Dantrolene
{{Short description|Chemical compound}}
{{Use dmy dates|date=June 2024}}
{{Infobox drug
| Verifiedfields = changed
| verifiedrevid = 459436942
| image = Dantrolene.svg
| alt = Structural formula of dantrolene
| width = 250
| image2 = Dantrolene 3D spacefill.png
| alt2 = Space-filling model of the dantrolene molecule
| tradename = Dantrium, Revonto, Ryanodex
| Drugs.com = {{drugs.com|monograph|dantrolene-sodium}}
| MedlinePlus = a682576
| DailyMedID = Dantrolene
| pregnancy_AU = B2
| pregnancy_AU_comment = {{cite web | title=Dantrolene Use During Pregnancy | website=Drugs.com | date=9 December 2019 | url=https://www.drugs.com/pregnancy/dantrolene.html | access-date=6 July 2020}}
| routes_of_administration = By mouth, intravenous
| ATC_prefix = M03
| ATC_suffix = CA01
| ATC_supplemental =
| legal_AU =
| legal_AU_comment =
| legal_BR =
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment = {{cite web | title=Product monograph brand safety updates | website=Health Canada | date=6 June 2024 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=8 June 2024}}
| legal_DE =
| legal_DE_comment =
| legal_NZ =
| legal_NZ_comment =
| legal_UK = POM
| legal_US = Rx-only
| legal_US_comment =
| legal_EU = Rx-only
| legal_UN =
| legal_UN_comment =
| legal_status = Rx-only
| bioavailability = 70%
| protein_bound =
| metabolism = Liver
| elimination_half-life =
| excretion = Bile duct, kidney
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 7261-97-4
| PubChem = 2952
| IUPHAR_ligand = 4172
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01219
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2847
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = F64QU97QCR
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D02347
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 4317
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201288
| IUPAC_name = 1-
imidazolidine-2,4-dione
| C=14 | H=10 | N=4 | O=5
| smiles = [O-][N+](=O)c3ccc(c2oc(C=NN1C(=O)NC(=O)C1)cc2)cc3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OZOMQRBLCMDCEG-UHFFFAOYSA-N
}}
Dantrolene sodium, sold under the brand name Dantrium among others, is a postsynaptic muscle relaxant that lessens excitation-contraction coupling in muscle cells.{{cite web | title=Dantrium- dantrolene sodium capsule | website=DailyMed | date=1 February 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57b4eec1-49e1-432c-95ae-0fe36e32d64b | access-date=6 July 2020}}{{cite web | title=Ryanodex dantrolene sodium- dantrolene sodium injection, suspension | website=DailyMed | date=2 January 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f7b3ac0-604d-4c78-b545-5e0f8ea3d698 | access-date=6 July 2020}}{{cite web | title=Revonto- dantrolene sodium injection, powder, lyophilized, for solution | website=DailyMed | date=4 May 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=78801254-73a0-44ca-9222-7b3581af82d8 | access-date=6 July 2020}} It achieves this by inhibiting Ca2+ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors.{{cite journal | vauthors = Zucchi R, Ronca-Testoni S | title = The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states | journal = Pharmacological Reviews | volume = 49 | issue = 1 | pages = 1–51 | date = March 1997 | doi = 10.1016/S0031-6997(24)01312-7 | pmid = 9085308 }} 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{{cite journal | vauthors = Kumar S, Barker K, Seger D | year = 2002 | title = Dinitrophenol-Induced Hyperthermia Resolving With Dantrolene Administration. Abstracts of the North American Congress of Clinical Toxicology | journal = Clin Toxicol | volume = 40 | issue = 5| pages = 599–673 | doi=10.1081/clt-120016859| s2cid = 218865517 }}{{cite journal | vauthors = Barker K, Seger D, Kumar S | title = Comment on "Pediatric fatality following ingestion of Dinitrophenol: postmortem identification of a 'dietary supplement'" | journal = Clinical Toxicology | volume = 44 | issue = 3 | pages = 351 | year = 2006 | pmid = 16749560 | doi = 10.1080/15563650600584709 | s2cid = 3057662 }} or by the related compounds dinoseb and dinoterb.
The most frequently occurring side effects include drowsiness, dizziness, weakness, general malaise, fatigue, and diarrhea.
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.{{cite journal | vauthors = Musselman ME, Saely S | title = Diagnosis and treatment of drug-induced hyperthermia | journal = American Journal of Health-System Pharmacy | volume = 70 | issue = 1 | pages = 34–42 | date = January 2013 | pmc = 4306034 | doi = 10.1186/1753-6561-9-S1-A32 | pmid = 23261898 | doi-access = free }}
Contraindications
Oral dantrolene is contraindicated for{{cite web |title=DailyMed Database |url=https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=57b4eec1-49e1-432c-95ae-0fe36e32d64b#LINK_ed77cb86-74ac-446b-b685-c6be50e26206 |accessdate=22 January 2024}}
- 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.{{cite journal| author=Yang HS, Choi JM, In J, Sung TY, Kim YB, Sultana S| title=Current clinical application of dantrolene sodium. | journal=Anesth Pain Med (Seoul) | year= 2023 | volume= 18 | issue= 3 | pages= 220–232 | pmid=37691593 | doi=10.17085/apm.22260 | pmc=10410554 }}
=Pregnancy and breastfeeding=
Interactions
Dantrolene may interact with the following drugs:{{cite web|year=2008|title=Dantrolene Drug Interactions|url=https://online.epocrates.com/u/104574/dantrolene|work=Epocrates Online|publisher=Epocrates}} Retrieved on 31 December 2008.
