A21: Antidotes in Depth

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.

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.

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 muscle weakness but not complete paralysis, and this plateau effect may be related to its low water solubility. This plateau effect (achieved at a serum concentration of 4.2 μg/mL) produces a 75% reduction of skeletal muscle twitch contraction and a 42% reduction in hand grip strength.⁸ Dantrolene does not change the electrical properties or excitation of nerve, excitation–contraction coupling at the neuromuscular junction, or skeletal muscle, and it does not alter sarcoplasmic calcium reuptake. Because dantrolene does not bind to the cardiac ryanodine receptor (RYR-2), it has minimal cardiac effects^10,32,35 and no effect on smooth muscle.

Dantrolene is indicated for treatment of skeletal muscle hypermetabolism characteristic of MH and, following an acute episode of MH, to prevent recrudescence. Long-term oral dantrolene therapy is used rarely to treat chronic spasticity.¹⁵ Historically, dantrolene was used prophylactically in MH-susceptible individuals; however, current practice is simply to avoid exposure to MH-triggering xenobiotics during anesthesia in potentially susceptible patients (Table 30–1). Dantrolene should be considered for patients with severe hypermetabolism when the diagnosis of MH cannot be excluded with certainty, especially when there is coexisting respiratory and metabolic acidosis, coagulopathy, hyperthermia, and rhabdomyolysis.⁷ In typical fulminant MH, the diagnosis is not subtle, and the course of treatment is obvious once the diagnosis is considered. This is not true when the clinical presentation is atypical. Atypical clinical presentations of MH in the presence or absence of triggering anesthetics are reported, especially in MH-susceptible individuals.

Dantrolene has been used to treat acute hyperthermia other than that caused by MH, including neuroleptic malignant syndrome,²⁴ heat stroke,² serotonin toxicity,¹² monoamine oxidase inhibitor overdose,¹³ methylenedioxymethamphetamine (“ecstasy”) overdose,^20,26 intrathecal baclofen withdrawal,¹⁴ and thyroid storm.⁵ Given the lack of evidence-based support, dantrolene therapy is not recommended for indications other than MH. However, because (a) the differential diagnosis of a hyperthermic syndrome does not necessarily exclude (and often includes) MH, (b) the definitive diagnosis of a hyperthermic syndrome may be subtle or delayed, and (c) MH may occur simultaneously with another hyperthermic syndrome,²¹ consideration should be given to dantrolene therapy when MH cannot be specifically excluded; its use may be lifesaving. It bears emphasis that dantrolene given for hyperthermia is not a substitute for aggressive cooling.

The alkaline pH of the reconstituted dantrolene causes venous irritation (pain) and thrombophlebitis with an incidence of 9%.³ Unintended extravasation can cause tissue necrosis, highlighting that dantrolene should only be given through a central vein or a large peripheral vein. There is no evidence to suggest allergic cross-reactivity with dantrolene in patients with prior phenytoin allergy.

When given to healthy persons or for MH prophylaxis or treatment, dantrolene causes skeletal muscle weakness (but not paralysis) in 15% to 22% of cases, as well as diaphragm weakness (dyspnea).^3,34 In healthy volunteers, dantrolene 2.5 mg/kg does not reduce respiratory rate, vital capacity, or peak expiratory flow rate.⁸ However, in patients with diminished respiratory reserve (eg, end-stage pulmonary disease, preexisting neuromuscular disease), dantrolene may precipitate respiratory failure.^3,17 Dantrolene may cause gastrointestinal upset, nausea, and vomiting. Other reported side effects include dizziness, somnolence, disorientation, ptosis, blurred vision, and difficulty swallowing.^3,8,34 Uncommonly, compartment syndrome is observed and, even though likely secondary to MH or trauma, may be associated with dantrolene administration.³

Dantrolene and verapamil should not be used in combination because of the risk of hyperkalemia and hypotension; however, the mechanistic details of this drug interaction remain unclear.^17,25,27 IV calcium salts are safe to administer with dantrolene if needed, such as for the treatment of cardiac dysrhythmias or hyperkalemia (during an episode of MH).

