Myopathy, drug-related

Vahyil, R. and L. Christopher-Stine (2010). Drug-related myopathies of which the clinician should be aware. Curr Rheumatol Rep 12(3) 213-220. 

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

In a placebo-controlled study of 1142 hypercholestero-lemic patients treated with pravastatin for 8-16 weeks, the numbers of adverse drug experiences were similar in the treated and untreated individuals (1). Rash was the only adverse clinical event that was different (4.0 versus 1.1%). However, in the same patients withdrawal of therapy during follow-up was thought to be necessary in 3.2% of those given pravastatin alone. Myopathy was observed in one instance only, and increases in creatine kinase activity in those taking pravastatin did not differ significantly from controls. There were marked persistent increases in transaminases in 1.1%, with no cases of symptomatic hepatitis. Pravastatin is believed to have a particularly low potential for nervous system-related adverse effects, as it has not been shown to enter the cerebrospinal fluid, and clinical experience suggests that muscle toxicity occurs less often with pravastatin than with lovastatin (2). 

Considerable neuromuscular involvement also occurs in patients with AIDS.47 100 Peripheral neuropathies, myopathies, and various CNS manifestations (dementia, other psychological manifestations) can occur directly from HIV infection or secondarily, due to some other opportunistic infection.31 85 100 Likewise, peripheral neuropathies are a common side effect of certain anti-HIV drugs (didanosine, stavudine, zal-citabine), and myopathies are a side effect of zidovudine therapy.63 Patients with HIV disease often have painful symptoms such as joint pain, back pain, and pain related to neuropathies and myopathies.100 Hence, HIV disease can often be regarded as a degenerative neuromuscular disorder from the standpoint of a rehabilitation professional. Therapists can therefore help improve function and decrease pain in patients with HIV infection and AIDS.1 33... 

All the statins have been variously implicated in muscle-related adverse drug reactions such as myalgia, myopathy and rhabdomyolysis, which are thought to occur as a direct effect of HMG GoA-reductase inhibition in a dose-dependent marmer [30]. There have been fatalities. If patients have increased exposure to a drug due to a reduction in first-pass or subsequent metabolism by hepatocytes, these adverse effects are more likely to occur. 

Since HMG CoA reductase inhibitors (statins) are partially or completely metabolized by CYP3A4, drug interactions with protease inhibitors can be expected. When nelfinavir was combined with atorvastatin and simvastatin, their AUCs increased by 74 and 505% respectively (17). As myopathy and rhabdomyolysis are concentration-related, simvastatin is contraindicated with any protease inhibitor, not just nelfinavir. Based on the data, the starting dose of atorvastatin should be reduced by about 50%. 

Huynh T, Cordato D, Yang F, Choy T, Johnstone K, Bagnall F, Hitchens N, Dunn R. HMG CoA reductase-inhibitor-related myopathy and the influence of drug interactions. Intern Med J 2002 32(9-10) 486-90. 

The lactic acidosis seen with these drugs has ranged from mild and chronic to acute, severe, and fatal [95-106]. The acidosis generally develops after several months of therapy. Patients with NRTl-associated lactic acidosis present with symptoms of nausea, vomiting and abdominal pain. Other features often include elevated liver enzymes, hepatic steatosis, pancreatitis and elevated creatinine kinase with evidence of a myopathy, and liver failure. The lactic acidosis may persist for many weeks despite discontinuation of the NRTl [95-106]. NRTl-related mitochondrial toxicity may also present with rhabdomyolysis and acute kidney failure [110]. Mortality related to NRTl-induced acute lactic acidosis is high, in the range of 50% to 100%, despite drug discontinuation. 

Vonderfecht, S. L., M. L. Stone., R. R. Eversole, M. F. Yancey, M. R. Schuette, B. A. Duncan, and J. A. Ware. 2004. Myopathy related to administration of a cationic amphiphilic drug and use of multidose drug distribution analysis to predict occurrence. Toxicologic Pathology 32 318-325. 

Irreversible retinopathy and ototoxicity can result from high daily doses (>250 mg) of chloro-quine or hydroxychloroquine that lead to cumulative total doses of more than 1 g of base per kilogram body weight, such as those used for treatment of diseases other than malaria. Retinopathy can be avoided if the daily dose is 50 mg. Prolonged therapy with high doses of 4-aminoquinoline also can cause toxic myopathy, cardiopathy, and peripheral neuropathy these reactions improve if the drug is withdrawn promptly. Rarely, neuropsychiatric disturbances, including suicide, may be related to overdose. 

One of the ways blood statin levels can become elevated is if the interacting drug inhibits the metabolism of the statin, with the result that it is cleared from the body more slowly and it begins to accumulate (see pharmacokinetics below). The overall risk of myopathy with the statins is quite low and commonly quoted as 0.5%, although one report puts the incidence of mild myopathies with a statin alone as up to 7%. The incidence seems to rise markedly if other drugs are being taken concurrently. Thus a literature review of published reports for the period 1985 to 2000 found 15 cases of rhabdomyolysis with statins alone, but 54 cases when combined with other drugs. Other patient-related risk factors for myopathy in-clude ... 

Background It is well known that hypercholesterolemia is a major risk factor in the progression of atherosclerosis, the major cause of cardiovascular diseases. Statins are widely used to treat hypercholesterolemia. The mechanism of action of these drugs is to reduce the endogenous production of cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase. Atorvastatin (ATV, Lipitor) is one of the top-selling prescribed oral medications. The only known adverse effect is skeletal muscle toxicity (myopathy) that may be related to the formation of the lactone of the acidic side chain on the molecule. 

The method was applied in a clinical stndy to quantify ATV and its metabolites over a 12 h post-dosing period in blood samples from kidney transplant patients receiving ATV and immunosuppressive drugs (Table 4.1). The main nse of the technique is the (previously unattainable) simultaneous determination of the concentrations of the parent drug and all its primary metabolites for pharmacokinetic studies. Although the mechanism of ATV-related myopathy is not known, the lactone-to-parent concentration ratio may have utility as a diagnostic marker. 

---