Clinical significance of drug-nutrient interactions

33

TIPS - January 1986

affect a whole class of nutrients such as fat-soluble vitamins or trace minerals. Drugs may decrease nutrient bioavailability by a variety of mechanisms including adsorption of the nutrient itself or of bile acids thus inhibiting the intraluminal phase of fat digestion and absorption. Drugs may form insoluble precipitates or chelate with a nutrient. Drugs may affect the chemical environment of the gastrointestinal lumen through changes in pH, motility or bacterialflora. Some drugs m a y damage the intestinalmucosa and destroy the structure of the villi and microvilli resulting in an inhibition of brush border enzymes and intestinal transport systems needed for nutrient absorption. The malabsorptive effect of colchicine, neomycin and aminosalicylic acid appear to be the result of such mucosal

Clinical significance of drug-nutrient interactions Jeffrey B. Blumberg Not every drug interacts with a nutrient to induce a clinically significant effect. Risk factors increasing the occurrence of drug-nutrient interactions include: multiple drug treatments, chronic drug therapy, nutritionally marginal diets, age- or disease-related malabsorption disorders and inadequate attention to these factors by biomedical researchers. Jeffrey Blumberg argues that diet and other variables affecting the nutritional state of the body must be considered in the design of drug efficacy and safety studies. Diet and nutrition can have a profound effect on the therapeutic and toxic outcome of drug treatment. In spite of this, pharmacologists have been slow to recognize the need to control these variables in their experiments. Conversely, drugs may induce sufficient alterations in appetite and nutritional status to produce symptoms of nutrient deficiency. However, clinicians frequently overlook drug-nutrient interactions as a cause of adverse drug reactions. This review examines drugnutrient interactions, principally from a clinical point of view, and draws attention to the impact they may have in research. Drug e f f e c t s o n nutritional status Nutritional status can be quite markedly affected by drugs.

Effects on food intake A variety of drugs have been noted to alter food intake primarily through changes in appetite, changes in taste and smell, or adverse gastrointestinal side effects 1 (Table I). Psychotropic agents such as the phenothiazines and benzodiazepines improve mood and psychological function with a consequent increase in food intake in some individuals. However, in elderly patients, whose rate of drug metabolism is slow, these drugs may induce somnolence and disinterest in food. Amytriptyline and related tricyclic antidepressants appear to stimulate appetite but sometimes cause behavioral agitation which may interfere with eating. The oral hypoglycemic agents may stimulate appetite via pancreatic reJeffrey B. Blumberg is Associate Professor of Nutrition, Chief, Nutritional Immunology and Toxicology Laboratory, Tufts University, 711 Washington Street, Boston, MA 02111, USA.

lease of insulin. Brief or prolonged periods of anorexia associated with pharmacological therapy are often due to effects on the GI tract. Antineoplastic drugs induce nausea, vomiting and aversion to food. Cardiac glycosides produce anorexia accompanied by nausea and may produce cachexia. Some drugs affect appetite by altering taste sensitivity; chelation of zinc or copper by thiol-containing drugs like penicillamine and griseofulvin appears to be the mechanism of action for the reduced taste acuity. Some drugs, e.g. lithium carbonate, produce abnormal, unpleasant taste sensations (dysgeusia).

inju~.

Drugs may also interfere with nutrient absorption through secondary mechanisms. Drugs can indirectly impair digestion of food via initial adverse effects on gastric or intestinal secretion, pancreatic exocrine function, or hepatic bile secretion. Cimetidine and other H2-blockers, because of their inhibitory effect on gastric acid production, reduce the liberation of vitamin B12from its protein-bound state, making it less available for association with 'intrinsic factor'4. Chronic effects of hepatotoxic drugs, notably alcohol, include maldigestion with reduced absorption of fats and fat-soluble vitamins. Direct systemic effects of a drug on one nutrient may have secondary consequences for another nutrient. For example, drugs such as isoniazid and cimetidine which inhibit the hepatic or renal

