Dantrolene

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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
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability70%
MetabolismLiver
ExcretionBile duct, kidney
Identifiers
  • 1-{[5-(4-nitrophenyl)-2-furyl]methylideneamino}
    imidazolidine-2,4-dione
JSmol)
  • [O-][N+](=O)c3ccc(c2oc(C=NN1C(=O)NC(=O)C1)cc2)cc3
  • 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) checkY
  • Key:OZOMQRBLCMDCEG-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)
The sodium salt of dantrolene (shown) is an orange crystalline solid.

Dantrolene sodium, sold under the brand name Dantrium among others, is a postsynaptic

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]

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]

Interactions

Dantrolene may interact with the following drugs:[13]

Pharmacology

Dantrolene depresses

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

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

Dantrolene was widely used in the management of spasticity[17] 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.[18] 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,[19] and confirmed epidemiologically in 1993.[20] Before dantrolene, the only available treatment for malignant hyperthermia was procaine, which was associated with a 60% mortality rate in animal models.[18]

Society and culture

Legal status

In March 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Agilus, intended for the treatment of malignant hyperthermia in combination with adequate support measures.[21] The applicant for this medicinal product is Norgine B.V.[21] In the formulation of Agilus, the mannitol and sodium hydroxide have been replaced with hydroxypropyl-beta-cyclodextrin (HP-β-CD) and Macrogol 3350 to shorten the preparation time and improve the ease of use.[21] It was designated an orphan drug.[21][22]

References

  1. ^ "Dantrolene Use During Pregnancy". Drugs.com. 9 December 2019. Retrieved 6 July 2020.
  2. ^ "Dantrium 25mg Capsules - Summary of Product Characteristics (SmPC)". (emc). 28 February 2020. Retrieved 6 July 2020.
  3. ^ a b "Dantrium- dantrolene sodium capsule". DailyMed. 1 February 2018. Retrieved 6 July 2020.
  4. ^ a b "Ryanodex dantrolene sodium- dantrolene sodium injection, suspension". DailyMed. 2 January 2019. Retrieved 6 July 2020.
  5. ^ "Revonto- dantrolene sodium injection, powder, lyophilized, for solution". DailyMed. 4 May 2020. Retrieved 6 July 2020.
  6. PMID 9085308
    .
  7. S2CID 218865517
    .
  8. S2CID 3057662
    .
  9. ^
    S2CID 18537509
    .
  10. PMID 23261898
    .
  11. ^ "DailyMed Database". Retrieved 22 January 2024.
  12. PMID 37691593.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  13. ^ "Dantrolene Drug Interactions". Epocrates Online. Epocrates. 2008. Retrieved on December 31, 2008.
  14. ^
    PMID 18047479
    .
  15. ^
    PMID 6048486
    .
  16. PMID 4712630
    .
  17. S2CID 7936488
    .
  18. ^
    PMID 9924249
    .
  19. S2CID 72069279
    .
  20. PMID 8346828
    .
  21. ^ a b c d "Agilus EPAR". European Medicines Agency. 21 March 2024. Retrieved 23 March 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  22. ^ "EMA Approves Two Hybrid Medicines". Medscape. 22 March 2024. Retrieved 23 March 2024.
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