubChem CID 2952
IUPHAR ligand 4172
DrugBank DB01219 Yes
ChemSpider 2847 Yes
UNII F64QU97QCR Yes
KEGG D02347 
ChEBI CHEBI:4317 Yes
ChEMBL CHEMBL1201288 
Chemical data
Formula C14H10N4O5
314.253 g/mol
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The sodium salt of dantrolene (shown) is an orange crystalline solid.

Dantrolene sodium is a postsynaptic muscle relaxant that acts by abolishing excitation-contraction coupling in muscle cells. It achieves this by inhibiting the release of Ca2+ ions by the sarcoplasmic reticulum and may also act as an antagonist for ryanodine receptors.[1] 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), serotonin syndrome, and 2,4-dinitrophenol poisoning.[2] 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.[3]

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.[4] Dantrolene underwent extensive further development, and its action on skeletal muscle was described in detail in 1973.[5]

Dantrolene was widely used in the management of spasticity[6] 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.[7] 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,[8] and confirmed epidemiologically in 1993.[9] Before dantrolene, the only available treatment for malignant hyperthermia was procaine, which was associated with a 60% mortality rate in animal models.[7]

Contraindications

Oral dantrolene cannot be used by:

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.[2]

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.[2]

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.[2]

The poor water solubility of dantrolene leads to certain difficulties in its use.[2][10] A more water-soluble analog of dantrolene, azumolene, is under development for similar indications.[10] Azumolene has a bromine residue instead of the nitro group found in dantrolene, and is 30 times more water-soluble.[2]

Drug interactions

Dantrolene may interact with the following drugs:[11]

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

References

  1. ↑ Zucchi, R; Ronca-Testoni, S (March 1997). "The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states.". Pharmacological reviews 49 (1): 1–51. PMID 9085308.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F (2004). "Dantrolene – a review of its pharmacology, therapeutic use and new developments". Anaesthesia 59 (4): 364–73. doi:10.1111/j.1365-2044.2004.03658.x. PMID 15023108.
  3. ↑ Yeung EYH, Munroe J (2015). "Development of a malignant hyperthermia protocol" (PDF). BMC Proceedings 9 (Suppl1): A32. doi:10.1186/1753-6561-9-S1-A32. PMC 4306034.
  4. ↑ Snyder HR, Davis CS, Bickerton RK, Halliday RP (September 1967). "1-[(5-arylfurfurylidene)amino]hydantoins. A new class of muscle relaxants". J Med Chem 10 (5): 807–10. doi:10.1021/jm00317a011. PMID 6048486.
  5. ↑ Ellis KO, Castellion AW, Honkomp LJ, Wessels FL, Carpenter JE, Halliday RP (June 1973). "Dantrolene, a direct acting skeletal muscle relaxant". J Pharm Sci 62 (6): 948–51. doi:10.1002/jps.2600620619. PMID 4712630.
  6. ↑ Pinder, RM; Brogden, RN; Speight, TM; Avery, GS (January 1977). "Dantrolene sodium: a review of its pharmacological properties and therapeutic efficacy in spasticity.". Drugs 13 (1): 3–23. PMID 318989.
  7. ↑ 7.0 7.1 Harrison GG (January 1975). "Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium". Br J Anaesth 47 (1): 62–5. doi:10.1093/bja/47.1.62. PMID 1148076. A reprint of the article, which became a "Citation Classic", is available in Br J Anaesth 81 (4): 626–9. PMID 9924249 (free full text).
  8. ↑ Kolb ME, Horne ML, Martz R (April 1982). "Dantrolene in human malignant hyperthermia". Anesthesiology 56 (4): 254–62. doi:10.1097/00000542-198204000-00005. PMID 7039419.
  9. ↑ Strazis KP, Fox AW (March 1993). "Malignant hyperthermia: review of published cases". Anesth Analg 77 (3): 297–304. doi:10.1213/00000539-199377020-00014.
  10. ↑ 10.0 10.1 Sudo RT, Carmo PL, Trachez MM, Zapata-Sudo G (March 2008). "Effects of azumolene on normal and malignant hyperthermia-susceptible skeletal muscle". Basic Clin Pharmacol Toxicol 102 (3): 308–16. doi:10.1111/j.1742-7843.2007.00156.x. PMID 18047479.
  11. ↑ "Dantrolene Drug Interactions". Epocrates Online. Epocrates. 2008. Retrieved on December 31, 2008.
  12. ↑ Snyder, H. R.; Davis, C. S.; Bickerton, R. K.; Halliday, R. P. (1967). "1-[5-Arylfurfurylidene)amino]hydantoins. A New Class of Muscle Relaxants". Journal of Medicinal Chemistry 10 (5): 807–10. doi:10.1021/jm00317a011. PMID 6048486.

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