Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dantrolene sodium or dantrolene1 is 1([5-(nitrophenyl)furfurylidend] amino) hydantoin sodium hydrate. It is indicated for use in chronic disorders characterised by skeletal muscle spasticity, such as spinal cord injury, stroke, cerebral palsy and multiple sclerosis. Dantrolene is believed to act directly on the contractile mechanism of skeletal muscle to decrease the force of contraction in the absence of any demonstrated effects on neural pathways, on the neuromuscular junction, or on the excitable properties of the muscle fibre membranes. Controlled trials have demonstrated that dantrolene is superior to placebo in adults or children with spasticity from various causes, as evidenced by clinical assessments of disability and daily activities, and by muscle and reflex responses to mechanical and electrical stimulation. It is somewhat less effective in patients with multiple sclerosis than in those with spasticity from other causes. There has been a general clinical impression in controlled trials that dantrolene caused less sedation than would have been expected from therapeutically comparable doses of diazepam. In 2 controlled trials, there was no significant difference between dantrolene and diazepam in terms of reductions in spasticity, clonus, and hyperreflexia, but side-effects such as drowsiness and inco-ordination occurred significantly more frequently on diazepam. Long-term studies have indicated continuing benefit for patients taking dantrolene, though the incidence of side-effects has often been high and there has been a suggestion of exacerbation of seizures in children with cerebral palsy. Dantrolene may be of value in the medical treatment of spasm of the external urethral sphincter due to neurological and non-neurological disease, and animal studies suggest a potential use in the management of malignant hyperpyrexia. Chemical evidence of liver dysfunction may occur in 0.7 to 1% of patients on long-term treatment with dantrolene, with symptomatic hepatitis in 0.35 to 0.5% and fatal hepatitis in 0.1 to 0.2%. The drug commonly causes transient drowsiness, dizziness, weakness, general malaise, fatigue and diarrhoea at the start of therapy. Muscle weakness may be the principal limiting side-effect in ambulant patients, particularly in those with multiple sclerosis, and therapy could be hazardous in patients with pre-existing bulbar or respiratory weakness. The dosage of dantrolene has been fixed in most controlled trials, though long-term studies have indicated the need for individualisation of dosage. The initial dose is usually 25mg once daily, increasing to 25mg two, three or four times daily, and then by increments of 25mg up to as high as 100mg two, three or four times daily. The lowest dose compatible with optimal response is recommended.
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PMID:Dantrolene sodium: a review of its pharmacological properties and therapeutic efficacy in spasticity. 31 89

Dantrolene, a direct acting muscle relaxant used orally for spasticity, has appeared to be effective in the prevention and treatment of malignant hyperthermia in man and animals when administered intravenously. Its pharmacokinetics following intravenous administration have been studied in dogs. Concentrations of dantrolene and its metabolites in plasma, urine, and bile were determined by high-performance liquid chromatography. Recovery of unchanged drug and reduced metabolites was negligible; of the hydroxy metabolite 2% was found in the urine and about 25% in the bile. The half-life of 5-hydroxydantrolene was shorter than that of the parent drug as demonstrated by administration of the metabolite. The apparent renal clearance of 5-hydroxydantrolene was independent of creatinine clearance, urine flow and pH, and appeared to be reduced in the presence of probenecid. Bile to plasma ratios of the hydroxy metabolite were high with biliary concentrations far exceeding the maximum solubility in water. The results of this pilot study indicate that hydroxylation is primarily responsible for the excretion of the dantrolene molecule from the body.
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PMID:Pharmacokinetics of intravenously administered dantrolene and its 5-hydroxy metabolite in dogs. 207 79

Dantrolene sodium is a drug used in the treatment of spasticity and malignant hyperthermia. It is known to have a myorelaxant effect related to inhibition of the "release" of calcium by the sarcoplasmic reticulum of striated skeletal muscle. A direct cardiac effect which has only recently been suspected was demonstrated in vitro on isolated preparations of sheep Purkinje fibres and ventricular myocardium. Dantrolene caused a spectacular lengthening of the duration of the action potential of Purkinje fibres. This could be due either to an action on the slow calcium current or to stimulation of an ingoing sodium current sensitive to tetrodotoxin (TTX). This effect on the cardiac action potentials could explain the antiarrhythmic properties of dantrolene sodium during attacks of malignant hyperthermia.
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PMID:[In vitro electrophysiological effects of sodium dantrolene on isolated preparations of Purkinje fibers and ventricular myocardium of sheep]. 242 77

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.
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PMID:Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity. 352 59

A 29-year-old man with C6 tetraplegia (ASIA A) using an implanted baclofen pump and intrathecal catheter infusion system for spasticity control developed severe spasticity, hyperthermia, hypotension, rhabdomyolysis, and disseminated intravascular coagulation after catheter disconnection. Tracheal intubation and mechanical ventilation were necessary. Extensive workup for a concurrent infection was negative except for urine cultures. The patient remained febrile for 10 days despite empirical antibiotic trials. Administration of high-dose benzodiazepines was inadequate for spasticity control. Spasticity control and his clinical condition, including body temperature, did not improve until his catheter was surgically replaced and intrathecal baclofen administration was resumed. The pharmacopathology of abrupt baclofen withdrawal and the similarities between this presentation, sepsis, neuroleptic malignant syndrome, and malignant hyperthermia are discussed. High-dose dantrolene was not used; however, based on similarities between this patient's presentation and neuroleptic malignant syndrome, it may have been the drug of choice.
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PMID:Hyperthermia, rhabdomyolysis, and disseminated intravascular coagulation associated with baclofen pump catheter failure. 952 93

