Identification

Summary

Dantrolene is a direct-acting skeletal muscle relaxant used for the treatment of management of the fulminant hypermetabolism of skeletal muscle leading to malignant hyperthermia crisis.

Brand Names
Dantrium, Revonto, Ryanodex
Generic Name
Dantrolene
DrugBank Accession Number
DB01219
Background

Chemically, dantrolene is a hydantoin derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as phenytoin.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 314.257
Monoisotopic: 314.065119438
Chemical Formula
C14H10N4O5
Synonyms
  • 1-((5-(p-nitrophenyl)furfurylidene)amino)hydantoin
  • Dantrolene
  • Dantroleno
  • Dantrolenum

Pharmacology

Indication

For use, along with appropriate supportive measures, for the management of the fulminant hypermetabolism of skeletal muscle characteristic of malignant hyperthermia crises in patients of all ages. Also used preoperatively, and sometimes postoperatively, to prevent or attenuate the development of clinical and laboratory signs of malignant hyperthermia in individuals judged to be malignant hyperthermia susceptible.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Dantrolene is classified as a direct-acting skeletal muscle relaxant. It is currently the only specific and effective treatment for malignant hyperthermia. In isolated nerve-muscle preparation, Dantrium has been shown to produce relaxation by affecting the contractile response of the muscle at a site beyond the myoneural junction. In skeletal muscle, Dantrium dissociates excitation-contraction coupling, probably by interfering with the release of Ca2+ from the sarcoplasmic reticulum. In the anesthetic-induced malignant hyperthermia syndrome, evidence points to an intrinsic abnormality of skeletal muscle tissue. In selected humans, it has been postulated that “triggering agents” (e.g.,general anesthetics and depolarizing neuromuscular blocking agents) produce a change within the cell which results in an elevated myoplasmic calcium. This elevated myoplasmic calcium activates acute cellular catabolic processes that cascade to the malignant hyperthermia crisis. It is hypothesized that addition of Dantrium to the “triggered” malignant hyperthermic muscle cell reestablishes a normal level of ionized calcium in the myoplasm.

Mechanism of action

Dantrolene depresses excitation-contraction coupling in skeletal muscle by binding to the ryanodine receptor 1, and decreasing intracellular calcium concentration. Ryanodine receptors mediate the release of calcium from the sarcoplasmic reticulum, an essential step in muscle contraction.

TargetActionsOrganism
ARyanodine receptor 1
antagonist
Humans
Absorption

Bioavailability is 70%.

Volume of distribution

Not Available

Protein binding

Significant, mostly to albumin.

Metabolism

Hepatic, most likely by hepatic microsomal enzymes. Its major metabolites in body fluids are 5-hydroxydantrolene and an acetylamino metabolite of dantrolene. Another metabolite with an unknown structure appears related to the latter. Dantrium may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid.

Hover over products below to view reaction partners

Route of elimination

Not Available

Half-life

The mean biologic half-life after intravenous administration is variable, between 4 to 8 hours under most experimental conditions, while oral is 8.7 hours for a 100mg dose.

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Oral LD50 in rats is 7400 mg/kg. Symptoms which may occur in case of overdose include, but are not limited to, muscular weakness and alterations in the state of consciousness (e.g., lethargy, coma), vomiting, diarrhea, and crystalluria.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of adverse effects can be increased when Dantrolene is combined with 1,2-Benzodiazepine.
AcebutololThe risk or severity of hyperkalemia can be increased when Acebutolol is combined with Dantrolene.
AceclofenacThe risk or severity of hyperkalemia can be increased when Dantrolene is combined with Aceclofenac.
AcemetacinThe risk or severity of hyperkalemia can be increased when Dantrolene is combined with Acemetacin.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Dantrolene.
AcetophenazineThe risk or severity of adverse effects can be increased when Acetophenazine is combined with Dantrolene.
Acetylsalicylic acidThe risk or severity of hyperkalemia can be increased when Acetylsalicylic acid is combined with Dantrolene.
AclidiniumDantrolene may increase the central nervous system depressant (CNS depressant) activities of Aclidinium.
AgomelatineThe risk or severity of adverse effects can be increased when Dantrolene is combined with Agomelatine.
AlclofenacThe risk or severity of hyperkalemia can be increased when Dantrolene is combined with Alclofenac.
Interactions
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Food Interactions
  • Take with or without food. The absorption is unaffected by food.

