Chapter A24: Dantrolene Sodium

INTRODUCTION

Dantrolene produces relaxation of skeletal muscle without causing complete paralysis. It is the only therapy proven to be effective for both treatment and prophylaxis of malignant hyperthermia (MH).⁸ Malignant hyperthermia is a rare life-threatening condition that is triggered by the use of either an inhalational anesthetic or succinylcholine. It is a syndrome of hypermetabolism involving the skeletal muscle, which overwhelms the ability of the body to supply oxygen, remove carbon dioxide, and regulate body temperature and can quickly lead to circulatory collapse if untreated. Typical signs include severe hyperthermia, increased CO₂ production and oxygen consumption, hemodynamic instability, mixed respiratory and metabolic acidosis, hyperkalemia, muscle rigidity, and rhabdomyolysis.

HISTORY

Dantrolene was first synthesized in 1967.³³ Four years later, it was used in oral form to treat skeletal muscle spasticity secondary to neurologic disorders.⁶ The ability of intravenous (IV) dantrolene to rapidly reverse MH was first reported in swine in 1975¹¹ and subsequently 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

Dantrolene is a hydantoin derivative that is structurally similar to local anesthetics and anticonvulsants but possess neither property.^17,37 It is highly lipophilic and relatively insoluble in water. Widespread use had to wait until a there was a suitable IV preparation. Today mannitol is added to the lyophilized dantrolene to improve solubility. In plasma, dantrolene is bound to plasma proteins, especially albumin. Oral dantrolene exhibits variable absorption by the small intestine, bioavailability is up to 70%, and peak blood concentrations are achieved 3 to 6 hours after ingestion.¹⁷

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

Dantrolene is metabolized in the liver by 5-hydroxylation of the ­hydantoin ring or by reduction of the nitro group to an amine.³⁷ Up to 20% of ­administered dantrolene is excreted in the urine as the 5-­hydroxydantrolene, which is an active metabolite that is half as potent as the parent drug.³⁷ In adults, the elimination half-lives are 6 to 9 hours for dantrolene and 15.5 hours for the 5-hydroxydantrolene metabolite.³⁷ In one study of children ages 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) receptor on sarcoplasmic reticulum membrane of skeletal muscle,²⁴ causing a dose-dependent inhibition of ...