Diphenoxylate

Numerous articles have appeared recently in the medical literature and in the lay press that describe the frequency and significance of adverse drug events, including those occurring in older patients. With the continuing growth of the older segment of the U.S. population, and in the volume of drugs prescribed for these patients, the risks for adverse events caused by drug interactions are of growing concern.

And although physicians are often advised of drug-drug interactions, food-drug interactions are rarely discussed. Grapefruit juice, caffeine, and aged cheeses are just a few of the everyday foods and beverages recently identified as having potentially significant interactions with a variety of medications. [Editor's note: Foods in the cover photograph--smoked salmon, asparagus, avocado, red leaf lettuce, caviar, and red wine--have all been implicated in food-drug interactions.]

The older patient is at particularly high risk for food-drug interactions. (1) Not only are older patients more likely to be on multiple medications, but medication effects are frequently altered by age-related physiologic changes affecting drug absorption, distribution, metabolism and excretion, as well as drug action. In addition, endocrine dysfunction, restrictive diets, and alcoholism in many patients may further potentiate these interactions. Additional age-related factors that affect drug action and risks for interactions include:

* decreases in gastrointestinal functioning, such as gastric emptying and intestinal motility

* decreases in the ratio of lean body weight to body fat

* diminished binding of drugs by serum proteins

* decreases in renal and hepatic functioning.

The table summarizes clincally-significant food-drug interactions known to be issues in geriatric practice. Whereas most U.S. hospitals have started programs to manage drug-drug interactions, most have not addressed the issue of drug-nutrient interactions. (2,3) Current standards of the Joint Committee on the Accreditation of Healthcare Organizations (JCAHO) include the requirement of patient education regarding food and drug interactions. Paramount to such programs are hospitals' pharmacists and dietitians. These professionals not only assess the risks for these interactions but provide counseling to patients as well. Regularly updated pharmaceutical and dietary references are key. (4-6) Because an enterprising patient can find anecdotal, non-scientific information on the Internet regarding possible interactions with food, physicians need to be prepared to respond appropriately. For the most part, however, issues of drug-food interactions are rarely discussed in the medical literature in practical terms, much less in authoritative lay publications. This article will discuss known critical food-drug interactions encountered in clinical geriatric practice today.

Mechanisms of food-drug interactions

Food-drug interactions can be either pharmacodynamic (relating to the action of the drug) or pharmacokinetic (relating to the drug's absorption, distribution, metabolism, and excretion). Both of these pharmacologic properties can be potentiated or antagonized by food. (9) For example, vegetables high in vitamin K (eg, asparagus, red leaf lettuce) pharmacodynamically antagonize the anticoagulation effects of warfarin, making it essential to counsel patients to limit any variability in vitamin K intake. (4) Increased dietary sodium can negate the effectiveness of many antihypertensive agents such as thiazides, and can alter the renal excretion of lithium. However, pharmacokinetic effects represent the more sigfnificant mechanism for food-drug interaction.

Drug absorption may be the most prominent of all food-drug interactions. (9,10) Aging itself is associated with slowing of gastric emptying, diminished gut wall function, and an increase in gastric pH. Concomitant ingestion of food with many medications can often have additional significant effects on drug absorption due to drug-nutrient binding, alterations in gastric emptying, and/or changes in gastric pH. These actions may reduce, increase, delay, or accelerate drug absorption. (11) Heavy meals, particularly those with high fat content, slow gastric emptying, just as many medications do. Drugs with anticholinergic properties (eg, traditional antihistamines; diphenoxylate HCl with atropine sulfate) slow gastric emptying and can delay drug absorption and onset of action. Antacids, H2-blockers, and proton pump inhibitors also alter gastric pH, which affects the rate of dissolution of many drugs. Milk and milk products can raise the gastric pH and cause enteric-coated tablets to dissolve prematurely. This can result in altered drug absorption as well as gastric irritation.

As a rule, drugs are more promptly absorbed when taken with water. Inhibition of absorption can occur with some drugs when they are taken with acidic fruit juices, vegetable juices, carbonated beverages, or caffeine. In older patients, where congestive heart failure or urinary incontinence frequently requires fluid restriction, drugs may be taken with too little fluid resulting in delayed dissolution and absorption. (11) Physicians may want to remind older patients to drink at least one-half cup of water when taking pills to help ease potential stomach or esophageal irritation as well as improve absorption.

Food can also alter transport mechanisms important in the drug absorption process. Milk and other products containing calcium can produce a complexation with some drugs, such as fluoroquinolones (ciprofloxacin, norfloxacin, and others), impairing their absorption. In addition, nutrients can affect intestinal transit time, splanchnic and hepatic blood flow, and can act as a physical barrier by hindering drug product (tablet, capsule) dissolution, binding to the drug, or preventing the drug from getting to the mucosal surface of the GI tract. (9) In some instances, the mechanism for altering absorption remains unknown.

Occasionally, almost any ingested food or liquid can alter absorption of certain medications, the most important example of which are the bisphosphonates used for management of osteoporosis (alendronate, risedronate, and tiludronate). Bisphosphonate absorption is prevented by food, orange juice, coffee, calcium products, other medications, and most anything except water. For this reason, patients are instructed to take these agents on an empty stomach with 6 to 8 ounces of water only and to stay upright and consume nothing else for at least 30 minutes.

The absorption of most antibiotics can be affected by food in a variety of ways. Chelation by dietary cations (calcium and magnesium) found in milk and other dairy products will decrease the absorption of tetracyclines and the fluoroquinolones as mentioned above. As such, physicians need to remind older patients to take these drugs only with water and limit taking dairy products within one or two hours of taking these drugs.

