Indian Journal of Rheumatology

REVIEW ARTICLE
Year
: 2019  |  Volume : 14  |  Issue : 5  |  Page : 27--36

Drug-induced myopathy


Manesh Manoj, Rasmi Ranjan Sahoo, Kasturi Hazarika, Prashant Bafna, Anupam Wakhlu 
 Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India

Correspondence Address:
Dr. Rasmi Ranjan Sahoo
and Rheumatology, King George's Medical University, Lucknow - 226 018, Uttar Pradesh
India

Abstract

A number of medications, including very commonly used ones, have been described as causing myopathy. Drug-induced myopathy is defined as an acute or subacute adverse effect of a drug on the muscular system, which may range from asymptomatic increase in serum creatine kinase and simple myalgias to life-threatening rhabdomyolysis. It is necessary for the treating physician to recognize these manifestations early and manage promptly; in order to prevent treatment-related morbidity and mortality. A PubMed search was conducted using the MeSH terms “drug AND myopathy” and “drug AND rhabdomyolysis.” The consensus of the authors was sought to finalize a group of 60 articles for further review. With the large number of drugs available to the treating physician today, and the significant drug interactions that can occur, knowledge about the various drugs causing myopathy, their characteristic features if any, and the optimal management of these adverse effects is imperative.



How to cite this article:
Manoj M, Sahoo RR, Hazarika K, Bafna P, Wakhlu A. Drug-induced myopathy.Indian J Rheumatol 2019;14:27-36


How to cite this URL:
Manoj M, Sahoo RR, Hazarika K, Bafna P, Wakhlu A. Drug-induced myopathy. Indian J Rheumatol [serial online] 2019 [cited 2020 Aug 3 ];14:27-36
Available from: http://www.indianjrheumatol.com/text.asp?2019/14/5/27/272157


Full Text



 Introduction



Drug-induced myopathies are probably one of the most common causes of myopathy, and are potentially reversible, if detected early. They encompass a broad spectrum of clinical manifestations ranging from trivial muscle aches to life-threatening rhabdomyolysis with associated renal failure. A number of drugs have been consistently shown to cause muscle damage and several other drugs have been implicated in case reports. Knowledge of the various drugs causing myopathy and their pathological mechanisms may enable clinicians to reduce treatment-related morbidity and mortality. This review aims to analyze the various drugs causing myopathy, their characteristic features, and their specific management, if any, with a focus on commonly used drugs, especially in the specialty of rheumatology.

Muscles comprise one of the largest organ systems of the body. It may be broadly divided into striated (skeletal) muscle and smooth muscle depending on their structure and function. Drug-induced myopathy affects striated muscles. There are two major striated muscle fiber types – type 1 (“slow twitch,” oxidative metabolism, more lipids, and mitochondria) and type 2 (“fast twitch,” glycogen for energy) fibers. Type 2 fibers are further subdivided according to cellular characteristics into 2A, 2B, and 2X fibers. Certain muscle fibers may be preferentially involved with some drugs, such as type 2 fiber involvement with glucocorticoids (GCs). A detailed review of striated muscle physiology and structure is indexed for interested readers.[1],[2],[3]

 Search Strategy



PubMed engine was used to search for articles with the MeSH terms “drug AND myopathy” and “drug AND rhabdomyolysis.” About 300 articles were initially selected, of which mainly review articles and case-based review articles were selected for further analysis. Articles on focal myopathy were not considered. Articles selected were those published in the English language and recent literature was preferred. With the consensus of the authors, about 60 articles were selected and the references in each article were also reviewed where necessary.

 Pathophysiology



Drugs can affect the muscle through a number of pathophysiological mechanisms. Certain drugs act through more than one pathway, and a few drugs can cause both immunologically and nonimmunologically mediated muscle damage and can produce a varied spectrum of presentations such as that seen with the ubiquitous statins.[4] Any drug given parenterally, especially into the muscle can cause a focal type of myopathy which is nonspecific or a local reaction and will not be delved into further in this review (e.g. Nicolau syndrome;[5] fibrotic reaction with pentazocine abuse,[6] etc). According to the major mechanism of muscle damage, drugs can be grouped as shown in [Table 1].[7]{Table 1}

