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Drugs and nutrition in old age
Life Sciences, Vol. 39, pp. 1027-1036 Printed in the U.S.A.
Pergamon Journals
MINIREVIEW DRUGS AND NUTRITION IN OLD AGE Lora E. Rikans Department of Pharmacology, College of Medicine University of Oklahoma Health Sciences Center Oklahoma City, OK 73190
Summary Drug effects are influenced by physiologic and pathologic changes that occur as a consequence of aging. The elderly may be more disposed to drug-induced nutrient depletion because of chronic illness, inadequate diet and long-term drug use. Digoxln, isoniazid, cortlcosterolds, diuretics and psychoactive agents pose special hazards to the nutritional status of elderly patients. On the other hand, dietary factors, such as protein levels or vitamin deficiencies, may be important determinants of age-related changes in drug disposition or toxicity. There has been growing interest in the relationships between drugs and nutrition in the aged individual (I-5). Although most of our information on the subject is based on clinical impressions and anecdotal observations, it is generally accepted that certain drugs are harmful to the nutritional status of elderly patients. It seems likely that old people are at greater risk for drug-lnduced nutrient depletion because they require more drugs than younger individuals and because they are more likely to have marginal nutrient intakes, due to chronic illness or inadequate diet. Conversely, subclinical malnutrition may be responsible for a part of the increased incidence of drug toxicity seen in the elderly. It is the intent of this review to explore some drug/nutrlent/aging interrelations and to provide a personal perspective on the subject rather than a comprehensive treatise. Drus Use b 7 the Elderl 7 Four of every five of the elderly (individuals 65 or more years of age) are afflicted with chronic conditions such as heart disease, hypertension, arthritis and diabetes; 35% have three or more of these health problems (6). Cardiovascular drugs (digitalis glycosides, diuretics, antlarrhythmlcs, antihypertenslves and anticoagulants) are the medications most often prescribed for older patients, followed by psychoactive drugs (antipsychotics and sedatlve-hypnotics) and gastrointestinal drugs (7-12). Nonprescrlption drugs are also used extensively by the elderly, with nonnarcotic analgesics (acetamlnophen and aspirin) at the top of the llst. Other popular over-thecounter agents include laxatives, vitamins, antacids and antihistamines. Surveys show that the majority of elderly people take two to five different drugs daily (7,10,11). They experience about two to three times more adverse drug effects than younger individuals, and most of the serious reactions are from cardiovascular and psychoactive agents. Both the incidence of drug usage and the number of drugs taken per person increase with age (7-11). This fact alone may account for most of the increase in the incidence of adverse drug reactions. 0024-3205/86 $3.00 + .00 Copyright (c) 1986 Pergamon Journals Ltd.
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Influence of Aging on Drug Disposition and Drug Response Pharmacokinetics. The intensity of response produced by a therapeutic agent is proportional to its concentration at the site of action. The processes that affect blood and tissue concentrations of drugs (absorption, distribution, metabolism and excretion) are subject to modification by the aging process. This subject has been reviewed extensively in recent years (8,9,12-14) and only a brief summary is provided here. The great majority of drugs are transported across the gastrointestinal epithelium and into the blood supply by simple diffusion. However, some drugs are absorbed by active transport or by pinocytosis, and some are absorbed directly into the lymphatic system. Although careful studies of the effects of aging on drug absorption are few, all of the available evidence suggests that no major alterations occur with advancing age (12). After being absorbed into the blood stream a drug may bind to plasma proteins, diffuse into various tissues, or accumulate via intracellular binding or partioning into fat. Binding to plasma proteins is generally decreased in old age, partly because of a reduction in plasma albumin. In addition, there is a decline in lean body mass and an increase in body fat, which affects the distribution of drugs. For example, Klotz et al. demonstrated that the apparent volume of distribution for diazepam, a lipid-soluble drug, was 2 to 3 times greater in elderly subjects than in young ones (15). Drugs normally are administered in multiple doses. The altered drug distribution resulting from changes in body composition or plasma protein binding does not change steady-state plasma concentrations of (free) drug, since the steady-state concentrations depend only on the dose rate for the drug and its clearance. Thus, changes in drug distribution probably do not play a major role in the enhanced drug toxicity experienced by elderly persons
