For nurses, the once-simple task of administering medications is not what it used to be. Between 3% and 7% of hospital admissions in the United States are estimated to be for treatment of adverse drug reactions. Additionally, each time a person is hospitalized (regardless of the cause), the risk of having at least one adverse drug reaction is 10% to 20%.¹ Among the adverse reactions are drug-drug interactions. These interactions usually involve prescription drugs but may involve the addition of nonprescription (over-the-counter) drugs, and most commonly include interactions with aspirin, antacids, and decongestants.²

In one retrospective study of more than 400 adverse drug events, 158 were responsible for hospital admission or extension of the hospital stay. Of these, 96 (62.3%) were considered preventable, and 23 (24%) were considered severe to life-threatening.³ Of the preventable adverse drug event cases, 80% had documented toxic drug concentrations or abnormal laboratory values, and 26% were documented to be the result of drug-drug interactions.³

A drug interaction occurs whenever the diagnostic, preventive, therapeutic, or toxic action of a drug is modified in or on the body by another substance, such as occurs in combination with the presence or absence of food or composition of the diet, or the concomitant action/counteraction of another medication or chemical substance (e.g., prescription drugs, over-the-counter [OTC] medications, nutraceuticals/nutriceuticals, or recreational drugs).² Some interactions are intentional and beneficial to patients; however, the majority are unintentional and may have deleterious effects. Unfortunately, when patients need treatment with multidrug regimens, it is not always possible to avoid an interaction among prescribed drugs or other elements involved in the proper administration of those drugs.

Drugs may interact in many ways. A drug may duplicate or oppose the intended effect of another drug or may alter rates of absorption, metabolism, or excretion.² These events usually occur as a result of a drug-drug interaction or a drug-food interaction, but may also occur as a direct result of the counter effects of concomitant disease on the intended activity of the drugs. This is especially true of concomitant diseases that change digestive processes, modify gastrointestinal (GI) absorption, or alter hepatic metabolic processes, as well as of drugs (IV or oral) affecting metabolic processes of drugs taken orally.

Absorption

Drug absorption through the GI tract may be affected by the formulation of the medications, by interactions between and among them, by elements of the gastric environment, or by diet and digestion or disease factors.^2,4

1. Some drugs affect the absorption of other drugs.⁴ Morphine and codeine may increase drug absorption by prolonging emptying time within the small intestine, while cathartics and antacids interfere with the absorption of oral medications through the stomach and intestinal tract walls by increasing peristalsis or coating (blocking) mucosal linings, preventing the release of acids and enzymes necessary for drug absorption.

2. Drugs interact with each other during absorption.⁴ Antifungals, as a class, have many precautions about drug-drug interactions that modify absorption. Phenobarbital inhibits the absorption of the oral antifungal agent, griseofulvin, lowering serum concentrations and impairing its effectiveness. In cases such as this, administration times should be staggered so that doses of each drug are at least one hour to two hours apart.^5,6 When taken orally, imidazole compounds like ketoconazole may enhance the anticoagulant effect of coumarin-like drugs. Ketoconazole tablets may alter the metabolism of cyclosporine and methylprednisolone, resulting in elevated plasma concentrations of the latter drugs.⁷

3. Drugs modify absorption by altering the contents of the GI tract. Histamine (H2) antagonists, such as sucralfate, and antacids can alter the pH and affect the solubility and stability of medications, thereby reducing or increasing absorption. Antacids reduce the absorption of drugs recommended to be taken on an “empty stomach,” as do fluoroquinolones and barbiturates,⁶ by altering the pH or by binding with other agents, such as digoxin and tetracycline products.⁸

Even the ingredients used in the antacids make a difference. Antacids containing only aluminum increase the absorption of benzodiazepines, while magnesium-aluminum hydroxide antacids diminish the rate, but not the extent, of benzodiazepine absorption. Some antacids tax the renal elimination process and should not be used on patients with renal insufficiency. Antacids should be taken at least two hours before or after the administration of most drugs, with the exception of steroids, regular aspirin, and nonsteroidal antiinflammatory drugs, which are often recommended to be taken with something serving as gastric protection (e.g., antacids or food).^9,10

4. Foods and digestive disorders can affect drug absorption and bioavailability. High-fiber foods may bind with a drug and prevent it from being absorbed. Laxatives or diarrhea speed the passage of substances through the digestive tract, thereby reducing drug absorption.⁴

Distribution

1. Many drugs are extensively bound to plasma proteins. While protein-bound, drugs cannot perform their intended therapeutic actions or be eliminated from the body. An increase in unbound drugs in the plasma not only enhances the pharmacologic effect but also promotes the renal and/or hepatic elimination of the drug. Therefore, the interaction of two drugs, each of which is highly protein bound, will produce an increased amount of free drug of one or both of the drugs in the plasma, since they compete for the same binding sites. This effect may be beneficial (see next section) or detrimental, depending on the drugs involved.