Most review articles focused on the above mentioned or similar pathophysiological classifications while describing these drugs. In this review, we attempt to describe the drugs according to the clinical situations in which they are used and seek to examine all the varied mechanisms of muscle injury by a particular drug together as we feel that would be more relevant in a clinical scenario. [Table 2] describes the various drugs causing myopathy according to the clinical situation where they are usually used.{Table 2}

 Drugs Used in Rheumatology



Glucocorticoids

GCs are extensively used in rheumatological and immunological disorders and in a number of other specialties and are associated with a characteristic myopathy, especially in higher doses. This myopathic effect has been seen to be more prevalent among the older age groups and those in a severe catabolic state such as malignancy.[8] A similar presentation may be seen in Cushing's disease.[9]

Pathogenesis

GCs are known to have a catabolic effect on muscle.[10] They suppress insulin-like growth factor 1 and Akt-1 (intracellular signaling molecule with protein kinase activity) which in turn increases levels of ATROGIN-1 which is a ubiquitin ligase leading to myocyte protein degradation.[11],[12] GCs also downregulate the transcription factor myogenin, leading to decreased myogenesis along with increased levels of myostatin.[13] Mitochondrial dysfunction has also been shown in the affected muscle.

Clinical features and diagnosis

A gradual-onset, slowly progressive, proximal muscle weakness is seen and may develop weeks to months after initiation of treatment. There is no myalgia or muscle tenderness. Rarely, in patients in a catabolic state, especially with malignancies, respiratory muscle involvement has also been described.[14] Even a single dose of steroid has been seen to precipitate myopathy.[15] Low doses (≤10 mg/day prednisolone equivalent) are rarely associated with myopathy, which is usually seen in doses ranging from 40 to 60 mg/day. Inhaled GCs (in higher doses) can rarely be associated with myopathy.[16] Fluorinated compounds such as dexamethasone and triamcinolone are considered to have a higher risk of myopathy.[8],[17]

Serum creatine kinase (CK) is characteristically normal and electromyography (EMG) may either be normal or reveal only subtle myopathic changes. Muscle biopsy shows a preferential atrophy of the fast twitch, glycolytic type 2B fibers, which are not detected by routine EMG using low level of effort.[8] There is no inflammation or necrosis of fibers. A reduction in dose, if possible, can differentiate between drug effect and disease activity in inflammatory myositis, as the latter will worsen after dose reduction.

Treatment

Recovery starts after cessation or significant reduction in dose (to ≤10 mg/day prednisolone equivalent) but may take 2 to 4 weeks. The appropriate and timely use of steroid-sparing agents can avoid this complication. There is complete resolution after cessation of steroids,[18] though irreversible fatty replacement of atrophied muscle with consequent residual weakness can occur.

Other mechanisms of glucocorticoid muscle damage

Critical illness myopathy

Usually seen in intensive care unit (ICU) patients in whom high-dose GCs are used, usually with concurrent use of neuromuscular blocking agents (especially for mechanical ventilation). They present with severe proximal and distal muscle weakness with raised muscle enzymes and a myopathic EMG. Biopsy shows myopathy with loss of myosin. Patients usually recover after cessation of steroid use, but the major issue is the prolonged ICU stay required in these clinical situations.[19],[20]

Hypokalemic myopathy

GCs can cause electrolyte imbalances, especially hypokalemia which, in turn, can cause a myopathy by muscle cell membrane hyperpolarization and secondary excessive permeability to sodium. Hence, close monitoring of electrolytes during treatment with steroids is warranted.

Colchicine

Colchicine has been used as the cornerstone of therapy in crystal arthritides, especially gout, and is also used in Behçet's syndrome, IgA vasculitis, familial fever syndromes, etc.

Pathogenesis

The drug affects microtubules and alters the myocyte cytoskeletal framework. There is lysosomal dysfunction leading to muscle damage. A similar mechanism is thought to play in the associated neuropathy.

Clinical features and diagnosis

It is associated with a lower limb predominant, insidious, proximal muscle weakness in patients on a therapeutic dose for several years. The affected individuals are usually >50 years, have a deranged renal function or are prescribed CYP3A4 enzyme inhibitors concurrently.[21] There is usually an associated neuropathy as well.[22] Acute-onset myopathy has also been described, especially with overdose. CK is elevated and EMG and nerve conduction studies (NCS) show both myopathy and an axonal polyneuropathy.[22] Myotonic discharges may occasionally be seen. Muscle biopsy reveals vacuolar changes of lysosomal origin and there is predominant Type 1 fiber involvement.[23]

Management

Discontinuation of treatment usually leads to a slow (days to weeks) resolution of myopathy, but neuropathy recovers even more slowly.[22] Adequate care regarding appropriate dosage reduction in renal dysfunction and the avoidance of concurrent CYP3A4 inhibitors can reduce the incidence of myopathy.