(8). Biotransformation in the liver is one of the principal means by which the body eliminates drugs. For many drugs the initial step is an oxidation reaction catalyzed by the cytochrome P-450-dependent enzyme system in the endoplasmic reticulum. Age-related alterations in hepatic microsomal drug metabolism are well established in animal models (14,16-19). Drug metabolism activities either decrease or increase, because aging has differential affects on the individual isozymes of cytochrome P-450 (20-22). The same is apparently true for humans. Pharmacokinetic studies suggest that diminished hepatic metabolism reduces the clearance of many drugs (8), but the decline is not universal for all compounds metabolized by the cytochrome P-450 system. Animal studies show that conJugative pathways in the endopiasmic reticuium and the cytosol (glucuronidation, sulfation, and conjugation with glutathione) also are affected by the aging process in a substrate-specific fashion (23-25). However, age-dependent alterations in conJugative reactions have not been demonstrated in humans. Finally, changes in the hepatic clearance of certain drugs (e.g., propanolol) also occur as a consequence of reduced hepatic blood flow (26). Diminished renal function is probably the single factor most responsible for altered drug levels in the elderly. A decline in glomerular filtration rate (35 to 50% between the ages of 20 and 70 years) reduces the elimination of many drugs, including digoxin, practolol, cimetidine, procainamide and most antimicrobial agents (27). Since total clearance declines in proportion to the reduction in glomerular filtration rate, appropriate adjustments in drug dosage regimens can be made on the basis of endogenous creatinine clearance. Tissue Sensitivity. Limited data indicate that changes in the drug receptor or in the intrinsic properties of the responding tissue can result in
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altered drug reactivity. For example, studies with diazepam and nitrazepam have shown that central nervous system depression at any given level of benzodiazepine sedative-hypnotic is greater in older patients than in young ones (28,29). Age-related changes in tissue responsiveness to drug action have been demonstrated also for the volatile anesthetic halothane, for coumarin anticoagulants and for beta-adrenergic agonists and antagonists (isoproterenol and propranolol). Mechanisms for age-related alterations in target tissue sensitivity could include changes in receptor number and/or affinity, in receptor regulation or in the translation of receptor binding into a response (30). Aging also can affect the sensitivity of target tissue to the toxic effects of drugs. For example, the incidence and severity of hepatic disease associated with isoniazid or dantrolene therapy increase with increasing age (31, 32). Our group has determined the extent of liver injury produced by the in vivo administration of hepatotoxicants to rats of various ages. Damage from bromobenzene, carbon tetraehloride or galactosamine essentially was unaffected by age, but allyl alcohol-induced hepatotoxicity was considerably more severe in older rats than in young ones (33). This age-dependent increase in allyl alcohol toxicity was observed also in isolated hepatocytes (34). Likewise, the nephrotoxicity of gentamycin and cephaloridine was increased with age in rats (35,36), indicating that the susceptibility of the kidney to toxic drug effects also is affected by aging. Effects of Dru~s on Nutritional
Status
General Principles. Drug-induced nutritional deficiencies can occur because of decreased absorption, increased elimination or accelerated metabolism of nutrients. The inhibition of gastrointestinal absorption of vitamins by cholestyramine, the enhancement of potassium, magnesium and zinc excretion by thiazide diuretics and the acceleration of vitamin D metabolism by the anticonvulsant drugs, phenytoin, phenobarbital and primidone, are well-known examples. In addition, certain drugs act as vitamin antagonists. For example, the coumarin anticoagulants exert their pharmacological effects by antagonizing the actions of vitamin K, and methotrexate is a folic acid antagonist. Whether or not clinical malnutrition ensues as the result of drug administration depends on a number of factors. The nutritional hazards in geriatric patients are greatest in those with pre-existing subclinical nutritional deficiencies and in those for whom long-term drug therapy is necessitated by chronic illness. The problem may be exacerbated when more than one of the drugs being taken has the potential of vitamin or mineral depletion. For example, chronic therapy with cholestyramine and phenytoin would have additive effects on vitamin D and calcium status. The use and misuse of nonprescription drugs, such as laxatives, antacids or analgesics, can further complicate the picture. The subject of drug/nutrient interactions has been extensively reviewed (37-40). Some examples of drugs which can precipitate nutritional deficiencies in the elderly are discussed below. Diaoxin. Digoxin is prescribed for congestive heart failure and other cardiac disorders. The drug has a narrow margin of safety, and toxicity is frequent in the elderly because of a marked reduction in the rate of its renal clearance (41-44). The most serious toxic effects are disturbances in cardiac rhythm. However, it is the non-cardiac symptoms of digitalis toxicity that are harmful to the nutritional status of elderly patients. Fatigue, listlessness, anorexia and nausea occur in 50-95% (45). These symptoms can produce significant reductions in food intake and cachexia (46). Digoxin toxicity should be suspected in any digitalized elderly patient who exhibits substantial weight loss.