Alteration of nutrient absorption The best described and most frequent type of drug-nutrient interaction results from druginduced alteration of nutrient absorption 2. Drugs cause malabsorption by exerting an effect in the intestinal lumen or impairing the absorptive ability of the gastrointestinal mucosa. These effects can be limited to a particular nutrient or they can be general and TABLE I. Drug-induced nutrient deficiencies

potential drug antacids aluminum and magnesium hydroxides anticonvulmnts phenobarbital, phenytoin dluretlr~ benzothiadiazides

nutrient

mechanism

clinical outcome

phosphate

insoluble salt formation

malaise, paresthesias

vitamin D

hepatic microsomal

rickets, osteomalacia

enzyme induction potassium

renal reabsorption reduction

hypokalemia

vitamin Bs

pyridoxalhydrazone complex excretion

peripheral

antltuberculous drugs cylosedne, isoniazid

neuropathy

1986, Elsewer Science Publishers B.V., Amsterdam

0165 - 61471861502.00

34

TIPS -January 1986 TABLE II. Food effects on drug action food

drug

effect

protein

levodopa

fiber (bran)

digoxin

citrus fruit juices

quinidine

charcoal-broiled meat

theophylline

broccoli, cabbage, lettuce, turnips

coumarin

neutral amino a c i d s competitively inhibit drug transport adsorption of drug reduces absorption altered urinary pH enhances tubular reabsorption polycyclic aromatic hydrocarbons induce drug metabolizing enzymes vitamin K content inhibits hypoproothrombinemic raspose

hydroxylation of vitamin D and those such as phenytoin and phenobarbital which promote catabolism of vitamin D metabolites, produce a functional deftciency of vitamin D with a secondary impairment in Ca 2+ absorption. Several classes of over-the-counter (OTC) drugs may induce adverse nutritional effects. It has been suggested that drug-induced malnutrition in the elderly is commonly due to excessive use of OTC drugs such as antacids, laxatives and non-narcotic analgesics s. Antacids formulated with aluminum and magnesium hydroxides form non-absorbable phosphates in the gut lumen and may induce hypophosphatemia with the development of proximal limb muscle weakness, malaise, paresthesias, anorexia and secondary syndromes of hypomagnesemia/ tetany and osteomalacia. Excessive use of sodium bicarbonate can result in Na + overload and may render the pH of the jejunum sufficiently alkaline to decrease the absorption of folic acid. Laxative abuse is not uncommon, especially among the elderly. Stool softeners like mineral oil, if taken at mealtime or in the postprandial absorptive period, prevent the absorption of carotenes and fat-soluble vitamins via solubilization. Overuse of diphenylmethane derivatives including phenolpthalein and bisacodyl may result in severe malabsorption with steatorrhea, decreased glucose, Ca 2+, K + and vitamin D absorption and proteinlosing enteropathy.6 Osteomalacia resulting from excessive laxative use has been rePorted. Laxatives

therapeutic response

decreased decreased increased

decreased

decreased

such as dioctylsulfosuccinate which alter electrolyte transport have also been associated with K + deficiency due to gastrointestinal losses and failure of colonic reabsorption. Laxative-induced malabsorption may be related to loss of structural integrity of intestinal epithelial cells and protein-losing enteropathy secondary to potassium depletion. Anti-inflammatory drugs such as acetylsalicylic acid and indometacin produce multiple small hemorrhages of the gastrointestinal mucosa leading to iron deficiency anemia and decreased absorption of vitamin C. Chronic acetylsalicylic acid therapy is also associated with folacin deficiency and macrocytic anemia with the greatest risk occurring in patients with low folacin intake. Colchicine has been noted to decrease the absorption of protein, fat, lactose, carotene, vitamin B12, sodium, potassium and bile acids as a result of villous damage. Hypolipidemic drugs may improve lipid status and decrease risk of coronary artery disease but pose nutritional hazards 7. Cholestyramine is a basic anionexchange resin which binds bile salts and impairs the absorption of a number of nutrients including carotene, vitamins A, B12, D, K and folic acid, calcium iron, and zinc.

