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Mitochondrial Toxicity

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Join us this month to take a big picture look at agents that are toxic or potentially harmful to the mitochondria. 

Dr. Katherine Sims from Massachusetts General Hospital shares information important to everyone concerned about their health, and explains why recognizing potentially toxic agents - from medications to environmental factors - can be especially worrisome and detrimental for children and adults who have a mitochondrial disorder.

Katherine Sims MD is an associate professor of Neurology at Harvard Medical School and Director of the Developmental Neurogenetics clinic at MGH in Boston, MA.  Dr. Sims is also chair of MitoAction's Medical Advisory Committee and works in research collaboration with Dr. Vamsi Mootha at the Broad Institute toward clinical phenotyping and metabolic profiling for mitochondrial disorders.  Dr. Sims oversees the MGH Mitochondrial Disorders Clinical Registry and Tissue Bank.

 View the Table of Agents which cause Mitochondrial Toxicity

Introduction  Recognizing potentially toxic agents is important for everyone, but especially those with mitochondrial disease. Dr. Katherine Sims from Boston's Massachusetts General Hospital explains why identifying potential toxic agents from medications to environmental factors is an essential part of managing the disease. Dr. Sims has a special link to the mitochondrial disease community serving as the Chair of MitoAction's Medical Advisory Committee.

As both a pediatric neurologist and researcher, Dr. Sims notes that discussing any aspect of mitochondrial disease is a challenge because diseases associated with mitochondria were not discovered until the late 1980's and early 1990's. We are still learning about the mitochondria and how they relate to human disease. Today's discussion will focus on optimizing disease management from the patient's point of view. In addition, it is important for patients and doctors to register all observations in an organized way so that we can begin to understand how to treat symptoms while at the same time avoid aggravating the underlying mitochondrial disease.

There are many reasons why certain substances may be toxic to the mitochondria. For instance, if the electron transport chain (ETC) is inhibited, patients with mitochondrial diseases may be severely affected because oxidative-phosphorylation is disrupted. Also, harmful free radicals can be formed from reactive oxygen species and disrupt mitochondrial functions. In primary mitochondrial disease we use a variety of drugs that may help with the numerous symptoms of the disease or may be needed to treat co-morbidities (other diseases or conditions that the patient may have which may or may not be related to the mitochondrial disease).  Some of these drugs may actually be harmful to the mitochondria themselves so we need to always balance the medical need with potential harmful side effects to the mitochondria.

Mechanisms of Toxicity  Anything can be toxic if it inhibits the electron transport chain.  Oxidative-phosphorylation disease is affected by any disruption in the ETC.  What appears to be a necessity , ie, oxygen, can in itself be damaging. There are many ways that free radicals can be formed and these free oxygen radicals can be toxins if not handled appropriately. Free radical damage can cause increased energy needs with a cascading effect of further damage.  The key is to attempt to balance the treatment needs with the side effects of the treatment.

The pathobiology of mitochondrial toxicity is not well understood.  Toxicity may be exacerbated by other problems and treatments, so always be watchful and observant of all symptoms. Mitochondrial function needs to be supported, not impeded. The types of toxic agents include: pharmaceutical products (medications), anesthesia, surgery, environmental agents, diet, stress related endogenous agents, and  mitochondrial cofactors. A table of the various agents discussed here will be included as an attachment to this summary.

Pharmaceutical products Establishingmitochondrial toxicity is not an FDA requirement for drug approval, so there is no real way of knowing which agents are truly toxic. Nor is there an absolute contraindication against any particular agent, BUT there are those that we know should be avoided.  Some agents have been shown (either through research studies or anecdotal evidence) to have direct toxicity to the mitochondria. These agents directly inhibit or disrupt the ETC, protein production, DNA transcription, etc. Agents that cause indirect toxicity are those that increase free radicals, decrease the production of endogenous antioxidants, or deplete nutrients that are needed.

Anticonvulsants Specifically, most anticonvulsants are well tolerated except  valproate (Depakote).  This drug can inhibit many mitochondrial functions.  It is known to play important role in carnitine utilization by the mitochondria and has been shown to particularly inhibit complex IV. It can also cause liver dysfunction. This does not mean it should never be used, but caution needs to be taken regarding liver function. If used, plasma carnitine levels need to be monitored and maintained carefully.

