Dantrolene

314.257

314.25

230-684-8

DTXSID7022881

CRYSTALS FROM AQ DIMETHYLFORMAMIDE

M - Musculo-skeletal system

2934990002

121

1.7

Crystals (in aqueous DMF). (NTP, 1992)

1.57 g/cm3

279 °C

175-177ºC

1.715

H2O: Low (146 mg/L)

PKA ABOUT 7.5 (FREE ACID)

ODORLESS; TASTELESS /DANTROLENE SODIUM SALT HYDRATE/|DECOMP BETWEEN 225 & 230 °C /DANTROLENE SODIUM SALT HYDRATE/

Slightly water soluble. This chemical may be sensitive to heat and air (NTP, 1992).

Amines, Phosphines, and Pyridines

A nitrated amine derivative. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

NONH for all modes of transport

STABLE IN LIGHT, AIR & HEAT; HYDROLYZES IN WATER /DANTROLENE SODIUM SALT HYDRATE/

REVIEW DISCUSSING DANTROLENE BIOTRANSFORMATION & CHOLESTASIS.[PLAA GL, HEWITT WR; BIOTRANSFORMATION PRODUCTS AND CHOLESTASIS; PROG LIVER DIS 7: 179 (1982)]

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

STORAGE PRECAUTIONS: You should store this material in a refrigerator. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Mild, asymptomatic serum aminotransferase elevations during dantrolene therapy are relatively uncommon (1%), but clinically over liver injury is estimated to occur in 1 to 2 per thousand treated persons (0.1% to 0.2%). The liver injury can be severe; cases of acute liver failure and even death have been described (Case 1). The latency to onset of clinically apparent liver injury ranges from one week to several months, but is usually within the first 6 months of starting therapy (Case 2). More serious cases are associated with a sudden onset with jaundice, nausea and fatigue, and rapid progression. Allergic manifestations such as fever, rash and eosinophilia are rare, as are autoimmune features. The pattern of enzyme elevations is predominantly hepatocellular. Liver histology demonstrates an acute-hepatitis like picture. Recovery is usually complete within 1 to 3 months. Women, the elderly, and patients taking higher doses appear to be more susceptible to developing dantrolene hepatotoxicity.

CENTRAL EFFECTS OF DANTROLENE MAY BE ENHANCED BY SEDATIVE-ANTIANXIETY DRUGS.

Dantrolene is a muscle relaxant used for treatment of chronic spasticity that differs from other commonly used muscle relaxants in acting peripherally on muscle, rather than centrally on the spinal cord or brain. Dantrolene can cause acute liver injury which can be severe and even fatal.

Autonomic Agents: Muscle Relaxants, Central

Muscle Relaxants, Central|DANTROLENE PROVIDES SIGNIFICANT & SUSTAINED REDUCTION OF SPASTICITY & IMPROVES FUNCTIONAL CAPACITY FOR MAJORITY OF PARAPLEGIC & HEMIPLEGIC PATIENTS; CLONUS, MASS-REFLEX MOVEMENTS & ABNORMAL RESISTANCE TO PASSIVE STRETCH ARE REDUCED. ABOUT 1/2 OF PT WITH ATHETOID CEREBRAL PALSY OR MULTIPLE SCLEROSIS ARE...SUFFICIENTLY IMPROVED...|.../ACTION HELPFUL/ FOR PRE- & POST OPERATIVE MANAGEMENT OF MALIGNANT HYPERTHERMIA. ...OF SOME BENEFIT IN PATIENTS WITH EXTERNAL SPHINCTER HYPERTONICITY WHO HAVE EXCESSIVE RESIDUAL URINE VOLUME & HIGH URETHRAL PRESSURE. /DANTROLENE SODIUM/|...SHOULD BE ADMIN IV AS SOON AS SYNDROME OF MALIGNANT HYPERTHERMIA IS RECOGNIZED; ... NECESSARY FOR 1 TO 3 DAYS TO PREVENT RECURRENCE... /DANTROLENE SODIUM/|For more Therapeutic Uses (Complete) data for DANTROLENE (9 total), please visit the HSDB record page.

