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Phentermine Drug Interactions

Drug-Nutrient Interactions

J. A. Thomas, Ph.D.-

Nutrition status plays a significant role in a drug's pharmacodynamics. Some disease states and other special conditions affect nutrient status and a drug's therapeutic efficacy. Many classes of drugs, including antimicrobials, hypoglycemics, and hypocholesterolemic agents, can be affected by the presence of food, with the geriatric patient particularly at risk. While a drug's pharmacokinetic profile can usually be predicted, it can be modified by nutrients and by certain pathophysiologic conditions, including aging, hepatic dysfunction, and micronutrients.

Introduction

Similar to drug-drug interactions, drug-nutrient (or drug-food) interactions may represent significant clinical problems resulting in adverse reactions or toxicity. In some instances such interactions may lead to therapeutic failures and even nutrition deficiencies.

1,2

Drug-food interactions are a significant problem in clinical practice and may interfere with the pharmacokinetic process.

3

Nutrition status plays an important role in a drug's pharmacologic response.

4,5

Food ingestion can profoundly affect a drug's pharmacodynamics.

6

Findings by Welling

6,7

showed that 51 of 55 and 100 of 130 drugs tested exhibited abnormal absorption when taken with food. In clinical conditions where prolonged medication is prescribed, potential interactions between food and drugs may be increased.

8

Patient counseling programs can potentially aid in educating consumers about drug-food interactions.

5,9

The pharmacist and the nutritionist should play an important role in identifying food-drug interactions and should participate in patient education and counseling programs. However, a recent nationwide survey reveals that most major hospitals do not have formal drug-food interaction counseling programs.

9

Increasing attention has been focused on nutrient-drug interaction because many drugs have become more potent and have greater specificity. Likewise, drugs with extended durations of action have increased the incidence of nutrient-drug interactions. Additionally, an aging population using more prescription drugs has increased the likelihood of drugs affecting the nutrition status of the older person.

10-12

Old age and conditions such as pregnancy, lactation, and malnutrition are all factors that can lead to food-drug interactions.

Drugs and nutrients share common characteristics and physicochemical properties that may affect biochemical actions and other dose-related toxicities. Often, a drug's mechanism of action may involve a nutrient(s) in a way similar to that of a nonnutrient component(s). Sites of nutrient-drug interactions include the gastrointestinal tract, the blood, or at the drug's cellular receptor(s). Some drugs may actually modify body composition, as is the case with the cationic amphophilic drugs (e.g., amantadine, amiodarone, chloroquine, chlorpromazine, phentermine, etc.) that affect phospholipid storage.

13

Many factors contribute to nutrient-drug interactions, although all patients do not experience the same degree of risk for nutrient-drug interactions." The elderly are at particular risk, due to pathophysiologic changes related to aging, endocrine dysfunction, alcoholism, and the common ingestion of restricted diets, either by prescription or choice.

15-20

Many factors are important in assessing the potential for nutrient-drug interactions" (Table 1). Nutrition-drug interactions are especially important in diabetes mellitus

16

(thiazide diuretics, corticoids, nonsteroidal anti-inflammatory drugs

NSAIDS

, etc.), in cardiovascular disease

17

(diuretics, digitalis, etc.), and in certain genetic disorders (lactose intolerance).

21,22

There are many factors that affect a drug's disposition over and above those factors affecting interactions. Renal function, age, diet, genetic traits, gender, and pregnancy can affect a drug's action. Stress, pre-existing disease states, and pharmacologic variables (dose, route, etc.) can likewise impact on a drug's disposition and hence, its potential for interaction.

