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

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.

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.

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.

absorption

Bioavailability is 70%.

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.

drug interactions

Atazanavir: Atazanavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if atazanavir is initiated, discontinued or dose changed.

Clarithromycin: Clarithromycin may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if clarithromycin is initiated, discontinued or dose changed.

Conivaptan: Conivaptan may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if conivaptan is initiated, discontinued or dose changed.

Darunavir: Darunavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if darunavir is initiated, discontinued or dose changed.

Delavirdine: Delavirdine may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if delavirdine is initiated, discontinued or dose changed.

Fosamprenavir: Fosamprenavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if fosamprenavir is initiated, discontinued or dose changed.

Imatinib: Imatinib may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if imatinib is initiated, discontinued or dose changed.

Indinavir: Indinavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if indinavir is initiated, discontinued or dose changed.

Isoniazid: Isoniazid may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if isoniazid is initiated, discontinued or dose changed.

Itraconazole: Itraconazole may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if itraconazole is initiated, discontinued or dose changed.

Ketoconazole: Ketoconazole may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if ketoconazole is initiated, discontinued or dose changed.

Lopinavir: Lopinavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if lopinavir is initiated, discontinued or dose changed.

Methotrimeprazine: Concomitant therapy may result in additive CNS depressant effects. The dosage of dantrolene should be decreased by 50% prior to initiating concomitant therapy. Monitor for increased CNS depression.

Nefazodone: Nefazodone may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if nefazodone is initiated, discontinued or dose changed.

Nelfinavir: Nelfinavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if nelfinavir is initiated, discontinued or dose changed.

Nicardipine: Nicardipine may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if nicardipine is initiated, discontinued or dose changed.

Posaconazole: Posaconazole may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if posaconazole is initiated, discontinued or dose changed.

Quinidine: Quinidine may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if quinidine is initiated, discontinued or dose changed.

Ritonavir: Ritonavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if ritonavir is initiated, discontinued or dose changed.

Saquinavir: Saquinavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if saquinavir is initiated, discontinued or dose changed.

Telithromycin: Telithromycin may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if telithromycin is initiated, discontinued or dose changed.

Triprolidine: The CNS depressants, Triprolidine and Dantrolene, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if voriconazole is initiated, discontinued or dose changed.