.../IT/ TENDS TO INDUCE GENERALIZED MUSCLE WEAKNESS THAT CAN BE DETRIMENTAL TO FUNCTIONAL IMPROVEMENT. ...PT SHOULD BE CAUTIONED AGAINST DRIVING OR PARTICIPATING IN HAZARDOUS OCCUPATIONS. ... DANTROLENE SHOULD BE USED WITH CAUTION IN PT WITH IMPAIRED PULMONARY FUNCTION OR SEVERE MYOCARDIAL DISEASE.|DANTROLENE IS CONTRAINDICATED IN LIVER DISEASE...& WHEN GROSS POSTURAL ABNORMALITIES RESULT FROM ITS USE. IT SHOULD PROBABLY BE WITHHELD IN PEPTIC ULCER PT.|DANTROLENE IS NOT INDICATED IN FIBROSITIS, RHEUMATOID SPONDYLITIS, BURSITIS, ARTHRITIS OR ACUTE MUSCLE SPASM OF LOCAL ORIGIN. .../IT/ SHOULD NOT BE GIVEN TO PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS, FOR THESE INDIVIDUALS HAVE VERY LOW TOLERANCE TO MUSCLE WEAKNESS INDUCED BY DANTROLENE. ...HEPATOCELLULAR INJURY...HAS BEEN FATAL IN SOME CASES. RISK APPEARS TO BE GREATEST IN PATIENTS OVER 30 YEARS, ESP WOMEN OVER 35 YEARS, WHO HAVE RECEIVED MORE THAN 300 MG DAILY FOR 60 DAYS OR LONGER. ...ROUTINE BASELINE HEPATIC FUNCTION STUDIES SHOULD BE PERFORMED PRIOR TO THERAPY, & SGOT OR SGPT & ALKALINE PHOSPHATASE LEVELS SHOULD BE DETERMINED MONTHLY DURING THERAPY. /DANTROLENE SODIUM/|ALTHOUGH WEAKNESS MAY BE TRANSIENT OR MILD, ITS PERSISTENCE IN SOME AMBULATORY PT MAY COMPROMISE THERAPEUTIC BENEFIT. ...DIARRHEA THAT OCCURS IN SOME PT CAN USUALLY BE CONTROLLED BY MORE GRADUAL INCR IN DOSAGE, IT MAY NECESSITATE WITHDRAWAL OF DRUG.|For more Drug Warnings (Complete) data for DANTROLENE (7 total), please visit the HSDB record page.

TOLERANCE TO ITS THERAPEUTIC EFFECT DOES NOT APPEAR /TO DEVELOP/.

A heterogeneous group of drugs used to produce muscle relaxation, excepting the neuromuscular blocking agents. They have their primary clinical and therapeutic uses in the treatment of muscle spasm and immobility associated with strains, sprains, and injuries of the back and, to a lesser degree, injuries to the neck. They have been used also for the treatment of a variety of clinical conditions that have in common only the presence of skeletal muscle hyperactivity, for example, the muscle spasms that can occur in MULTIPLE SCLEROSIS. (From Smith and Reynard, Textbook of Pharmacology, 1991, p358) (See all compounds classified as Muscle Relaxants, Central.)

ABSORPTION...FROM GI TRACT IS SLOW & INCOMPLETE BUT SUFFICIENTLY CONSISTENT TO PROVIDE DOSE-RELATED PLASMA CONCN. MEAN HALF LIFE OF DRUG IN ADULTS IS ABOUT 9 HR AFTER 100-MG DOSE. IT IS SLOWLY METABOLIZED BY LIVER, & THE 5-HYDROXY & ACETAMIDO METABOLITES ARE EXCRETED WITH UNCHANGED DRUG IN URINE.

DANTROLENE IS METABOLIZED BY THE HEPATIC MIXED FUNCTION OXIDASE SYSTEM TO 5-HYDROXYDANTROLENE WHICH IS CONJUGATED WITH GLUCURONIC ACID OR WITH SULFATE. IT IS ALSO METABOLIZED BY NITROREDUCTASE TO AMINODANTROLENE WHICH INHIBITS THE HEPATIC MIXED FUNCTION OXIDASE SYSTEM. ACETYLATION OF AMINODANTROLENE BLOCKS THE INHIBITORY EFFECTS. INTERMEDIATES IN THE NITROREDUCTASE PATHWAY FORM GLUCURONIDE & MERCAPTURIC ACID CONJUGATES. THE MERCAPTURIC ACID CONJUGATION REACTION IS A DETOXIFICATION MECHANISM FOR AN ELECTROPHILIC METABOLITE OF DANTROLENE.