Psychotropics Certain psychotrophic drugs have been shown to be potentially toxic.  Certain antidepressants such as Prozac, Elavil, and Cipramil can cause autonomic dysfunction. Other psychotropic drugs such as antipsychotics, barbituates, and antianxiety medications also inhibit various mitochondrial functions.

Cholesterol Medications Cholesterol lowering drugs (especially statins) have been shown to reduce endogenous CoEnzynme Q10 is produced in the same metabolic pathway as  cholesterol, so in this way these drugs can be said to be potentially toxic. Other cholesterol medications such as cholestyramine that bind to bile acids can distrupt the ETC.

Analgesics  and Anti-inflammatories Pain relievers such as acetimenophen (sp?), Indocin,  naproxen, Aspirin and the NSAIDS (non steriodal anti inflammatory drugs), all  increase oxidative stress, and therefore could potentially be toxic. Aspirin is contraindicated for children, but it can be harmful for patients with mitochondrial disease as well because of the potential for Reye Syndrome (acute liverfailure). However, patients should keep in mind that it is important to avoid fevers in Mito patients. Therefore, the benefits of some of these medications as fever-reducers may outweigh their potential side-effects.

Antiobiotics Antibiotics, (specifically tetracycline, minocycline, chloramphenical, and aminoglycosides), can be harmful to the mitochondria because they inhibit mtDNA translation and protein synthesis. They can cause hearing loss as well as cardiac and renal toxicity.  

Steroids Steroids may reduce transmembrane mitochondrial potential. However, steroids used in local delivery (such as inhaled steroids that only target lungs or injected steroids that target specific locations) are generally recognized as safe.

Other drugs which are used less by the Mito population but have potential toxicity include amiodarone which is used as an anti-arrhythmic (rapid heart rate), antivirals like interferon, antiretrovirals (used for  HIV/AIDS), and cancer drugs.  Metformin, used for diabetes, is also considered toxic to mitochondria. Beta blockers could have possible toxicity due to increased oxidative stress, and may also contribute to feelings of fatigue. Diuretics are usually not harmful to the mitochondria themselves, but they may cause fluid imbalances, which can be potentially difficult for Mito patients

In all cases of the drugs mentioned here, the objective is to balance the need for use of these drugs with the damage they may cause.

Anesthesia  In mitochondrial disease, there seems to be an increased sensitivity to anesthesia, especially the volatile drugs (ie, those inhaled). For this reason, there should be very close management of any anesthesia used even when IV (for example, propofal).  Often  a decreased dosage is adequate.  The smallest dose over the shortest period of time should be the goal of all anesthesia for mitochondrial disease patients. Patients with mitochondrial diseases should make sure that their anesthesiologist is informed and knowledgeable about their condition so that they use the upmost caution and safety while using anesthetics.

Surgery Surgery is a huge metabolic stressor for those with mitochondrial disease and must be managed very carefully. Acid-base balance status must be monitored closely because acidosis can be particularly harmful for those with mitochondrial disease. Fasting should be avoided as much as possible. For example, do not schedule surgery for the end of the day when the patient has been fasting since the night before. Instead, be sure the Mito patient's surgery is the first of the day. Also be sure a Dextrose IV with electrolytes (if indicated) is put in early before surgery to maintain adequate fluid and electrolyte balance and to deter catabolism.

Environmental Agents Tobacco smoke (primary or secondary inhalation) and alcohol are both potentially toxic for patients with mitochondrial diseases. Other environmental factors may not be as controllable, but patients should be aware of their toxicity. These include rotenone (chemical used in insecticides and pesticides) and fat soluble chemicals with benzene rings such as hair dye and paint fumes.

Diet The Ketogenic diet (used sometimes for those with seizure disorders) can be a stressor for those with mitochondrial disease. This diet increases cellular utilization of thebeta oxidation pathway.  This diet can behelpful for those with a pyruvate dehydrogenase disorder. Avoid diet deficiencies of any kind. It is important for patients to have a balanced diet including pyridoxine (B6), ferrodoxin, iron, copper, riboflavin (B2), zinc, and selenium  as well as other vitamins and/or minerals. Avoid fasting! A state of hyperglycemia can also be toxic and lead to problems similar to those of diabetics. Hyperglycemiacan cause increased superoxide production (oxygen free radical) in the endothelium, which can lead to a vascular endotheliopathy (vessel wall dysfunction and metabolic derangement). Some foods like peas, beans, legumes, and almonds have substances in them that can be toxic to the mitochondria.