23,27

Metabolism and Bioavailability

The metabolism of drugs occurs by two basic reactions referred to as Phase I and Phase II reactions. Phase I reactions include oxidation, hydroxylation, and reduction or hydrolysis leading to changes in functional group(s) on the drug molecule. The mixed-function oxidase system (MFOS) is an inducible enzyme system that catalyzes the oxidation of a wide variety of drugs. The MFOS is found primarily in the endoplasmic reticulum of the liver and other tissues. Phase II reactions include conjugation of glucuronate or glutathione and acetylation or sulfonation of functional group(s) on the drug's molecule. Modifications of functional groups usually render the drug more water soluble and thus more readily excreted by the kidney. Conjugation enzymes are present in the endoplasmic reticulum or the cytoplasm. Many oxidized products of the MFOS are substrates for conjugating enzymes.

The metabolism of drugs occurring by Phase I and Phase II reactions is catalyzed by different enzymes, and the formation of metabolites requires that other substances be provided by the body via nutrient intake. Many nutrients and micronutrients can affect Phase I oxidation reactions.

27

Low-protein diets reduce NADPH-dependent enzymes and decrease rates of Phase I biotransformation. In children with protein-calorie malnutrition, the excretion of sulfadiazene, antipyrine, and chloramphenicol may be impaired. Phase II reactions involving conjugation depend upon the body to provide carbohydrates, amino acids, fats, and proteins. Acute starvation may depress MFOS and hence influence the metabolism of a drug.

Bioavailability denotes that a portion of the drug's dosage that effectively reaches the systemic circulation is metabolically unaltered.

28

Several factors that affect bioavailability can be altered by food. Affecting bioavailability may modify a drug's pharmacokinetics and alter its pharmacodynamics. Food can affect drug bioavailability through physicochemical or chemical interactions between a specific nutrient or other food component(s) and the drug. Additionally, gastrointestinal processes can also affect a drug's bioavailability. Many factors can affect drug disposition" (Table 2).(Table 2 omitted)

Factors Affecting Gastrointestinal Absorption

The effect of food and fluid volume on the route and extent to which oral dosage forms of drugs are absorbed has only been under investigation for less than two decades.

23

Absorption is undoubtedly the most common mechanism responsible for food-drug interactions. Simply put, most drugs are taken by mouth. Fortunately, the majority of drugs in clinical use are well absorbed in the gastrointestinal tract, whether taken with food or on an empty stomach.

The most clinically significant nutrient-drug interactions involve the absorption process. Few drugs are absorbed to any significant degree in the stomach with the exception of ethanol, which can be readily absorbed in the stomach. Drugs that are acidic or basic are usually absorbed in the small intestine. Gastric function exerts a major effect upon both the rate and degree of drug absorption. Changes in gastric motility can affect the residence time of the food and/or drug in the gastrointestinal tract. The composition of the diet and the timing of meals can affect a drug's absorption from the gastrointestinal tract. Delays in gastric emptying time caused by fatty foods can likewise affect a drug's absorption.

Foods can either accelerate (Table 3) or retard (Table 4) drug absorption.

24-26

(Tables 3 and 4 omitted) There are many possible mechanisms whereby food and drugs can interact, resulting in an altered pharmacologic effect. Such mechanisms may involve physiologic alterations in the blood levels of the drug by food, either increasing or decreasing its absorption rate. Certain physiologic interactions between drugs and nutrients include factors by which a drug affects processes related to eating, sensory appreciation of food, swallowing, digestion, gastric emptying, nutrient absorption, nutrient metabolism, or renal excretion of nutrients.

18

The mechanism(s) of food-drug interactions continues to be poorly understood and involves both direct and indirect factors (Table 5).(Table 5 omitted) Indirect mechanisms include changes in gastrointestinal motility and malabsorption syndromes. Direct mechanisms involve pH changes as well as alterations in bioavailability and in drug binding. Certain foods can decrease or increase the absorption of drugs, thus altering their bioavailability. This can lead to changes in their solubility in gastric fluid and a modification of gastric emptying time.' Delayed drug absorption does not always mean that less total drug is absorbed, but rather, that it may require a longer period of time to reach its peak blood level. Drugs that bind or complex to nutrients are often unavailable for absorption or may undergo delayed absorption.

