Pharmacogenic Myopathy: Symptoms, Types, Causes and Treatment

Pharmacogenic myopathy refers to muscle disorders that are triggered or exacerbated by medications. In our modern era of expanding pharmacotherapy, especially for chronic diseases, these myopathies are increasingly recognized as an important cause of muscle pain, weakness, and, in severe cases, life-threatening complications. Understanding the symptoms, types, causes, and treatments of pharmacogenic myopathy is essential for clinicians, patients, and caregivers alike.

Symptoms of Pharmacogenic Myopathy

Medications can affect muscles in subtle or dramatic ways. The symptoms of pharmacogenic myopathy often mimic those of other muscle disorders, which can make diagnosis challenging. However, recognizing the hallmark features can help prompt timely intervention and medication review.

Symptom	Frequency	Severity Range	Sources
Myalgia	Common	Mild to moderate	1, 2, 4, 5
Weakness	Moderate	Mild to severe	1, 4, 5
Cramps	Occasional	Mild	4, 5
Rhabdomyolysis	Rare	Severe, life-threatening	1, 2, 4, 5
Fatigue	Common	Mild to moderate	4, 5
Elevated CK	Variable	Asymptomatic to severe	1, 4, 5
Muscle Swelling	Rare	Mild to moderate	4, 5

Table 1: Key Symptoms

Understanding the Clinical Presentation

Pharmacogenic myopathy encompasses a wide spectrum of muscle symptoms.

Myalgia and Muscle Weakness

• Myalgia (muscle pain) is the most frequently reported symptom, often described as diffuse and aching. It may be accompanied by muscle cramps or stiffness. These symptoms can be mild and sometimes mistaken for common aches, especially in older adults or those with comorbidities 1, 4, 5.
• Muscle weakness can range from mild to profound, affecting daily activities or, in severe cases, leading to difficulty in walking or lifting 1, 4.

Rhabdomyolysis

• Rhabdomyolysis is a rare but serious manifestation. It involves the rapid breakdown of muscle tissue, leading to the release of muscle enzymes (such as creatine kinase, CK) and myoglobin into the bloodstream. This can cause acute kidney injury and requires urgent medical attention 1, 2, 4, 5.
• Symptoms include profound weakness, muscle swelling, dark urine (from myoglobinuria), and sometimes fever 4, 5.

Subclinical Presentations

• Not all patients experience symptoms. Some may have asymptomatic elevations in CK or mild, nonspecific fatigue 1, 4.
• Muscle swelling and cramps are less common and tend to occur in more severe or chronic cases 4, 5.

Onset and Course

• Symptoms can appear within days to weeks of starting a new medication or after dose escalation. In some cases, symptoms develop slowly over months, making attribution to a drug more challenging 4, 5.

Types of Pharmacogenic Myopathy

Pharmacogenic myopathies are diverse, reflecting the wide variety of drug mechanisms and patient susceptibilities. Classification is usually based on clinical presentation and underlying pathology.

Type	Features	Common Drugs	Sources
Myalgia	Pain without weakness	Statins, SGLT2 inhibitors, steroids	1, 2, 4, 5, 7
Myopathy	Weakness with/without pain	Statins, steroids, antimalarials, colchicine	1, 4, 5, 7
Rhabdomyolysis	Severe breakdown, AKI risk	Statins, antipsychotics, SGLT2 inhibitors	1, 2, 4, 5
Immune-mediated	Inflammatory, necrotizing	Statins, checkpoint inhibitors	1, 4, 5
Congenital triggers	Myopathy unmasked by drugs	Anesthetics (MH), statins	3, 8

Table 2: Types of Pharmacogenic Myopathy

Clinical and Pathological Subtypes

Myalgia and Myopathy

• Myalgia: Characterized by muscle pain without true muscle weakness. It is the most benign form and often reversible upon discontinuation of the offending agent 1, 4, 5.
• Myopathy: Involves actual muscle weakness, sometimes with accompanying atrophy, and can be confirmed by elevated CK or abnormal muscle biopsy 1, 4, 5.

Rhabdomyolysis

• The most severe form, rhabdomyolysis, results in massive muscle breakdown, often leading to acute kidney injury (AKI) and systemic complications. Prompt recognition and management are vital 1, 2, 4, 5.

Immune-mediated Myopathies

• Some drugs, notably statins and immune checkpoint inhibitors, can trigger immune-mediated necrotizing myopathies (IMNM) or inflammatory myopathies. These often present with progressive weakness, dramatically high CK, and may require immunosuppressive therapy in addition to drug withdrawal 1, 4, 5.

Drug-triggered Congenital Myopathies

• In people with underlying genetic mutations (e.g., RYR1), certain drugs like volatile anesthetics can trigger conditions such as malignant hyperthermia (MH) or unmask underlying congenital myopathies 3, 8.

Causes of Pharmacogenic Myopathy

Understanding the causes of pharmacogenic myopathy involves looking at both the drugs involved and the patient-specific factors, including genetics and comorbidities.

Cause	Mechanism	Example Agents	Sources
Direct toxicity	Mitochondrial dysfunction, membrane disruption	Statins, colchicine	1, 4, 5
Immune-mediated	Autoimmune attack	Statins, checkpoint inhibitors	1, 4, 5
Genetic susceptibility	Pharmacogenetic variants	Statins, anesthetics (RYR1)	1, 3, 7, 8
Drug interactions	Increased serum drug levels	Statins + CYP inhibitors	1, 4, 7
Metabolic stress	Energy depletion	SGLT2 inhibitors, steroids	2, 4, 5

Table 3: Causes of Pharmacogenic Myopathy

Mechanisms Behind Drug-Induced Myopathy

Direct Muscle Toxicity

• Some drugs cause direct toxicity to muscle cells. Statins, for instance, may disrupt mitochondrial function, impair calcium signaling, and increase pro-apoptotic pathways in muscle fibers. Colchicine interferes with microtubule assembly, leading to muscle fiber degeneration 1, 4, 5.