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Diuretics. Diuretics are prescribed for congestive heart failure and for hypertension. Hypokalemia with associated muscle weakness, cardiac arrhythmias and digitalis toxicity, and hypovolemia with associated hypotension are major side effects. Geriatric patients are more susceptible to the complications of diuretic therapy than young patients because of reduced potassium intake and diminished homeostatic control of blood pressure (47). Attention should be paid to the dietary intake of potassium in all elderly patients on diuretics or other potassium-losing drugs, and potassium supplementation should be considered to correct or prevent disturbances attributable to hypokalemia. The use of diuretics can also result in the depletion of other essential minerals, such as magnesium and zinc. Psychoactive DruBs. Aged patients in extended care facilities frequently receive medication for behavior disorders, depression, anxiety, cognitive impairment and sleep disturbances. Sedative-hypnotics and antipsychotics are the drugs most frequently prescribed (48-50). An age-related increase in sensitivity to the neurologic side effects of phenothiazines, the most widely used antipsychotic agents, has been recognized for many years (51,52). The sedative effects, like those of the benzodiazepine sedative-hypnotics, also are more pronounced in older patients. Increased somnolence from sedative drugs may produce a disinterest in eating with ensuing malnutrition (38). In contrast, therapy with tricyclic antidepressants, the primary agents for treatment of depression in the elderly, often result in overnutrition. A recent clinical study reported that excessive appetite and craving for sweet foods occur frequently in elderly patients taking tricyclics (53). These side effects are especially troublesome for those who also suffer from diabetes or high blood pressure. Isoniazid. One of the more interesting examples of interrelations between aging, nutritional status and drug toxicity involves isoniazid and vitamin B6. This drug, considered to be the primary agent for the treatment of tuberculosis, forms a hydrazone of pyridoxal and pyridoxal phosphate, rendering them unavailable for participation in enzymatic reactions. Since the hydrazone is readily excreted in the urine, isoniazid also increases the excretion of vitamin B6. The neuropathologic ch@nges produced by isoniazidinduced pyridoxine depletion can be prevented by the concurrent administration of the vitamin. Hepatic disease is another adverse effect associated with isoniazid therapy. Although the mechanisms are not known for certain, studies suggest that the production of acetylhydrazine, a metabolite of ~soniazid, is important for the liver damage, and that pyridoxine inhibits toxicity by forming a hydrazone with acetylhydrazine (54). The incidence of isoniazidinduced hepatic disease increases dramatically as a function of age (32,55). Increased acetylhydrazine production is an unlikely cause because aging does not enhance the rate of isoniazid acetylation (56,57). On the other hand, pyridoxine deficiency is common in older persons (58). Supplementation with pyridoxine is especially important for elderly patients taking isoniazid, not only to prevent neuropathy, but also to prevent hepatopathy. Corticosteroids. When corticosteroids, such as prednisone, methylprednisolone or dexamethasone, are administered for long periods in doses large enough to suppress inflammation, they can produce disabling and potentially lethal effects in patients of all ages. The elderly are especially susceptible to the muscle wasting and osteoporotic effects of these drugs because of increased protein requirements and decreased vitamin D and calcium absorption. The mechanism of steroid myopathy is unknown, but it is a serious complication because recovery after withdrawal of therapy may be incomplete (59). Steroid-induced osteoporosis is observed most frequently in postmenopausal women. Bone loss occurs because the steroids inhibit bone formation by suppressing osteoblastic function and enhance bone reabsorption by stimulating osteoclastic function (60). The latter is the result of
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inhibited calcium absorption from the gut and increased parathyroid secretion. In addition, corticosteroids may enhance the conversion of 1,25-(OH)~D3, the active form of vitamin D, to an inactive metabolite; however, the da~a relative to this effect are contradictory. Treatment with vitamin D or its metabolites may be of benefit (61). Effects of Nutrients on Dru 8 Reactivity Dietary factors can affect both drug disposition and target tissue sensitivity. Although it seems reasonable to assume that nutritional influences may contribute substantially to the altered drug responsiveness of old age, experimental evidence in support of this premise is scanty. In light of the variation exhibited by the elderly in response to administered drugs, any information on the association between nutritional status and drug reactivity in the elderly would be beneficial. Pharmacokinetics. Most drugs are administered by the oral route. The rate of their gastrointestinal absorption is affected by the presence of food, but for most drugs the rate of entry into the systemic circulation is of little importance (62). The extent of absorption is affected only rarely. A well-known example of decreased absorption is the effect of milk products on tetracycline antibiotics. Absorption is impaired in the presence of food and food supplements because the tetracyclines form unabsorbable metal complexes with calcium, magnesium and iron. Extensive animal research demonstrates that nutritional factors are important determinants of drug metabolism, especially biotransformation catalyzed by the hepatic cytochrome P-450 system (63,64). Hepatic drug metabolism is affected by macronutrient ratios, vitamin deficiencies, mineral deficiencies, fasting and inducing compounds. Of these numerous influences only a few have been found to have clinical significance in man; proteinenergy malnutrition, changes in carbohydrate/protein ratio, long-term ascorbic acid deficiency and inductJon by indole-containing vegetables or charcoalbroiled meat. Studies in underdeveloped countries indicate that drug metabolism is markedly decreased in infants and children with protein-energy malnutrition, compared with their age-matched controls (65,66). On the other hand, studies in fasted or anorexic adults have not demonstrated changes in drug clearance (67,68). The protein/carbohydrate ratio of calorically adequate diets produces consistent effects on hepatic drug biotransformation in human volunteers; drug clearance is decreased by low-protein/high-carbohydrate diets (69). Whether protein-energy malnutrition or changes in protein/carbohydrate ratio affect drug metabolism in the aged has not been determined. Information from studies in aging animals is scarce. One study found that the effect of dietary protein level on hepatic microsomal drug metabolism in aging Syrian hamsters was variable, depending on sex and generation (70). In our studies, rats were fed either a semipurified diet (AIN-76, ICN Nutritional Biochemicals) or a commercial ration (Purina). Although cytochrome P-450 contents and cytochrome c reductase activities were 30-90% greater in the rats fed the commercial ration, the age-related decreases in these microsomal enzymes were smaller and occurred at a later age (Table I). The results are consistent with the idea that dietary composition modulates the effects of aging on the hepatic microsomal enzyme system. Vitamin C deficiency in guinea pigs decreases the oxidative metabolism of a variety of drugs (71,72), but data for humans are contradictory. Short term studies in humans showed no effect of ascorbic acid deficiency on drug metabolism (73-75). Although vitamin C concentrations in plasma or blood cells were decreased dramatically by the short-term deprivations, hepatic
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TABLE I Influence of Diet on Age-Related Changes in the Hepatic Microsomal Cytochrome P-450 System Age (Mo)
Diet
Body Wt ($)
Micros Prot (mg/g liver)
Cyt P-450 (nmol/mg prot)
Cyt c Reductase (nmol/min/mg prot)
4 14 24
C C C
300 _+ 4 400 ,+ 5 430 _+ 4
32 ,+ 1 32 + I 35 ± 2
1.02 _+ 0.05 0.98 ± 0.07 0.78 _+ 0.05
320 ± 30 270 ± 20 220 ± 20
4 14 24
S S S
320 ,+ 2 530 ,+ 3 480 ± 7
29 + 1 30 _+ 1 32 _+ I
0.79 ,+ 0.01 0.54 ,+ 0.03 0.55 ± 0.03
240 _+ 10 140 _+ lO 120 ,+ I0
Values are means ,+ SEM for 6 or more male Fischer 344 rats fed a commercial ration (C) or a semipurified diet (S) (17,33).