DANTROLENE /PRODUCES RELAXATION &/ REDUCES CONTRACTION OF SKELETAL MUSCLE BY DIRECT ACTION ON EXCITATION-CONTRACTION COUPLING, PERHAPS BY DECR AMT OF CALCIUM RELEASED FROM SARCOPLASMIC RETICULUM. ...IT DOES NOT IMPAIR POLYSYNAPTIC REFLEXES PREFERENTIALLY AS DO CENTRALLY ACTING MUSCLE RELAXANTS. DANTROLENE DIMINISHES FORCE OF ELECTRICALLY INDUCED TWITCHES...WITHOUT ALTERING MUSCLE ACTION POTENTIALS.../&/ REDUCES REFLEX MORE THAN VOLUNTARY CONTRACTION. .../IT/ DOES NOT AFFECT NEUROMUSCULAR TRANSMISSION, NOR...CHANGE ELECTRICAL POTENTIAL PROPERTIES OF SKELETAL MUSCLE MEMBRANES. IN PATIENTS WITH UPPER MOTONEURON LESIONS, SPASTICITY IS GENERALLY DIMINISHED...& FUNCTIONAL CAPACITY IS OFTEN IMPROVED.|DANTROLENE & 5-HYDROXYDANTROLENE INHIBITED RAT MUSCLE CONTRACTION RESPONSES IN DOSE-DEPENDENT MANNER IN VIVO & IN VITRO. 5-HYDROXYDANTROLENE WAS LESS POTENT THAN DANTROLENE.|DANTROLENE INHIBITS CALCIUM 2+ ION (CA2+) RELEASE FROM THE SARCOPLASMIC RETICULUM OF FROG MUSCLE.|IN RAT DIAPHRAGM PREPN DANTROLENE HAD NO EFFECT ON CONTRACTURES INDUCED BY 2,4-DINITROPHENOL, BUT REDUCED SIGNIFICANTLY THE CONTRACTURE PRODUCED BY K+. THE MAJOR ACTION OF DANTROLENE APPEARS TO BE ON THE SARCOLEMMA, WHICH MAY BE THE SITE OF THE MALIGNANT HYPERPYREXIA ABNORMALITY.|DANTROLENE ADDED TO PREPN OF VOLTAGE-CLAMPED MYELINATED FROG NERVE FIBERS SHIFTED THE POTENTIAL-DEPENDENT PARAMETERS DESCRIBING SODIUM ION (NA+) PERMEABILITY TOWARDS MORE NEGATIVE MEMBRANE POTENTIALS. APPARENTLY, A CHANGE IN THE NEGATIVE SURFACE CHARGE OF THE MEMBRANE IS INDUCED.

SYMPTOMS: When ingested, symptoms of exposure may include drowsiness, dizziness, weakness, general malaise, fatigue, diarrhea, constipation, gastrointestinal bleeding, anorexia, abdominal cramps, hepatitis, speech disturbance, seizure, headache, light-headedness, insomnia, tachycardia, phlebitis, mental depression, mental confusion, nervousness, abdominal hair growth, rash, sweating, backache, chills and fever. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

DANTROLENE HAS SERIOUS POTENTIAL TO CAUSE HEPATOTOXICITY. FATAL HEPATITIS HAS BEEN REPORTED IN APPROX 0.1 TO 0.2% OF PATIENTS TREATED...FOR 60 DAYS OR LONGER. SYMPTOMATIC HEPATITIS MAY OCCUR IN 0.5% OF PATIENTS TREATED...FOR MORE THAN 60 DAYS, WHILE CHEMICAL ABNORMALITIES OF HEPATIC FUNCTION ARE NOTED IN UP TO 1%. ... MOST COMMON MAJOR SIDE EFFECT...IS WEAKNESS, WHICH IS PROBABLY EXTENSION OF ITS EFFECT ON SKELETAL MUSCLE. ... EUPHORIA, LIGHT-HEADEDNESS, DIZZINESS, DROWSINESS & FATIGUE OFTEN OCCUR EARLY IN TREATMENT, BUT...ARE GENERALLY TRANSIENT...|...DIARRHEA.../IS ONE OF/ MOST COMMON REACTIONS. .../IT/ MAY BE PERSISTENT & REQUIRE TREATMENT, A REDUCTION IN DOSE, OR TEMPORARY CESSATION OF THERAPY. ANOREXIA, NAUSEA, VOMITING, & AN ACNE-LIKE RASH ARE ALSO SIGNIFICANT SIDE EFFECTS. LESS FREQUENTLY...HEADACHE, NERVOUSNESS /&/ INSOMNIA...HAVE OCCURRED. PLEUROPERICARDIAL REACTIONS & VISUAL DISTURBANCES DEVELOP RARELY. /DANTROLENE SODIUM/|USE...IN ACUTE HYPERTHERMIC EMERGENCIES OR FOR PREOPERATIVE PREPN OF PATIENTS SUSCEPTIBLE TO MALIGNANT HYPERTHERMIA IS NOT ASSOC WITH RISKS OF HEPATOTOXICITY & PLEURAL EFFUSION THAT CAN OCCUR DURING ITS PROLONGED ADMIN. HOWEVER, LARGE DOSES USED FOR PREMEDICATION MAY PRODUCE NAUSEA & DIARRHEA, BLURRED VISION, MUSCLE WEAKNESS & INCOORDINATION. /DANTROLENE SODIUM/|INTERFERENCE WITH MUSCLE FUNCTION MAY CAUSE ASTHENIA...POOR POSTURE WITH CONSEQUENT BACKACHE & MYALGIA, FEELING OF SUFFOCATION, DIFFICULTIES IN SWALLOWING... OTHER ADVERSE EFFECTS INCL CONSTIPATION...ABDOMINAL CRAMPS, GASTRIC IRRITATION, GI BLEEDING, INCR URINARY FREQUENCY, LACRIMATION, SWEATING, DISORDERS OF TASTE, HYPERTENSION, TACHYCARDIA, HYPERTRICHOSIS, PRURITIS, URTICARIA...ECZEMATOID DERMATITIS...CHILLS & FEVER. /DANTROLENE SODIUM/|For more Human Toxicity Excerpts (Complete) data for DANTROLENE (6 total), please visit the HSDB record page.