- 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.
Chemistry
File:Azumolene.svg 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.{{cite journal | vauthors = Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F | title = Dantrolene--a review of its pharmacology, therapeutic use and new developments | journal = Anaesthesia | volume = 59 | issue = 4 | pages = 364–373 | date = April 2004 | pmid = 15023108 | doi = 10.1111/j.1365-2044.2004.03658.x | s2cid = 18537509 | doi-access = free }}
The poor water solubility of dantrolene leads to certain difficulties in its use.{{cite journal | vauthors = Sudo RT, Carmo PL, Trachez MM, Zapata-Sudo G | title = Effects of azumolene on normal and malignant hyperthermia-susceptible skeletal muscle | journal = Basic & Clinical Pharmacology & Toxicology | volume = 102 | issue = 3 | pages = 308–316 | date = March 2008 | pmid = 18047479 | doi = 10.1111/j.1742-7843.2007.00156.x | doi-access = free }} A more water-soluble analog of dantrolene, azumolene, is under development for similar indications. Azumolene has a bromine residue instead of the nitro group found in dantrolene, and is 30 times more water-soluble.
=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.
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. Dantrolene underwent extensive further development, and its action on skeletal muscle was described in detail in 1973.{{cite journal | vauthors = Ellis KO, Castellion AW, Honkomp LJ, Wessels FL, Carpenter JE, Halliday RP | title = Dantrolene, a direct acting skeletal muscle relaxant | journal = Journal of Pharmaceutical Sciences | volume = 62 | issue = 6 | pages = 948–951 | date = June 1973 | pmid = 4712630 | doi = 10.1002/jps.2600620619 }}
Dantrolene was widely used in the management of spasticity{{cite journal | vauthors = Pinder RM, Brogden RN, Speight TM, Avery GS | title = Dantrolene sodium: a review of its pharmacological properties and therapeutic efficacy in spasticity | journal = Drugs | volume = 13 | issue = 1 | pages = 3–23 | date = January 1977 | pmid = 318989 | doi = 10.2165/00003495-197713010-00002 | s2cid = 7936488 }} 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.{{cite journal | vauthors = Harrison GG | title = Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium | journal = British Journal of Anaesthesia | volume = 47 | issue = 1 | pages = 62–65 | date = January 1975 | pmid = 1148076 | doi = 10.1093/bja/47.1.62 | s2cid = 21991166 | doi-access = free }} A reprint of the article, which became a "Citation Classic", is available in {{cite journal | vauthors = Harrison GG | title = Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. 1975 | journal = British Journal of Anaesthesia | volume = 81 | issue = 4 | pages = 626–9; discussion 625 | date = October 1998 | pmid = 9924249 | doi = 10.1093/bja/81.4.626 | doi-access = free }} 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,{{cite journal | vauthors = Kolb ME, Horne ML, Martz R | title = Dantrolene in human malignant hyperthermia | journal = Anesthesiology | volume = 56 | issue = 4 | pages = 254–262 | date = April 1982 | pmid = 7039419 | doi = 10.1097/00000542-198204000-00005 | s2cid = 72069279 | doi-access = free }} and confirmed epidemiologically in 1993.{{cite journal | vauthors = Strazis KP, Fox AW | title = Malignant hyperthermia: a review of published cases | journal = Anesthesia and Analgesia | volume = 77 | issue = 2 | pages = 297–304 | date = August 1993 | pmid = 8346828 | doi = 10.1213/00000539-199377020-00014 | doi-access = free }} Before dantrolene, the only available treatment for malignant hyperthermia was procaine, which was associated with a 60% mortality rate in animal models.
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.{{cite press release | title=Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 18-21 March 2024 | website=European Medicines Agency | date=22 March 2024 | url=https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-18-21-march-2024 | access-date=13 June 2024}} The applicant for this medicinal product is Norgine B.V.{{cite web | title=Agilus EPAR | website=European Medicines Agency | date=21 March 2024 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/agilus | access-date=23 March 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. 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. It was designated an orphan drug.{{cite web | title=EMA Approves Two Hybrid Medicines | website=Medscape | date=22 March 2024 | url=https://www.medscape.com/viewarticle/ema-approves-two-hybrid-medicines-2024a10005gg?form=fpf | access-date=23 March 2024}} Dantrolene sodium, hemiheptahydrate (Agilus) was approved for medical use in the European Union in May 2024.
References
{{reflist}}
{{Muscle relaxants}}
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Category:Chemical substances for emergency medicine