Immune-mediated Mechanisms

• Certain medications can trigger immune-mediated myopathies. Statins may induce anti-HMGCR antibodies, leading to necrotizing myopathy. Immune checkpoint inhibitors can provoke autoimmune muscle inflammation as part of a broader immune activation 1, 4, 5.

Genetic and Pharmacogenetic Predisposition

• Genetic variants significantly influence susceptibility:
  • SLCO1B1 polymorphisms (notably rs4149056) increase statin exposure and risk for statin-associated muscle symptoms (SAMS) 1, 7.
  • RYR1 mutations predispose to malignant hyperthermia when exposed to certain anesthetics, and may also increase the risk for drug-induced rhabdomyolysis 3, 8.
  • Other gene variants (e.g., LILRB5, HLA-DRB1*11:01) and rare metabolic myopathy genes (e.g., CACNA1S, CPT2) can contribute 1, 3, 7.

Drug Interactions and Metabolic Stress

• Drug-drug interactions can raise serum concentrations of myotoxic drugs, especially statins, increasing risk of toxicity. Common culprits include CYP3A4 inhibitors and certain antifungals 1, 4, 7.
• Drugs like SGLT2 inhibitors, especially when combined with statins, may increase metabolic stress in muscle, although the exact mechanism remains unclear 2.

Other Factors

• Advanced age, pre-existing muscle disease, high-dose therapy, and comorbidities (e.g., diabetes, renal insufficiency) are additional risk factors 1, 4, 5, 7.

Treatment of Pharmacogenic Myopathy

Managing pharmacogenic myopathy is multifaceted, requiring prompt identification, withdrawal or adjustment of the offending agent, and supportive care. In some cases, targeted therapies or immunosuppression are necessary.

Treatment	Approach	Indication	Sources
Drug withdrawal	Stop/switch medication	All types	1, 4, 5, 7
Dose adjustment	Reduce drug dosage	Mild cases, essential therapy	1, 4, 5, 7
Supportive care	Hydration, electrolyte balance	Rhabdomyolysis	1, 2, 4, 5
Immunosuppression	Steroids, IVIG, others	Immune-mediated myopathy	1, 4, 5
Pharmacogenetic-guided therapy	Personalized drug selection	Statins, anesthetics	1, 3, 7, 8
Novel therapies	Epigenetic drugs, CAIs	Congenital/myopathic variants	6, 8

Table 4: Treatment Approaches

Standard and Emerging Treatment Strategies

Drug Withdrawal and Dose Adjustment

• Immediate withdrawal of the suspected drug is the cornerstone of management. Most cases of myalgia and mild myopathy resolve completely with cessation 1, 4, 5, 7.
• Where the medication is essential (e.g., statins for cardiovascular prevention), dose reduction or switching to a less myotoxic alternative (e.g., hydrophilic statins) may be attempted 1, 4, 7.

Supportive and Symptomatic Care

• In cases of rhabdomyolysis, aggressive hydration and correction of electrolyte imbalances are critical to prevent kidney damage 1, 2, 4, 5.
• Monitor for complications such as hyperkalemia and acute renal failure.

Immune-mediated Myopathy Management

• Immune-mediated necrotizing myopathies may require immunosuppressive therapy (e.g., corticosteroids, IVIG, or other immunosuppressants) in addition to drug withdrawal 1, 4, 5.
• Early rheumatology or neurology input is recommended.

Pharmacogenetic-Guided Therapy

• Pharmacogenetic testing can identify individuals at increased risk:
  • SLCO1B1 genotyping informs statin selection and dosing 1, 7.
  • RYR1 mutation screening is recommended before anesthesia in susceptible individuals 3, 8.
• Personalized medicine approaches are increasingly being integrated into clinical practice.

Emerging and Targeted Therapies

• Novel treatments, such as epigenetic drugs (HDAC and DNA methyltransferase inhibitors), show promise for congenital myopathies linked to genetic mutations like RYR1 8.
• For muscle ion channelopathies, certain sodium channel blockers (e.g., mexiletine) and carbonic anhydrase inhibitors (e.g., acetazolamide) have shown efficacy, with response varying based on genetic background 6.

Conclusion

Pharmacogenic myopathy is a dynamic and complex field, with implications for anyone taking chronic medications. With increased awareness, early detection, and tailored treatment, most cases are reversible, and severe complications can be prevented.

Key points covered in this article:

• Symptoms of pharmacogenic myopathy range from mild myalgia and fatigue to severe muscle weakness and life-threatening rhabdomyolysis.
• Types include myalgia, myopathy with weakness, rhabdomyolysis, immune-mediated myopathies, and drug-triggered congenital muscle disorders.
• Causes involve direct toxicity, immune mechanisms, genetic predisposition, drug interactions, and metabolic stress.
• Treatment centers on drug withdrawal, dose adjustment, supportive care, immunosuppression for immune-mediated cases, and increasingly, pharmacogenetic-guided and novel targeted therapies.

By staying vigilant and informed, healthcare professionals and patients can work together to minimize the risk and impact of pharmacogenic myopathy, ensuring safer and more effective medication use.