Alteration of nutrient metabolism Drugs may act to inhibit the essential intermediary metabolism of a nutrient or to promote the catabolism of a nutrient. While these actions are sometimes put to therapeutic advantage, e.g. with oral anticoagulants and antineoplastics, examples of unwanted

interference should not go unrecognized. Drug interference of vitamin D metabolism with secondary impairment of Ca 2+ absorption can result in osteomalacia. It has been proposed that anticonvulsants interfere with osteocalcin-related bone mineralization processes by interruption of vitamin K metabolism 8. Anticonvulsants and sedative/hypnotics which induce hepatic microsomal drug metabolizing enzymes increase the demand for folate and may cause signs of deficiency. Isoniazid and hydralazine may inhibit pyridoxal kinase sufficiently to produce clinical symptoms of vitamin B6 deficiency.

Alteration of nutrient excretion Drugs may act to increase the excretion of a nutrient by displacement from plasma protein binding sites, chelation or reduction of renal reabsorption. Acetysalicylic acid competes for folate binding sites on serum proteins and enhances folate excretion 9. Chronic administration of penicillamine for rheumatoid arthritis results in chelation of essential minerals such as copper and zinc. While diuretic therapy effectively decreases the reabsorption of Na +, it also enhances the renal excretion of Ca 2+, K +, Mg 2+, and Zn 2+.

Effects of food on drug therapy While drugs can affect nutritional states, conversely food itself can adversely interact with drug therapy.

Food~nutrient alteraffon of drug bioavailability The clinical effect of foods on drug absorption and disposition, particularly during chronic treatment, has generally not been studied. However, food and food components have been shown to interact with drugs in various ways 1°. Food and its constituents can influence drug absorption as a result of physical or chemical interactions between the food product and drug or because of physiological changes in the GIT induced by eating or drinking (Table II). The net effect of this interaction may be that drug absorption is reduced, slowed or increased by food intake 11. In the stomach food can act to alter the rate of gastric emptying and drug dissolution. Food can also increase the viscosity of the

35

TIPS - January 1986

gastric medium decreasing the rate of drug diffusion to mucosal absorption sites. Food can act as a mechanical barrier preventing drug access to the mucosal surface. Food components can also act to complex or chelate drugs. The effect of food on drug absorption may also be dependent upon drug formulation; generally, entericcoated tablets appear most affected by foods while drugs in solution are least affected. Food-related alterations in gastrointestinal functions that affect drug bioavailability include changes in stomach emptying time, intestinal motility and splanchnic blood flow and alterations in the secretion of bile, gastric acid and digestive enzymes. The ~blocking drugs, propranolol and metoprolol, are better absorbed after meals due to food-related increases in splanchnic blood flow and reduced first pass metabolism in the intestinal mucosa or liver 12. When the effect of food on drug absorption is related to interactions between the food and the drug in the GIT, then the timing of drug intake in relation to meal time is of practical importance. Acetaminophen absorption is five times slower following consumption of a high carbohydrate meal containing large amounts of pectin than after fasting. Drugs such as levodopa and methyldopa with structures similar to amino acids are absorbed by transport mechanisms for amino acids. Competition for transport between the drug and amino acids from protein in the diet diminishes drug uptake and may be responsible for the 'on--off' phenomenon of levodopa in parkinsonian patients 13. The effects of changes in gastric emptying time on drug absorption are dependent on the water solubility of the drug; drugs with very low solubility are better absorbed when they remain longer in the stomach as they will after large, high-fat meals. For drugs which are weak bases such as amitriptyline, diazepam and pentazocine, gastric emptying rate is critical as absorption occurs in the less acidic intestine. Food-induced decreases in gastric clearance can increase metabolism of drugs such as digoxin, levodopa and peniciUins in the stomach and less of the unchanged drug to be available for absorption, resulting in an erratic