2. Some drugs are intentionally prescribed for their effect on the protein-binding of another. The therapeutic effect of warfarin, a highly protein-bound anticoagulant, is a direct result of the amount of free (or unbound) warfarin in the blood.¹¹ Aspirin (ASA) is sometimes intentionally administered with this drug for an additive effect — ASA competes for the same binding site, pushes warfarin off, and increases its anticoagulant effect.

Likewise, thiazide diuretics displace the oral antidiabetic drug, glyburide, from plasma protein, thus inhibiting its hypoglycemic effect, promoting loss of glucose control and resulting hyperglycemia.¹² A similar blocking effect occurs during the simultaneous IV administration of nitroglycerin and heparin because nitroglycerin keeps the heparin tightly bound.¹³ If nitroglycerin is stopped first, heparin is quickly unbound and the flood of drug in plasma may precipitate bleeding. To diminish this reaction, give the drugs in different extremities or discontinue the heparin first.

3. Some drugs displace other medications from tissue-binding sites. Quinidine, an antidysrhythmic, and calcium-channel blockers, displace digoxin from its binding sites in skeletal muscle.¹⁴ If these drugs are given concurrently, the digoxin dosage usually needs to be reduced by 35% to 50% to prevent digitalis toxicity.

Metabolism

Newborns and elderly patients metabolize drugs more slowly than children and young adults do. Patients with kidney or liver disease have greater difficulty eliminating drugs and their metabolites.⁴

Liver enzymes convert drugs to active metabolites or inactive drugs. The P-450 enzymes are the primary mechanism for chemically altering drugs. The levels of P-450 enzymes control the rate at which many drugs are metabolized, and they can become overburdened when concomitant medications impose on the same metabolic system.⁴

1. Differences in the P-450 enzyme system profoundly influence drug effects.⁴ Biotransformation, mediated largely by the liver, is one determinant of drug concentration.⁴ Any change in the activity of drug-metabolizing enzymes in the liver may affect drug action. This activity is influenced by drugs that increase enzyme activity through enzyme induction and those that inhibit enzyme activity.  However, enzyme induction does not occur with the first dose of a drug. It occurs gradually after seven to 10 doses. Also, this effect may last until, or even two weeks after, the drug is discontinued.

2. Some drugs stimulate the hepatic P-450 system. Phenobarbital is a classic stimulator (inducer) of liver drug metabolism.⁶ It induces the liver to produce more microsomal enzymes, which, in turn, increases the biotransformation of a variety of drugs, including itself, and decreases their plasma concentration. The effect of phenobarbital on drug metabolism is usually seen within a few days and its maximum effect after two weeks to three weeks. Other well-known enzyme inducers are rifampin and phenytoin. If phenobarbital, rifampin, or phenytoin are administered, the dose of the other drug should be increased.⁶

3. A few drugs inhibit the hepatic P-450 system. With enzyme inhibition, one drug inhibits the metabolism of another, decreasing the activity of drug-metabolizing enzymes. Enzyme inhibitors include such drugs as cimetidine, allopurinol, oral anticoagulants, tricyclic antidepressants, erythromycin, ciprofloxacin, fluoxetine, ketoconazole, and omeprazole.

Enzyme inhibition takes place more quickly than enzyme induction. In fact, it takes place as soon as there is sufficient therapeutic concentration of the drug.⁴ This results in high plasma concentrations and an enhanced pharmacologic effect on other drugs, so that dosing may need modifications. Antiretroviral medications and drugs used in the management of opportunistic infections and primary care (e.g., macrolide antibiotics, azole antifungals, cholesterol-lowering medications), are particularly prone to drug interactions. As new information on drug metabolism and transport becomes available, the interpretation of the clinical significance of these interactions may change.¹⁵

4. Some drugs affect the biotransformation of other drugs. Commonly used substances also affect drug biotransformation.² Alcohol acts as an inducing drug, building tolerance to sedatives and other drugs.² Tobacco has been known to increase the metabolism of theophylline and phenytoin.¹⁶ Patients who smoke or who are exposed to second-hand (passive) smoke may need larger doses of theophylline or phenytoin to maintain therapeutic plasma levels.

