Dantrolene

Last updated

Dantrolene
Dantrolene.svg
Dantrolene 3D spacefill.png
Clinical data
Trade names Dantrium, Revonto, Ryanodex
AHFS/Drugs.com Monograph
MedlinePlus a682576
License data
Pregnancy
category
Routes of
administration 		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 70%
Metabolism Liver
Excretion Bile duct, kidney
Identifiers
  • 1-{[5-(4-nitrophenyl)-2-furyl]methylideneamino}
    imidazolidine-2,4-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.027.895 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H10N4O5
Molar mass 314.257 g·mol−1
3D model (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) Yes check.svgY
  • Key:OZOMQRBLCMDCEG-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)
The sodium salt of dantrolene (shown) is an orange crystalline solid. DantroleneSodiumSalt.JPG
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. [5] [6] [7] It achieves this by inhibiting Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors. [8] 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 [9] [10] or by the related compounds dinoseb and dinoterb. [11]

Contents

The most frequently occurring side effects include drowsiness, dizziness, weakness, general malaise, fatigue, and diarrhea. [5] [6]

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. [12]

Contraindications

Oral dantrolene is contraindicated for [13]

There are no contraindications for intravenous dantrolene used for prophylaxis or management of malignant hyperthermia. [14]

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. [11]

Interactions

Dantrolene may interact with the following drugs: [15]

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. [11]

Chemistry

Skeletal formula of azumolene. The bromine atom replacing the nitro group found in dantrolene may be seen at left. Azumolene.svg
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. [11]

The poor water solubility of dantrolene leads to certain difficulties in its use. [11] [16] A more water-soluble analog of dantrolene, azumolene, is under development for similar indications. [16] Azumolene has a bromine residue instead of the nitro group found in dantrolene, and is 30 times more water-soluble. [11]

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: Davis and Snyder; U.S. patent 3,415,821 (1968 to Norwich Pharma Co). Dantrolene synthesis.png
Dantrolene synthesis: 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. [17] Dantrolene underwent extensive further development, and its action on skeletal muscle was described in detail in 1973. [18]

Dantrolene was widely used in the management of spasticity [19] 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 . [20] 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, [21] and confirmed epidemiologically in 1993. [22] Before dantrolene, the only available treatment for malignant hyperthermia was procaine, which was associated with a 60% mortality rate in animal models. [20]

Society and culture

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. [4] [23] The applicant for this medicinal product is Norgine B.V. [4] 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. [4] It was designated an orphan drug. [4] [24] Dantrolene sodium, hemiheptahydrate (Agilus) was approved for medical use in the European Union in May 2024. [4]

References

  1. ↑ "Dantrolene Use During Pregnancy". Drugs.com. 9 December 2019. Retrieved 6 July 2020.
  2. ↑ "Product monograph brand safety updates". Health Canada . 6 June 2024. Retrieved 8 June 2024.
  3. ↑ "Dantrium 25mg Capsules - Summary of Product Characteristics (SmPC)". (emc). 28 February 2020. Retrieved 6 July 2020.
  4. 1 2 3 4 5 6 "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.
  5. 1 2 "Dantrium- dantrolene sodium capsule". DailyMed. 1 February 2018. Retrieved 6 July 2020.
  6. 1 2 "Ryanodex dantrolene sodium- dantrolene sodium injection, suspension". DailyMed. 2 January 2019. Retrieved 6 July 2020.
  7. ↑ "Revonto- dantrolene sodium injection, powder, lyophilized, for solution". DailyMed. 4 May 2020. Retrieved 6 July 2020.
  8. ↑ 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. doi:10.1016/S0031-6997(24)01312-7. PMID   9085308.
  9. ↑ Kumar S, Barker K, Seger D (2002). "Dinitrophenol-Induced Hyperthermia Resolving With Dantrolene Administration. Abstracts of the North American Congress of Clinical Toxicology". Clin Toxicol. 40 (5): 599–673. doi:10.1081/clt-120016859. S2CID   218865517.
  10. ↑ Barker K, Seger D, Kumar S (2006). "Comment on "Pediatric fatality following ingestion of Dinitrophenol: postmortem identification of a 'dietary supplement'"". Clinical Toxicology. 44 (3): 351. doi:10.1080/15563650600584709. PMID   16749560. S2CID   3057662.
  11. 1 2 3 4 5 6 Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F (April 2004). "Dantrolene--a review of its pharmacology, therapeutic use and new developments". Anaesthesia. 59 (4): 364–373. doi: 10.1111/j.1365-2044.2004.03658.x . PMID   15023108. S2CID   18537509.
  12. ↑ Musselman ME, Saely S (January 2013). "Diagnosis and treatment of drug-induced hyperthermia". American Journal of Health-System Pharmacy. 70 (1): 34–42. doi: 10.1186/1753-6561-9-S1-A32 . PMC   4306034 . PMID   23261898.
  13. ↑ "DailyMed Database" . Retrieved 22 January 2024.
  14. ↑ 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. PMC   10410554 . PMID   37691593.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ↑ "Dantrolene Drug Interactions". Epocrates Online. Epocrates. 2008. Retrieved on 31 December 2008.
  16. 1 2 Sudo RT, Carmo PL, Trachez MM, Zapata-Sudo G (March 2008). "Effects of azumolene on normal and malignant hyperthermia-susceptible skeletal muscle". Basic & Clinical Pharmacology & Toxicology. 102 (3): 308–316. doi: 10.1111/j.1742-7843.2007.00156.x . PMID   18047479.
  17. 1 2 Snyder HR, Davis CS, Bickerton RK, Halliday RP (September 1967). "1-[(5-arylfurfurylidene)amino]hydantoins. A new class of muscle relaxants". Journal of Medicinal Chemistry. 10 (5): 807–810. doi:10.1021/jm00317a011. PMID   6048486.
  18. ↑ Ellis KO, Castellion AW, Honkomp LJ, Wessels FL, Carpenter JE, Halliday RP (June 1973). "Dantrolene, a direct acting skeletal muscle relaxant". Journal of Pharmaceutical Sciences. 62 (6): 948–951. doi:10.1002/jps.2600620619. PMID   4712630.
  19. ↑ 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. doi:10.2165/00003495-197713010-00002. PMID   318989. S2CID   7936488.
  20. 1 2 Harrison GG (January 1975). "Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium". British Journal of Anaesthesia. 47 (1): 62–65. doi: 10.1093/bja/47.1.62 . PMID   1148076. S2CID   21991166. A reprint of the article, which became a "Citation Classic", is available in Harrison GG (October 1998). "Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. 1975". British Journal of Anaesthesia. 81 (4): 626–9, discussion 625. doi: 10.1093/bja/81.4.626 . PMID   9924249.
  21. ↑ Kolb ME, Horne ML, Martz R (April 1982). "Dantrolene in human malignant hyperthermia". Anesthesiology. 56 (4): 254–262. doi: 10.1097/00000542-198204000-00005 . PMID   7039419. S2CID   72069279.
  22. ↑ Strazis KP, Fox AW (August 1993). "Malignant hyperthermia: a review of published cases". Anesthesia and Analgesia. 77 (2): 297–304. doi: 10.1213/00000539-199377020-00014 . PMID   8346828.
  23. ↑ "Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 18-21 March 2024". European Medicines Agency (Press release). 22 March 2024. Retrieved 13 June 2024.
  24. ↑ "EMA Approves Two Hybrid Medicines". Medscape. 22 March 2024. Retrieved 23 March 2024.
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