Products

Products2
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Product Ingredients
IngredientUNIICASInChI Key
Dantrolene sodium287M0347EV24868-20-0LTWQNYPDAUSXBC-CDJGKPBYSA-L
Product Images
International/Other Brands
Dantamacrin (Spepharm)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DantriumInjection20 mg/60mLIntravenousPar Pharmaceutical2009-04-20Not applicableUS flag
DantriumCapsule50 mg/1OralProcter & Gamble Pharmaceuticals2006-03-28Not applicableUS flag
DantriumCapsule50 mg/1OralPar Pharmaceutical, Inc.2008-08-012022-02-28US flag
DantriumInjection20 mg/60mLIntravenousProcter and Gamble Pharmaceuticals2006-02-06Not applicableUS flag
DantriumCapsule25 mg/1OralProcter & Gamble Pharmaceuticals2006-03-28Not applicableUS flag
DantriumCapsule25 mg/1OralPar Pharmaceutical, Inc.2008-08-01Not applicableUS flag
DantriumCapsule100 mg/1OralProcter & Gamble Pharmaceuticals2006-03-28Not applicableUS flag
DantriumCapsule100 mg/1OralPar Pharmaceutical, Inc.2008-08-012015-07-31US flag
Dantrium Cap 100mgCapsule100 mgOralNorwich Eaton Canada Inc.1979-12-311996-09-16Canada flag
Dantrium Cap 25mgCapsule25 mgOralNorwich Eaton Canada Inc.1979-12-311996-09-16Canada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DantroleneInjection, powder, for solution20 mg/1IntravenousWest-Ward Pharmaceuticals Corp2017-06-19Not applicableUS flag
Dantrolene SodiumCapsule25 mg/1OralAvera McKennan Hospital2016-09-132017-05-24US flag
Dantrolene SodiumCapsule25 mg/1OralPar Pharmaceutical2013-04-082020-05-31US flag
Dantrolene SodiumCapsule25 mg/1OralLannett Company, Inc.2005-10-26Not applicableUS flag
Dantrolene SodiumCapsule25 mg/1OralCardinal Health2008-09-25Not applicableUS flag
Dantrolene SodiumCapsule100 mg/1Oralbryant ranch prepack2016-03-28Not applicableUS flag
Dantrolene SodiumCapsule50 mg/1OralPar Pharmaceutical2016-03-28Not applicableUS flag
Dantrolene SodiumInjection, solution20 mg/60mLIntravenousUS WorldMeds, LLC2007-10-032010-12-13US flag
Dantrolene SodiumCapsule25 mg/1OralAmneal Pharmaceuticals of New York Llc2005-03-01Not applicableUS flag
Dantrolene SodiumCapsule25 mg/1OralAmerican Health Packaging2008-09-29Not applicableUS flag

Categories

ATC Codes
M03CA01 — Dantrolene
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
F64QU97QCR
CAS number
7261-97-4
InChI Key
OZOMQRBLCMDCEG-VIZOYTHASA-N
InChI
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)/b15-7+
IUPAC Name
1-[(E)-{[5-(4-nitrophenyl)furan-2-yl]methylidene}amino]imidazolidine-2,4-dione
SMILES
[O-][N+](=O)C1=CC=C(C=C1)C1=CC=C(O1)\C=N\N1CC(=O)NC1=O

References

Synthesis Reference

Davis, C.S. and Snyder, H.R. Jr.; US. Patent 3,415,821; December 10, 1968; assigned to The Norwich Pharmacal Company.