Food can affect the bioavailability of drugs by directly binding to the drug by components in foods or by changing luminal pH, gastric emptying, intestinal transit, mucosal absorption, or modifying splanchnic-hepatic blood flow.

25

Food-induced changes in the bioavailability of some drugs may be partially dependent upon hepatic biotransformation as evidenced by absorbed nutrients competing with drugs for first-pass metabolism in the intestine or the liver. Some drugs can undergo metabolic transformation by enteric microorganisms and since nutrients might also affect these microorganisms, they can influence the drug's metabolism.

Excretion

Drugs are eliminated from the body either unchanged or as their metabolites. The organs of excretion (kidney, skin, liver, and lungs) eliminate polar compounds (i.e., water soluble) more efficiently than drugs that are lipid soluble. Generally, lipid-soluble drugs are poorly excreted unless they have been biotransformed to render them more water soluble.

The kidney is a major organ of excretion of drugs and their metabolites. The renal excretion of drugs involves three processes: (1) glomerular filtration, (2) active tubular secretion, and (3) passive tubular absorption. Drugs excreted in the feces are primarily unabsorbed orally ingested drugs (or their metabolites) that have been excreted into the bile and that have not been reabsorbed from the gastrointestinal tract.

Organic acid and base renal transport mechanisms have an important role in the elimination of nonfilterable molecular species. Many drugs undergo elimination processes via these organic acid and organic base systems.

29

Some drugs' mechanism of action may be dependent upon these transport systems, while other drugs require proximal tubular transport systems as a major route of elimination from the body. Drugs transported by the organic ion system may produce nephrotoxicity either directly or indirectly.

Drugs that are rapidly metabolized or that undergo conjugation are usually more readily eliminated by the kidney. Protein binding of a drug (i.e., bound vs. free or unbound) can affect its rate of metabolism. Drugs that modify electrolytes can also affect the excretion of a drug

29

(Table 6). Loop of Henle and thiazide diuretics increase urinary excretion of sodium, potassium, and magnesium, and loop diuretics may also increase the urinary excretion of calcium. Cardiac glycosides may enhance potassium excretion while anti-inflammatory steroids and certain antihypertensive agents may cause sodium retention.

Several nephropathies produced by drugs/chemicals can exacerbate drug-nutrient interactions

29

(Table 2). The magnitude of nephrotoxicity is related to the dose, duration of treatment/exposure, and other factors known to affect pharmacologic activity such as age, sex, and hepatic function. Aminoglycoside antibiotics can commonly cause proximal tubular injury. Similarly, amphotericin B and cis-platinum can produce damage to the proximal tubules.

Special Interactions

Antimicrobials

The importance of food on the absorption of antimicrobials is well documented. The relationship between circulating levels of antibiotics and their therapeutic efficacy has been well studied relative to other classes of pharmacologic agents.

7

Food and fluid volumes affect the absorption of ingested antimicrobials and are directly related to their efficacy.

30,31

The absorption of several antimicrobial agents, such as tetracyclines and certain fluoroquinolones, may be decreased by chelation with dietary cations (e.g., Ca sup +4 , Mg) found in milk and other dairy products.

1

The absorption of certain antibiotics may be reduced by food (i.e., certain penicillins and tetracyclines), delayed by food (e.g., sulfonamides), or remain unaffected by food (e.g., ampicillin and amoxicillin). Still other antibiotics may actually have their absorption enhanced by the presence of food (e.g., griseofulvin, nitrofurantoin).

7

Different formulations of erythromycin are affected differently by the presence of food (delayed, reduced, increased, or unaffected). The effect of food on the bioavailability of ingested erythromycin is influenced by the chemical derivative, the dosage formulation, and the timing of the meal relative to the administration of the antibiotic.

