A good amount of attention is given to the potential for adverse interactions between natural supplements and prescription drugs. Most of this attention is focused on how certain supplements (i.e.: St. John’s Wort) can adversely affect drug metabolism. These are important considerations, however, the focus of this issue will be on the potentially negative effects that a few prescription drugs may have on certain nutrients and intestinal bacteria. The clinical significance for your patients will be discussed in detail.

Statin Drugs: Coenzyme Q10 (CoQ10) Depletion

• Statin drugs inhibit the production of mevalonate, a precursor of both cholesterol and CoQ10. Numerous studies show that statin use decreases plasma and intra-cellular levels of CoQ10.1,2
• Although this fact is well established, few physicians encourage their patients to supplement with CoQ10 when they write for statin drugs. There are typically two reasons for this lack of recommending CoQ10. The first is that the medical community is unconvinced that there is any clinical relevance of this depletion. The second is due to the prohibitive cost of CoQ10 (which has recently come down in price).

Clinical Studies

• The one definitive study showing the negative effects of lower CoQ10 levels because of statin drug therapy has not been done. Part of the reason is that this would, in reality, be a very difficult study to design due to the fact that the negative effects of CoQ10 reductions could take many years to manifest. The question then becomes whether we can gain any insight from other CoQ10 studies to help form a better clinical opinion of whether or not to recommend this supplement.
• CoQ10 has been shown to exert a favorable effect on chronic heart failure, angina and hypertension. One review study concluded that the literature demonstrated favorable effects of CoQ10 on ejection fraction, exercise tolerance, cardiac output, and stroke volume.3
  A randomized, double-blind placebo-controlled trial of patients with acute myocardial infarction showed that patients given 120 mg/day of CoQ10 had statistically significantly (P < 0.05) fewer events of angina pectoris (9.5% vs. 28.1% placebo), total arrhythmias (9.5% vs. 25.3% placebo), and poor left ventricular function (8.2% vs. 22.5% placebo).4 The same study showed less total cardiac events in the CoQ10 patients (15% vs. 30.9% placebo, P < 0.02).
• Other than cardiovascular concerns, there are also implications for neurodegenerative diseases and cancer with depletions of CoQ10.
• Low plasma levels of CoQ10 were shown to be a powerful and independent prognostic factor for the progression of melanoma.5 Decreased levels of CoQ10 were found in plasma of women with breast cancer, and in cancerous breast tissue, and low levels correlated with a worse prognosis.10
• A number of studies have shown benefit of CoQ10 for the protection of the brain with implications for Parkinson’s disease, Alzheimer’s and ataxia. 6-9

Dosing Issues & Cost

• The benefits of CoQ10 supplementation became wide known after the positive Parkinson’s disease trial results were published in 2002.7 The problem was that these positive results were seen with doses of 1,200 mg/day of CoQ10. Referring to this data I have heard many doctors tell patients that there is no benefit of taking a lower dose CoQ10. There are numerous studies showing benefit of CoQ10 at 100-200 mg/day. One such study is quoted above where 120 mg/day of CoQ10 was utilized.
• I have seen 10-20 point systolic reductions in blood pressure in many patients taking 100 mg/day of CoQ10.
• An explanation as to why higher doses were needed for benefit in the Parkinson’s study is that we are talking about patients with advanced neurodegenerative disease. Other studies have shown increases in brain CoQ10 levels at much lower doses and with neuro-protective effects.6
• Another important consideration is that the cost of CoQ10 has been a prohibitive factor for many patients. Luckily, at the writing of this article the wholesale price of CoQ10 has just come down significantly. The cost of taking 100 mg/day of CoQ10 is a manageable $25/month.

Summary/Clinical Recommendations

• Statin drugs lower the levels of CoQ10 in patients. This reduction in CoQ10 can have negative implications for cardiovascular, neurological, and immune health.
• The definitive study showing the negative effects of this CoQ10 depletion has not been done and will probably not be done.
• Looking to other studies we find that CoQ10 supplementation does indeed impart a benefit on cardiovascular, neurological, and immune health.
• CoQ10 has come down in price and doses of 100 - 200 mg/day have been shown to be of benefit.
• It is important to let our patients know that statin drugs reduce levels of CoQ10 and to inform them that we are not certain what this implies. However, the choice should be given to them to take this supplement when they are given a prescription for a statin drug.
• Patients at high risk and with a history of cardiovascular or neurological events should be given the recommendation to start CoQ10 supplementation if they are on statin therapy.

