Antidotes in De..

Dantrolene produces relaxation of skeletal muscle without causing complete paralysis, and is the only xenobiotic proven to be effective for both treatment and prophylaxis of malignant hyperthermia (MH). Although dantrolene is a hydantoin derivative that is structurally similar to local anesthetics and anticonvulsants, it possesses none of their properties.14,29 The drug is available as Dantrium&reg; and in generic forms.

MH should be considered when hyperthermia is associated with severe hypermetabolism, increased CO2 production, metabolic acidosis with elevated lactate, hyperkalemia, and/or rhabdomyolysis, especially when the course is fulminating and refractory to supportive therapy.

Dantrolene was first synthesized in 1967.25 Four years later, the xenobiotic was first used clinically to treat muscular spasticity caused by neurological disorders.4 The ability of dantrolene to reverse MH was first reported in swine in 19758 and in humans in 1982.13 The delay from dantrolene discovery to clinical use was in part because of the difficulty encountered in formulating a parenteral (water-soluble) solution of the lipid-soluble drug.

Dantrolene is highly lipophilic and relatively insoluble in water. Dantrolene exhibits variable absorption by the small intestine. Oral bioavailability is up to 70% and peak blood concentrations are achieved 3 to 6 hours after ingestion.14 In plasma, dantrolene is reversibly bound to plasma proteins, especially albumin. Most of the drug is eliminated by the liver; however, dantrolene is first metabolized in the liver by 5-hydroxylation of the hydantoin ring or by reduction of the nitro group to an amine.29 Up to 20% of administered dantrolene is excreted in the urine as the 5-hydroxydantrolene metabolite, which is half as potent as the parent drug.29 In adults, elimination half-life is 6 to 9 hours for dantrolene and 15.5 hours for the 5-hydroxydantrolene metabolite.29 In one study of children aged 2 to 7 years, the dantrolene elimination half-life was 10 hours and that for 5-hydroxydantrolene was 9 hours.16

Quantitative analysis of dantrolene and its metabolites has been performed using high-performance liquid chromatography.15 After a 2.4 mg/kg intravenous (IV) dose, the mean serum dantrolene concentration is 4.2 μg/mL,6 which results in a 75% reduction in skeletal muscle with contraction.6 The therapeutic serum concentration in humans is estimated at 2.8 to 4.2 μg/mL.6

At therapeutic concentrations, dantrolene inhibits binding of [3H]ryanodine to the ryanodine receptor type 1 (RYR-1).7 [3H]Dantrolene and [3H]ryanodine appear to bind to the same sites on sarcoplasmic reticulum membrane fractions.20 Dantrolene acts primarily at skeletal muscle RYR-1, causing a dose-dependent inhibition of both the steady and peak components of sarcoplasmic calcium release.26 This reduces the free myoplasmic calcium, thereby directly inhibiting excitation—contraction coupling.17 Dantrolene causes skeletal muscle weakness but not complete paralysis, and this plateau effect may be related to its low water solubility. This plateau effect occurs at approximately a 75% reduction of skeletal muscle twitch contraction....

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