When dantrolene is given orally for more than 2 months to treat skeletal muscle spasticity, there is a 1.8% risk of dose- and duration-related chronic hepatitis, including elevated aminotransferase concentrations, hyperbilirubinemia, or jaundice³¹ that may not be fully reversible after dantrolene is discontinued.⁴

Dosing during pregnancy is based on total body weight. Dantrolene crosses the placenta and is excreted in breast milk. When the maternal blood concentration achieved 0.99 μg/mL, the neonatal cord blood and serum concentration was 0.68 and 0.72 μg/mL, respectively.²⁸ The neonatal drug elimination half-life is about 20 hours.²⁸ Peak concentrations of dantrolene in breast milk 36 hours after maternal dantrolene 2.5 mg/kg given intravenously were 1.2 μg/mL, and the elimination half-life was 9 hours from breast milk.⁹ At the concentrations achieved in serum or breast milk, there are no reports of significant adverse affects on the neonate; however, it is suggested the breast feeding resume 48 hours after the last dose of dantrolene.⁹

The initial dose of dantrolene for treatment of acute MH is an IV bolus of 2 to 3 mg/kg in the adult and pediatric population.¹⁸ For a typical adult, 10 bottles of dantrolene are simultaneously reconstituted for the initial dose. Also, initial dosing probably should be determined by total body weight given that dantrolene is lipophilic; however, its pharmacokinetics in obesity are not determined.⁸ Redosing of 2 to 3 mg/kg IV is repeated every 15 minutes until the signs of hypermetabolism are reversed or until a total dose of approximately 10 mg/kg has been administered. Occasionally, however, doses in excess of 10 mg/kg have been required. The key point is that the total dose of dantrolene is determined by titration to a metabolic end point–resolution of skeletal muscle hypermetabolism. When an effective dose of dantrolene is given, signs of muscle hypermetabolism start to normalize usually within 30 minutes.¹⁶

Following successful termination of the acute episode of hypermetabolism, it is recommended that dantrolene therapy be continued 1 mg/kg IV every 6 hours for at least 24 hours to prevent recrudescence. Alternatively, a maintenance infusion can be started 5 hours after the initial dose (ID) according to the formula:

For example, if the ID of dantrolene is 5 mg/kg, it is continued as an infusion 5.48 mg/kg/24 h.²³

Dantrolene is supplied as a sterile lyophilized powder in a 70 mL vial that contains 20 mg dantrolene sodium, 3 g mannitol (to maintain tonicity), and sodium hydroxide (to maintain a pH of 9.5 after reconstitution in 60 mL of sterile water). The dantrolene powder must be reconstituted in preservative-free sterile water for injection (and not 0.9% sodium chloride or dextrose-containing solutions) as this hastens dissolution and prevents precipitation. Prewarming the water to a maximum of 102°F (39°C) may decrease the time to dissolve the powder; this can be accomplished by storing sterile water in a warmed cabinet. There is, however, no evidence that prewarming improves clinical outcome, and the current formulation of Dantrium reconstitutes in about 20 seconds. After addition of 60 mL sterile water to each vial, the dantrolene bottles are shaken until the solution becomes clear (indicating the powder is fully dissolved). The final solution is isotonic and has pH of approximately 9.5. The extreme alkalinity of the reconstituted solution can corrode glass and thus must not be transferred into a glass bottle.

• Dantrolene is the only specific antidote to treat malignant hyperthermia. The initial dose of dantrolene for treatment of acute MH is an IV bolus of 2 to 3 mg/kg in the adult and pediatric population, which is repeated every 15 minutes until clinical signs of hypermetabolism are corrected.

• The therapeutic serum concentration in humans is estimated at 2.8 to 4.2 μg/mL. Most of the drug is eliminated by the liver; it is metabolized by 5-hydroxylation of the hydantoin ring or by reduction of the nitro group to an active metabolite.

• Dantrolene is relatively lipophilic and crosses the placenta and is excreted in breast milk.

• MH Hotline: 800-644-9737.

References