concentrations of the vitamin may not have been sufficiently depleted to affect the microsomal drug-metabolism system. (Ascorbic acid status in plasma does not necessarily reflect its status in other tissues) (76,77). Studies which did show an effect of vitamin C deficiency on hepatic drug metabolism were investigations in patients with long-term deficiency. Decreased elimination of drugs metabolized by the liver was associated with pre-existing vitamin C deficiency in the aged and in patients with mild maturity-onset diabetes; supplementation with the vitamin restored drug elimination rates to normal levels (78,79). The precise involvement of ascorbic acid in the hepatic microsomal drug-metabolism system is poorly defined. One idea is that the vitamin is intimately associated with cytochrome P-450 and is needed for efficient interaction with NADPH-cytochrome c (P-450) reductase (80,81). The importance of vitamin C in maintaining the hepatic microsomal enzyme system has been demonstrated also in the rat. Cytochrome P-450 and drug-metabolism activities are lower in mutant rats unable to synthesize ascorbic acid than in control rats or mutant rats supplemented with the vitamin (82). Membrane-bound ascorbic acid (83) and drug biotransformation (16-22) both decrease with age in rat liver. We found that the decline in microsomal ascorbic acid did not coincide with the age-related decline in cytochrome P-450 (Table 2). Nevertheless, the results raise the possibility of an increased requirement for ascorbate in aged liver. The effect of marginal vitamin C deficiency may be more significant in elderly individuals than in young ones. Dietary constiutents can affect drug metabolism also by inducing the activity of drug metabolizing enzymes. Although numerous inducing agents have been identified in animal studies, the only dietary constituents known to induce these enzymes in humans are cabbage, brussel sprouts and charcoalbroiled meat (84). The ability of the liver to respond to inducing drugs is modified in old age, both in animals (22,85) and in humans (86). However, neither the effect of aging on inducibility by dietary constituents nor the effect of dietary influences on age-related changes in inducibility has been investigated. Age-dependent loss of kidney function produces a marked decrease in the clearance of drugs eliminated primarily by renal excretion. The development of glomerular disease in animals can be delayed by making food available only on alternate days or by limiting the amount eaten on an ad libitum schedule.
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TABLE II Ascorbic Acid and Cytochrome P-450 in Hepatic Microsomes of Aging Rats Age (Mo)
Ascorbic Acid (nmol/m 8 prot)
Cytochrome P-450 (nmol/mg prot)
4 14 24
1.74 -+ 0.11 1.27 -+ 0.06 0.94 -+ 0.05
0.79 -+ 0.01 0.54 -+ 0.03 0.55 -+ 0.04
Ascorbic acid and cytochrome P-450 contents were determined in washed liver mlcrosomes. Values are means ± SEM for 6 or more male Fischer 344 rats (87).
Dietary protein is also important; glomerular sclerosis in rats subjected to renal ablation is enhanced by feeding high-protein diets and diminished by reducing dietary protein content. On the basis of these on other findings, Brenner and his colleagues have proposed that modern eating habits (highprotein diets, ad libitum) have imposed a functional burden on the human kidney that ultimately results in the deterioration of glomerular structure and function (88). It is intriguing to think that the progressive decline in human kidney function might be minimized by modifying eating habits. Tissue Sensitivity. The issue of nutritional influences on age-related changes in tissue sensitivity to drugs is one that is largely unexplored. As mentioned above, isoniazid toxicity may be enhanced in the elderly because of vitamin B6 deficiency. In addition, foods contain natural and synthetic antioxidants (tocopherol, butylated hydroxytoluene, butylated hydroxyanisole) which play a protective role by scavenging free radicals produced by drugs (89). It is conceivable that age-assoclated changes in dietary patterns might affect the intake of these substances and influence drug toxicity. Conclusions The extent to which aging affects drug-induced nutrient depletio~ Js undetermined. It is important, however, that nutritional allowances for the elderly take into account the increased prevalence of chronic illnesses and the extensive use of drugs in older persons. Drug-induced nutritional deficiencies should be avoided by supplementing the diets of geriatric patients with the appropriate nutrients. Finally, there is a need to investigate the role of nutritional factors in modifying age-associated changes in drug disposition and drug toxicity. References I. 2. 3. 4. 5. 6. 7. 8. 9.