Acetaminophen (Tylenol®): Glutathione Depletion

• Glutathione is a tripeptide of L-glutamine, L-cysteine, and glycine. It is an extremely important antioxidant and cell protectant. The liver has the highest stores of Glutathione where it is used as a detoxification conjugate. It is also a co-factor for a number of other enzymes.
• Acetaminophen use can deplete the liver of Glutathione and lead to liver failure.
• The FDA Public Board of Inquiry met in 2004 and determined that stronger label warnings were needed on acetaminophen products. This was due in part to the unintentional 12,000 E.R. visits and 100 deaths per year as caused by this class of drugs. Most of these events were due to liver failure.
• I have the Adobe PDF report from the FDA for the above listed statistics. If you are interested, contact me and I will email it to you.
• The argument put forth is that the taking of acetaminophen products is safe if a patient follows dosing directions. I do not necessarily disagree. The problem is that a large number of patients do not gain any symptom benefit from the suggested dose, but they do at a higher dose. It is not at all uncommon, if not typical, to have a patient take higher than the recommended dose of acetaminophen. Thus, their chance of experiencing an adverse or deadly side-effect from this drug increases.
• N-acetylcysteine (NAC) is an established antidote for acetaminophen overdose. NAC provides a supply of L-cysteine which often limits the in-vivo production of glutathione when deficient. Following its intestinal absorption, NAC is converted to circulating cysteine and can effectively replenish liver glutathione levels.11
• It is important to assess the regular acetaminophen intake of a patient. If a patient takes frequent or daily doses of this drug, it is a prudent recommendation an intake of 1,000 mg of NAC per day as a dietary supplement.
• NAC is easy to find and is inexpensive.

Antibiotics: Intestinal Bacterial Imbalance

• A common side-effect of oral antibiotic therapy is acute diarrhea. A meta-analysis of available randomized placebo-controlled studies reveals that probiotics (friendly bacteria) significantly reduced antibiotic-associated diarrhea by 52% (95% CI 35-65%).12, 15
  The clinical consideration of antibiotic side-effects should go beyond the immediately identifiable symptoms of diarrhea. Antibiotic use influences the intestinal colonization of healthy bacteria which are essential for proper gut function.13, 14,18 The implication is that the disruption of the ratio of healthy bacteria to opportunistic and/or pathogenic bacteria can have a negative long-term effect on gut function. Thus, antibiotic mediated gut bacterial changes may possibly lead to future intestinal and extra-intestinal diseases.
• Some of the potential intestinal diseases include inflammatory bowel disease, irritable bowel syndrome, Helicobacter pylori induced gastritis, atopic diseases, and cancer.14
• The use of any oral antibiotic therapy can have immediate and future negative effects on gut and, I would then argue, whole body health. A number of studies have investigated the connection between microflora disruption and the increased incident of allergies, asthma and chronic sinusitis.14, 16-17 The mechanism of host immunity disruption is not completely understood. However, the relationship between microflora disruption and these diseases is strong. One study conclusion stated:

  “The cumulative data are beginning to support the notion that probiotic and prebiotic strategies be considered for patients coming off of antibiotic therapy.” 16

• The clinical decision-making then moves to what recommendation to give your patient. The common recommendation involves the eating of yogurt to prevent symptoms. There are a couple of problems with this recommendation. The first deals with the fact that many patients will eat the yogurt with their antiobiotcs. This could potentially decrease the effectiveness of the antibiotic therapy as a portion of the antibiotic may act upon the live bacteria within the yogurt. Thus, the beneficial bacteria provided within the yogurt are destroyed and the antibiotic strength could be diminished before being absorbed into the patient’s body.
• The second problem with recommending yogurt is that the amount of beneficial bacteria is limited to one species and is supplied in relatively low amounts (millions vs. billions). Newer studies suggest that mixtures of beneficial bacteria may hold the highest benefits for our patients.14
• My recommendation is that you tell patients to consider purchasing a probiotic supplement. Let them know that a blend of multiple strains is best. You can direct them to our clinic, www.ZimmerNutrition.com, or the local health food store. To decrease the chances of this supplement interacting with the antibiotic I tell patients to take the dose of probiotic just before bed and immediately upon waking. I usually suggest that they keep the bottle on their bedside table for better compliance.