Malignant hyperthermia (MH) is a genetic, potentially life-threatening disorder of the skeletal muscle presenting during or following general anaesthesia. Trigger agents are volatile anaesthetics and depolarising muscle relaxants. Dantrolene is the only available drug for effective and specific MH therapy, which reduces significantly the mortality rate. Dantrolene is a skeletal muscle relaxant that depresses the excitation-contraction coupling,however, the specificity of action remains unknown. Recent studies identified the ryanodine receptor, the calcium release channel of the sarcoplasmic reticulum, as the direct molecular target of dantrolene. In addition to its use for MH, dantrolene is used in other disorders such as neuroleptic malignant syndrome and spasticity. Since dantrolene is weakly water soluble, the clinical preparation is time and manpower consuming. New agents have been synthesized, but because of economic considerations no registration for clinical usage has been realised.
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PMID:[Dantrolene. Pharmacological and therapeutic aspects]. 1266 6

Baclofen (Lioresal) is a drug of choice to treat spasticity and is increasingly being administered intrathecally via an implantable pump in cases refractory to oral therapy. Emergency physicians will likely treat patients with baclofen withdrawal or overdose as this treatment becomes more widespread. The syndrome of baclofen withdrawal presents with altered mental status, fever, tachycardia, hypertension or hypotension, seizures, and rebound spasticity, and may be fatal if not treated appropriately. Baclofen withdrawal may mimic other diseases including sepsis, meningitis, autonomic dysreflexia, malignant hyperthermia, or neuroleptic malignant syndrome. Treatment consists of supportive care, reinstitution of baclofen, benzodiazepines, and diagnosis and eventual repair of intrathecal pump and catheter malfunction.
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PMID:Intrathecal baclofen withdrawal mimicking sepsis. 1274 45

Human malignant hyperthermia is a life-threatening genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking drugs occurring during or after anaesthesia. The skeletal muscle relaxant dantrolene is the only currently available drug for specific and effective therapy of this syndrome in man. After its introduction, the mortality of malignant hyperthermia decreased from 80% in the 1960s to < 10% today. It was soon discovered that dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. However, its precise mechanism of action and its molecular targets are still incompletely known. Recent studies have identified the ryanodine receptor as a dantrolene-binding site. A direct or indirect inhibition of the ryanodine receptor, the major calcium release channel of the skeletal muscle sarcoplasmic reticulum, is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration. Dantrolene is not only used for the treatment of malignant hyperthermia, but also in the management of neuroleptic malignant syndrome, spasticity and Ecstasy intoxication. The main disadvantage of dantrolene is its poor water solubility, and hence difficulties are experienced in rapidly preparing intravenous solutions in emergency situations. Due to economic considerations, no other similar drugs have been introduced into routine clinical practice.
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PMID:Dantrolene--a review of its pharmacology, therapeutic use and new developments. 1547 27

Dantrolene is the drug of choice for the treatment of malignant hyperthermia (MH) and is also useful for treatment of spasticity or muscle spasms associated with several clinical conditions. The current study examines the mechanisms of dantrolene's action on skeletal muscle and shows that one of dantrolene's mechanisms of action is to block excitation-coupled calcium entry (ECCE) in both adult mouse flexor digitorum brevis fibers and primary myotubes. A second important new finding is that myotubes isolated from mice heterozygous and homozygous for the ryanodine receptor type 1 R163C MH susceptibility mutation show significantly enhanced ECCE rates that could be restored to those measured in wild-type cells after exposure to clinical concentrations of dantrolene. We propose that this gain of ECCE function is an important etiological component of MH susceptibility and possibly contributes to the fulminant MH episode. The inhibitory potency of dantrolene on ECCE found in wild-type and MH-susceptible muscle is consistent with the drug's clinical potency for reversing the MH syndrome and is incomplete as predicted by its efficacy as a muscle relaxant.
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PMID:Enhanced excitation-coupled calcium entry in myotubes expressing malignant hyperthermia mutation R163C is attenuated by dantrolene. 1817 28

Intrathecal baclofen (ITB) is increasingly being used to reduce spasticity among children with cerebral palsy, dystonia, and spinal cord injuries. However, complications such as withdrawal, which is a potentially life-threatening condition, can occur. Intrathecal baclofen withdrawal should be differentiated with autonomic dysreflexia, malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome. We report a case of ITB withdrawal secondary to low residual volume in the pump reservoir and resembling serotonin syndrome in an adolescent with cerebral palsy. He presented with agitation, diaphoresis, increasing spasticity, rigidity, jitteriness, hyperreflexia, clonus, tachycardia, hypertension, and rhabdomyolysis. Treatment consisted of emergent refilling of the pump, intravenous diazepam, and oral cyproheptadine. We also emphasize the importance of prompt recognition of ITB withdrawal among high-risk patients.
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PMID:Intrathecal baclofen withdrawal resembling serotonin syndrome in an adolescent boy with cerebral palsy. 1924 Jun 73


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