therapeutic response 14. Changes in gastric emptying will mainly affect drugs that are rapidly absorbed or have a short biological half-life. Food~nutrient alteration of drug metabolism Diet and nutritional status may have a marked effect on the way drugs are metabolized 15. A decrease in dietary intake of protein depresses creatinine clearance and renal plasma flow and impairs the clearance of drugs like phenazone, oxipurinol and theophylline 16. Reduced antipyrine clearance has been demonstrated in lactovegetarians whose diet is characterized by a low protein intake. High carbohydrate diets appear to produce opposite influences on drug metabolism relative to high protein diets. In experimental animals, the amount of lipid and the unsaturated:saturated fatty acid ratio in the diet can markedly affect the activity and inducibility of the mixed function oxidase system although this effect has not been unequivocally demonstrated in man. In severely malnourished adults with nutritional edema, drug metabolism is impaired with significant increases in plasma half-life of the drug. Natural non-nutrient components of the diet may exert a profound influence on the rate of drug metabolism and these effects may occur rapidly after food ingestion. Indolic compounds in vegetables of the brassica family, e.g. cabbage and brussel sprouts, stimulate the rate of human drug metabolism. Flavones (bioflavonoids) occurring in fruits and polycyclic aromatic hydrocarbons generated during charcoal broiling stimulate liver microsomal drug metabolism 17. Alterations of intestinal microflora produced by changes in the dietary level or source of protein or fiber can influence intestinal drug metabolism. Vitamin supplements have been noted to produce alterations of some drug effects. Megadoses of vitamin E potentiate the action of the anticoagulant warfarin and produce hemorrhage by further depressing the levels of vitamin Kdependent coagulation factorsTM. Vitamin D supplements can induce hypercalcemia and precipitate cardiac arrhythmias in

patients receiving digitalis 19. The administration of supplemental Ca2+ can cause a recurrence of atrial fibrillation in patients maintained on verapamil. Excessive doses of vitamin C acidify the urine and promote reabsorption of acidic drugs and excretion of weak bases. Large doses of vitamin C may also inhibit the anticoagulant response of warfarin. Niacin supplements have an additive vasodilating effect producing postural hypotension in patients receiving sympatholytic antihypertensive drugs like clonidine. An increase in seizure frequency and a corresponding decrease in serum phenytoin levels have been reported in epileptic patients receiving folic acid supplements. References 1 Levitsky, D. A. (1984) in Drugs and Nutrients - The Interactive Effects (Roe, D. A. and Campbell, T. C., eds), pp. 375408, Marcel Dekker, New York 2 Roe, D. A. (1984) Nutr. Rev. 42, 141-154 3 Roe, D. A. (1985) in Nutritional Pathology (Sidransky, H., ed.), pp. 357-379, Marcel Dekker, New York 4 Streeter, A. M., Goldston, K. H., Bathur, F. A., Hilmer, R.S., Crane, G.G. and Pheils, M. T. (1982) Dig. Dis. Sci. 27, 1316 5 Roe, D. A. (1984) in Drugs and Nutrition in the Geriatric Patient (Roe, D. A., ed.), pp. 121-133, Churchill Livingstone, New York 6 Fleming, B. J., Genuth, S.M., Gould, A. B. and Kaminokowski, M. D. (1975) Ann. Intern. Med. 83, 60-62 7 Miettinen, T. A. (1981) Adv. Lipid Res. 18, 65-97 8 Keith, D. A., Gundberg, C. M., Japour, A., Aronoff, J., Alvarez, N. and Gallop, P.M. (1983) Clin. Pharmacol. Ther. 34, 529-532 9 Lawrence, V. A., Lowenstein, J. E. and Eichner, E. R. (1984) J. Lab. Clin. Med. 103, 944-948 10 Roe, D. A. (1984) World Rev. Nutr. Diet 43, 80-94 11 Toothaker, R. D. and Welling, P.G. (1980) Annu. Rev. Pharmacol. Toxicol. 20, 173-199 12 McLean, A. J., Isbister, C., Bobik, A. and Dudley, F. J. (1981) Clin. Pharmacol. Ther. 30, 31-34 13 Nutt, J. G., Woodward, W. R., Hammerstad, J.P., Carter, J.H. and Anderson J. L. (1984) N. Engl. J. Med. 310, 483--488 14 Lamy, P. P. (1983) Clin. Nutr. 2, 9-14 15 McDaneU, R. E. and McLean, A. E. M. (1985) in Nutritional Pathology (Sidransky, H., ed.), pp. 321-356, Marcel Dekker, New York 16 Belinger, W. G., Pork, G. D. and Sector, R. (1985) N. Engl. J. Med. 313, 771-776 17 Lasker, J. M., Wuang, M. T. and Conney, A. H. (1982) Science 216, 1419-1421 18 Anonymous (1983) Nutr. Rev. 41, 268270 19 Garbadian-Ruffalo, S. M. (1984) Int. Med. 5, 129-137