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E. GINTER and J. VEJMOLOVA, Br. J. Clin. Pharmacol. 12 256-258 (1981). P.H. SATO and V.G. ZANNONI, J. Pharmaeol. Exp. Ther. 198 295-307 (1976). L.E. RIKANS, J. Nutr. 112 1796-1800 (1982). F. HORIO, K. OZAKI, A. YOSHIDA, S. MAKINO and Y. HAYASHI, J. Nutr. 115 1630-1640 (1985). B.K. PATNAIK, Nature 218 393 (1968). A.P. ALVAREZ, E.J. PANTUCK, K.E. ANDERSON, A. KAPPAS and A.H. CONNEY, Drug Metab. Rev. 9 185-205 (1979). L.E. RIKANS and B.A. NOTLEY, Biochem. Pharmacol. 31 2339-2343 (1982). S.A.M. SALEM, P. RAJJAYABUN, A.M.M. SHEPHERD and I.H. STEVENSON, Age and Ageing ~ 68-73 (1978).
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L.E. RIKANS, Nutritional Aspects of Aging Vol. II, L.H. Chen, ed., p. 3-18, CRC Press, Boca Raton, 1986. B.M. BRENNER, T.W. MEYER and T.N. HOSTETTER, N. Eng. J. Med. 307 652-659 (1982). C.J. CARR, Ann. Eev. Pharmacol. Toxicol. 22 19-29 (1982).
Pergamon Journals
MINIREVIEW DRUGS AND NUTRITION IN OLD AGE Lora E. Rikans Department of Pharmacology, College of Medicine University of Oklahoma Health Sciences Center Oklahoma City, OK 73190
Summary Drug effects are influenced by physiologic and pathologic changes that occur as a consequence of aging. The elderly may be more disposed to drug-induced nutrient depletion because of chronic illness, inadequate diet and long-term drug use. Digoxln, isoniazid, cortlcosterolds, diuretics and psychoactive agents pose special hazards to the nutritional status of elderly patients. On the other hand, dietary factors, such as protein levels or vitamin deficiencies, may be important determinants of age-related changes in drug disposition or toxicity. There has been growing interest in the relationships between drugs and nutrition in the aged individual (I-5). Although most of our information on the subject is based on clinical impressions and anecdotal observations, it is generally accepted that certain drugs are harmful to the nutritional status of elderly patients. It seems likely that old people are at greater risk for drug-lnduced nutrient depletion because they require more drugs than younger individuals and because they are more likely to have marginal nutrient intakes, due to chronic illness or inadequate diet. Conversely, subclinical malnutrition may be responsible for a part of the increased incidence of drug toxicity seen in the elderly. It is the intent of this review to explore some drug/nutrlent/aging interrelations and to provide a personal perspective on the subject rather than a comprehensive treatise. Drus Use b 7 the Elderl 7 Four of every five of the elderly (individuals 65 or more years of age) are afflicted with chronic conditions such as heart disease, hypertension, arthritis and diabetes; 35% have three or more of these health problems (6). Cardiovascular drugs (digitalis glycosides, diuretics, antlarrhythmlcs, antihypertenslves and anticoagulants) are the medications most often prescribed for older patients, followed by psychoactive drugs (antipsychotics and sedatlve-hypnotics) and gastrointestinal drugs (7-12). Nonprescrlption drugs are also used extensively by the elderly, with nonnarcotic analgesics (acetamlnophen and aspirin) at the top of the llst. Other popular over-thecounter agents include laxatives, vitamins, antacids and antihistamines. Surveys show that the majority of elderly people take two to five different drugs daily (7,10,11). They experience about two to three times more adverse drug effects than younger individuals, and most of the serious reactions are from cardiovascular and psychoactive agents. Both the incidence of drug usage and the number of drugs taken per person increase with age (7-11). This fact alone may account for most of the increase in the incidence of adverse drug reactions. 0024-3205/86 $3.00 + .00 Copyright (c) 1986 Pergamon Journals Ltd.