General References
  1. Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F: Dantrolene--a review of its pharmacology, therapeutic use and new developments. Anaesthesia. 2004 Apr;59(4):364-73. [Article]
KEGG Drug
D02347
KEGG Compound
C06939
PubChem Compound
6914273
PubChem Substance
46504976
ChemSpider
5290202
BindingDB
50198767
RxNav
3105
ChEBI
4317
ChEMBL
CHEMBL1201288
ZINC
ZINC000002568036
Therapeutic Targets Database
DNC001623
PharmGKB
PA449208
Guide to Pharmacology
GtP Drug Page
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Dantrolene
MSDS
Download (43 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentHeat Stroke1
2RecruitingBasic ScienceHealthy Subjects (HS)1
2RecruitingTreatmentLumbar Spine Injury1
2TerminatedTreatmentDrug Toxicity Psychotropic Agents Psychostimulants1
2, 3RecruitingTreatmentVentricular Tachycardia (VT)1
2, 3TerminatedTreatmentHyperthermia1
1, 2Active Not RecruitingTreatmentAtaxia / Diabetes Mellitus / Optic Nerve Atrophy / Wolfram Syndrome1
1, 2CompletedTreatmentCerebral Vasospasm After Subarachnoid Hemorrhage1
1, 2CompletedTreatmentSubarachnoid Hemorrhage / Vasospasm, Cerebral1
1, 2RecruitingTreatmentMultiple Sclerosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Amerisource Health Services Corp.
  • DSM Corp.
  • Global Pharmaceuticals
  • JHP Pharmaceuticals LLC
  • Kaiser Foundation Hospital
  • Medisca Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Norwich Pharmaceuticals Inc.
  • Southwood Pharmaceuticals
  • US WorldMeds
  • Warner Chilcott Co. Inc.
Dosage Forms
FormRouteStrength
CapsuleOral
CapsuleOral100 mg/1
CapsuleOral25 mg/1
CapsuleOral50 mg/1
InjectionIntravenous20 mg/60mL
Injection, powder, for solutionIntravenous
Powder, for solutionIntravenous
Syrup
CapsuleOral100 mg
CapsuleOral25 mg
Powder, for solutionIntravenous20 mg / vial
Injection, powder, for solutionParenteral
Injection, powder, for solutionIntravenous20 mg/1
Injection, solutionIntravenous20 mg/60mL
Injection, powder, lyophilized, for solutionIntravenous20 mg/60mL
Injection, suspensionIntravenous250 mg/5mL
Prices
Unit descriptionCostUnit
Dantrium 20 mg vial106.37USD vial
Dantrolene sodium 20 mg vial97.2USD vial
Dantrolene sodium powder17.6USD g
Dantrium 100 mg capsule2.4USD capsule
Dantrolene sodium 100 mg capsule2.03USD capsule
Dantrium 50 mg capsule1.93USD capsule
Dantrolene sodium 50 mg capsule1.63USD capsule
Dantrium 25 mg capsule1.29USD capsule
Dantrolene sodium 25 mg capsule1.09USD capsule
Dantrium 100 mg Capsule0.8USD capsule
Dantrium 25 mg Capsule0.4USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8685460No2014-04-012023-02-15US flag
US7758890No2010-07-202025-07-01US flag
US8110225No2012-02-072022-12-24US flag
US8604072No2013-12-102022-12-24US flag
US9884044No2018-02-062022-06-13US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)279-280 °CDavis, C.S. and Snyder, H.R. Jr.; US. Patent 3,415,821; December 10, 1968; assigned to The Norwich Pharmacal Company.
water solubilityLow (146 mg/L)Not Available
logP1.70JANSEN,ACA ET AL. (1991)
Predicted Properties
PropertyValueSource
Water Solubility0.0805 mg/mLALOGPS
logP1.65ALOGPS
logP1.26ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)8.23ChemAxon
pKa (Strongest Basic)-1.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area118.05 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity77.87 m3·mol-1ChemAxon
Polarizability30.02 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9974
Blood Brain Barrier+0.9581
Caco-2 permeable-0.5587
P-glycoprotein substrateNon-substrate0.6562
P-glycoprotein inhibitor INon-inhibitor0.8977
P-glycoprotein inhibitor IINon-inhibitor0.978
Renal organic cation transporterNon-inhibitor0.8656
CYP450 2C9 substrateNon-substrate0.81
CYP450 2D6 substrateNon-substrate0.8935
CYP450 3A4 substrateSubstrate0.5848
CYP450 1A2 substrateInhibitor0.8916
CYP450 2C9 inhibitorNon-inhibitor0.8808
CYP450 2D6 inhibitorNon-inhibitor0.9203
CYP450 2C19 inhibitorNon-inhibitor0.8752
CYP450 3A4 inhibitorNon-inhibitor0.8985
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7676
Ames testAMES toxic0.8925
CarcinogenicityNon-carcinogens0.8732
BiodegradationReady biodegradable0.5901
Rat acute toxicity2.5390 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7215
hERG inhibition (predictor II)Non-inhibitor0.9223
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering muscle contraction following depolarization of T-tu...
Gene Name
RYR1
Uniprot ID
P21817
Uniprot Name
Ryanodine receptor 1
Molecular Weight
565170.715 Da
References
  1. Britt BA, Scott E, Frodis W, Clements MJ, Endrenyi L: Dantrolene--in vitro studies in malignant hyperthermia susceptible (MHS) and normal skeletal muscle. Can Anaesth Soc J. 1984 Mar;31(2):130-54. [Article]
  2. Harrison GG: Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. 1975. Br J Anaesth. 1998 Oct;81(4):626-9; discussion 625. [Article]
  3. Flewellen EH, Nelson TE: Dantrolene dose response in malignant hyperthermia-susceptible (MHS) swine: method to obtain prophylaxis and therapeusis. Anesthesiology. 1980 Apr;52(4):303-8. [Article]
  4. Tonner PH, Scholz J, Richter A, Loscher W, Steinfath M, Wappler F, Wlaz P, Hadji B, Roewer N, Schulte am Esch J: Alterations of inositol polyphosphates in skeletal muscle during porcine malignant hyperthermia. Br J Anaesth. 1995 Oct;75(4):467-71. [Article]
  5. Zhao X, Weisleder N, Han X, Pan Z, Parness J, Brotto M, Ma J: Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor. J Biol Chem. 2006 Nov 3;281(44):33477-86. Epub 2006 Aug 31. [Article]
  6. Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F: Dantrolene--a review of its pharmacology, therapeutic use and new developments. Anaesthesia. 2004 Apr;59(4):364-73. [Article]
  7. Gerbershagen MU, Fiege M, Krause T, Agarwal K, Wappler F: [Dantrolene. Pharmacological and therapeutic aspects]. Anaesthesist. 2003 Mar;52(3):238-45. [Article]
  8. Paul-Pletzer K, Yamamoto T, Bhat MB, Ma J, Ikemoto N, Jimenez LS, Morimoto H, Williams PG, Parness J: Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. J Biol Chem. 2002 Sep 20;277(38):34918-23. Epub 2002 Jul 11. [Article]
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Major thyroid hormone transport protein in serum.
Gene Name
SERPINA7
Uniprot ID
P05543
Uniprot Name
Thyroxine-binding globulin
Molecular Weight
46324.12 Da
References
  1. CYTOMEL (liothyronine) FDA label [File]

Drug created at June 13, 2005 13:24 / Updated at November 28, 2021 11:56