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Published: 1 June 2017

Mitochondrial Disorders: Medicines to Avoid

Prescriber Update 38(2): 29-30
June 2017

Key Messages

  • Medicines can affect a variety of mitochondrial functions.
  • Medicines that are toxic to mitochondrial functions should be avoided in patients with mitochondrial disorders.
  • Due to the great diversity in mitochondrial disease manifestations differing outcomes can be reported in different patients for the same medicine.


Mitochondrial disorder (disease) is a collective term for a group of disorders that can affect many different organs. There is no specific treatment for these disorders although the symptoms they cause may be managed with medicines, surgery or diet. One of the important aims of managing patients with mitochondrial disorders is to avoid medicines that are toxic to mitochondrial functions1,2.

Mitochondria are thought originally to be free-living aerobic bacteria that were captured into non-bacterial cells. Mitochondria have their own DNA that replicates independently of nuclear DNA under the control of enzymes similar to those in bacteria. Mitochondria are responsible for energy production via the respiratory chain and oxidative phosphorylation. Other functions include beta-oxidation, iron metabolism, copper metabolism, heat production, apoptosis, calcium signalling, haem synthesis, steroid synthesis and amino acid metabolism2-4.

Genetic mitochondrial diseases are due either to mutations in the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). Mitochondrial disease can affect the brain, heart, liver, skeletal muscles, kidney, endocrine system and respiratory systems. The symptoms within these systems are diverse and may be due to a number of different defects within the mitochondria 1,5.

Medicines can affect many of the different functions within the mitochondria. The mitochondrial respiratory chain (MRC) is composed of five enzyme complexes: I-V and uses cytochrome c and coenzyme Q10, which act as electron carriers. Pharmacotherapy induced MRC dysfunction may result from the direct inhibition of one or more of the enzyme complexes or uncoupling of oxidative phosphorylation. As the enzyme complexes are susceptible to free radical-induced oxidative damage, medicines that cause oxidative stress may also result in MRC toxicity. The replication of mtDNA and protein synthesis may also be affected by medicines 2,4.

High quality evidence of the effects of medicines in people with mitochondrial disease is sparse. Much of the available information is derived from in vitro or animal studies. Additionally, due to the great diversity in mitochondrial disease manifestations, conflicting outcomes can be reported in different patients for the same medicine. Consensus appears to be lacking on which medicines should be completely avoided and which may be used with close monitoring1–5. A summary of the available data is provided in Table 1.

Table 1: Medicines to avoid in patients with mitochondrial disease1-5*

Medicine Proposed mechanism Adverse effects related to mitochondrial toxicity
Amiodarone Inhibits MRC I and III and beta oxidation Pulmonary toxicity, microvesicular steatosis and liver failure
Antibiotics:
gentamicin, chloramphenicol, tetracycline
Reduces mt protein synthesis Deafness, renal failure, myopathy
Anti-cancer medicines: doxorubicin, cisplatin mtDNA mutation Cardiomyopathy
Antipsychotics: haloperidol, risperidone, clozapine Inhibits MRC I, increases reactive oxygen species, inhibits oxidative phosphorylation Extrapyramidal symptoms, metabolic syndrome
Aspirin Inhibits oxidative phosphorylation and beta oxidation Causes a Reye-like syndrome
Beta-blockers: metoprolol, propranolol Inhibits MRC I Case report of muscle wasting
Ciprofibrate Inhibits MRC I, weak peroxisome proliferator activated receptor ligand Myopathy and rhabdomyolysis
Corticosteroids Inhibit mt membrane potential, generate reactive oxygen species Myopathy
Fluoxetine Inhibits MRC I and V, interferes with cytochrome c Gastrointestinal damage
Isoflurane Inhibits MRC I Hepatotoxicity
Isoflurane / halothane / sevoflurane Inhibits MRC I Hepatotoxicity, neurotoxicity cardiac effects
Linezolid Inhibits mt protein synthesis Polyneuropathy and lactic acidosis
Local anaesthetics: bupivicane, lidocaine Inhibtis MRC V, increases reactive oxygen species, inhibits oxidative phosphorylation Myopathy
Metformin Inhibits MRC I Causes lactic acidosis
Nicotine Inhibits respiratory chain  
Non-steroidal anti-inflammatory drugs:
ibuprofen, diclofenac, naproxen
Inhibits oxidative phosphorylation and beta oxidation Hepatotoxicity
Nucleoside reverse transcriptase inhibitors:
zidovudine, didanosine, lamivudine, abacavir
mtDNA depletion which then affects all functions Encephalomyopathy, anaemia, polyneuropathy, pancreatitis and lactic acidosis
Paracetamol (overdose) MRC I Hepatotoxicity
Phenytoin Inhibits mt ATPase Case report of intestinal pseudo obstruction, may cause hepatotoxicity
Pioglitazone Inhibits MRC I, weak, peroxisome proliferator activated receptor ligand Increases anaerobic glycolysis
Propofol (particularly > 4 mg/kg/h for > 48 hours) Inhibition of free fatty acid entry to mt, beta oxidation Propofol infusion syndrome: metabolic acidosis, rhabdomyolysis, heart failure, hepatomegaly, asystole
Sertraline Inhibits MRC I and V, inhibits oxidative phosphorylation Hepatotoxicity
Simvastatin (other statins have weaker effects) Inhibits MRC I, reduces coenzyme Q10 levels, weak peroxisome proliferator activated receptor ligand Causes myopathy, rhabdomyolysis
Sodium valproate Inhibits oxidative phosphorylation, beta-oxidation Liver failure, hyperammoninaemia, hypoglycaemia, steatosis and encephalopathy
Tricyclic antidepressants:
amitriptyline, clomipramine
Inhibits MRC Extrapyramidal symptoms, memory impairment

*Table in alphabetical order, which is not the same as order of importance of the medicines.

mt = mitochondria

References
  1. Finsterer J, Segall L. 2010. Drugs interfering with mitochondrial disorders. Drug and Chemical Toxicology 33(2): 138–51.
  2. Moren C, Juarez-Flores DL, Cardellach F, et al. 2016. The role of therapeutic drugs on acquired mitochondrial toxicity. Current drug metabolism 17: 648–62.
  3. Hargreaves IP, Al Sharhrani M, Wainwright L, et al. 2016. Drug-induced mitochondrial toxicity. Drug Safety 39: 661–74.
  4. Nadanaciva S, Will Y. 2011. Investigating mitochondrial dysfunction to increase drug safety in the pharmaceutical industry. Current Drug Targets 12: 774–82.
  5. Radboud Center for Mitochondrial Medicine. 2016. URL: rcmm.info/ (accessed 13 April 2017).
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