Which medications are contraindicated or should be avoided in patients with mitochondrial disease?

Medications Contraindicated or Requiring Caution in Mitochondrial Disorders

Valproic acid is absolutely contraindicated in patients with known or suspected mitochondrial disorders caused by POLG mutations, and should be avoided in all children under two years of age with clinically suspected mitochondrial disease due to high risk of fatal hepatotoxicity. 1

Absolute Contraindications

Valproic Acid

• Valproic acid is contraindicated in patients with confirmed POLG mutations (the gene for mitochondrial DNA polymerase γ), as it causes acute liver failure and liver-related deaths at substantially higher rates in these patients. 1
• Children under two years with clinically suspected mitochondrial disorders must not receive valproate due to fatal hepatotoxicity risk. 1
• POLG-related disorders should be suspected when patients present with unexplained encephalopathy, refractory epilepsy, status epilepticus, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. 1
• In patients over two years with suspected hereditary mitochondrial disease, valproate should only be used after all other anticonvulsants have failed, and requires intensive monitoring with regular clinical assessments and serum liver tests. 1

Medications Requiring Extreme Caution

Anesthetic Agents

• Avoid prolonged propofol infusions for maintenance of anesthesia in mitochondrial patients, as propofol can cause propofol infusion syndrome with mitochondrial dysfunction. 2, 3
• Use neuromuscular relaxants judiciously, though no specific agent is absolutely contraindicated based on available evidence. 2
• Volatile anesthetics and nondepolarizing muscle relaxants should be used with heightened vigilance. 3
• Certain local anesthetics may interfere with mitochondrial function and warrant careful consideration. 3

Cardiovascular Medications

• Statins and fibrates carry risk of myopathy in mitochondrial patients due to their effects on mitochondrial function, and should be avoided when possible or monitored closely. 3, 4
• Beta-blockers may impair mitochondrial function and require careful monitoring. 3
• Amiodarone interferes with mitochondrial oxidative phosphorylation and should be used cautiously. 3

Antidiabetic Agents

• Metformin poses risk of lactic acidosis in mitochondrial patients due to impaired lactate metabolism, though it is widely used with apparent safety in patients without severe renal or hepatic impairment. 2, 3
• Thiazolidinediones (glitazones) should be avoided as they cause mitochondrial dysfunction. 3
• Biguanides require caution due to potential exacerbation of lactic acidosis. 3

Antiepileptic Drugs Beyond Valproate

• Phenytoin and barbiturates interfere with mitochondrial function and should be used with caution. 3
• Alternative antiepileptic drugs should be considered first-line when treating seizures in mitochondrial patients. 3, 4

Antimicrobial Agents

• Certain antibiotics, particularly aminoglycosides and some other classes, may impair mitochondrial function. 3
• Nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV treatment cause mitochondrial toxicity and should be avoided when alternatives exist. 3, 5

Chemotherapeutic Agents

• Anthracyclines (doxorubicin), cisplatin, and other chemotherapeutics cause direct mitochondrial cardiotoxicity and respiratory chain dysfunction. 3, 5
• These agents should only be used when absolutely necessary with intensive cardiac monitoring. 5

Psychiatric Medications

• Certain neuroleptics may cause extrapyramidal signs through mitochondrial dysfunction. 3
• Tricyclic antidepressants should be avoided due to risk of hypotension, worsening heart failure, and arrhythmias; selective serotonin reuptake inhibitors are safer alternatives. 2

Corticosteroids

• Corticosteroids can cause steroid myopathy through mitochondrial toxicity and should be used sparingly. 3
• When required, use the lowest effective dose for the shortest duration. 3

Critical Perioperative Management

Metabolic Support

• Commence lactate-free intravenous fluids (5% dextrose in 0.9% saline) during the preoperative fasting period to prevent lactic acidosis, as mitochondrial patients are particularly vulnerable to metabolic stress. 2
• Maintain normoglycemia throughout the perioperative period, as excessive glycolytic oxidation can increase plasma lactate levels. 2
• Avoid prolonged fasting, which exacerbates the tendency toward lactic acidosis. 2

High-Risk Populations

• Patients with Leigh's disease, especially those with documented variable respiratory drive, are at greatest risk for respiratory failure and metabolic decompensation after general anesthesia. 2
• Patients with severe, progressive neuro-metabolic disease require intensive monitoring as they may develop acute deterioration with respiratory failure and metabolic acidosis within 24 hours post-procedure. 2

Monitoring Requirements When Mitochondrion-Toxic Drugs Are Unavoidable

• Monitor creatine kinase and lactate levels closely during treatment with any potentially mitochondrion-toxic medication. 4
• Perform regular clinical assessments for new symptoms including unexplained weakness, exercise intolerance, neurological changes, or gastrointestinal symptoms. 4
• Discontinue the offending agent immediately if signs of mitochondrial decompensation appear (rising lactate, new myopathy, unexplained organ dysfunction). 3, 4

Common Pitfalls to Avoid

• Do not assume that "therapeutic" drug levels are safe in mitochondrial patients—these individuals may develop toxicity at standard doses due to impaired cellular energy metabolism. 4
• Do not overlook the cumulative effect of multiple medications—patients on multiple potentially mitochondrion-toxic drugs face exponentially higher risk. 3
• Do not delay discontinuation of suspected toxic agents—in some cases hepatic or other organ dysfunction progresses despite drug discontinuation, making early recognition critical. 1
• Avoid the combination of surgical stress, fasting, and mitochondrion-toxic anesthetics without appropriate metabolic support. 2