Brands, Medical Use, Clinical Data
- Muscle Relaxants, Central
- Powder for solution
Brands / Synonyms
Dantrium; Dantrium Intravenous; Dantrolene Sodium; Dantrolene [USAN:BAN:INN]; Dantroleno [INN-Spanish]; Dantrolenum [INN-Latin]
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.
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.
Bioavailability is 70%.
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.
Biotrnasformation / Drug 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.
Dantrium is metabolized by the liver, and it is theoretically possible that its metabolism may be enhanced by
drugs known to induce hepatic microsomal enzymes. However, neither phenobarbital nor diazepam appears to affect
Dantrium metabolism. Binding to plasma protein is not significantly altered by diazepam, diphenylhydantoin, or
phenylbutazone. Binding to plasma proteins is reduced by warfarin and clotibrate and increased by tolbutamide.
Cardiovascular collapse in patients treated simultaneously with varapamil and dantrolene sodium is rare. The
combination of therapeutic doses of intravenous dantrolene sodium and verapamil in halothane/a-chloralose anesthetized swine has resulted in ventricular fibrillation and cardiovascular collapse in
association with marked hyperkalemia. It is recommended that the combination of intravenous dantrolene sodium and
calcium channel blockers, such as verapamil, not be used together during the management of malignant hyperthermia
crisis until the relevance of these findings to humans is established.
Administration of dantrolene may potentiate vecuronium-induced neuromuscular block.