Elimination

Drug elimination usually involves the urinary and intestinal tracts, in different proportions. Drugs bound to plasma proteins are not filtered; only unbound drugs are contained in the filtrate.

Kidney function can be impaired by many disorders (e.g., hypertension, diabetes, and recurring infections), by exposure to high levels of toxic chemicals, and by age-related changes.⁴ To be extensively excreted in urine, a drug or metabolite must be water soluble and not bound tightly to proteins. The acidity of urine, which is affected by diet, drugs, and kidney disorders, may affect the rate at which the kidneys excrete some drugs.⁴

1. Interference with urinary excretion may delay or enhance drug effects. When some drugs are administered together, interference with the elimination of one or both drugs may occur. This interference may be used to achieve a therapeutic effect. Probenecid, which is used to treat gout, may be combined with penicillin to reduce the excretion of penicillin by the kidney, lengthening its duration of activity. Another example of an adverse effect may occur with the excretion of digoxin, which is proportional to the glomerular filtration rate. Some drug classes (including diuretics, antihypertensives, antiarrhythmics, antiparkinson agents, anticoagulants, psychoactives, hypoglycemics, and analgesic drugs) pose special risks for older patients as a result of age-related reduced urinary clearance.¹⁶

Warfarin sulfate affects the metabolism and excretion of other drugs. Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a result of warfarin’s interference with either their metabolism or excretion.¹¹

2. Some drugs, dietary elements, and diseases change urinary pH, which may enhance urinary excretion of medications (referred to as “ionic trapping”). The clinical impact of effects on drug elimination rates, stemming from changes in urinary pH, depends on what proportion of the total elimination is derived from renal elimination. Acidification of urine increases reabsorption (i.e., decreases excretion) of weak acids and decreases reabsorption (i.e., increases excretion) of weak bases.¹⁷ The opposite occurs after alkalinization of urine. For example, making urine more basic may enhance the excretion of weak acids, such as aspirin. This is one way to rapidly eliminate aspirin in cases of aspirin overdose.

Drug-Food Interactions

Individual food components may enhance, retard, or decrease drug absorption. Deficiency of such nutrients as calcium, magnesium, or zinc may impair drug metabolism. High-protein diets may enhance the rate of drug metabolism in part by stimulating the induction of cytochrome P-450. Diets that alter the bacterial flora may markedly affect the overall metabolism of certain drugs. Energy and protein deficiencies reduce tissue levels of enzymes and may impair body response to drugs by reducing absorption and causing liver dysfunction.¹⁸

1. The absorption of oral medications depends on the length of time they remain within the stomach or the intestine, and food alters this time period. Nurses should teach patients to take their medications consistently, with or without food as recommended in the prescribing information, so the same amount of drug is absorbed or available with each dose.

2. Food impairs drug absorption by binding with the drug or by interfering with its metabolism. The most important interactions are those associated with a high risk of treatment failure arising from a significantly reduced bioavailability. These interactions have the following dynamics:¹⁹

• Chelation with components in food (e.g., with alendronic acid, clodronic acid, didanosine, etidronic acid, penicillamine, tetracycline) or in dairy products (e.g., with ciprofloxacin, norfloxacin)
• Other direct interactions between drugs and specific food components (e.g., with avitriptan, indinavir, itraconazole solution, levodopa, melphalan, mercaptopurine, perindopril)
• Food-altered rates of physiologic response (e.g., rates of gastric acid secretion or hepatic metabolic rates) may reduce the bioavailability of certain drugs (e.g., ampicillin, azithromycin capsules, didanosine, erythromycin stearate or enteric coated, isoniazid, methylxanthines)
• Altered vitamin and mineral metabolism (eg, diuretics, corticosteroids, purgatives [potassium depletion]; cortisol, aldosterone, estrogen-progestin, phenylbutazone [sodium retention]), thereby potentially altering the activity of concomitant drugs dependent on those specific vitamin or mineral levels for efficacy¹⁹

3. Foods decrease the absorption of some oral medications. Certain high-protein foods may decrease the absorption of drugs in the intestine because certain drugs compete with the protein-metabolism output of amino acids for active transport across the intestinal wall. Protein intake is best spread equally in three to six meals a day to minimize these reactions.