Antimalarials

Antimalarials used in rheumatology include chloroquine and hydroxychloroquine. The antimalarials have been considered under drugs used in rheumatology rather than for infectious disease as myopathy is usually associated with long-term usage, which rarely can occur with long-term malaria prophylaxis. Antimalarials have been reported to cause myopathy, neuropathy, and even cardiomyopathy.[24]

Pathogenesis

These group of drugs have an amphiphilic structure, and hence, they interact with the anionic phospholipids of cell membranes and organelles leading to formation of complexes which cannot be digested easily by lysosomes and these accumulate, forming the characteristic myeloid and curvilinear bodies seen on biopsy.[24]

Clinical features and diagnosis

Patients present with a slowly progressive, mild, painless, proximal muscle weakness which is associated with normal or mildly elevated CK levels. Duration of drug intake is usually several years, but rare case reports of myopathy occurring within the 1st year of usage have been reported.[24] EMG and NCS may reveal both myopathy and an axonal polyneuropathy. Myotonic discharges may be seen. Muscle biopsy shows the characteristic autophagic vacuoles with a preferential involvement of type 1 fibers. These vacuoles reveal the presence of myeloid and curvilinear bodies on electron microscopy (EM).[25] Hydroxychloroquine tends to cause a less severe myopathy and the histological features are less prominent.

A characteristic cardiomyopathy may be rarely associated with long-term usage of these drugs and is associated with conduction system abnormalities or congestive cardiac failure and even death. Echocardiography and cardiac magnetic resonance imaging (MRI) reveals restrictive cardiomyopathy.[26] Biopsy shows features similar to skeletal muscle.

Management

Resolution occurs very slowly but completely with discontinuation of the drug (weeks to months) but rarely the myopathy, especially cardiomyopathy, may progress inexorably leading to death.[27] The dosages recommended for ophthalmological safety have not been proven to prevent myopathy but maintaining such a dosage ceiling may reduce the long-term adverse effects of these agents.

Tumor Necrosis Factor Inhibitors

Tumor necrosis factor inhibitors (TNFi) have revolutionized the management of a number of rheumatological disorders, but there is increasing evidence of a number of autoimmune diseases as side effects. These agents have been rarely shown to be associated with an immunologically mediated myopathy with features similar to dermatomyositis (DM) and polymyositis (PM).

Pathogenesis

According to the cytokine-shift hypothesis, TNFi changes the cytokine profile to one where type 1 interferons (IFNs) production is increased. Type 1 IFNs are implicated in the pathogenesis of inflammatory myopathies. TNFi possibly disrupt the normal apoptotic process leading to the incomplete clearance of apoptotic bodies and hence de novo autoantibody formation.[28] TNFi associated myopathy has been seen to occur in RA patients with ANA (antinuclear antibodies) and myositis-specific antibodies (MSA) positivity, especially anti-Jo1.[29]

Clinical features and diagnosis

Patients may present with classic features of DM or PM with symmetrical proximal muscle weakness and the associated characteristic rash in case of DM. Most occurred during treatment of rheumatoid arthritis.[30] Some also developed an associated interstitial lung disease.[28] These occurred 2 weeks to 2 years after initiating treatment with TNFi.[28] Raised CK levels are the norm.

Management

Withdrawal of TNFi is necessary. Most cases require additional immunosuppression with high dose steroids and steroid-sparing agents such as methotrexate, azathioprine, or mycophenolate mofetil. Some refractory cases may need intravenous immune globulin (IVIG) or rituximab (RTX).[31]

Calcineurin Inhibitors

Cyclosporine (CsA) and tacrolimus (TAC) are increasingly being used for rheumatological disorders at doses lower than that used in transplant patients.