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Influence of Aging on Drug Disposition and Drug Response Pharmacokinetics. The intensity of response produced by a therapeutic agent is proportional to its concentration at the site of action. The processes that affect blood and tissue concentrations of drugs (absorption, distribution, metabolism and excretion) are subject to modification by the aging process. This subject has been reviewed extensively in recent years (8,9,12-14) and only a brief summary is provided here. The great majority of drugs are transported across the gastrointestinal epithelium and into the blood supply by simple diffusion. However, some drugs are absorbed by active transport or by pinocytosis, and some are absorbed directly into the lymphatic system. Although careful studies of the effects of aging on drug absorption are few, all of the available evidence suggests that no major alterations occur with advancing age (12). After being absorbed into the blood stream a drug may bind to plasma proteins, diffuse into various tissues, or accumulate via intracellular binding or partioning into fat. Binding to plasma proteins is generally decreased in old age, partly because of a reduction in plasma albumin. In addition, there is a decline in lean body mass and an increase in body fat, which affects the distribution of drugs. For example, Klotz et al. demonstrated that the apparent volume of distribution for diazepam, a lipid-soluble drug, was 2 to 3 times greater in elderly subjects than in young ones (15). Drugs normally are administered in multiple doses. The altered drug distribution resulting from changes in body composition or plasma protein binding does not change steady-state plasma concentrations of (free) drug, since the steady-state concentrations depend only on the dose rate for the drug and its clearance. Thus, changes in drug distribution probably do not play a major role in the enhanced drug toxicity experienced by elderly persons
(8). Biotransformation in the liver is one of the principal means by which the body eliminates drugs. For many drugs the initial step is an oxidation reaction catalyzed by the cytochrome P-450-dependent enzyme system in the endoplasmic reticulum. Age-related alterations in hepatic microsomal drug metabolism are well established in animal models (14,16-19). Drug metabolism activities either decrease or increase, because aging has differential affects on the individual isozymes of cytochrome P-450 (20-22). The same is apparently true for humans. Pharmacokinetic studies suggest that diminished hepatic metabolism reduces the clearance of many drugs (8), but the decline is not universal for all compounds metabolized by the cytochrome P-450 system. Animal studies show that conJugative pathways in the endopiasmic reticuium and the cytosol (glucuronidation, sulfation, and conjugation with glutathione) also are affected by the aging process in a substrate-specific fashion (23-25). However, age-dependent alterations in conJugative reactions have not been demonstrated in humans. Finally, changes in the hepatic clearance of certain drugs (e.g., propanolol) also occur as a consequence of reduced hepatic blood flow (26). Diminished renal function is probably the single factor most responsible for altered drug levels in the elderly. A decline in glomerular filtration rate (35 to 50% between the ages of 20 and 70 years) reduces the elimination of many drugs, including digoxin, practolol, cimetidine, procainamide and most antimicrobial agents (27). Since total clearance declines in proportion to the reduction in glomerular filtration rate, appropriate adjustments in drug dosage regimens can be made on the basis of endogenous creatinine clearance. Tissue Sensitivity. Limited data indicate that changes in the drug receptor or in the intrinsic properties of the responding tissue can result in
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altered drug reactivity. For example, studies with diazepam and nitrazepam have shown that central nervous system depression at any given level of benzodiazepine sedative-hypnotic is greater in older patients than in young ones (28,29). Age-related changes in tissue responsiveness to drug action have been demonstrated also for the volatile anesthetic halothane, for coumarin anticoagulants and for beta-adrenergic agonists and antagonists (isoproterenol and propranolol). Mechanisms for age-related alterations in target tissue sensitivity could include changes in receptor number and/or affinity, in receptor regulation or in the translation of receptor binding into a response (30). Aging also can affect the sensitivity of target tissue to the toxic effects of drugs. For example, the incidence and severity of hepatic disease associated with isoniazid or dantrolene therapy increase with increasing age (31, 32). Our group has determined the extent of liver injury produced by the in vivo administration of hepatotoxicants to rats of various ages. Damage from bromobenzene, carbon tetraehloride or galactosamine essentially was unaffected by age, but allyl alcohol-induced hepatotoxicity was considerably more severe in older rats than in young ones (33). This age-dependent increase in allyl alcohol toxicity was observed also in isolated hepatocytes (34). Likewise, the nephrotoxicity of gentamycin and cephaloridine was increased with age in rats (35,36), indicating that the susceptibility of the kidney to toxic drug effects also is affected by aging. Effects of Dru~s on Nutritional
Status
General Principles. Drug-induced nutritional deficiencies can occur because of decreased absorption, increased elimination or accelerated metabolism of nutrients. The inhibition of gastrointestinal absorption of vitamins by cholestyramine, the enhancement of potassium, magnesium and zinc excretion by thiazide diuretics and the acceleration of vitamin D metabolism by the anticonvulsant drugs, phenytoin, phenobarbital and primidone, are well-known examples. In addition, certain drugs act as vitamin antagonists. For example, the coumarin anticoagulants exert their pharmacological effects by antagonizing the actions of vitamin K, and methotrexate is a folic acid antagonist. Whether or not clinical malnutrition ensues as the result of drug administration depends on a number of factors. The nutritional hazards in geriatric patients are greatest in those with pre-existing subclinical nutritional deficiencies and in those for whom long-term drug therapy is necessitated by chronic illness. The problem may be exacerbated when more than one of the drugs being taken has the potential of vitamin or mineral depletion. For example, chronic therapy with cholestyramine and phenytoin would have additive effects on vitamin D and calcium status. The use and misuse of nonprescription drugs, such as laxatives, antacids or analgesics, can further complicate the picture. The subject of drug/nutrient interactions has been extensively reviewed (37-40). Some examples of drugs which can precipitate nutritional deficiencies in the elderly are discussed below. Diaoxin. Digoxin is prescribed for congestive heart failure and other cardiac disorders. The drug has a narrow margin of safety, and toxicity is frequent in the elderly because of a marked reduction in the rate of its renal clearance (41-44). The most serious toxic effects are disturbances in cardiac rhythm. However, it is the non-cardiac symptoms of digitalis toxicity that are harmful to the nutritional status of elderly patients. Fatigue, listlessness, anorexia and nausea occur in 50-95% (45). These symptoms can produce significant reductions in food intake and cachexia (46). Digoxin toxicity should be suspected in any digitalized elderly patient who exhibits substantial weight loss.