4. Foods enhance the absorption of some oral medications. Concomitant food intake may result in an increase in drug bioavailability. The mechanisms involved are —

• Food-induced increase in drug solubility (albendazole, atovaquone, griseofulvin, isotretinoin, lovastatin, mefloquine, saquinavir, and tacrolimus)
• Food-induced increase in the secretion of gastric acid (itraconazole capsules) or bile (griseofulvin and halofantrine)¹⁹

Acidic foods, such as tomatoes, fruits, and vegetables and some fruit juices, cause drugs, such as penicillin G and erythromycin, to break down more quickly in the intestine.²⁰ These agents are best taken with water. Grapefruit juice has recently been associated with increasing the absorption and thus the plasma level of several drugs — cyclosporine, and several calcium-channel blockers. Grapefruit juice also inhibits the metabolism of some drugs (macrolide antibiotics).^2,20 Grapefruit juice directly inhibits intestinal uptake of some drugs. It diminishes oral bioavailability of fexofenadine sufficiently to be clinically pertinent.²¹ Therefore, it is best to use water to take all drugs unless otherwise instructed.

High-protein diets may enhance the rate of drug metabolism in part by stimulating the induction of cytochrome P450.¹⁹ The presence of protein in the gut increases the absorption/distribution of theophylline, which has a narrow therapeutic margin, leading to the potential for toxicity. Patients should be taught to separate their protein intake equally into three to six meals/day. On the other hand, a high-carbohydrate diet may result in subtherapeutic plasma levels of theophylline. While taking theophylline, instruct patients not to eat large amounts of charcoal-grilled foods or burnt foods (charcoal encrusted), which may reduce plasma half-life of theophylline by increasing enzymes in the liver that biotransform theophylline.

5. Some food-drug combinations reduce the effectiveness of drugs already absorbed. Both natural licorice and tyramine-rich foods reduce the effectiveness of antihypertensives. Licorice is related to and acts like aldosterone, enhancing sodium retention and potassium excretion in the distal tubule of the kidney, thus elevating blood pressure. Tyramine-rich substances — aged or fermented foods (e.g., cheese, bananas, yogurt, sour cream) — enhance the release of norepinephrine from sympathetic axons, resulting in vasoconstriction and hypertension.¹⁸ These same types of foods also need to be avoided when MAO inhibitors, such as tranylcypromine sulfate, are being taken.

Diet and Drugs

1. Dietary excesses or insufficiencies may predispose some patients to untoward effects from certain drugs.

Excesses of caffeine (a stimulant) may have an antagonistic effect with central nervous system depressants. Sucrose may depress the sexual drive when taken in excess, particularly in patients also taking large doses of aspirin. Because it acidifies urine, vitamin C may increase the excretion of weak basic drugs, such as atropine or quinidine, and decrease their activity. Conversely, this vitamin may decrease the excretion of weak acids, such as barbiturates, aspirin, and sulfonamides, and potentiate their activity.¹⁸ Patients taking isoniazid (INH) should limit their intake of Swiss cheese and tuna; the high histamine content of these foods may interact with isoniazid to cause severe headaches, redness and itching of the eyes and face, chills, palpitations, pulse rate variations, and loose stools.

2. Some drugs precipitate dietary deficiencies by causing malabsorption of nutrients.

Long-term anticonvulsants may cause folate and vitamin D deficiencies, which are manifested by muscle weakness, breathlessness, or bone pain.¹⁸ Increasing folate and vitamin D-rich foods in the diet may be helpful. However, supplementation may require greater doses of phenytoin. Phenytoin and phenobarbital may also cause intestinal malabsorption of calcium,¹⁸ which may lead to the development of osteomalacia.