Pathogenesis

These agents cause myocyte degeneration by destabilizing the lipophilic muscle membrane, attributed to their cholesterol-lowering effects. Mitochondrial and lysosomal dysfunction have also been postulated.[32] Calcineurin has also been postulated to play an important role in the growth of skeletal muscle.[33]

Clinical features and diagnosis

Myopathy is rare at doses used in rheumatological disorders, but concurrent use of other drugs that predispose to myopathies such as colchicine and statins increases the risk. TAC, on the other hand, has been associated with hypertrophic cardiomyopathy and congestive cardiac failure.[34] Generalized myalgias and proximal muscle weakness are seen to develop sometimes months after initiation of these agents. Rarely, rhabdomyolysis has also been reported with CsA. CK levels are usually elevated and EMG may show increased muscle fiber excitability and myotonic potentials. Biopsy reveals preferential type 2 fiber atrophy with scattered myocyte necrosis. CsA has also been associated with ragged-red fibers and lipid vacuoles due to mitochondrial and lysosomal dysfunction respectively.[32]

Management

Discontinuation of the drug usually reverses the myopathy including the cardiomyopathy over several months.

D-penicillamine

Autoimmune myasthenia gravis and inflammatory myopathy have been seen with D-penicillamine.[35],[36] Muscle biopsy may show perifascicular cellular infiltration as well as muscle fiber necrosis and regeneration.[36] High-dose GCs are usually required in moderate-to-severe cases which can be tapered slowly along with drug discontinuation. Myasthenia gravis may require cholinesterase inhibitors.[37]

Leflunomide has been associated with PM in one case report and is known to be associated with increased serum CK during treatment.[38]

 Drugs Used in Endocrinology and Metabolism



Statins

Statins have become ubiquitous in today's world as a lipid-lowering and cardioprotective agents. Adverse effects on muscle have been extensively researched. A spectrum of presentations from vague muscle aches to rhabdomyolysis (0.1% of treated patients)[39] and also an autoimmune myopathy has been described (statin-associated muscle symptoms [SAMS]).[40] Statins are characteristically associated with a necrotizing myopathy, which may be nonautoimmune or autoimmune (statin-associated necrotizing autoimmune myopathy [SANAM]). Even in asymptomatic patients on statin therapy, ultrastructural changes in the muscle have been described.[4] Risk of myopathy is lowest with fluvastatin and pitavastatin.[41],[42]

Pathogenesis

Nonautoimmune necrotizing myopathy

Statin myopathy may be related to polymorphisms in the cytochrome P450 genes. A recently discovered variant (rs4149056 with simvastatin) of the SLCO1B1 gene responsible for hepatic uptake of statins revealed the importance of variation in drug metabolism predisposing to myopathy.[43] Statins reduce the levels of coenzyme Q10 (CoQ10) in muscle and also alters the normal fatty acid metabolism in myocytes leading to muscle damage.[44] It also increases levels of ATROGIN1, which is involved in ubiquitination, leading to increased muscle protein degradation.[45]

Statin-associated necrotizing autoimmune myopathy

Statins can upregulate the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in muscle and other tissues[46] which could lead to aberrant processing by antigen processing cells and formation of autoantibodies. The formation of anti-HMGCR antibodies (seen in almost 60% of patients with SANAM) may have a direct pathogenic effect on muscle by complement-mediated immune injury.[47] Certain HLA Class 2 alleles (HLA-DRB1*11:01 and 07:01) are associated.

Clinical features and diagnosis

A gradual-onset, usually symmetrical, proximal muscle weakness occurring weeks to months after initiating statins is seen. In patients with mild symptoms, increased fatigue may be the only complaint.[4] Rhabdomyolysis usually is seen with concurrent administration of another drug with myopathic potential or cytochrome P450 enzyme inhibitors. Muscle biopsy reveals a macrophagic infiltrate with no inflammation, but with muscle fiber necrosis and increased MHC class 1 expression in nonautoimmune necrotizing myopathy.[48] In SANAM, an inflammatory infiltrate and the presence of anti-HMGCR antibodies (in about 60% patients) are characteristic. Increased risk of SAMS is associated with older age (<80 years), female sex, liver or renal dysfunction.[49] Inflammatory myopathy has also been described with statins.[50],[51]

