Hepatotoxicity dantrolene

Dantrolene is the mainstay of MH treatment. It has long been available for the treatment of muscle spasm in cerebral palsy and similar diseases. It is a hydantoin derivative that was first synthesized in 1967, and reported to be effective in the treatment of porcine MH in 1975. Also in 1975, dantrolene was shown to be more effective than procainamide in the treatment of human MH, which until that time was the drug of choice. However, the intravenous preparation was not made available until November 1979. It significantly lowered mortality. The half-life of dantrolene is estimated to be 6-8 hr. Dantrolene s primary mode of action is the reduction in calcium release by the sarcoplasmic reticulum. Dantrolene also exerts a primary antiarrhythmic effect by increasing atrial and ventricular refractory periods. Side effects of dentrolene include hepatotoxicity, muscle weakness, ataxia, blurred vision, slurred speech, nausea, and vomiting. Dantrolene is not contraindicated in pregnancy, but it does cross into breast milk and its effect on the neonate is unknown. 

Hepatotoxicity from dantrolene consists mainly of minor hver function disturbances (in 1% of patients), with... 

The absorption of oral dantrolene can be significantly increased by metoclopramide (15). As the risk of hepatotoxicity has been related to the dosage of dantrolene, increased clinical surveillance is necessary to avoid toxicity of dantrolene during concurrent treatment with metoclopramide. 

Treatment of MH depends on cessation of anesthesia, mechanical means to reduce the temperature, and the correction of blood electrolyte and gas parameters to normal. In addition, dantrolene (Figure 18-3) is infused initially intravenously and then may be given orally. Dantrolene brings about the reduction in contraction of skeletal muscles by decreasing the amount of Ca released from the sarcoplasmic reticulum. A serious side effect of dantrolene use is its potential hepatotoxicity. The hepatotoxicity is fatal to 0.1 to 0.2 percent of patients treated for 60 days or longer. Thus, use of dantrolene for longer than 45 days requires monitoring of hepatic markers. 

In addition to its use in managing an acute attack of malignant hyperthermia see above), dantrolene has been used in the treatment of spasticity and hyperreflexia. Dantrolene causes a generalized weakness thus, its use should be restricted to nonambulatory patients with severe spasticity. Hepatotoxicity has been reported with continued use, requiring hver function tests. 

C. Black Box warning. Potential for fatal hepatotoxicity (hypersensitivity hepatitis) reported after chronic therapy. May also be dose related (more common with 800 mg/day). Transaminases are elevated in about 10% of patients treated with dantrolene. 

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