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Diuretics. Diuretics are prescribed for congestive heart failure and for hypertension. Hypokalemia with associated muscle weakness, cardiac arrhythmias and digitalis toxicity, and hypovolemia with associated hypotension are major side effects. Geriatric patients are more susceptible to the complications of diuretic therapy than young patients because of reduced potassium intake and diminished homeostatic control of blood pressure (47). Attention should be paid to the dietary intake of potassium in all elderly patients on diuretics or other potassium-losing drugs, and potassium supplementation should be considered to correct or prevent disturbances attributable to hypokalemia. The use of diuretics can also result in the depletion of other essential minerals, such as magnesium and zinc. Psychoactive DruBs. Aged patients in extended care facilities frequently receive medication for behavior disorders, depression, anxiety, cognitive impairment and sleep disturbances. Sedative-hypnotics and antipsychotics are the drugs most frequently prescribed (48-50). An age-related increase in sensitivity to the neurologic side effects of phenothiazines, the most widely used antipsychotic agents, has been recognized for many years (51,52). The sedative effects, like those of the benzodiazepine sedative-hypnotics, also are more pronounced in older patients. Increased somnolence from sedative drugs may produce a disinterest in eating with ensuing malnutrition (38). In contrast, therapy with tricyclic antidepressants, the primary agents for treatment of depression in the elderly, often result in overnutrition. A recent clinical study reported that excessive appetite and craving for sweet foods occur frequently in elderly patients taking tricyclics (53). These side effects are especially troublesome for those who also suffer from diabetes or high blood pressure. Isoniazid. One of the more interesting examples of interrelations between aging, nutritional status and drug toxicity involves isoniazid and vitamin B6. This drug, considered to be the primary agent for the treatment of tuberculosis, forms a hydrazone of pyridoxal and pyridoxal phosphate, rendering them unavailable for participation in enzymatic reactions. Since the hydrazone is readily excreted in the urine, isoniazid also increases the excretion of vitamin B6. The neuropathologic ch@nges produced by isoniazidinduced pyridoxine depletion can be prevented by the concurrent administration of the vitamin. Hepatic disease is another adverse effect associated with isoniazid therapy. Although the mechanisms are not known for certain, studies suggest that the production of acetylhydrazine, a metabolite of ~soniazid, is important for the liver damage, and that pyridoxine inhibits toxicity by forming a hydrazone with acetylhydrazine (54). The incidence of isoniazidinduced hepatic disease increases dramatically as a function of age (32,55). Increased acetylhydrazine production is an unlikely cause because aging does not enhance the rate of isoniazid acetylation (56,57). On the other hand, pyridoxine deficiency is common in older persons (58). Supplementation with pyridoxine is especially important for elderly patients taking isoniazid, not only to prevent neuropathy, but also to prevent hepatopathy. Corticosteroids. When corticosteroids, such as prednisone, methylprednisolone or dexamethasone, are administered for long periods in doses large enough to suppress inflammation, they can produce disabling and potentially lethal effects in patients of all ages. The elderly are especially susceptible to the muscle wasting and osteoporotic effects of these drugs because of increased protein requirements and decreased vitamin D and calcium absorption. The mechanism of steroid myopathy is unknown, but it is a serious complication because recovery after withdrawal of therapy may be incomplete (59). Steroid-induced osteoporosis is observed most frequently in postmenopausal women. Bone loss occurs because the steroids inhibit bone formation by suppressing osteoblastic function and enhance bone reabsorption by stimulating osteoclastic function (60). The latter is the result of
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inhibited calcium absorption from the gut and increased parathyroid secretion. In addition, corticosteroids may enhance the conversion of 1,25-(OH)~D3, the active form of vitamin D, to an inactive metabolite; however, the da~a relative to this effect are contradictory. Treatment with vitamin D or its metabolites may be of benefit (61). Effects of Nutrients on Dru 8 Reactivity Dietary factors can affect both drug disposition and target tissue sensitivity. Although it seems reasonable to assume that nutritional influences may contribute substantially to the altered drug responsiveness of old age, experimental evidence in support of this premise is scanty. In light of the variation exhibited by the elderly in response to administered drugs, any information on the association between nutritional status and drug reactivity in the elderly would be beneficial. Pharmacokinetics. Most drugs are administered by the oral route. The rate of their gastrointestinal absorption is affected by the presence of food, but for most drugs the rate of entry into the systemic circulation is of little importance (62). The extent of absorption is affected only rarely. A well-known example of decreased absorption is the effect of milk products on tetracycline antibiotics. Absorption is impaired in the presence of food and food supplements because the tetracyclines form unabsorbable metal complexes with calcium, magnesium and iron. Extensive animal research demonstrates that nutritional factors are important determinants of drug metabolism, especially biotransformation catalyzed by the hepatic cytochrome P-450 system (63,64). Hepatic drug metabolism is affected by macronutrient ratios, vitamin deficiencies, mineral deficiencies, fasting and inducing compounds. Of these numerous influences only a few have been found to have clinical significance in man; proteinenergy malnutrition, changes in carbohydrate/protein