Final Thought

It is important to be mindful of how any treatment we suggest for a patient may affect them in both the short-run and in the long-run. It is also important to inform our patients of options they can pursue to aide in a better therapeutic outcome. We, as clinicians, should not predetermine that something might be too expensive or that a patient would not want to take a supplement in addition to their prescription. I believe that it is important to give them the information, give them our recommendations, and then let them decide.

• You can contact Dr. Zimmer with any questions, requests, or responses at This e-mail address is being protected from spambots. You need JavaScript enabled to view it or at 317-813-1998 / toll free 1-888-813-1998.

References

1. Mabuchi H, Higashikata T, et al. Reduction of serum ubiquinol-10 and ubiquinone-10 levels by atorvastatin in hypercholesterolemic patients. J Atheroscler Thromb. 2005;12(2):111-9.
2. Passi S, Stancato A, Aleo E, et al. Statins lower plasma and lymphocyte ubiquinol/ubiquinone without affecting other antioxidants and PUFA. Biofactors. 2003;18(1-4):113-24.
3. Tran MT, Michell TM, Kennedy DT, Giles JT. Role of coenzyme Q10 in chronic heart failure, angina and hypertension. Pharmacotherapy. 2001 Jul;21(7):797-806.
4. Singh RB, Wander GS, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc Drugs Ther. 1998 Sep;12(4):347-53.
5. Rusciani L, Proietti I, et al. Low plasma coenzyme Q10 levels as an independent prognostic factor for melanoma progression. J Am Acad Dermatol. 2006 Feb;54(2):234-41. Epub 2005 Dec 27.
6. Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci USA 1998 Jul 21;95(15):8892-7.
7. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson’s disease: evidence of slowing functional decline. Arch Neurol 2002; 59:1541-1550.
8. Artuch R, Brea-Calvo G, et al. Cerebellar ataxia with coenzyme Q10 deficiency: diagnosis and follow-up after coenzyme Q10 supplementation. J Neurol Sci. 2006 Jul 15;246(1-2):153-8. Epub 2006 May 3.
9. Li G, Zou L, Jack CR Jr. Yang Y, Yang ES. Neuroprotective effect of Coenzyme Q10 on ischemic hemisphere in aged mice with mutations in the amyloid precursor protein. Neurobiol Aging 2006 Jun 26.
10. Jolliet P, Simon N, Barre J, et al. Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences. Int J Clin Pharmacol Ther 1998;36:506-509.
11. Traber J, Suter M, Walter P, et al. In vivo modulation of total and mitochondrial glutathione in rat liver. Biochem Pharmacol 1992;43:961-4.
12. Sazawal S, Hiremath G, Dhingra U, et al. Efficacy of probiotics in prevention of acute diarrhea: a meta-analysis of masked, randomized, placebo-controlled studies. Lancet Infect Dis. 2006 Jun;6(6):374-82.
13. Westerbeek EA, van de Berg A, et al. The intestinal bacterial colonization in preterm infants: A review of the literature. Clin Nutr. 2006 Jun;25(3) 361-8. Epub 2006 May 4.
14. Broekae LI, Walker WA. Probiotics and chronic disease. J Clin Gastroenterol. 2006 Mar; 40(3) 270-4.
15. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006 Apr;101(4) 812-22.
16. Noverr MC, Huffnagle GB. The ‘microflora hypothesis’ of allergic disease. Clin Exp Allergy 2005 Dec;35(12): 1511-20.
17. Chan-Yeung M, Becker A. Primary prevention of childhood asthma and allergic disorders. Curr Opin Allergy Clin Immunol. 2006 Jun;6(3): 146-51.
18. Plummer SF, Garaiova I, Sarvotham T, et al. Effects of probiotics on the composition of the intestinal microbiota following antibiotic therapy. Int J Antimicrob Agents. 2005 Jul;26(1): 69-74.