Paradoxically, there may be circumstances when the food-antibiotic interaction reduces the absorption of the antimicrobial, but the presence of the food lessens the gastrointestinal side effects attributed to the drug. However, these special circumstances need not compromise the therapeutic efficacy of the antibiotic.

Drug-Ethanol Interactions

In the presence of other drugs, ethyl alcohol can cause clinically significant interactions. Not surprisingly, these interactions are more frequent in alcoholics than in persons who consume only small amounts of ethanol. Liebel

32

has recently reviewed the mechanisms involving ethanol-drug-nutrition interactions.

Chronic alcoholism is a major cause of liver disease leading to abnormal drug metabolism. The use of therapeutic agents in the alcoholic person is complicated by underlying hepatic disease and by acute and chronic ethanol-drug interactions. Drug metabolism is affected by both the acute and chronic use of ethanol. Chronic use of ethanol results in enzyme induction, which tends to increase a drug's metabolism, which leads to greater doses in order to achieve the desired therapeutic effect. The acute use of alcohol may simply overwhelm metabolic enzymes, causing a reduction of normal hepatic metabolism.

The action of several different classes of drugs can be affected by alcohol

27,32

(Table 7).(Table 7 omitted) The acute ingestion of ethanol and sedatives leads to greater psychomotor impairment than that caused by a single agent. A number of mechanisms may explain these interactions, including a combined central nervous system (CNS) depressant action, altered drug metabolism by ethanol, or acute impairment of degradation processes of the sedative(s). At least 12 different sites of ethanol-drug interaction have been described, including the liver (several sites), stomach, plasma protein binding, certain enzymes, and other peripheral sites. The majority of ethanol metabolism is catalyzed by alcohol dehydrogenase (ADH) in the liver, yet ADH is only marginally involved in alcohol-drug interactions.

The induction of the microsomal ethanol oxidizing system (MEOS) following chronic ethanol consumption affects various other drug-metabolizing systems in hepatic microsomes, leading to a generalized acceleration of drug metabolism. Chronic alcohol-drug interactions cause enhanced hepatic drug metabolism and may be referred to as metabolic drug tolerance, whereby alcoholics often display a tolerance to other drugs as well. Tolerance may be partially attributed to both CNS and metabolic adaptation.

Perhaps the best known interaction of a drug with ethanol is its reaction with disulfiram, prescribed therapeutically as an alcohol-abuse deterrent. Disulfiram inhibits acetaldehyde dehydrogenase, resulting in the accumulation of acetaldehyde. This produces nausea and vomiting within minutes of alcohol ingestion. Metronidazole has been reported to cause a disulfiram-like reaction when used concurrently with alcohol. Other drugs, such as cephalosporins containing methyltelrazolethiol side chains in their structures, can also interact with alcohol to cause a similar reaction.

1

The mechanism of these drug-alcohol interactions appears to be linked to the inhibition of ADH and the subsequent accumulation of acetaldehyde.

Drug-Vitamins

Drugs can alter the body's needs for vitamins.

10,33,34

Vitamin-drug interactions can occur with either water-soluble or fat-soluble vitamins (Table 8).(Table 8 omitted) Because antibiotics can sometimes modify enteric microorganisms, the absorption of fat-soluble vitamins may be affected. The interaction usually involves impaired absorption of the vitamin by a particular drug. Some drugs, however, can induce enzyme systems that can accelerate the metabolism of the particular vitamin. Ethanol consumption can depress hepatic levels of vitamin A. Glutathione, which acts as one of the scavenging mechanisms for toxic free radicals, can be reduced by acute ethanol administration. Glutathione can spare and potentiate vitamin E, but ethanol can interfere with these metabolic events.