Dantrium

DANTRIUM (NORWICH-EATON). ORAL: CAPSULES 25, 50 & 100 MG. INTRAVENOUS: POWDER (STERILE, LYOPHILIZED) 20 MG FOR RECONSTITUTION TO 60 ML. /DANTROLENE SODIUM/

ADDITION OF SMALL AMT OF NAOH PREVENTS...HYDROLYSIS TO SOME EXTENT, BUT THIS PROCEDURE IS COMPLICATED BY PPTN OF DANTROLENE SODIUM (COMMON-ION EFFECT); AMT REMAINING IN SOLN DEPENDS ON IONIC SPECIES & STRENGTH. /DANTROLENE SODIUM/

ANALYSIS OF CAPSULES CAN BE CARRIED OUT WITHIN 30 MIN WITH AN ACCURACY OF 3.1% USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY.|COLUMN CHROMATOGRAPHY & FLUOROMETRY ARE USED TO DETERMINE DANTROLENE IN BIOLOGICAL SPECIMENS.|DANTROLENE AND ITS METABOLITES ARE DETECTED SPECTROPHOTOMETRICALLY AT 375 NM. DETECTION LIMITS ARE 0.02 MG/L. A PRELIMINARY EXTRACTION STEP INTO CHLOROFORM-BUTANOL MIXT IS REQUIRED FOR THE PLASMA SAMPLES. METHOD IS SUITABLE FOR PHARMACOKINETIC STUDIES OF DANTROLENE.

HPLC TECHNIQUE FOR DETERMINATION OF DANTROLENE SODIUM IN HUMAN PLASMA & URINE IS DESCRIBED. MINIMUM DETECTABILITY IS 8 NG.|THE PH OF HUMAN PLASMA SAMPLES WAS ADJUSTED TO 4.0 WITH ACETATE BUFFER, & DANTROLENE & 5-HYDROXYDANTROLENE EXTRACTED WITH ETHYL ACETATE. HPLC SYSTEM USED CONSISTED OF LICHROSORB RP-18 COLUMN & A UV DETECTOR SET AT 310 NM. THE MOBILE PHASE WAS METHANOL-0.1 MOLAR PH 7.4 ACETATE BUFFER (1:1). BENZANILIDE WAS THE INTERNAL STD. LIMIT OF DETECTION WAS APPROX 0.03 MUG/ML FOR DANTROLENE & ITS METABOLITE.|DANTROLENE AND ITS METABOLITES ARE DETECTED SPECTROPHOTOMETRICALLY AT 375 NM. DETECTION LIMITS ARE 0.02 MG/L. A PRELIMINARY EXTRACTION STEP INTO CHLOROFORM-BUTANOL MIXT IS REQUIRED FOR THE PLASMA SAMPLES. METHOD IS SUITABLE FOR PHARMACOKINETIC STUDIES OF DANTROLENE.

Pharmaceuticals