Dantrolene

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Abstract
Synopsis: Dantrolene sodium1 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. Pharmacodynamic Studies: Experimental evidence suggests that dantrolene acts intracellularly in skeletal muscle fibres by inhibiting the release of calcium. Consequently, dantrolene produces a marked reduction in muscle contraction to electrical stimulation or stimulation by pharmacological agents without affecting action potential patterns. However, whether dantrolene acts by preventing release of calcium from the sarcoplasmic reticulum, or by inhibiting an earlier stage involving the release of ‘trigger’ amounts of calcium from the triadic junctions, remains to be confirmed. In vivo studies in malignant hyperthermia-susceptible pigs show that dantrolene inhibits abnormal excitation-contraction coupling and reverses and prevents development of malignant hyperthermia. However, in vitro studies using isolated skeletal muscle from susceptible animals produced variable results, with inhibition, no effect or potentiation of halothane- and caffeine-induced muscle contraction. Dantrolene appears to have some effects on smooth muscle and cardiac tissue in vitro, but these are inconsistent and negligible. There is some evidence of antiarrhythmic activity and protective effects against ischaemic injury. Efficacy in voiding problems in spinal patients is more likely to be due to decreased sphincter muscle tone than to effects on the urinary bladder smooth muscle. Dantrolene may affect calcium release from nerve terminals and nerve terminal responses, and appears to have a marked GABAergic effect, but is devoid of anticonvulsant and anaesthetic properties. Pharmacokinetic Studies: About 70% of a single oral dose of dantrolene is absorbed, with peak plasma concentrations of about 1 mg/L occurring 4 to 6 hours after administration of a 100mg dose. Dantrolene is bound to human serum albumin, plasma proteins and to skeletal muscle sarcoplasmic reticulum. Dantrolene is metabolised in the liver primarily to 5-hydroxydantrolene which has similar pharmacological action to the parent compound and upon repeated administration may exceed the serum concentrations of dantrolene. 15 to 25% of dantrolene is excreted in the urine (primarily as the hydroxy metabolite) with negligible faecal excretion. The elimination half-lives of dantrolene and 5-hydroxydantrolene are about 6 to 9 hours and 15.5 hours, respectively. There appears to be a direct correlation between the plasma concentrations of the drug and its therapeutic effects. Therapeutic Trials: Hypercatabolic disorders of metabolism such as malignant hyperthermia, neuroleptic malignant syndrome and heat stroke are rare but very severe conditions requiring immediate therapy. Prior to dantrolene, no consistently effective treatments existed. Consequently, it is not possible to conduct controlled or comparative therapeutic trials in such patients. However, in a number of case reports of individual patients with anaesthetic-induced malignant hyperthermia, intravenous or oral dantrolene has proven very effective in rapidly reversing the clinical symptoms (hyperthermia, muscle rigidity, arrhythmias, tachycardia, hypercapnia, altered blood pressure) and biochemical abnormalities (metabolic acidosis, myoglobinuria, increased serum creatine kinase levels). Dantrolene is also effective in preventing acute malignant hyperthermia in predisposed individuals when given prophylactically before surgery, although often some postoperative dantrolene therapy may be required. Failure of dantrolene to prevent the often fatal consequences of malignant hyperthermia is usually due to late diagnosis and therapy. Dantrolene has similarly proven invaluable in reversing the similar signs and symptoms in several cases of the neuroleptic malignant syndrome and a few cases of heat stroke. In many patients with disorders of muscle spasticity, dantrolene is effective in reducing muscle tone, clonus, muscle cramps and spasms, and improving stretch and tendon reflexes, neurological and motor function, and urinary control. However, not all patients respond to dantrolene and with prolonged therapy diminished muscle strength is commonly seen. Patients with spasticity due to muscular dystrophy, cerebral palsy and spinal cord injury (hemiplegia, paraplegia, quadriplegia) tend to respond better than patients with multiple sclerosis. Similarly, those with rigid paralysis show greater benefits from dantrolene therapy than those with flaccid paralysis. Side Effects: The side effect profile of dantrolene is primarily of concern in those patients treated over long periods for muscle spasticity. In these patients muscular weakness, drowsiness/dizziness and general malaise commonly occur with gastrointestinal disturbances being less frequently seen. Some adverse effects may disappear with continued therapy. Other more serious adverse reactions have occasionally been attributed to dantrolene, of which drug-induced hepatic dysysfunction after long term therapy gives rise to the most concern. Dosage and Administration: Intravenous dantrolene 1 mg/kg should be considered the minimum initial dose in cases of malignant hyperthermic or neuroleptic malignant syndrome, with continued administration until symptoms subside or a maximum cumulative dose of 10 mg/kg is reached. Reappearance of symptoms should be treated similarly, or subsequent to intravenous therapy oral administration of dantrolene 4 to 8 mg/kg/day for 1 to 3 days given to prevent recurrence. Prophylactic oral dantrolene 4 to 8 mg/kg for 1 to 2 days prior to surgery may prevent malignant hyperthermia in known susceptible individuals although it is becoming more accepted to administer intravenous dantrolene 2.5 mg/kg prior to anaesthesia. In the prevention of spasticity and related neuromuscular deficit, oral dantrolene should be titrated according to individual response and tolerance within the range of 25mg once daily to 100mg 4 times daily. In children the range is 0.5 mg/kg twice daily to 3 mg/kg 4 times daily.