32

Several mechanisms of drug-folate interaction have been reported

35,36

(Table 9).(Table 9 omitted) Several different classes of drugs are capable of affecting folate metabolism. The mechanism of action(s) includes impaired absorption, competitive binding to serum proteins, and enzyme inhibition. Folate may be required as a cofactor in the hydroxylation of different drugs. Because folate absorption is strongly pH dependent, gastric atrophy and atrophic gastritis with achlorhydria and hypochlorhydria can cause malabsorption of folate metabolism and increase its excretion. Folate levels are often reduced in those who chronically abuse alcohol, and because folate conjugase may decrease with age, an apparently folate-sufficient diet may not supply sufficient folate in some elderly.

10

Agents that cause folate antagonism decrease the availability of substrates required for nucleic acid biosynthesis. Inhibition of nucleic acid metabolism is a probable mechanism responsible for developmental toxicity caused by drugs such as methotrexate and aminopterin.

37

Drug-Minerals

Hathcock

38,39

has reviewed the literature concerning the effects of minerals on drug metabolism. There are three types of drug-mineral interactions: (1) malabsorption of the mineral and/or drug, (2) mineral depletion and retention, and (3) drug-mineral interactions induced by simultaneous antacid ingestion.

40

At least six major minerals and half a dozen minor or trace elements are considered essential for physiologic processes. Due to their relative abundance in foods, minerals such as sodium, potassium, magnesium, calcium, and phosphorous are often involved in drug interactions

41

(Table 10).(Table 10 omitted) Minor elements include arsenic, cobalt, chromium, copper, fluoride, iron, iodide, manganese, molybdenum, nickel, selenium, silicon, tin, vanadium, and zinc. Although these trace elements have important physiologic functions, most do not significantly affect drug-mineral interactions. Although most drug-mineral interactions are not clinically significant, people with chronic diseases and with malnutrition, and the elderly, are more likely to exhibit these interactions.

25,42,43

The administration of certain drugs may cause malabsorption of minerals by the drug directly preventing the absorption of one or more minerals. Primary malabsorption involves direct binding with the nutrient through chemical complexing (e.g., chelation) or via a direct adverse action by the drug on the gastrointestinal mucosa. Drugs can also secondarily prevent mineral absorption by influencing its pharmacodynamics. Although drugs may cause mineral depletion through primary and secondary malabsorption processes, depletion can also be caused by diuretics acting upon the kidney. Zinc, iodine, magnesium, and potassium deficiencies can decrease drug oxidation and drug clearance.

38,39

The largest group of agents recognized to cause interactions along the gastrointestinal tract are gastric antacids. Antacids may alter a drug's dissolution by modifying gastric pH and through chelation.

31,42,44

. They also interfere with a drug's absorption. Aluminum, a constituent of many antacids, can produce a relaxing effect on gastric smooth muscle, which leads to a delay in gastric emptying time. Increasing gastric pH leads to diminished absorption of calcium, iron, magnesium, and zinc.

45

Drugs may have their pharmacologic actions modified by minerals.

25

Calcium, iron, magnesium, and zinc can interfere with gastrointestinal absorption of tetracyclines, while iron can reduce the absorption of penicillamine. Iron levels in the liver are quite stable during mineral deficiency; dietary iron deprivation increases certain MFOS activities and decreases other degradative functions. The direct role of iron on MFOS suggests that its deficiency should increase, yet this has not been a consistent finding.

38,39

The Elderly

The elderly are particularly at risk for adverse and clinically important outcomes of drug-nutrient interactions.

19

Increased risks are due to multiple drug usage, age-related modifications in drug disposition, and geriatric pathologies that impair drug clearance and cause nutrition deficencies. The gastrointestinal tract of the elderly is often more vulnerable to drug-nutrient interactions.

Due to the various conditions associated with aging, older people commonly take many more drugs than do younger people. The elderly may consume more over-the-counter (OTC) drug products such as laxatives, vitamin/mineral preparations, and antacids. By the year 2000, it has been estimated that about 50% of all chronic care drugs will be OTC products.

44

Mineral deficiencies caused by the frequent use of diuretics leading to potassium and magnesium loss is a common cause of drug-nutrient interactions in this age group.

