Chemistry:Dantrolene

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Short description: Chemical compound
Dantrolene
Structural formula of dantrolene
Space-filling model of the dantrolene molecule
Clinical data
Trade namesDantrium, Revonto, Ryanodex
AHFS/Drugs.comMonograph
MedlinePlusa682576
License data
Pregnancy
category
  • AU: B2[1]
  • US: C (Risk not ruled out)[1]
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability70%
MetabolismLiver
ExcretionBiliary, kidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC14H10N4O5
Molar mass314.257 g·mol−1
3D model (JSmol)
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The sodium salt of dantrolene (shown) is an orange crystalline solid.

Dantrolene sodium, sold under the brand name Dantrium among others, is a postsynaptic muscle relaxant that lessens excitation-contraction coupling in muscle cells.[3][4][5] It achieves this by inhibiting Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors.[6] It is the primary drug used for the treatment and prevention of malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia or drugs. 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 poisoning by 2,4-dinitrophenol[7][8] or by the related compounds dinoseb and dinoterb.[9]

The most frequently occurring side effects include drowsiness, dizziness, weakness, general malaise, fatigue, and diarrhea.[3][4]

It is marketed by Par 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 totaling 720 mg, sufficient for a 70-kg person.[10]

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. 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.

Mutagenicity and carcinogenity

It is unclear whether dantrolene has carcinogenic effects.

Contraindications

Oral dantrolene is contraindicated for[11]

  • patients with active hepatic disease
  • patients in whom spasticity is utilized to maintain upright posture and balance
  • patients with a hypersensitivity to dantrolene

There are no contraindications for intravenous dantrolene used for prophylaxis or management of malignant hyperthermia. [12]

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.[9]

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

Interactions

Dantrolene may interact with the following drugs:[13]

  • 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.

Pharmacology

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]

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.[9]

The poor water solubility of dantrolene leads to certain difficulties in its use.[9][14] A more water-soluble analog of dantrolene, azumolene, is under development for similar indications.[14] 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:[15] Davis and Snyder; U.S. Patent 3,415,821 (1968 to Norwich Pharma Co).

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.[16] Dantrolene underwent extensive further development, and its action on skeletal muscle was described in detail in 1973.[17]

Dantrolene was widely used in the management of spasticity[18] 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.[19] 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,[20] and confirmed epidemiologically in 1993.[21] Before dantrolene, the only available treatment for malignant hyperthermia was procaine, which was associated with a 60% mortality rate in animal models.[19]

References

  1. ↑ 1.0 1.1 "Dantrolene Use During Pregnancy". 9 December 2019. https://www.drugs.com/pregnancy/dantrolene.html. 
  2. ↑ "Dantrium 25mg Capsules - Summary of Product Characteristics (SmPC)". 28 February 2020. https://www.medicines.org.uk/emc/product/1098/smpc. 
  3. ↑ 3.0 3.1 "Dantrium- dantrolene sodium capsule". 1 February 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57b4eec1-49e1-432c-95ae-0fe36e32d64b. 
  4. ↑ 4.0 4.1 "Ryanodex dantrolene sodium- dantrolene sodium injection, suspension". 2 January 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f7b3ac0-604d-4c78-b545-5e0f8ea3d698. 
  5. ↑ "Revonto- dantrolene sodium injection, powder, lyophilized, for solution". 4 May 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=78801254-73a0-44ca-9222-7b3581af82d8. 
  6. ↑ "The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states". Pharmacological Reviews 49 (1): 1–51. March 1997. PMID 9085308. 
  7. ↑ "Dinitrophenol-Induced Hyperthermia Resolving With Dantrolene Administration. Abstracts of the North American Congress of Clinical Toxicology". Clin Toxicol 40 (5): 599–673. 2002. doi:10.1081/clt-120016859. 
  8. ↑ "Comment on "Pediatric fatality following ingestion of Dinitrophenol: postmortem identification of a 'dietary supplement'"". Clinical Toxicology 44 (3): 351. 2006. doi:10.1080/15563650600584709. PMID 16749560. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 "Dantrolene--a review of its pharmacology, therapeutic use and new developments". Anaesthesia 59 (4): 364–373. April 2004. doi:10.1111/j.1365-2044.2004.03658.x. PMID 15023108. 
  10. ↑ "Diagnosis and treatment of drug-induced hyperthermia". American Journal of Health-System Pharmacy 70 (1): 34–42. January 2013. doi:10.1186/1753-6561-9-S1-A32. PMID 23261898. 
  11. ↑ "DailyMed Database". https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57b4eec1-49e1-432c-95ae-0fe36e32d64b#LINK_ed77cb86-74ac-446b-b685-c6be50e26206. Retrieved 22 January 2024. 
  12. ↑ Yang HS, Choi JM, In J, Sung TY, Kim YB, Sultana S (2023). "Current clinical application of dantrolene sodium.". Anesth Pain Med (Seoul) 18 (3): 220-232. doi:10.17085/apm.22260. PMID 37691593. PMC 10410554. https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=37691593. 
  13. ↑ "Dantrolene Drug Interactions". Epocrates Online. Epocrates. 2008. https://online.epocrates.com/u/104574/dantrolene.  Retrieved on December 31, 2008.
  14. ↑ 14.0 14.1 "Effects of azumolene on normal and malignant hyperthermia-susceptible skeletal muscle". Basic & Clinical Pharmacology & Toxicology 102 (3): 308–316. March 2008. doi:10.1111/j.1742-7843.2007.00156.x. PMID 18047479. 
  15. ↑ "1-[(5-arylfurfurylidene)amino]hydantoins. A new class of muscle relaxants". Journal of Medicinal Chemistry 10 (5): 807–810. September 1967. doi:10.1021/jm00317a011. PMID 6048486. 
  16. ↑ "1-[(5-arylfurfurylidene)amino]hydantoins. A new class of muscle relaxants". Journal of Medicinal Chemistry 10 (5): 807–810. September 1967. doi:10.1021/jm00317a011. PMID 6048486. 
  17. ↑ "Dantrolene, a direct acting skeletal muscle relaxant". Journal of Pharmaceutical Sciences 62 (6): 948–951. June 1973. doi:10.1002/jps.2600620619. PMID 4712630. 
  18. ↑ "Dantrolene sodium: a review of its pharmacological properties and therapeutic efficacy in spasticity". Drugs 13 (1): 3–23. January 1977. doi:10.2165/00003495-197713010-00002. PMID 318989. 
  19. ↑ 19.0 19.1 "Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium". British Journal of Anaesthesia 47 (1): 62–65. January 1975. doi:10.1093/bja/47.1.62. PMID 1148076.  A reprint of the article, which became a "Citation Classic", is available in "Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. 1975". British Journal of Anaesthesia 81 (4): 626–9; discussion 625. October 1998. doi:10.1093/bja/81.4.626. PMID 9924249. 
  20. ↑ "Dantrolene in human malignant hyperthermia". Anesthesiology 56 (4): 254–262. April 1982. doi:10.1097/00000542-198204000-00005. PMID 7039419. 
  21. ↑ "Malignant hyperthermia: a review of published cases". Anesthesia and Analgesia 77 (2): 297–304. August 1993. doi:10.1213/00000539-199377020-00014. PMID 8346828. 

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