Clinical and Health Affairs
Drug-Nutrient Interactions
A Case and Clinical Guide
By Gregory A. Plotnikoff, M.D., M.T.S., FACP
■ Advances in pharmacokinetics and pharmacodynamics require new competencies related to pharmaceutical prescribing. First, both physicians and pharmacists need to recognize the potential negative impact of nutrients and dietary supplements on the absorption, metabolism, and utilization of prescription drugs. Second, physicians, even more than pharmacists, need to recognize the potential negative effects of pharmaceuticals on the absorption, metabolism, and utilization of nutrients. This article discusses common drug-nutrient interactions and presents a case that illustrates how unrecognized nutrient disruption may negatively affect a patient’s health and potentially result in unnecessary prescribing of medications. In presenting the case, we also provide a conceptual framework for assessing and treating this patient and a summary of current knowledge regarding drug-nutrient interactions.
In recent years, we have become increasingly aware of the potential negative effects of nutrients on the absorption, metabolism, and utilization of prescription medications. Classic examples described in the medical literature include the effect of calcium on thyroid medications,1 iron on levodopa or methyldopa,2 and iron and zinc on tetracyclines and quinolones.3-5 In addition, both grapefruit juice6 and St. John’s wort7 have been shown to affect the functioning of the gastrointestinal cytochrome P450 enzyme CYP3A4 (Table 1, Table 2). The potential for compromised efficacy or enhanced toxicity is of particular concern for patients taking medications with narrow therapeutic margins such as digoxin, lithium, phenytoin, and theophylline or for those taking drugs such as coumadin and cyclosporine, which require careful monitoring.
Until now, this concern has been excessively one-dimensional, focusing on the effect of nutrients on medications. However, knowledge of the opposite effect—drug-induced nutrient deficiencies—may be as or even more important. For example, recent articles have reported on the adverse effects of proton pump inhibitors on key nutrients such as B12, calcium, magnesium, and iron.8,9
Many commonly used pharmaceuticals can adversely affect nutrient status (Table 3) and precipitate development of new symptoms such as anxiety, depression, fatigue, fibromyalgia, or insomnia. Yet few articles in the medical literature summarize what is known about mechanism-based and idiosyncratic adverse drug reactions.10,11 This article attempts to raise awareness of the growing body of knowledge about the interaction between pharmaceuticals and nutrients and show how it might be used in clinical practice. It presents the case a patient who was seen in our clinic after his psychiatrist wanted to add a costly drug to his regimen to treat his ongoing depression and describes the testing that was done to determine whether his symptoms may have been caused by nutritional deficiencies. It also describes our approach to treatment.
Is Abilify Needed?
Mr. T is a 49-year-old white male who presented with significant fatigue as well as depression and insomnia that have severely affected his quality of life and capacity to work. His past history is remarkable for GERD, for which he has taken a proton pump inhibitor for seven years; worsening depression that has required trials of both SSRI and SNRI medications in increasing doses; borderline diabetes requiring exercise and weight loss; and hypertension requiring a thiazide diuretic. He has difficulty maintaining a normal potassium level despite supplemental prescription dosing. Mr. T recently started taking zolpidem (Ambien) and has noticed some improvement in his sleep. He reports drinking 4 to 6 ounces of alcohol per week and eating a diet high in processed foods that are rich in saturated fat. Despite his best efforts, he has failed to lose weight. He takes no supplements other than the prescribed potassium and has had to give up exercise because of his symptoms. His psychiatrist, concerned about the refractory depression, has recommended that he take aripiprazole (Abilify). Mr. T is concerned about both the cost of the drug ($450 per month) and its extensive toxicity profile. He came to our clinic asking whether this medication was necessary and what else he could do to control his depression.
The addition of aripiprazole to Mr. T’s regimen represents one medically appropriate approach to treating his symptoms. There is another one, however. Before writing another prescription, we might consider whether Mr. T has nutritional deficiencies that may be causing or exacerbating his symptoms or affecting the way his medications are working. Clinical indications for medical assessment of altered nutritional status include significant changes in affect, energy, memory, pain, sleep, or strength—symptoms that affect Mr. T.
To begin with, we considered whether Mr. T was making enough serotonin for his SSRI to work. If he was not making sufficient serotonin, he could not make melatonin, which is necessary for sleep. Could his need for a hypnotic agent and increased dosing of his SSRI suggest significant disruption of neurotransmitter production? And might any of his symptoms be attributed to adverse drug-nutrient interactions?