15,46

In the elderly, drug-nutrient interactions have been classified as physicochemical, physiologic, and pathophysiologic.

18

Physicochemical interactions are characterized by chelation, chelation complexes, and modifications in the stability of the nutrient. Physiologic interactions include drug-induced changes in appetite, digestion, gastric emptying, biotransformation, and renal clearance. Pathophysiologic interactions occur when a drug impairs nutrient absorption or its toxicity produces an inhibition of metabolic processes.

Nutrition changes in the elderly suggest that alterations in micronutrients or micronutrient constituents of the diet can affect gene expression.

47

Evidence for dietary modulation of gene expression has been derived primarily from animal studies. Dietary restriction retards age-related changes in hepatic enzymes, hormonal actions, lens protein, collagen, and age pigment. The effect of various substrates and micronutrients on enzymatic activity has been related to post-translational modifications of different gene products or to an alteration in the stoichiometry of certain enzymes.

47

For example, glucose can modulate gene expression in cultured hepatocytes.

Nutrition problems in the elderly are related not only to multiple drug use but also to the consumption of specialized diets for one or more chronic illnesses. Several mechanisms are involved in drug-nutrient interactions in the elderly

47

(Table 11). A drug's side effects (e.g., nausea, vomiting, and diarrhea) can secondarily affect drug-nutrient interactions, as is the case with cytotoxic drugs that can damage mucosal cells in the gastrointestinal tract, thus affecting absorption.

Drug-induced adverse outcomes can compromise the therapy by affecting the nutrition status of the geriatric patient. Hypertension, cardiac failure, and renal insufficiency are of particular concern in the elderly when using certain drugs.

18

Digoxin, an important therapeutic agent for congestive heart disease, possesses anorexic properties including nausea and vomiting. Loop diuretics facilitate the loss not only of sodium, but also potassium, magnesium, calcium, and thiamin. Postmenopausal women receiving loop diuretics may experience an increased calcium loss, thereby exacerbating the risk of osteoporosis.

As the aging process can profoundly affect a drug's pharmacokinetics, it should be evident that the elderly represent a particular at-risk population with respect to drug-nutrient interactions.

Hypoglycemic Agents

It is well known that an injection of insulin can provoke a sensation of hunger in people both with and without diabetes. Insulin-induced hypoglycemia, however, can also be associated with nausea and a sensation of weakness, rather than the desire for food.

19

The use of appetite stimulants is desirable in people with dementia who are at risk for protein malnutrition, but these drugs can produce obesity and aggravate diabetes mellitus.

Because people with diabetis mellitus and renal and/or hepatic disease are often more susceptible to hypoglycemia, some of the oral antidiabetic agents must be used with clinical discretion. The coadministration of sulfonylurea drugs with thiazide diuretics can lead to a loss of glycemic control. A decreased alcohol tolerance may also affect the response to taking sulfonylurea agents. Other drugs may enhance the hypoglycemic actions of the sulfonylurea drugs including propranolol, salicylates, phenylbutazone, chloramphenicol, probenecid, and the sulfonamides. Tolbutamide and chlorpropamide purportedly increase appetite in some diabetics by stimulating the release of pancreatic insulin.

48

Some antibiotics can affect hypoglycemia.

8

Cotrimoxazole or fluconazole can enhance the action of oral hypoglycemic agents. Conversely, rifampin can antagonize the action(s) of oral hypoglycemics. Although interest continues in developing new hypoglycemic agents, recent research has been devoted to compounds that act directly upon the gastrointestinal tract.

49

The absorption of simple and complex carbohydrates is mediated by enzymes called alpha-glucosidases. The alpha-glucosidases hydrolyze oligo- or polysaccharides to monosaccharides. The inhibition of alpha-glucosidases leads to a delay in the absorption of carbohydrates. Acarbose and miglitol are alpha-glucosidase inhibitory drugs. Acarbose is a reversible competitive inhibitor of glucoamylase and sucrase.

