A majority of adult Americans take at least one medication and many of these people take four or more medications, also known as polypharmacy, which increases the risk of drug interactions. When a drug interaction occurs, it is considered an adverse drug reaction (ADR) and a preventable medical error. Drug interactions are an expensive and potentially dangerous phenomenon and can lead to increased morbidity and mortality; interruption of necessary drug therapy, clinic, or hospital visits; increased length of hospital stays; increased health care expenses; lost wages, etc. In addition to taking multiple medications, there are other factors that put a person at an increased risk of experiencing a drug interaction, including the use of multiple pharmacies and/or multiple prescribers, acute medical conditions, age extremes (very young or elderly), decreased kidney or liver function, human immunodeficiency virus, female sex, metabolic or endocrine conditions, pharmacogenetics, and use of medications that have a narrow therapeutic index. Drug interactions can be described as drug–drug, drug–food, drug–nutrient, drug–herb, and drug–disease interactions.
When a patient experiences a drug–drug interaction, it typically occurs via a pharmacodynamics pathway or a pharmacokinetic pathway. The term pharmacodynamics refers to the effect a drug has on the body, and pharmacodynamic interactions occur when one drug modulates the pharmacological effect of another drug at the receptor-site level or in similar physiological systems to enhance or antagonize the effects of the other drug. This adverse interaction occurs without affecting the medications’ blood concentrations. The term pharmacokinetics refers to the effect the body has on the drug through drug absorption, distribution, metabolism, and excretion. Drug interactions at this level occur when one drug modulates the effect of another drug by altering its concentration. Drug–food, drug–nutrient, drug–herb, and drug–disease interactions can occur via similar pathways. This entry will focus on drug–drug interactions and some key principles of drug–food interactions.
Pharmacodynamic interactions are additive, synergistic, or antagonistic in nature. An additive interaction occurs when two drugs activate the same receptors in the body, leading to an enhanced effect. This type of interaction can also occur when two drugs are administered that work by activating different receptors, but the effects of both activated receptors are similar. In both cases, the effects are additive, meaning that one could quantify the effect of each drug by adding the effects of each individual drug to predict the combined outcome. A good example of this would be if two drugs were prescribed that have the same side effect of drowsiness, and after taking both, the patient predictably feels overly tired or sleepy.
Synergy is another interaction that enhances an effect, but the end result is magnified beyond an additive effect. Take the above example, and instead of the patient becoming overly tired, the patient unpredictably becomes lethargic or nonresponsive. Instead of the effects being additive in nature, a synergistic effect could be seen as more profound or exponential.
An antagonistic interaction occurs when a drug decreases or blocks the effect of another drug by being a receptor antagonist to the receptor a drug requires to exert its effect. This type of interaction can also occur when a patient is given two drugs that have opposing effects (unrelated to a specific receptor). A good example of this would be if a patient was given a drug that is a central nervous system stimulant and another drug that depresses the same system via a different pathway. The effects of these drugs may cancel each other out, or if one is more potent it may still be effective but to a lesser degree. A third way this type of reaction could occur is via competitive inhibition. In this situation, two drugs compete for use of the same receptor. The drug that has a higher affinity for the receptor wins out and the other drug’s effect is diminished.
The pharmacokinetics of a drug can be described as how the body processes the drug via its absorption from the gastrointestinal (GI) tract, its distribution throughout the body, its metabolism into other products (active and nonactive), and its elimination from the body. A pharmacokinetic drug interaction can occur via any of these mechanisms, but typically a drug interaction caused by a pharmacokinetic mechanism is the result of absorption or metabolism. The focus of this section will be on drug–drug interactions that occur due to changes related to these two pathways.
Absorption. Interactions involving absorption are usually related to changes in GI motility, changes in GI pH, potential for chelation, and inhibition of transport proteins. Most oral drugs are absorbed from the stomach or small intestine. If a patient is taking a drug that increases or decreases GI motility, it may alter the efficacy of other medications. Some medications require an acidic environment for absorption. Medications like antacids can increase pH, making the environment less acidic, which in turn can decrease the effectiveness of other medications that rely on an acidic environment for proper absorption. Chelation can occur when a medication is bound to another medication or element that makes it hard to absorb. The most common cause of this type of interaction is the use of antacids and multivitamins that contain calcium. There are a number of medications that will chelate with calcium, which in turn leads to decreased absorption. Medications that may chelate should be separated from the offending agent for at least two to four hours. Some drugs require transport proteins to move them across cell membranes. If a patient is taking a medication that requires a transport protein for absorption out of the intestine, but is also taking another medication that inhibits this transport protein, less of the drug will be absorbed, thus rendering the drug less effective.
Metabolism. Metabolism is an important part of pharmacokinetics. Many drugs require metabolism in the liver to break down the medication into nonactive metabolites in order to prevent potential toxic effects and to enhance elimination. Other drugs require metabolism to change an inactive parent drug into an active metabolite for the medication to be effective.
There are two phases of liver metabolism: Phase I metabolism includes oxidation, reduction, and hydrolysis via isoenzymes found in hepatocytes known as the cytochrome (CY) P450 system; phase II metabolism are conjugation reactions that occur via glucuronidation, acetylation, and sulfation.
