Hepatitis dantrolene

The skeletal muscle relaxants are contraindicated in patients with known hypersensitivity. Baclofen is contraindicated in skeletal muscle spasms caused by rheumatic disorders. Carisoprodol is contraindicated in patients with a known hypersensitivity to meprobamate. Cyclobenzaprine is contraindicated in patients with a recent myocardial infarction, cardiac conduction disorders, and hyperthyroidism, hi addition, cyclobenzaprine is contraindicated within 14 days of the administration of a monoamine oxidase inhibitor. Oral dantrolene is contraindicated in patients with active hepatic disease and muscle spasm caused by rheumatic disorders and during lactation. See Chapter 30 for information on diazepam. 

Chronic use of neuroleptics can, on occasion, give rise to hepatic damage associated with cholestasis. A very rare, but dramatic, adverse effect is the malignant neuroleptic syndrome (skeletal muscle rigidity, hyperthermia, stupor) that can end fatally in the absence of intensive countermeasures (including treatment with dantrolene, p. 182). 

Metabolism - Dantrolene is found in measurable amounts in blood and urine. Mean half-life in adults is 9 hours after a 100 mg oral dose and 4 to 8 hours after IV administration. Because it is probably metabolized by hepatic microsomal enzymes, metabolism enhancement by other drugs is possible. 

If symptoms of hepatitis accompanied by liver function test abnormalities or jaundice appear, discontinue therapy. If caused by dantrolene and detected early, abnormalities may revert to normal when the drug is discontinued. See Warning Box. 

The most prominent and often limiting feature of dantrolene administration is dose-dependent muscle weakness. Other side effects are drowsiness, dizziness, malaise, fatigue, and diarrhea. Symptomatic hepatitis is reported in 0.5% of patients receiving it and fatal hepatitis in up to 0.2%. Contraindications include respiratory muscle weakness and liver disease. It is suggested that patients on dantrolene therapy be given regular liver function tests. 

Treatment with dantrolene is usually initiated with 25 mg daily as a single dose, increasing to a maximum of 100 mg four times daily as tolerated. Only about one third of an oral dose of dantrolene is absorbed, and the elimination half-life of the drug is approximately 8 hours. Major adverse effects are generalized muscle weakness, sedation, and occasionally hepatitis. 

Most muscle relaxants are absorbed fairly easily from the gastrointestinal tract, and the oral route is the most frequent method of drug administration. In cases of severe spasms, certain drugs such as methocarbamol and orphenadrine can be injected intramuscularly or intravenously to permit a more rapid effect. Likewise, diazepam and dantrolene can be injected to treat spasticity if the situation warrants a faster onset. As discussed earlier, continuous intrathecal baclofen administration may be used in certain patients with severe spasticity, and local injection of botulinum toxin is a possible strategy for treating focal dystonias and spasticity. Metabolism of muscle relaxants is usually accomplished by hepatic microsomal enzymes and the metabolite or intact drug is excreted through the kidneys. 

Once mobilized, a large proportion of the cytosolic calcium load is extruded from the cell across the plasma membrane. This extrusion can be demonstrated by measuring the efflux of radiocalcium from previously labeled cells. All stimulation of adrenal, hepatic and vascular smooth muscle cells preloaded with radioactive calcium induces a marked increase in efflux of the radiolabel. This increased efflux is transient, peaking between 4 and 5 minutes after All addition and is observed in the absence of extracellular calcium [39]. Furthermore, under conditions of zero calcium, treatment of cells with dantrolene prior to hormonal stimulation abolishes the All-induced calcium efflux [40], confirming that the radiocalcium lost from the cell is mobilized from a component of the ER. 

Tenamfetamine ( ecstasy, MDMA methylenedioxymethamphetamine) is structurally related to mescaline as well as to amphetamine. It was originally patented in 1914 as an appetite suppressant and has recently achieved widespread popularity as a dance drug at rave parties (where it is deemed necessary to keep pace with the beat and duration of the music popular names reflect the appearance of the tablets and capsules and include White Dove, White Burger, Red and Black, Denis the Menace). Tenamfetamine stimulates central and peripheral a-and p-adrenoceptors thus the pharmacological effects are compounded by those of physical exertion, dehydration and heat. In susceptible individuals (poor metabolisers who exhibit the CYP450 2D6 polymorphism) a severe and fatal idiosyncratic reaction may occur with fulminant hyperthermia, convulsioirs, disseminated intravascular coagulation, rhabdomyolysis, and acute renal and hepatic failure. Treatment includes activated charcoal, diazepam for convulsions, P-blockade (atenolol) for tachycardia, a-blockade (phentolamine) for hypertension, and dantrolene if the rectal temperature exceeds 39°C. 

Chronic active hepatitis may develop with prolonged use of methyldopa, isoniazid, dantrolene and nitrofurantoin. 

Utih R, Boitnott JK, Zimmerman HJ. Dantrolene-associated hepatic injury. Incidence and character. Gastroenterology 1977 72(4 Pt 1) 610-16. 

Dantrolene, isoniazid, phenytoin, nitrofurantoin, and trazodone have been reported in association with a type of autoimmune-mediated disease in the liver. Patients experience periods of symptomatic hepatitis followed by periods of convalescence, only to repeat the experience months later. It is a progressive disease with a high mortality rate and is more common in females than males. Antinuclear antibodies appear in most patients. These drugs appear to form... 

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. 

The reported side effects of dantrolene are drowsiness, dizziness, weakness, hepatitis, constipation, increased nri-nary freqnency, crystalluria, seizures, visual disturbances, prnritis, nrticaria, acne, and skin eruption. 

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. 

---