Endogenous  Stress Related Hormones Stress hormones such as adrenalin, catecholamines, and testosterone can be harmful for Mito patients. Stress of any kind should be avoided as much as possible so as not to compromise mitochondrial function.  

Co Factors CoEnzyme Q10 can become an oxygen radical and cause trouble if the dosage is too high. The most common dosage is 10 - 20 mg/kg/day.  There is a small study that used 60 mg/kg/day for a short term and it was tolerated well. Usually, however, above 20mg (of ubiquinone) is NOT tolerated well; For Ubiquinol the dosage is usually under 10 mg/kg/day (range of 6-8mg/kg/day). In high doses riboflavin, L-carnitine and L-arginine can be harmful, so they also need careful monitoring.

Conclusion There are some substances which are clearly toxic to the mitochondria and we have some idea how they work; these should be avoided. There are many more that are only suspected of being toxic; of these we should take care in their use, monitor any effects carefully and make good observations and records of any effects. When using new treatments, we should add one new medication at a time in order to monitor the effect (both positive and negative). All of this information should be included in the developing registry.

In general, there are some things which we do know for both children and adults, and we can use this knowledge to guide our recommendations. Still, there is a lot more that we don't know. Many of our recommendations are based on anecdotal evidence or very small studies. For example, though there is a long list of psychotropic drugs which "may be toxic", many of them probably are not contraindicated but rather should be used with frequent observations and records about how they affect the patient, and changes should occur one drug at a time. Again, a key point to keep in mind is that the life-saving benefit of some of these drugs outweighs their possible side-effects. It is imperative to isolate the offending agent because we need to be able to use some medical treatments, and we have some control over which agent/drug we use.

It appears that some effects from a mitochondrial toxin are reversible. Deficiencies need to be identified and dealt with. The problem often is finding out just what the particular vulnerabilities are for each particular patient. Certain medications may trigger toxic reactions, but the challenge is to figure out whether these symptoms are from ongoing mitochondrial damage, natural history of the disease, or the use of new drugs.

When toxic agents can't be avoided, improving overall mitochondrial function is possible by including key elements such as CoenzymeQ10, L-carnitine, B Vitamins, antioxidants (Vitamin C, Vitamin E, Alpha-Lipoic Acid, selenium ), and others. Minimizing stress and illness is also important!

 

A compassionate clinician and excellent speaker, Dr. Sims has also helped patients and families understand Mito genetics in her presentation, "Fact vs Fiction: Genetic Inheritance Patterns for Mitochondrial Disease".

Your rating: None Average: 5 (3 votes)

Comments

mryanone's picture

mryanone

06/02/2010

I will try to attend. Have blocked off the time for the call. Thank you.

Mike Ryan

Hyperbaric Oxygen Chamber Technologist

HOPE-Connection.com

mryanone's picture

mryanone

06/02/2010

I will try to attend. Have blocked off the time for the call. Thank you.

Mike Ryan

Hyperbaric Oxygen Chamber Technologist

HOPE-Connection.com

mitoscottie's picture

mitoscottie

06/04/2010

This presentation by Dr Katherine Sims was very well organized and presented in an easy-to-understand way!  This topic is of great importance both for patients and clinicians.  Dr Sims has promised a summary presented in a table forms covering different classifications of drugs.

We need this information!  Thank you MitoAction!

Jean Shepherd, British Columbia, Canada

Adult patient

Cristy Balcells's picture

Cristy Balcells

06/04/2010

You are welcome Jean - thank you for the comment! Be sure to give it 5 stars up above in the rating scale too - eventually we'll know what topics are "the best" by their rating!

Cristy Balcells RN MSN

Executive Director

 

whelmka's picture

whelmka

06/09/2010

Dear friend in Mitova ...

I couldn't make the teleconference last week as my daughter is graduation high school and it is a busy time ... so I listened to the MP3 the other day ... wow very nice Dr. Sims.