Dietary fiber can impair the absorption of penicillins. Thus, physicians are prudent to review all dosing strategies with older adults whenever possible.

Ease of patient use has led to numerous slow-release formulations of many drugs--and these formulations are commonly prescribed for geriatric patients. The rate of the release may be influenced by alterations in pH, the content of the diet, and the transit time in the GI tract. For example, some sustained-release verapamil and theophylline products have demonstrated highly variable bioavailabilities when taken with meals compared with the fasting state. (9) It is important to consult product prescribing information, and to counsel the patient as to when to take medications in regards to meals.

Drug distribution. Many factors influence the physiologic distribution of drugs. Aging itself is associated with decreased total body water, increased body fat, and decreases in serum albumin and other carrier proteins. Improper diet can further bolster the fat content of the body. With increases in body fat, lipid-soluble drugs such as benzodiazepines are increasingly sequestered and their half-life is in the body and duration of action significantly prolonged. Prescription of more hydrophilic medications and shorter half-life alternatives may be preferred in the older patient.

Drug metabolism. Nutrients can either increase or decrease the metabolism of drugs. One well-publicized example is the effect grapefruit juice (GFJ) exerts on a large number of commonly used drugs. (7,8) By inhibiting intestinal--but not hepatic--cytochrome P450-3A enzymes, GFJ enhances the bioavailability and subsequent serum levels of several commonly used drugs. (7) Drugs affected include many of the calcium channel antagonists, most of the HMG-Co reductase inhibitors (statins), and tranquilizers.

The quantity and quality of food is also influential. High-protein, low-carbohydrate diets, recently popularized by the Atkins and South Beach diets, can accelerate the hepatic metabolism of several drugs; alcohol can have similar effects. A high-fat diet can compete with the binding sites on albumin-altering serum drug concentrations and distribution; this may be an issue for patients eating out (fast foods in particular) or consuming high quantities of highly processed foods. Alternately, there appears to be no appreciable effect of either high carbohydrate diets or vegetarian diets on liver metabolism. (11)

Elimination of drugs. Drugs are eliminated from the body either unchanged or as metabolites. Renal function, the major method of drug and metabolite elimination, can be altered by electrolyte disturbances or other factors that influence glomerular filtration and tubular reabsorption. Drugs that are eliminated via liver metabolism and biliary excretion may have varied reabsorption from the gastrointestinal tract depending on food intake.

Conclusions

Adverse drug events involving interactions with foods and other drugs have become an important public health issue. These events have been shown to cause hospitalizations, significant morbidity, and even death. The frequency and significance of important food-drug interactions is just beginning to reach the medical literature. Because of normal age-related changes, geriatric patients may be at increased risk for these adverse events. Primary care physicians can prevent key problems by carefully selecting drugs for geriatric patients and thoroughly educating patients about food-drug interactions and the need to take medications exactly as instructed.

References

(1.) Thomas JA, Burns RA. Important drug-nutrient interactions in the older patient. Drugs Aging 1998; 13(3):199-209.

(2.) Gauthier I, Malone M. Drug-food interactions in hospitalised patients. Drug Saf 1998; 18(6):383-93.

(3.) Cardona PD. Drug-food interactions. Nutr Hosp 1999; 14(suppl 2):129S-140S.

(4.) Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management. Edmunds, Wash: H & H Pub, 2003.

(5.) Tatro DS. Drug Interaction Facts 2002. St. Louis, Mo: Facts and Comparisons, 2002.

(6.) Pronsky Z. Food medication interaction. 11th ed. Birchrunville, Pa: Food-medication interactions; 2000.

(7.) Greenblatt DJ, Patki KC, von Moltke LL, Shader RL. Drug interactions with grapefruit juice: An update. J Clin Psychopharmacol 2001; 21(4):357-9.

(8.) Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc 2000; 75(9):933-42.

(9.) Singh BN. Effects of food on clinical pharmacokinetics. Clin Pharmacokinet 1999; 37(3):213-55.

(10.) Thomas JA. Drug-nutrient interactions. Nutr Rev 1995; 53(10):271-82.

(11.) Fleisher D, Li C, Zhou Y, Pao LH, Karim A. Drug, meal and formulation interactions influencing drug absorption after oral administration. Clinical implications. Clin Pharmacokinet 1999; 36(3):233-54.

(12.) Jefferson JW. Drug and diet interactions: Avoiding therapeutic paralysis. J Clin Psychiatry 1998; 59(suppl 16):31-9.

(13.) Williams L, Davis JA, Lowenthal DT. The influence of food on the absorption and metabolism of drugs. Med Clin North Am 1993; 77(4):815-29.

(14.) Kirk JK. Significant drug-nutrient interactions. Am Fam Physician 1995; 51(5):1175-82.

(15.) Mahan LK, Escott-Stump S. Krause's Food, Nutrition and Diet Therapy, 10th ed. Philadelphia, Pa: Saunders Company; 2000:399-414.

Dr. Leibovitch is senior attending physician and coordinator of internal medicine education, Ventura County Medical Center; and adjunct professor of medicine, University of California Los Angeles School of Medicine. Dr. Deamer is the former director of pharmacotherapy education and research, family practice residency program, department of medical education, Ventura County Medical Center, assistant clinical professor, University of California Los Angeles School of Medicine and University of Southern California School of Pharmacy; he is currently drug education program coordinator; Kaiser Permanente, Southern California. Ms. Sanderson is a clinical dietitian, dietary department, Santa Barbara Cottage Hospital, Santa Barbara, CA. Disclosure: The authors have no real or apparent conflicts of interest related to the subjects under discussion.

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