50

Miglitol, a compound that appears to mimic glucose, also inhibits alpha-glucoamylase and sucrase.

49

These drugs can reduce postprandial hyperglycemia and diminish insulin secretion.

Parenteral Nutrition

In a large series of patients receiving parenteral nutrition, Schneider and Mirtallo

51

reported that more than three-fourths of the drugs used were capable of altering nutrition support. Total parenteral nutrition (TPN) can affect the metabolism of drugs,

52

such as reducing hepatic clearance of barbiturates. Antipyrine pharmacokinetics can be altered by intravenous nutrition regimens leading to increased renal clearance and a shortened plasma half-life. Hence, antipyrine metabolism can be increased by nutrition repletion.

52

Several pharmacologic agents are associated with diarrhea in enteral-tube feeding, including sorbitol (aminophylline and theophylline solutions), magnesium (magnesium-containing antacids, magnesium citrate), and electrolyte solutions (potassium chloride, sodium phosphate).

53

Special considerations are necessary for the parenteral administration of complete amino acid mixtures in patients with severe alcoholic liver disease.

32

While dietary deficiencies may contribute to alcoholic liver injury, supplementation with S-adenosyl-L-methionine and polyunsaturated lecithin might offset aspects of ethanol-induced toxicity.

Because the growing specialty of nutrition support requires both multiple nutrient and medication modification, there is a particular concern for pharmacologic-nutrition interactions.

Miscellaneous Agents

Typically, people with hypercholesterolemia are middle-aged or older and are often taking medications for age-related conditions, such as hypertension. Hydroxymethylglutaryl-Coenyme A (HMG-CoA) reductase inhibitors include lovastatin, simvastatin, pravastatin, and lovastatin. These HMG-CoA reductase inhibitors do not appear to have any significant clinical interactions with diuretics, angiotensin-converting enzyme (ACE) inhibitors, or calcium-channel blockers.

Food may affect plasma lovastatin concentrations, as well as the bioavailability of pravastatin. Hepatic dysfunction can influence the pharmacokinetics of pravastatin. Foods high in fiber, such as oat bran, oatmeal, and soluble-fiber cereal, decrease the absorption of lovastatin, resulting in a substantially higher level of low-density lipoprotein cholesterol.

3

Conclusions

Many disease states can affect both the magnitude and the incidence and drug-nutrient interactions, and the action(s) of a number of pharmacologic agents can be altered by the presence of food in the gastrointestinal tract. Because aging, hepatic dysfunction, and other pathophysiologic factors can also have an impact on food-drug interactions, clinicians need to review the complete patient profile in order to make the most appropriate therapeutic recommendations.

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. Roe DA. Drug and nutrient interactions in elderly cardiac patients. Drug-Nutr Interact 1988;5:205-12

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. Hoyumpa AM, Schenker S. Major drug interactions: effect of liver disease, alcohol, and malnutrition. Annu Rev Med 1982;33:113-49

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. Winstanley PA, Orme MI'E. The effects of food on drug bioavailability. Br J Clin Pharmacol 1989;28: 621-8

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. Bennett WM, Porter GA. Overview of clinical nephrotoxicity. In: Hook JB, Goldstein RS, eds. Toxicology of the kidney, 2nd ed. Target Organ Toxicity Series. New York, NY: Raven Press, 1993:61

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. Toothaker RD, Welling PG. The effect of food on drug bioavailability. Annu Rev Pharmacol Toxicol 1980;20:173-99

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. Royer RJ, Debry G, Ulmer M, Bannwarth B. Food and drug interactions. World Rev Nutr Diet 1984;43: 117-28

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. Farrar HC, Blumer JL. Fetal effects of maternal drug exposure. Annu Rev Pharmacol Toxicol 1991;31: 525-47

