A21: Antidotes in Depth

INTRODUCTION

Dantrolene produces relaxation of skeletal muscle without causing complete paralysis, and it is the only xenobiotic proven to be effective for both treatment and prophylaxis of malignant hyperthermia (MH).⁸ MH should be considered when hyperthermia is associated with severe hypermetabolism, increased CO₂ production, metabolic acidosis with elevated lactate, hyperkalemia, and rhabdomyolysis, especially when the course is fulminating and refractory to supportive therapy.

HISTORY

Dantrolene was first synthesized in 1967.²⁹ Four years later, the xenobiotic was first used clinically in oral form to treat skeletal muscular spasticity caused by neurologic disorders.⁶ The ability of intravenous (IV) dantrolene to rapidly reverse MH (muscle rigor, acidosis, and temperature rise) was first reported in swine in 1975¹¹ and in humans in 1982.¹⁶ The delay from dantrolene discovery to clinical use was in part due to the difficulty encountered in formulating a parenteral (water-soluble) solution of the lipid-soluble drug.

PHARMACOLOGY

Although dantrolene is a hydantoin derivative that is structurally similar to local anesthetics and anticonvulsants, it possesses none of their properties.^17,33 The drug is highly lipophilic and relatively insoluble in water. It 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.¹⁷ Dantrolene is reversibly bound to plasma proteins, especially albumin.

Quantitative analysis of dantrolene and its metabolites has been performed using reverse phase, high-performance liquid chromatography.¹ After a 2.4 mg/kg IV dose, the mean serum dantrolene concentration is 4.2 μg/mL.⁸ This concentration produced a 75% reduction in twitch contraction of skeletal muscle.⁸ The therapeutic serum concentration in humans is estimated at 2.8 to 4.2 μg/mL.⁸

Pharmacokinetics are well described by a two-compartment model with an initial volume of distribution of 3.24 L and a secondary compartment volume of 22.4 L.²³ Most of the drug is eliminated by the liver; dantrolene is metabolized by 5-hydroxylation of the hydantoin ring or by reduction of the nitro group to an amine.³³ 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.³³ In adults, the elimination half-life is 6 to 9 hours for dantrolene and 15.5 hours for the 5-hydroxydantrolene metabolite.³³ 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.¹⁸

At therapeutic concentrations, dantrolene inhibits binding of [³H] ryanodine to the ryanodine receptor type 1 (RYR-1) on the sarcoplasmic reticulum membrane of skeletal muscle,²² causing a dose-dependent inhibition of both the steady state and peak concentrations of calcium release.³⁰ This reduces the free myoplasmic calcium, thereby directly inhibiting excitation–contraction coupling.¹⁹ Dantrolene causes skeletal ...