Management

In mild cases, a lower dose or a change to a low potency statin may be sufficient. A clinical index “SAMS-CI” has been developed in order to stratify patients and to decide on further course of management, though it is yet to be clinically validated.[52],[53] Concurrent use of drugs with a myopathic potential or CYP3A4 inhibitors should be avoided or used with extreme caution. Nonautoimmune necrotizing myopathy usually resolves with discontinuation of statins within weeks to months, whereas SANAM may progress even after statins have been stopped and hence may require further immunosuppression with steroids and steroid-sparing agents as used for inflammatory myopathies.[47] Vitamin D deficiency and hypothyroidism are two important conditions that have to be addressed before starting statins. Treatment with CoQ10 is not supported by evidence.[40]

Other Lipid-Lowering Agents

A number of other lipid-lowering agents (niacin, ezetimibe, gemfibrozil, and fenofibrate) have been associated with myopathy in case reports, though in most of these cases, patients also received statins concurrently. Of these drugs, the fibrate derivative gemfibrozil has been associated with a number of cases of rhabdomyolysis when coadministered with statins, probably by interfering with statin metabolism and increasing serum drug levels.[54] Ezetimibe appears to be relatively safer when used with statins.[55]

Oral Hypoglycemic Agents

Metformin antagonizes the anabolic actions of mTOR (mammalian target of rapamycin) pathway through activation of AMP-activated protein kinase and this has been suggested to cause sarcopenia. Sulfonylurea use has been associated with induction of cell apoptosis in vivo and this is postulated to cause muscle atrophy in patients.[56] Pioglitazone has been associated with rhabdomyolysis in case reports.[57]

 Drugs Used in Infectious Diseases



Antiretroviral therapy

Long-term usage of nucleoside reverse transcriptase inhibitors (NRTIs) is associated with a characteristic mitochondrial toxicity and may lead to hepatic steatosis, myopathy, neuropathy, and lactic acidosis. Zidovudine is the prototypical drug of this group. Other present-day NRTIs have a lesser propensity for causing mitochondrial myopathy.

Pathogenesis

Zidovudine inhibits DNA polymerase gamma which is required for mitochondrial DNA (miDNA) replication. This leads to mitochondrial dysfunction, increased oxygen free-radical production, and decreased energy production.[58] This, in turn, is considered to cause myopathy.

Clinical features and diagnosis

Patients may present with myalgias and progressive proximal muscle weakness. CK levels are usually elevated but may be normal. A large increase in CK levels point toward HIV-associated PM rather than a drug-induced mitochondrial myopathy. Muscle biopsy reveals the characteristic ragged-red fibers on EM and swollen mitochondria with loss of normal cristae.[59] There is a lack of significant endomysial inflammatory infiltrate. Associated hepatic steatosis, neuropathy, or life-threatening lactic acidosis may be present. EMG may reveal myopathy even in patients with normal CK levels.

Management

Discontinuation of the drug usually results in resolution of the myopathy including histopathological changes.

Other drugs in this group implicated in causing drug-induced myopathy include telbivudine[60],[61] (asymptomatic increase in CK levels, nonautoimmune necrotizing myopathy), voriconazole[62] (case report of myositis), alpha-interferon[63],[64] (DM/PM, Autoimmune myasthenia gravis), and antitubercular therapy[65],[66] (isoniazid with rhabdomyolysis; pyrazinamide with proximal myopathy).

 Drugs Used in Oncology



Immune checkpoint inhibitors

These groups of drugs act by enhancing antitumor activity through modulation of T-cell pathways. Major drugs in this group include antibodies targeting cytotoxic T-lymphocyte associated antigen 4 ipilimumab, antibodies against the programmed cell death 1 (anti-PD1) which include nivolumab and pembrolizumab and anti-PD1 ligand agents atezolizumab, durvalumab, and avelumab. A number of agents are under investigation for multiple malignancies. These drugs have been associated with a number of immune-related adverse events (irAEs).[67],[68]

Pathogenesis

It is suggested that these drugs uncover a genetic predisposition to an autoimmune condition which was previously kept under check. Another suggested mechanism is by molecular mimicry wherein the newly formed antitumor antibodies cross-react with normal tissue antigens and cause autoimmune manifestations.[69]

