NUTRIENT–DRUG INTERACTIONS

NUTRIENT–DRUG INTERACTIONS. The terms "nutrient-drug interaction" and "diet-drug interaction" refer to the process whereby the consumption of a food affects the absorption, metabolism, action, retention, and/or excretion of a drug, or conversely the process whereby taking a drug affects the absorption, metabolism, action, retention, and/or excretion of a nutrient.

Adverse consequences of nutrient-drug and diet-drug interactions are so common that in their 1996 accreditation standards, the Joint Commission on Accreditation of Healthcare Organizations began requiring hospitals to ensure that "patients are educated about the potential for drug-food interactions" by "[i]nstruction on potential drug-food interactions and counseling on nutrition intervention and/or modified diets, as appropriate" before they are discharged.

In the following discussion, we will first address the effects of diet and nutritional status on drug absorption, disposition, metabolism, and action; thereafter, we will address the effects of drugs on nutrient absorption, disposition, metabolism, and action, with attention to certain specific food/nutrient/drug interactions.

Terminology Used in Describing Nutrient-Drug Interactions

The following terms are useful when discussing nutrient-drug interactions:

• Pharmacokinetics: the characteristics of a drug's absorption, distribution, metabolic transformation (biotransformation), and excretion. Interactions affecting pharmacokinetics are the most common form of nutrient-drug interactions.
• Pharmacodynamics: the mechanisms of drug action and the relationships between a drug's concentration at the active site and its pharmacological effects. Interactions affecting pharmacodynamics are less common, and certainly less well-studied, forms of nutrient-drug interaction.
• Absorption: the rate at which, and the extent to which, a drug leaves its site of administration. Sites of drug absorption can include all surfaces of the body, and for drugs given by injection, the bloodstream. Specifically, drugs taken orally are absorbed to some extent in the mouth and stomach (if the formulation is designed for this purpose), but predominantly in the small intestine, the organ that is specifically designed for absorption. In order to be absorbed, drug particles must be broken down and dissolved in liquid, for example, by both stomach juices and the fluid you swallow when taking the pill, so that they can reach the cells of their absorption site successfully. Note, however, that there are some drugs that may be destroyed in the stomach—therefore many preparations are coated in order to pass through the stomach intact, and only be broken down when they reach the small intestine.
• Bioavailability: the extent to which a drug reaches its site of pharmacological action. In practice, bioavailability is measured as the extent to which the drug reaches the bodily fluid that bathes the tissue site where the drug should act. The bioavailability of a drug increases with increased absorption and distribution of the drug to its site of action, and decreases with increased metabolism and excretion of the drug before it can reach the site of action.
• Biotransformation: the process through which drugs, nutrients, and hormones can be metabolized, and thereby either activated or inactivated.

Host Factors Affecting the Development of Adverse Interactions between Foods and Drugs

The likelihood of adverse interactions between foods and drugs is affected by the following factors: (1) age, because older people have less metabolic reserve; (2) medical conditions, such as diabetes mellitus, that lead to abnormalities in both food and drug handling; (3) conditions, such as arthritis, that increase the likelihood that the person will be taking over-the-counter medications; (4) sex; (5) size and fat mass, which are related to a person's diet and nutritional status; (6) exclusionary diets, for example, diets from which all animal products are excluded (vegan diets); (7) the use of substances of abuse, such as alcohol, which alter the handling of both drugs and nutrients; and finally, (8) medical conditions that require the care of different specialists and multiple medications.

Effects of Foods and Food Components on Drug Absorption and Bioavailability

There are at least four ways in which foods and their components can affect the absorption and bioavailability of a drug:

• Physicochemical binding: The food component and the drug can bind to each other physicochemically, so that neither the drug nor the component can be absorbed. For example, the antibiotic tetracycline binds with calcium, magnesium, iron, and zinc; once bound, the antibiotic becomes unavailable—that is why this drug should not be taken with dairy products, which contain high amounts of these minerals.
• Stability: The food can alter the stability of the drug preparation in the stomach, so that it breaks down before it can be absorbed.
• Gastric emptying: The drug or food can change the rate at which the stomach empties, and therefore the rate at which the drug arrives in the small intestine. Gastric emptying is normally a three-phase process. When you begin to eat, a small amount of food mixed with stomach juices enters the small intestine. The presence of this mixture makes the small intestine send a signal to slow down gastric emptying. This slow-down allows the stomach time to thoroughly mix the food with the stomach juices, and to break down the food into small particles. Fatty foods are highly effective in slowing stomach emptying, while erythromycin, an antibiotic, increases the speed of gastric emptying.

A drug taken on an empty stomach is likely to be dumped rapidly into the small intestine. As a result, there will be only one peak in the curve describing the concentration of the drug in the blood across time. By contrast, a drug taken with food will arrive in the small intestine more slowly, and in small spurts (via the second phase of gastric emptying), so that there may be two or more peaks in this curve. Remember, though, that one job of the stomach is to break down pills into particles. If you take a pill on an empty stomach, it may arrive in the small intestine more quickly, but it may not be absorbed if the pill is not sufficiently broken up. Furthermore, a drug taken on an empty stomach will pass more rapidly through the small intestine, with the result that the time for absorption is shorter and less of the drug may be absorbed. Finally, in the third phase of gastric emptying, approximately every 24 hours, the normal stomach has a massive series of contractions that propel larger particles and any remaining material in the stomach into the small intestine. If there are any large drug particles left behind in the stomach, this "housekeeping" emptying may lead to a sudden dumping of a large quantity of the drug into the small intestine, with a corresponding sharp peak in the blood concentration of the drug. The duration and extent of the phases of gastric emptying in response to food vary considerably from individual to individual, but is longer in women than in men, and is much longer in chronic alcoholics. Smoking while eating also delays stomach emptying.

