Exploring Drug-Nutrient Interactions

Nutrition can have a critical impact on the way in which drugs affect the body.  In addition, drugs can alter the body’s nutritional requirements. A drug-nutrient interaction is defined as an “interaction resulting from a physical, chemical, physiological, or pathophysiologic relationship between a drug and a nutrient, multiple nutrients, food in general, or nutritional status.”^[1]  The outcomes of drug-nutrient interactions are typically associated with changes to the metabolism and/or the effect of the drug or nutrient, which can pose a serious threat to patient health. Individuals more at risk for drug-nutrient interaction complications are primarily those taking multiple medications including individuals with chronic disease conditions, the elderly, and individuals who may be immune or nutritionally compromised.^[2]

Drugs Impact on Nutrients and Nutritional Status

Many drugs can impact the overall nutritional status of an individual through alterations in appetite, gastrointestinal absorption, and nutrient metabolism. Drugs that alter appetite are either classified as orexigenic or anorexigenic, meaning increasing or decreasing appetite, respectively.^[3]  Therefore, a common listed side effect of specific drugs falling into these categories may be weight gain or weight loss. Patients should be informed when taking drugs with these potential side effects so that they can monitor and adjust dietary intake as needed.

Additionally, drugs can also impact the absorption, metabolism, or levels of the three macronutrients in the body: carbohydrates, fats, and proteins. Unlike drugs with orexigenic or anorexigenic side effects, drugs that impact macronutrients typically are utilized for these specific purposes.^[4] This is best represented by classes of antidiabetic drugs, which aim at maintaining blood glucose levels (carbohydrate) through various mechanisms. Furthermore, to manage blood lipid (fat) levels, drugs can be taken that either decrease fat absorption in the small intestine, or facilitate metabolism and excretion of blood lipids.^[5] Protein seems to be minimally affected by drugs; certain antibiotics’ mechanism of action is interference with bacterial protein synthesis. There is no evidence that this interference translates to mammalian cells.^[6]

Vitamins and minerals, also known as micronutrients, play important roles in overall health and assist in several key metabolic and enzymatic processes in the body. Therefore, the effects that drugs may have on the actions and/or levels of these micronutrients is critical to understand.  From a broad perspective, many drugs can alter the levels of vitamins and minerals in the body by interfering with absorption of these micronutrients in the gastrointestinal tract, distribution, metabolism, or excretion through urine or feces.^[7]

Vitamins are classified into two main categories, water soluble and fat soluble.  Water soluble vitamins include all of the B vitamins and vitamin C.  These vitamins are absorbed in the small intestine through energy-dependent and energy-independent transport mechanisms.  Due to the water-soluble nature of these vitamins, they are excreted fairly rapidly through the urine if an individual is sufficient and thus do not pose a great risk of toxicity.^[8]  Drugs that increase urinary excretion such as a diuretic or antihypertensive pose the highest risk for affecting water soluble vitamin levels (see Table 2.1 for more detail).^[9] Fat soluble vitamins include vitamin A (retinol), E (tocopherols and tocotrienols), D (calciferol), and K (phylloquinone and menaquinone).  This class of vitamins are absorbed in a similar mechanism to lipids and are not as readily excreted as water soluble vitamins, so toxicity is a considerable risk.^[10] Therefore, drugs that influence or interfere with lipid absorption pose the highest risk to fat soluble vitamin status.  An example of this interaction is bile acid sequestrants which interfere with bile acid absorption in the ileum, promoting the excretion of bile acids as well as fat soluble vitamins.^[11]

Importantly, any clinical manifestation of a drug-nutrient interaction may be patient-specific, as much as drug-specific. Development of an overt and severe micronutrient deficiency due to prescription drug use would be extremely rare. Instead, a lesser degree of micronutrient deficit(s) may be associated with clinical outcomes.^[12] Some examples of established drug-induced nutrient interactions include antibiotics and diuretics. Antibiotics are well understood to interfere with the absorption of iron from foods and thus individuals taking antibiotics frequently are at greater risk for development of iron deficiency anemia. Diuretics are commonly used to manage fluid levels in patients with edema or congestive heart failure by increasing urinary excretion of fluid. However, many electrolytes are excreted along with the fluid which can lead to dangerously low levels of key electrolytes such as sodium and potassium.^[13]

Many drug interactions with vitamins and minerals are due to interference with absorption or increases in excretion, leading to reduced levels of these micronutrients. However, there are some examples where drugs can increase the level of vitamins/minerals and may even be therapeutic.  For example, HMG-CoA reductase inhibitors (i.e. statins), a drug class used to treat elevated blood cholesterol, may improve vitamin D levels in the body through mechanisms that are still not fully understood.^[14]  An overview of common drugs and their known impacts on vitamin and mineral status’ is depicted in table 2.1 below.