I can attest first hand to many of the things she said ... the best advice I heard that is helpful is that you need never fast before sugery ... go in a day early as in inpatient, get D5 or D10 on board while the make you go NPO and the process of sugery and recovery will go much smoother.  I have severe anesthesia risk/complication previously, but had emergency upper and lover GI done a few years ago ... they put me in hosptital and I have IV Fluids all night before procedures over two days and my recovery was uneventful ... I can only imagine the awful casscade effect of having had fasted and not been physically prepared!

That is solid advice for all mito patients and their advocates!  The whole teleconferece was great!  Thank Cristy and Dr Sims for good solid and useful information.

Wendy Helmka, COX Complex IV, with other defects in complex I, II, III with profound Leukodystrophy

 

kbdvm51's picture

kbdvm51

06/17/2010

Great presentation. I particularly liked the introduction that summarized mitochondrial function; a complicated subject presesnted in a compact fashion. Dr. Sims covered an amazing amount of material in the allotted time. Every patient (or their parent(s)) and ideally their primary care clinician should listen to this or review the promised written materials. Before I was diagnosed I had been on one of the listed toxic medications for 3 years. My own intuition told me that it was bad for me; it was nice to have that feeling validated. Thank you Dr. Sims! Thank you Christy for this and all the other fine presentations that I have listened to on line.

Kathy Beck, Boston, MA Recently diagnosed as adult patient with mitochondrial myopathy; "final" diagnosis pending.

Garmhel's picture

Garmhel

03/07/2011

My son is very fast moving child, sometimes I even think that he has ADHD but thank God he doesn't. Now I'm also confident that he is not affected with MitoDZ.
LisaK's picture

LisaK

09/02/2011

Question: When dealing with repeated infection (sinus for example) is it best to treat longer with higher doses of one antibiotic or treat 10 -14 days with higher dose and/or switch types of antibiotics after 10-14 days?
bradleyost's picture

bradleyost

03/24/2012

just wondering if there are any MERRF patients out there? I am 56 years old and received a Clinical dx with several abnormal findings on my emg and nerve conduction study.Also had a muscle biopsy done but it came back inconclusive. Started out batteling neuropathic pain in my heels that was very intense. Didn't know what it was for sure so tried to ignore it.Also was trying to ignore muscle spasms, esp. around the shoulder blades, that would intensify with constant repetitive motion. I would get steroids injected directly into those muscles and if the shots were in the perfect area, I would get relief in about 3 days. Next were the nocturnal siezures which brought on severe sleep deprevation. I was only getting maybe 10 minutes a night of REM sleep according to my 3 sleep studies. Next was the unbeleiveable muscle pain, burning and weakness that would come from doing something as simple as washing my hair. Then the neuropathic pain started in my ears and inside of the elbows too. Always a little worse on my left side. And of course after several years of trying to find the right Doctor, I was also in a pretty bad depression. Went through some really bad times with hot flashes and intense sweating and heat intolerance. I have actually begun to enjoy the cold weather. Still have many days that I just want to crawl up into a ball, with all the lights turned off and attempt to conserve as much energy as I possibly can. Also battle photophobia, even indoors. I often shut out all the lights and put on my sunglasses to watch some TV.Otherwise I know an intense migrane type headache is coming on. Now I am having major problems with my cognitive skills. Lots of trouble remembering names or trying to tell a story about one of my precious Grandchildren that happened a few days ago. Also have more and more tremors in my hands.Muscles most affected now are the biceps, triceps, quadriceps, upper Back and calves. Also have a breakout of red dots in a ring around my neck when a down time is coming around. They are almost the size and shape of a pimple but they don't have a head on them
advocate's picture

advocate

05/10/2012

riboflavin, with or without coQ10, has been suggested to help prevent or treat photophobia and migraine headaches. the dose of riboflavin usually given is 400 mg a day. i have taken 1200 in one day. no noticeable ill effects. riboflavin reduces or activates vitamin E and vitamin C and presumably also oxidized coQ10. that is it may convert ubiquinone to ubiquinol which is the active, reduced form of coQ10. consider combining riboflavin supplementation with whatever else you are doing.
ritjain74's picture

ritjain74

06/29/2012

What could be the suggestable medication for Fever, Cold and cough, infections which usually occurs during Rain or winter season.