Dantrium - General Information
Chemically, dantrolene is a hydantoin derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as phenytoin.
Pharmacology of Dantrium
Dantrium 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.
Dantrium for patients
Based upon data in human volunteers, it will sometimes be appropriate to tell patients who receive Dantrium Intravenous that decrease in grip strength and weakness of leg muscles, especially walking down stairs, can be expected postoperatively. In addition, symptoms such as "lightheadedness" may be noted. Since some of these symptoms may persist for up to 48 hours, patients must not operate an automobile or engage in other hazardous activity during this time. Caution is also indicated at meals on the day of administration because difficulty swallowing and choking has been reported. Caution should be exercised in the concomitant administration of tranquilizing agents.
Hepatotoxicity seen with Dantrium Capsules: Dantrium (dantrolene sodium) has a potential for hepatotoxicity, and should not be used in conditions other than those recommended. Symptomatic hepatitis (fatal and non-fatal) has been reported at various dose levels of the drug. The incidence reported in patients taking up to 400 mg/day is much lower than in those taking doses of 800 mg or more per day. Even sporadic short courses of these higher dose levels within a treatment regimen markedly increased the risk of serious hepatic injury. Liver dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme elevations) has been observed in patients exposed to Dantrium for varying periods of time. Overt hepatitis has occurred at varying intervals after initiation of therapy, but has been most frequently observed between the third and twelfth month of therapy. The risk of hepatic injury appears to be greater in females, in patients over 35 years of age, and in patients taking other medication(s) in addition to Dantrium (dantrolene sodium). Dantrium should be used only in conjunction with appropriate monitoring of hepatic function including frequent determination of SGOT or SGPT.
Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with Dantrium therapy.
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.
Additional information about Dantrium
Dantrium 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.
Mechanism Of Action: Dantrium 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.
Drug Interactions: Not Available
Food Interactions: Take without regard to meals.
Generic Name: Dantrolene
Synonyms: Dantrolene Sodium; Dantroleno [INN-Spanish]; Dantrolenum [INN-Latin]
Drug Category: Muscle Relaxants, Central
Drug Type: Small Molecule; Approved
Absorption: Bioavailability is 70%.
Toxicity (Overdose): 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.
Protein Binding: Significant, mostly to albumin.
Biotransformation: 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.
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.
Dosage Forms of Dantrium: Powder, for solution Intravenous
Chemical IUPAC Name: 1-[[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione
Chemical Formula: C14H10N4O5
Dantrolene on Wikipedia: https://en.wikipedia.org/wiki/Dantrolene
Organisms Affected: Humans and other mammals