Clinical manifestations

Myositis is a common irAE reported with immune checkpoint inhibitors (ICIs).[70],[71],[72] Patients present with features suggestive of an inflammatory myopathy or with necrotizing myopathy. It may be associated with severe generalized weakness within a few days of initiating treatment or may present as a gradually progressive proximal muscle weakness over several weeks usually in the first 2 months of treatment. Rhabdomyolysis and death have also been described. Respiratory muscle involvement may occur. CK levels are usually highly elevated. Important features of ICI induced myositis are the absence of extramuscular clinical manifestations, the absence of MSAs, and the muscle biopsy showing a characteristic pattern of inflammation and necrosis of muscle fibers with a focal clustering of the necrotic myofibers. Ocular myositis may also be seen. Fatal outcomes due to myocardial and diaphragmatic involvement have been reported.[73]

Another important irAE is immune-related myasthenia gravis (irMG) associated with acetylcholine receptor antibodies or antimuscle-specific kinase antibodies (lower titer than idiopathic MG) which occurs early during treatment.[74] Seronegative irMG can occur. Myasthenic crisis and respiratory weakness tend to be more common in ICI-induced MG.[75]

Management

ICI-induced myositis usually requires GCs as the first-line agents (0.5–1 mg/kg/day of prednisolone equivalent) along with discontinuation of ICIs.[74] Severe disease may require pulse methylprednisolone up to 1 g/day. Some patients may require treatment escalation with plasma exchange, RTX, cyclophosphamide, IVIG, methotrexate, or azathioprine.[76] The half-life of ICIs are long, hence steroids should be tapered over a period of 2–3 months. Rechallenge with the drug entails the risk of recurrence of myositis.[74]

irMG may be treated with acetylcholine-esterase inhibitors, GCs, and discontinuation of the drug. Treatment response may be only partial in a few cases, and in them, the prognosis is poor. Severe cases are usually associated with features of coexisting myositis.[74]

Radiotherapy

Radiotherapy can cause a myopathy termed radiation-induced myopathy.[77],[78] It is usually seen after RT exposure to a large area of the neck and torso and is usually associated with a history of Hodgkin's disease.[79] Head drop is a characteristic feature seen in many cases. It usually presents several years after the RT (range 2–45 years). CK is slightly elevated or maybe normal. Respiratory muscle involvement may occur. EMG may be difficult to interpret in truncal muscles but shows a myopathic pattern.[78] Muscle biopsy reveals a nonspecific pattern with scattered necrosis of muscle fibers, occasional ragged red fibers, and occasional nonspecific inflammatory infiltrates. GCs are used in management along with IVIG in severe cases, but response to treatment is unsatisfactory and prognosis poor.

Radiation Recall Phenomenon

It is defined as the occurrence of inflammation at sites which were previously exposed to radiation during subsequent chemotherapy.[80] The usual site of involvement is the skin,[81] but rarely, it may affect the muscle. Drugs that have been implicated include gemcitabine, taxanes, capecitabine, anthracyclines, 5-fluorouracil, oxaliplatin, cisplatin, and vinorelbine. It is most commonly associated with gemcitabine and is considered to be an idiosyncratic hypersensitivity reaction. Patients may present with myalgias and myositis with MRI findings of muscle inflammation and EMG showing myopathy.[82] Nonsteroidal anti-inflammatory drugs (NSAIDs) or GCs at moderate-to-high doses may control the symptoms, along with drug discontinuation. Rechallenge after symptoms and signs have resolved does not usually cause a recurrence.[83]

Other Chemotherapeutic Agents

Other drugs in this class implicated in inducing myopathy include vincristine[7],[84] (proximal myopathy by disrupting microtubular function), imatinib mesylate[85] (myalgias, PM), docetaxel, and gemcitabine[86] (inflammatory myopathy with mitochondrial dysfunction).

 Drugs Used in Cardiology



Amiodarone

Amiodarone is an antiarrhythmic medication with an amphiphilic structure which interacts with membrane phospholipids and leads to formation of autophagic vacuoles. Patients present with a lower limb predominant muscle weakness of both proximal and distal muscles. An associated neuropathy may also be present.[87] Muscle biopsy shows scattered fibers with autophagic vacuoles and myeloid inclusions on EM. Muscle function improves very slowly over several months after drug discontinuation in view of the long half-life of amiodarone.[88]

Other drugs in this group, such as labetalol[7] (myalgias, necrotizing myopathy, vacuolar changes in biopsy) and procainamide[89] (myasthenia gravis, nonautoimmune necrotizing myopathy, and drug-induced lupus) have also been reported to cause myopathy.