Two of Mr. T’s prescription medications had the potential to block his ability to properly digest and absorb the key amino acids (phenylalanine, tyrosine, tryptophan, methionine, cysteine), minerals (copper, zinc), and B vitamins necessary for neurotransmitter production. Proton pump inhibitors are extremely effective at blocking acid production and shifting the mean gastric pH toward the alkaline end of the scale. As we have learned from bariatric surgery patients and years of animal studies, increased gastric pH may inhibit digestion of proteins and absorption of crucial micronutrients including iron and vitamin B12.12 In addition, thiazide diuretics can deplete the body of magnesium, potassium, and zinc.13,14 Concerning in Mr. T’s case was his significant need for potassium dosing and borderline hypokalemia. This is a sign of functionally insufficient magnesium.
We also considered whether his diet and alcohol consumption were exacerbating any potential adverse drug-nutrient interactions. Surgery, malabsorption syndromes, and consuming a diet high in processed foods or very low in calories or an insufficiently planned vegetarian diet can place a person at risk for poor nutritional status. Because Mr. T ate a typical American diet, that is, one that is heavy on processed foods that are high in saturated fat, and consumed alcohol, he was at increased risk for both low vitamin B6 and low magnesium.
We ordered standard laboratory tests specific to our concerns. Those included tests for homocysteine (to assess B6, B9, B12 function), fasting B6, fasting B12, serum or urine amino acid profile, magnesium, and potassium.
Mr. T’s homocysteine level returned markedly elevated at 14.3 ng/mL (<9 µmol/L) with a normal glomerular filtration rate (GFR) of >60. His B12 was cautiously low-normal at 320 (200 to 1,000 pg/mL), which, when combined with the markedly elevated homocysteine, is an indication for a methylmalonic acid test for functional B12 deficiency. His B6 was barely measurable at 2 µg/L (6 to 50 µg/L), and his serum magnesium was low at 1.8 mg/dL (1.8 to 2.6 mg/dL). Urine amino acid testing demonstrated hypoaminoaciduria including low tryptophan, cysteine, methionine, and taurine.
In this case, the combination of low tryptophan and B6 likely blocked the patient’s capacity to make serotonin, as serotonin is derived from tryptophan in the presence of B6 as pyridoxal- 5-phosphate (P5P). Melatonin, the neurotransmitter so important for sleep, and which plays a role in metabolic syndrome, weight control, type 2 diabetes, and insulin resistance,15 mood,16 and antioxidant activity,17 is two biochemical steps removed from serotonin. B vitamins, methionine, cysteine, and magnesium are required for the transformation of serotonin to melatonin.
Additionally, the low taurine may have been clinically significant. In brain cells, taurine is required for retention of calcium, magnesium, and potassium. Low levels of taurine, an inhibitory neurotransmitter, mean less neuroprotection against glutamate-induced excitatory states.18 Taurine is also an antioxidant; and low taurine is associated with excess oxidative damage and aldehyde production in inflammatory states.
Mr. T’s low vitamin B6 was also clinically important. Nearly 60 enzymes in amino acid metabolism require vitamin B6 as P5P, so multiple pathways may be affected. These include the pathways for the production of serotonin from tryptophan and taurine from cysteine. Additionally, magnesium (as Mg-ATP) is a crucial cofactor in more than 300 enzymatic reactions including those for protein, carbohydrate, and fatty acid metabolism as well as those for the activation of vitamin B6. The combination of Mr. T’s low magnesium, low B6, and low amino acids highlights the cumulative or synergistic risks that come with interactions of pharmaceuticals and diet.
In treating Mr. T, we recommended supplementation with vitamin B6 (a total of 50 mg/day), a multivitamin with B vitamins and minerals, magnesium glycinate 600 mg/day, and a broad amino acid supplement. While on this regimen and undergoing other interventions including cognitive behavioral therapy and exercise, Mr. T did improve clinically.
Conclusion
What was responsible for Mr. T’s improvement? In the absence of controlled trials, we cannot state that treating documented nutrient deficiencies accounted for his clinical improvement. However, the growing evidence about drug-induced nutrient deficiencies and our expanding understanding of the effect of various nutrients on biochemical processes provides a rationale for our treatment of Mr. T and for testing for nutrient deficiencies in other patients who present with similar symptoms and medical histories.
The case of Mr. T illustrates the potential value of the expanded differential and laboratory testing used in the emerging discipline of interventional nutrition. In the future, physicians likely will not only need to know when and how to prescribe pharmaceuticals but also when and how not to prescribe them. To this end, gaining knowledge of the potential drug-nutrient interactions is a crucial first step. MM
Gregory Plotnikoff is a senior consultant for the Allina Center for Health Care Innovation and a practicing internist at the Penny George Institute for Health and Healing at Abbott Northwestern Hospital in Minneapolis.
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