Dantrolene

Abstract

Dantrolene sodium acts primarily by affecting calcium flux across the sarcoplasmic reticulum of skeletal muscle. Recently, dantrolene has been used very successfully in the treatment of several rare hypercatabolic syndromes which have previously been associated with high mortality rates. In malignant hyperthermia, where early diagnosis and treatment usually with intravenous dantrolene in association with other supportive measures (and often subsequent dantrolene therapy) is performed, recovery is seen in virtually 100% of patients. There is a rapid resolution of hyperthermia, dysrhythmias, muscle rigidity, tachycardia, hypercapnia, mottled or cyanotic skin, and metabolic acidosis, and a slower normalisation of myoglobinuria and elevated serum creatine phosphokinase levels. In patients with family history or previous episodes of malignant hyperthermia, prophylactic treatment with dantrolene prior to anaesthesia prevents the syndrome occurring in most cases. Where malignant hyperthermia has developed patients have been successfully treated with further dantrolene therapy. Dantrolene has also been used successfully in the treatment of a few cases of heat stroke and the neuroleptic malignant syndrome--both of which have many similarities to malignant hyperthermia. Dantrolene is well established in the treatment of patients with muscle spasticity where it generally improves at least some of the components of spasticity (i.e. hyper/hypotonia, clonus, muscle cramps and spasms, resistance to stretch and flexor reflexes, articular movement, neurological and motor functions and urinary control). However, in some patients, particularly those with multiple sclerosis, dantrolene may not be effective, and in many cases muscular strength may diminish. Long term dantrolene therapy has been associated with hepatic toxicity and may cause problems in patients treated for disorders of muscle spasticity. Thus, dantrolene offers a unique advance in the therapy available for the treatment of hypercatabolic disorders and is also useful in the treatment of muscle spasticity of various aetiology.

Dantrolene Inhibition of Sarcoplasmic Reticulum Ca2+Release by Direct and Specific Action at Skeletal Muscle Ryanodine Receptors

“…The muscle relaxant dantrolene is a potent and specific inhibitor of skeletal muscle excitation-contraction (E-C) 1 coupling (1). Dantrolene (ϳ10 M) reduces skeletal muscle twitch force by approximately 75% (2) and shifts the sensitivity of contractile activation to higher voltages (3,4), these effects being attributed to a partial block by dantrolene of Ca 2ϩ release from the sarcoplasmic reticulum (SR) (1,5,6).…”

“…Dantrolene (ϳ10 M) reduces skeletal muscle twitch force by approximately 75% (2) and shifts the sensitivity of contractile activation to higher voltages (3,4), these effects being attributed to a partial block by dantrolene of Ca 2ϩ release from the sarcoplasmic reticulum (SR) (1,5,6). In contrast to these pronounced effects on skeletal muscle, effects of dantrolene on cardiac muscle contractility are mild or absent (1,5,7). Clinically, dantrolene has proven effective in the treatment of malignant hyperthermia (MH), a potentially fatal genetic disorder of skeletal muscle E-C coupling in which exposure to volatile anesthetics triggers uncontrolled SR Ca 2ϩ release, muscle contracture, and accelerated metabolism (8).…”

Dantrolene Inhibition of Ryanodine Receptor Ca2+Release Channels

“…Dantrolene inhibition of SR Ca 2ϩ release in skeletal muscle has provided a lifesaving treatment for the pharmacogenetic disorder malignant hyperthermia (MH). Thus, the uncontrolled SR Ca 2ϩ release, muscle contracture, and accelerated metabolism that threaten the MH-susceptible (MHS) patient exposed to volatile anesthetics during surgery are effectively suppressed upon treatment with dantrolene (9,10). Dantrolene also reverses the increased sensitivity of MHS muscle to activation by caffeine (11), which constitutes the basis of in vitro diagnostic tests of this syndrome (12,13).…”

“…Dantrolene also reverses the increased sensitivity of MHS muscle to activation by caffeine (11), which constitutes the basis of in vitro diagnostic tests of this syndrome (12,13). The efficacy of dantrolene in the treatment of MH is in large part a function of the selective action of this drug on SR Ca 2ϩ release in skeletal muscle, while exerting no comparable negative inotropic effect on the beating heart (6,10,14). Notably, the absence of major effects of dantrolene on SR Ca 2ϩ release in the heart is consistent with the possibility that dantrolene may act selectively on the RYR1 but not the RYR2 channel isoform (15).…”

Mobilization of dantrolene-sensitive intracellular calcium pools is involved in the cytotoxicity induced by quisqualate and N-methyl-D-aspartate but not by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate and kainate in cultured cerebral cortical neurons.

“…Dantrolene, which is used in the clinic in symptomatic treatment of conditions such as malignant hyperthermia, neuroleptic malignant syndrome, and certain types of muscle spasticity (10), has been reported to inhibit Ca2+ release from sarcoplasmic reticulum in skeletal muscle and from unidentified Ca2+ stores in other cell types (for references, see ref.…”