 Drugs Used in Anesthesiology



Propofol

Propofol is associated with the propofol infusion syndrome (PRIS), where infusions >4 mg/kg/hr have been seen to result in severe lactic acidosis, rhabdomyolysis, lipemic plasma and fatty liver and associated with a characteristic bradycardia leading to systolic arrest.[90]

Pathogenesis

Propofol is considered to cause mitochondrial dysfunction and uncouples fatty acid oxidation from energy production. It also increases levels of malonyl CoA, which in turn inhibits carnitine palmitoyltransferase 1.[91]

Clinical features and diagnosis

Any patient on propofol infusion with an increasing CK level should be suspected of having PRIS, especially after 24–48 h of continuous infusion. CK and triglyceride levels of patients on propofol infusion should be followed up. Early recognition can avert frank rhabdomyolysis and severe metabolic acidosis.[90]

Management

Prompt discontinuation of the drug with supportive management may reverse the process, although PRIS is difficult to manage once it develops.

Neuromuscular Depolarizing Agents

These agents are associated with critical illness myopathy when used in conjunction with high-dose GCs. This has been dealt with under the previous section on GCs. They may also be associated with the malignant hyperthermia (MH) syndrome.

 Drugs Used in Neurology



Phenytoin[92],[93] (myalgias, nonautoimmune necrotizing myopathy, DM) and lamotrigine[7] (inflammatory myopathy) are antiepileptic drugs associated with myopathy.

 Malignant Hyperthermia and Neuroleptic Malignant Syndrome



MH is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane, and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. Neuroleptic malignant syndrome is a rare, but potentially, life-threatening side effect that can occur in response to treatment with antipsychotic drugs. Symptoms commonly include hyperpyrexia, muscle rigidity, autonomic dysfunction, and altered mental status. These syndromes are an indirect cause of myopathy and are both associated with life-threatening rhabdomyolysis. The reader is referred to a few excellent articles for an in-depth review of these conditions.[94],[95]

 Miscellaneous Drugs



Antithyroid[96] drugs, especially methimazole and carbimazole (proximal or generalized myopathy), proton-pump inhibitors[97] (proximal or generalized myopathy), cimetidine[7] (inflammatory myopathy), syrup of ipecac[98] (nonautoimmune, necrotizing myopathy, and cardiomyopathy), and isotretinoin[99] (myalgias, rhabdomyolysis) have also been reported as causes of drug-induced myopathy.

 Muscle Biopsy



A muscle biopsy is possibly unnecessary in cases where the cause of myopathy is fairly certain and the offending drug is correctly identified and stopped, while observing for clinical and biochemical improvement. However, in certain situations, muscle biopsy may be required to rule out other causes or confirm characteristic findings associated with a particular drug. Deltoid, biceps, and quadriceps are most commonly used and imaging (MRI, USG) helps to select the site for biopsy. It may either be an open or needle biopsy. There is a need for error-free processing and storing of the sample to avoid aberrant reporting. The peroneus brevis muscle, in close proximity to the superficial peroneal nerve, may be used in cases with a neuromyopathy.[100]

 Conclusion



As our therapeutic drug repertoire increases, an increasing number of drugs continue to be reported as causing myopathy. A patient, on any recently initiated drug, presenting with myalgias or muscle weakness, should be suspected to have developed a drug-induced myopathy unless compelling evidence to the contrary and appropriate measures should be taken. Early recognition and discontinuation of the offending drug may go a long way in preventing severe adverse effects such as rhabdomyolysis and mortality. It also stands to reason that, in every patient with myopathy, a detailed drug/treatment history has to be obtained, and any recent changes duly noted. The various possible drug interactions have to be checked, especially in patients on a multitude of medications for different conditions. The use of agents such as high dose CoQ, lipoic acid, and creatine monohydrate in patients with drug-induced myopathies is not supported by evidence.

The aim of this review is to enlighten the reader regarding the vast array of drugs capable of causing myopathy, and the need to keep an open mind when approaching a patient with new-onset myopathy, who is being treated with other drugs for any underlying condition. The rarity of reported cases with some drugs precludes definitive guidelines for management, and in many cases, the treatment has to be individualized. Withdrawal of the offending drug is, most often, the only intervention required.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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