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Dantrolene

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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
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Oral, intravenous
Pharmacokinetic data
Bioavailability 70%
Metabolism Liver
Excretion Biliary, renal
Identifiers
CAS Registry Number  Y
ATC code M03
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  N
ChEBI  Y
ChEMBL  N
Chemical data
Formula C14H10N4O5
Molecular mass 314.253 g/mol
 N   
The sodium salt of dantrolene (shown) is an orange crystalline solid.

Dantrolene sodium is a postsynaptic

  • http://www.kompendium.ch/MonographieTxt.aspx?lang=de&MonType=fi Swiss Drug Compendium on oral Dantrolene (German)

External links

  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.  
  2. ^ a b c d e f 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.  
  3. ^ Yeung EYH, Munroe J (2015). "Development of a malignant hyperthermia protocol" (PDF). BMC Proceedings 9 (Suppl1): A32.  
  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.  
  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.  
  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.  
  7. ^ a b Harrison GG (January 1975). "Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium". Br J Anaesth 47 (1): 62–5.   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.  
  9. ^ Strazis KP, Fox AW (March 1993). "Malignant hyperthermia: review of published cases". Anesth Analg 77 (3): 297–304.  
  10. ^ a b 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.  
  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.  

References

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

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.

Synthesis

Dantrolene may interact with the following drugs:[11]

Drug interactions

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]

Chemically it is a hydantoin derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as phenytoin.[2]

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

Chemistry

Dantrolene depresses excitation-contraction coupling in skeletal muscle by binding to the ryanodine receptor, and decreasing free intracellular calcium concentration.[2]

Mechanism of action

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.

Mutagenicity and carcinogenity

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.

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.

Gastrointestinal effects include bad taste, decreased appetite, nausea, vomiting, abdominal cramps, and diarrhea.

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.

Adverse effects

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

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]

Pregnancy and breastfeeding

If the indication is a medical emergency, such as malignant hyperthermia, the only significant contraindication is hypersensitivity.

  • people with a pre-existing liver disease
  • people with compromised lung function
  • people with severe cardiovascular impairment
  • people with a known hypersensitivity to dantrolene
  • pediatric patients under five years of age
  • people who need good muscular balance or strength to maintain an upright position, motoric function, or proper neuromuscular balance

Oral dantrolene cannot be used by:

Contraindications

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]

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]

History

Contents

  • History 1
  • Contraindications 2
    • Pregnancy and breastfeeding 2.1
  • Adverse effects 3
  • Mutagenicity and carcinogenity 4
  • Mechanism of action 5
  • Chemistry 6
  • Drug interactions 7
  • Synthesis 8
  • References 9
  • External links 10

[3]

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