Phase I metabolism is more heavily involved in drug interactions. Drug interactions involving the P450 system occur due to enzyme induction or inhibition. There are many P450 enzymes that are known to be responsible for drug metabolism; the most common isoenzymes are 2C9, 2C19, 2D6, and 3A4. A drug that is metabolized via a specific (or multiple) isoenzyme(s) would be referred to as a substrate of that isoenzyme(s). For example, if a medication is metabolized by 3A4, it is a substrate of 3A4. Medications can also be inducers and/or inhibitors of various isoenzymes.
Drug interactions occur when a drug that is a substrate of a specific isoenzyme is administered with another drug that is an inducer or inhibitor of the same isoenzyme. If a drug that is metabolized via 3A4 is given with a 3A4 inducer, one would expect there to be a lower systemic concentration of the drug and potentially a decreased effect. If an inhibitor were administered, one would expect the opposite effect. The opposite would also be expected if the substrate drug is a prodrug (or parent drug). Prodrugs need to go through metabolism to convert to an active form. If metabolism of a prodrug is induced, one would expect there to be a more active drug and a potential for increased toxicity. If metabolism of a prodrug is inhibited, the opposite would occur and one would expect the drug to be less effective.ofnote, some P450 isoenzymes are affected by genetic variability, and this can lead people to be poor metabolizers or fast metabolizers; these differences can result in profound variability in drug interactions as well.
Transport proteins can also be involved in interactions that effect drug metabolism. Transport proteins in the liver are required by some drugs to reach the site of metabolism. Inhibition and induction of these proteins could alter drug metabolism.
Different approaches are taken with these types of drug interactions. The pertinence and severity of the interaction are taken into account, resulting in avoidance of some medications, dose increases or decreases, and so on.
In general, food can affect the bioavailability of an oral medication. Bioavailability is the portion of the administered drug that remains unchanged when it reaches systemic circulation. If a drug is administered intravenously, the bioavailability is 100 percent. Drug oral bioavailability is dependent on a variety of factors, including, but not limited to, the physical properties of the drug, drug dosage formulation, drug absorption, drug metabolism, metabolic differences, current disease states, etc. When taking a drug, it is important to know if food alters bioavailability. Some drugs’ bioavailability does not change with concurrent food ingestion. If the bioavailability is altered, the bioavailability may be decreased or increased, and care should be taken to separate the drug from food by at least two to four hours. There are many specific drug–food interactions; below is a sampling of a few of the most pertinent.
Grapefruit Juice. Ingestion of grapefruit juice can impact levels of drugs that are metabolized via CYP3A4 or transported via P-glycoprotein (P-gp) in the gut, as this juice inhibits both of these pathways. This potential interaction does not impact [intravenous] medications, as it only impacts 3A4 and P-gp found in the gut. The impact can last more than five days, and the amount of grapefruit juice known to be significant is controversial, with some sources stating the amount in small ounces and others in terms of liters or quarts. Most health care professionals feel it is safest to avoid grapefruit juice when taking chronic medications that require these pathways.
Vitamin K–Rich Foods. There is a large population of people who require chronic anticoagulation for a variety of disease states such as atrial fibrillation, history of stroke, heart valve abnormalities, and genetic hypercoagulable states. Many patients attain the appropriate anticoagulation level by using warfarin. Warfarin inhibits vitamin K–dependent clotting factors produced by the liver. When patients ingest foods that are high in vitamin K, the effect of warfarin is lessened, and the patient is not properly protected from clot formation. If a patient were eating foods that are high in vitamin K and then suddenly stopped, the anticoagulation effect would be increased, placing the patient at risk for bleeding. Large amounts of vitamin K can be found in, but are not limited to, green leafy vegetables, broccoli, Brussel sprouts, onions, certain soy preparations, and a number of multivitamins and nutritional supplements. Patients using warfarin need to have regular monitoring of blood coagulability, and they should be aware of what foods and supplements are high in vitamin K. The key to preventing major swings in anticoagulation with warfarin is to maintain a consistent diet. If a patient loves kale, a vitamin K–rich food, she or he should be instructed to eat a consistent amount of kale daily. With dietary consistency, the drug dose can be adjusted to accommodate the food and stabilize the anticoagulation.
Alcohol. Alcohol is metabolized via aldehyde dehydrogenase and CYP2E1. When a person is a chronic heavy drinker, CYP2E1 is induced and its activity increases more than tenfold. This induction of CYP2E1 can lead to a number of drug interactions. The most notable occurs with acetaminophen. With chronic heavy use, the metabolism of acetaminophen is induced, producing more of N-acetyl-p-benzo-quinone imine, a toxic metabolite that can damage the liver.ofnote, with acute ingestion there is competitive inhibition of CYP2E1 and less of the toxic metabolite is produced, so the potentially toxic interaction is associated with chronic heavy use and not occasional consumption. Alcoholics and patients who regularly drink large amounts of alcohol should avoid acetaminophen use.
Dairy. Dairy can decrease the absorption of a variety of medications, from certain antibiotics to thyroid medications to chemotherapy-like medications via a chelation interaction. People taking medications that have decreased absorption when taken with dairy should separate medications from dairy by at least two to four hours to ensure proper drug absorption.
With many Americans taking more than one medication, the risk of drug interactions is of real concern. There are many ways an interaction can occur, whether it is with another drug, food, supplement, or even a disease. Interactions can occur via pharmacodynamic or pharmacokinetic modalities. Education of health care providers and patients about the potential for drug interactions and potential remedies, whether through avoidance, dose adjustment, or other means, is vital to prevent potential adverse effects.
See Also: Adverse Drug Events Reporting Systems; Adverse Drug Reactions (ADR) and Adverse Events (AE).
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