Nutrients and Nutritional Status’ Impact on Drugs

A person’s nutritional status can also alter the impact of drugs. The most common example of this would be whether a drug is to be taken with or without food. If the prescription states to take with food, the drug likely is better absorbed with food and/or has adverse gastrointestinal side effects that are reduced when taken with food. On the contrary, prescription drugs may be taken without food if absorption is reduced in the presence of food.^[16]  Foods high in fiber and other bulking components can interfere with the drug reaching the intestinal absorptive cells and thus the drug ends up being partially absorbed and partially excreted.^[17]  There are two main types of fiber: soluble and insoluble. Both types interact with the gastrointestinal environment and its contents differently, causing alterations in GI function. Soluble fiber binds water and other hydrophilic compounds, slowing transit time through the intestine and adding bulk to stools. Because of its affinity for water, soluble fiber is commonly recommended for individuals dealing with diarrheal conditions.^[18] However, hydrophilic drugs may also bind soluble fiber, preventing complete absorption of the dose taken. Insoluble fiber acts differently because it doesn’t attract water and thus it speeds up transit time through the intestine. This means that drugs taken in the presence of insoluble fiber may have less time to be absorbed, which can result in lower bioavailability of the drug.^[19]

Aside from whether medication is taken with or without food, pre-existing nutrient deficiencies can also impact the way in which drugs interact with the body. For example, severe energy and protein malnutrition reduce enzyme levels involved in drug metabolism thereby reducing or altering their functions.^[20] Furthermore, overall dietary balance of macronutrients may influence drug action and efficacy. Clinical research studies have compared the effects of high-carbohydrate, high-fat, and high-protein diets on drug metabolism. In one clinical research study, three test diets were isocaloric and drug clearance of antipyrine and theophylline were analyzed for six normal male subjects.^[21] These drugs were utilized because of their dependence on liver CYP enzymes. Metabolic clearance for antipyrine and theophylline were significantly increased during the high-protein dietary period than during the other two diets. Conclusion of these studies indicated that substitution of protein for either dietary fat or carbohydrates can increase drug oxidation rates, whereas exchanging carbohydrate and fat has no major effect.^[22] Studies have also examined the effect of protein supplementation on drug clearance and demonstrated similar findings: higher protein loads are associated with increased rates of drug metabolism. Differences in dietary fat and carbohydrate intake do not confer similar effects.^[23]

The precise mechanism by which increasing dietary protein accelerates drug oxidation is unknown. Interestingly, this effect of protein can be leveraged within specific disease states. As an example, Parkinson’s patients may benefit from adhering to a low-protein diet.^[24] In Parkinson’s patients eating a high-protein diet, large neutral amino acids can inhibit the transport of levodopa across the blood-brain barrier, leading to reduced brain dopamine formation from exogenous levodopa.^[25] However, a “protein-redistribution diet”, where protein is restricted during the day and unrestricted near bedtime has been found to be beneficial in clinical studies. This is an example whereby dietary modifications augment pharmacological efficacy for a particular disease state.^[26]

From a micronutrient perspective, certain vitamins and minerals can alter drug metabolism and detoxification enzymes.  Many vitamin deficiencies and incidences of excess levels have been shown to alter hepatic phase 1 and phase 2 drug metabolism through various mechanisms.^[27]  While there are still many interactions that are not fully understood, some examples of known effects and mechanisms of these interactions are listed in Table 2.2 (Adapted from Raiten^[28])

Aside from broad effects on phase 1 and phase 2 drug metabolism, certain vitamins and minerals can also impact specific drug actions through interplay in pathways in which the drug is targeting. One of the most well-known examples of this is the effect of vitamin K on Warfarin (also known as Coumadin and Jantoven). Warfarin is an anti-coagulant agent used to prevent blood clots.^[29] Conversely, vitamin K’s primary function is to facilitate blood clotting, preventing wounds from bleeding excessively.  Therefore, patients who are taking warfarin or other blood thinners should be advised to maintain a consistent vitamin K intake while taking this drug, as changes in vitamin K levels can disrupt the drug action and efficacy.^[30] Interestingly, vitamin K is a recognized antidote for warfarin-induced bleeding. Another example of a vitamin that alters drug action is vitamin B6’s effect on levodopa. Vitamin B6 supplementation can enhance the peripheral conversion of levodopa to dopamine by dopa-decarboxylase so that less levodopa is able to cross the blood brain barrier and be converted to active dopamine there.^[31]

While many of the nutrient-drug interactions discussed above are detrimental, there are some instances where nutrition and medicine can be utilized together to improve outcomes. Selective Serotonin reuptake inhibitors (SSRIs) are a commonly used class of drugs used to treat depression/anxiolytic conditions. Previous research identified an association between low levels of folate and depression and that individuals with low folate levels were less likely to respond favorably to SSRI therapy.^[32] Interestingly, several studies have found that addition of folate supplementation (via L-methylfolate) to SSRI treatment significantly improved self-reported depression symptoms and greater satisfaction ratings of medication treatment.^[33] While the mechanism behind these improvements remains to be fully elucidated, these findings highlight an important interaction where nutrition modification and medication work synergistically to improve quality of life and overall health for patients.