The fourth way in which foods can affect the absorption and bioavailability of a drug is by:

• Competition for absorption: Many drugs use the intestine's natural transport systems—which normally transport food components—to cross the intestinal wall. They therefore compete with food components for transport. For example, L-dopa and methyldopa (drugs used to control Parkinson's disease) use the same transporter mechanism as aromatic amino acids from proteins, so absorption of these drugs is decreased if you eat a high-protein meal at the same time you take the drug.

In general, we can divide drugs into those that are best absorbed on an empty stomach (for example, most but not all antibiotics, digitalis preparations, captopril, and sucralfate); those absorbed best with food (for example, some hypertension medications such as chlorothiazide and spironolactone, and drugs for blood lipid abnormalities such as lovastatin and gemfibrozil), and those for which absorption varies by the type of preparation or formulation. For example, drugs that are enterically coated (so that they are not destroyed by stomach acid) may be more easily absorbed if they are taken with food, because a long stay in the stomach may weaken the coating just enough that it disintegrates more easily in the small intestine.

The examples given above are general rules and may not be true for the specific preparation you may be taking. Therefore, it is critical to check the package insert for your drug and to consult with your pharmacist. For example, theophylline, a commonly used asthma drug, comes in several different formulations, depending on the manufacturer. One version of theophylline is best absorbed when accompanied by a high-fat meal, while another is poorly absorbed. The rate of absorption of theophylline is extremely important because it is one of the many drugs that has a narrow therapeutic window; in other words, there is a very small difference between the concentration of drug that you need in your bloodstream for it to be effective, and the concentration at which the drug becomes toxic. For the drug to work properly, it is critical to maintain a steady level of the drug in the bloodstream—neither too little nor too much. Therefore, switching from one formulation to another has to be done carefully.

Effects of Foods and Food Components on Drug Biotransformation

Biotransformation can be divided into two phases: Phase I, in which compounds are transformed by enzymes (proteins that transform the structure of other molecules such as drugs to make them either inactive or more active), and Phase II, in which compounds are prepared for excretion in the urine by attaching a molecule that makes them soluble in water. The small intestine has some capacity for drug biotransformation, but the major site of biotransformation is the liver. Because blood from the small intestine must pass through the liver before it goes on to the rest of the body, some drugs that are readily absorbed may not be bioavailable, because they are inactivated by the liver before they can get to the site of action. Blood flow through the liver, and the size of the liver itself, decrease as people age, so some drugs may be effective at lower doses in the elderly than in the young.

The dietary factors that activate the liver enzymes are just beginning to be elucidated. These include both nutritive factors (protein, carbohydrate, and fat) and non-nutritive factors, compounds in charbroiled meat, in cruciferous vegetables such as cabbage, turnip, and broccoli, and in citrus fruits, especially grapefruit. If you are taking a drug that is activated or inactivated by liver enzymes, it is important to maintain a diet that does not vary much from day to day in order to assure a steady level of the active drug in your bloodstream. Note that large changes in macronutrient composition of your diet, for example, adoption of a low-protein diet, can also affect Phase II biotransformation, and therefore drug excretion.

Effects of Drugs on Food and Nutrient Intake and Function

Drugs can affect food and nutrient intake, either as a desired effect or as a side effect. They can alter appetite; cause nausea and vomiting; cause food aversions; alter the taste of food, decrease taste sensations, or cause the mouth to be painful; cause gastric irritation; and alter intestinal function. One class of drugs that can cause all of these problems consists of the anticancer drugs, which can potentially cause malnutrition because they can decrease food intake dramatically.

Specific Diet/Food-Drug Interactions

There is a large number of well-known food-drug interactions in which the drug's action is altered by specific dietary components. Common examples are diuretics used for hypertension, digoxin used for cardiovascular disease, coumarin anticoagulants used for blood thinning, and monoamine oxidase (MAO) inhibitors used for depression. Similarly, there are a number of drugs, such as the drugs designed to reduce stomach acidity, that affect vitamin and mineral status, requirements, and activity.

Drugs can inhibit enzymes that may be critical for the metabolism of toxic substances in food. In the case of disulfiram, a drug used to curb alcohol consumption, the enzyme inhibition is the desired therapeutic effect. This drug inhibits aldehyde dehydrogenase, the enzyme that breaks down the aldehyde derived from alcohol consumption. As a result, people taking the drug become ill when they drink alcohol, and thus learn to avoid alcohol. For most drugs, however, food-drug incompatibility is an undesirable side effect.

General Principles

The considerations we have discussed bring us to enunciate two important general principles:

1. First, if you are taking any drug, either prescription or over-the-counter, be sure to consult your pharmacist concerning any nutrient-drug interaction for that drug.
2. Second, be sure to take both drug and food on a regular basis, so that drug absorption, action, metabolism, and excretion are consistent and predictable.

See also Assessment of Nutritional Status; Disease: Metabolic Diseases; Enteral and Parenteral Nutrition; Health and Disease; Immune System Regulation and Nutrients; Intestinal Flora; Nutrients; Nutrition.

BIBLIOGRAPHY

Joint Commission on Accreditation of Healthcare Organizations. 1996 Comprehensive Accreditation for Hospitals. Regulation PF2.2.3. Oakbrook Terrace, Ill., 1995.

Utermohlen, V. "Diet, Nutrition, and Drug Interactions." In Modern Nutrition in Health and Disease, edited by M. E. Shils, J. A. Olson, M. Shike, and C. A. Ross, pp. 1619–1641. 9th ed. Baltimore: Williams and Wilkins, 1999.

Virginia Utermohlen