38

. Hathcock JN. Nutrient and non-nutrient effects of drugs on metabolism. Drug-Nutr Interact 1985;4: 217-34

39

. Hathcock JN. Metabolic mechanisms of drug-nutrient interactions. Fed Proc 1985;44:124-9

40

. Murray JJ, Healy MD. Drug-mineral interactions: a new responsibility for the hospital dietitian. J Am Diet Assoc 1991;91:66

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. Hazell T. Minerals in foods: dietary sources, chemical forms, interactions, bioavailability. World Rev Nutr Diet 1985;46:1/014193/

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. Hussar DA. Drug interactions in the older patient. Geriatrics 1988;43:20-30

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. Hansten PD, Horn JR. Drug interactions, 6th ed. Philadelphia, PA: Lea and Febiger, 1989

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. Cardinale V. Stemming the tide of polymedicine. Drug Top 1988;132:36-41

45

. D'Arcy PF, McElnay JC. Drug interactions in the gut involving metal ions. Rev Drug Metab Drug Interact 1985;5:83-99

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. Lamy PP. Effects of diet and nutrition on drug therapy. J Am Geriatr Soc 1982;30:S99-S112

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. Mooradian AD. Nutrition modulation of life span and gene expression. Ann Intern Med 1988;109:890-904

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. Thomas JA, Thomas MJ. Insulin, glucagon, somatostatin, and orally effective hypoglycemic drugs. In: Modern pharmacology, 4th ed. Boston, MA: Little Brown Company, 1994;797-808

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. Hulin B. New hypoglycaemic agents. Prog Med Chem 1994;31:1-58

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. Saperstein R, Chapin EW, Brady EJ, Slater EE. Effects of alpha sub 2 -adrenoceptor antagonist on glucose tolerance in the genetically obese mouse. Metabolism 1990;391:445-51

51

. Schneider PJ, Mirtallo JM. Medication profiles in TPN patients. Nutr Suppl Serv 1983;3:40-6

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. Anderson KE. Influences of diet and nutrition on clinical pharmacokinetics. Clin Pharmacokinet 1988;14: 325-46

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. Sacks GS, Brown RO. Drug-nutrient interactions in patients receiving nutritional support. Drug Therapy 1994;March:35-42

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Table 1. Risk Factors for Nutrient-Drug Interactions

14

Multiple medications

Eating habits

Nutrient loss by food processing and cooking

Restrictive diets

Anorexia/eating disorders

Alcoholism and/or drug addiction

Chronic wasting diseases

Renal and/or hepatic dysfunction

Socioeconomic status

Table 6. Drug-Induced Electrolyte Disturbances

29

Calcium

Aminoglycoside antibiotics

Hypocalcemia

Hypercalcemia

Thiazide diuretics

Vitamin D supplements

Potassium

Antibiotics

Anti-inflammatory steroids

Antihypertensive drugs (selected)

Cardiac glycosides

Diuretics

Hyperkalemia

Hypolakemia

Licorice

Potassium-sparing diuretics

Potassium supplements

Tocolytic agents

Phosphorus

Cytotoxic drugs

Hyperphosphatemia

Hypophosphatemia

Parenteral nutrition

Sodium

Anti-inflammatory steroids

Hypernatremia

Hyponatremia--drugs that impair water excretion

Table 11. Mechanism of Drug-Nutrient Interaction in the Elderly

47

Appetite suppression (anorexic)

Appetite stimulation

Diminished nutrient absorption; toxicity to mucosal cells

Facilitate renal elimination

Decreased nutrient use

Antagonism/competitive (e.g., coumarin and vitamin K)

Inhibition or facilitation with metabolism or transport system(s)

Hormonal effects of nutrients

Indirect effect due to components of drug formulation

*Dr. Thomas is Professor of Pharmacology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284- 7722, USA.

Copyright International Life Sciences Institute and Nutrition Foundation Oct 1995
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