Certain medications may block the absorption of essential vitamins and minerals. Salicylates increase the loss of vitamin C, potassium, and amino acids. Aluminum-based antacids decrease absorption of vitamin A. Oral contraceptives are associated with vitamin B6 and folate deficiency. Vitamin B12 malabsorption has been reported with aminosalicylic acid, slow-release potassium iodide, colchicine, trifluoperazine, and oral contraceptives.¹⁸

The Alcohol Connection

1. Alcohol interacts with many classes of drugs. Alcohol (ethanol) acts as an enzyme-inducing drug in the hepatic metabolic process, which accounts for the enhanced tolerance of alcoholics to sedatives and other CNS depressants.²² Alcohol interactions occur with antihypertensives, central nervous system (CNS) depressants, antipsychotic agents, analgesics, anticoagulants, diuretics, cardiotonics, antidysrhythmics, bronchodilators, and antidiabetic agents. Cimetidine and ranitidine interfere with the enzyme that begins the breakdown of alcohol in the stomach. As a result, men may feel the effects of alcohol faster than women because women do not produce this enzyme and therefore metabolize alcohol solely in the liver.²² Patients who take verapamil, cisapride, and metoclopramide, each of which cause a more rapid absorption of alcohol, may also feel this effect.

2. Alcohol intake may also cause an Antabuse-type reaction when consumed with certain drugs. Cephalosporins, sulfonylurea hypoglycemic agents, chloral hydrate, and metronidazole all produce the Antabuse reaction when combined with alcohol.^23,24 Severe nausea and vomiting also occur when alcohol is consumed with metformin.²⁴ The GI symptoms occur because lactic acidosis develops, and this condition may be severe or even life-threatening, depending on the amount of alcohol and the duration of symptoms. Patient teaching should include warning against drinking alcohol while taking these drugs.

“Risk-Benefit” Therapeutics

Drug therapy is justified only if the possible benefits outweigh risks. The term benefit-to-risk ratio is often used, but a more accurate term is benefit-to-risk analysis, since absolute mathematic ratios are usually not assigned in anticipation of drug selection.²⁵

Many drug combinations that produce dangerous interactions are still prescribed, despite reports in the literature. Many drug combinations may lengthen the QT interval of the cardiac cycle and may increase the likelihood of torsades de pointes and cardiac arrest. These medications include antidysrhythmics (quinidine, disopyramide, propranolol, and amiodarone) together with antibiotics, such as erythromycin, or the antifungals itraconazole and fluconazole, the coadministration of which affects cardiac rhythm.² Another serious complication, particularly in the acutely ill patient, is the coadministration of drugs that may individually cause eighth cranial nerve dysfunction; these medications include aminoglycosides, streptomycin, thiazide and loop diuretics, and cisplatin. When administered in combination, these agents may precipitate severe nerve damage, resulting in permanent deafness.

Reducing the Risk of Drug Interactions: The Nursing Role

Drug interactions may intensify or diminish a drug’s effects or worsen its adverse effects. Most drug-drug interactions involve prescription drugs, but some involve nonprescription OTC drugs.² Many drug interactions are preventable, as noted previously. In-depth history taking, knowledge of the illness being treated, definitive profiles of current and recent medications, and patient education all play a role in prevention. Specific considerations to help reduce the risk of drug interactions are as follows:²

• Ensure that the patient’s recorded history includes all drugs being taken, as well as those taken within the past six weeks, and that the prescribing physician is made aware of this list. This includes prescription drugs, OTC medications, alternative medicines or dietary supplements (nutraceuticals), recreational drugs, as well as alcohol, nicotine, and caffeine intake.²
• Determine how the patient takes oral drugs (full dose? simultaneously? with grapefruit juice? with milk? with food?).
• Determine whether or not the patient feels the medications were effective and whether there was adherence with the dosing regimen. Ask about improvement in specific aspects of the illnesses that are normally expected from medications.
• Ensure that the patient’s history includes a list of all medical illnesses, as well as surgeries; document any recurring symptoms not related to the illnesses already diagnosed and that could be drug related (e.g., heartburn, weakness). Ensure that the prescribing physician is aware of this list.²
• Learn the actions, dosage ranges, administration routes and timing, special administration considerations (e.g., empty stomach; take alone or with other drugs or food), and possible undesirable drug-drug interactions or adverse effects of the drugs being prescribed for your patients.²
• Determine whether or not the patient obtains all prescriptions from the same pharmacist or pharmacy. If there are separate pharmacies or prescription sources, obtain a list.² Contacting those sources may become necessary if there are drug interactions.
• Teach patients to be aware of prescribed drugs’ intended and unexpected effects and help them understand that drug interactions may either occur immediately or may be delayed for days or weeks.

Patient education is only one component in compliance with pharmacotherapy. A holistic approach encompasses considerations for culture, economic status, expectations and therapy goals, the patient’s perception of successful therapy, and the patient’s age and literacy level. Nurses need a valid perspective on all of these factors to treat patients effectively.