ratio, long-term ascorbic acid deficiency and inductJon by indole-containing vegetables or charcoalbroiled meat. Studies in underdeveloped countries indicate that drug metabolism is markedly decreased in infants and children with protein-energy malnutrition, compared with their age-matched controls (65,66). On the other hand, studies in fasted or anorexic adults have not demonstrated changes in drug clearance (67,68). The protein/carbohydrate ratio of calorically adequate diets produces consistent effects on hepatic drug biotransformation in human volunteers; drug clearance is decreased by low-protein/high-carbohydrate diets (69). Whether protein-energy malnutrition or changes in protein/carbohydrate ratio affect drug metabolism in the aged has not been determined. Information from studies in aging animals is scarce. One study found that the effect of dietary protein level on hepatic microsomal drug metabolism in aging Syrian hamsters was variable, depending on sex and generation (70). In our studies, rats were fed either a semipurified diet (AIN-76, ICN Nutritional Biochemicals) or a commercial ration (Purina). Although cytochrome P-450 contents and cytochrome c reductase activities were 30-90% greater in the rats fed the commercial ration, the age-related decreases in these microsomal enzymes were smaller and occurred at a later age (Table I). The results are consistent with the idea that dietary composition modulates the effects of aging on the hepatic microsomal enzyme system. Vitamin C deficiency in guinea pigs decreases the oxidative metabolism of a variety of drugs (71,72), but data for humans are contradictory. Short term studies in humans showed no effect of ascorbic acid deficiency on drug metabolism (73-75). Although vitamin C concentrations in plasma or blood cells were decreased dramatically by the short-term deprivations, hepatic
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TABLE I Influence of Diet on Age-Related Changes in the Hepatic Microsomal Cytochrome P-450 System Age (Mo)
Diet
Body Wt ($)
Micros Prot (mg/g liver)
Cyt P-450 (nmol/mg prot)
Cyt c Reductase (nmol/min/mg prot)
4 14 24
C C C
300 _+ 4 400 ,+ 5 430 _+ 4
32 ,+ 1 32 + I 35 ± 2
1.02 _+ 0.05 0.98 ± 0.07 0.78 _+ 0.05
320 ± 30 270 ± 20 220 ± 20
4 14 24
S S S
320 ,+ 2 530 ,+ 3 480 ± 7
29 + 1 30 _+ 1 32 _+ I
0.79 ,+ 0.01 0.54 ,+ 0.03 0.55 ± 0.03
240 _+ 10 140 _+ lO 120 ,+ I0
Values are means ,+ SEM for 6 or more male Fischer 344 rats fed a commercial ration (C) or a semipurified diet (S) (17,33).
concentrations of the vitamin may not have been sufficiently depleted to affect the microsomal drug-metabolism system. (Ascorbic acid status in plasma does not necessarily reflect its status in other tissues) (76,77). Studies which did show an effect of vitamin C deficiency on hepatic drug metabolism were investigations in patients with long-term deficiency. Decreased elimination of drugs metabolized by the liver was associated with pre-existing vitamin C deficiency in the aged and in patients with mild maturity-onset diabetes; supplementation with the vitamin restored drug elimination rates to normal levels (78,79). The precise involvement of ascorbic acid in the hepatic microsomal drug-metabolism system is poorly defined. One idea is that the vitamin is intimately associated with cytochrome P-450 and is needed for efficient interaction with NADPH-cytochrome c (P-450) reductase (80,81). The importance of vitamin C in maintaining the hepatic microsomal enzyme system has been demonstrated also in the rat. Cytochrome P-450 and drug-metabolism activities are lower in mutant rats unable to synthesize ascorbic acid than in control rats or mutant rats supplemented with the vitamin (82). Membrane-bound ascorbic acid (83) and drug biotransformation (16-22) both decrease with age in rat liver. We found that the decline in microsomal ascorbic acid did not coincide with the age-related decline in cytochrome P-450 (Table 2). Nevertheless, the results raise the possibility of an increased requirement for ascorbate in aged liver. The effect of marginal vitamin C deficiency may be more significant in elderly individuals than in young ones. Dietary constiutents can affect drug metabolism also by inducing the activity of drug metabolizing enzymes. Although numerous inducing agents have been identified in animal studies, the only dietary constituents known to induce these enzymes in humans are cabbage, brussel sprouts and charcoalbroiled meat (84). The ability of the liver to respond to inducing drugs is modified in old age, both in animals (22,85) and in humans (86). However, neither the effect of aging on inducibility by dietary constituents nor the effect of dietary influences on age-related changes in inducibility has been investigated. Age-dependent loss of kidney function produces a marked decrease in the clearance of drugs eliminated primarily by renal excretion. The development of glomerular disease in animals can be delayed by making food available only on alternate days or by limiting the amount eaten on an ad libitum schedule.
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TABLE II Ascorbic Acid and Cytochrome P-450 in Hepatic Microsomes of Aging Rats Age (Mo)
Ascorbic Acid (nmol/m 8 prot)
Cytochrome P-450 (nmol/mg prot)
4 14 24
1.74 -+ 0.11 1.27 -+ 0.06 0.94 -+ 0.05
0.79 -+ 0.01 0.54 -+ 0.03 0.55 -+ 0.04
Ascorbic acid and cytochrome P-450 contents were determined in washed liver mlcrosomes. Values are means ± SEM for 6 or more male Fischer 344 rats (87).
Dietary protein is also important; glomerular sclerosis in rats subjected to renal ablation is enhanced by feeding high-protein diets and diminished by reducing dietary protein content. On the basis of these on other findings, Brenner and his colleagues have proposed that modern eating habits (highprotein diets, ad libitum) have imposed a functional burden on the human kidney that ultimately results in the deterioration of glomerular structure and function (88). It is intriguing to think that the progressive decline in human kidney function might be minimized by modifying eating habits. Tissue Sensitivity. The issue of nutritional influences on age-related changes in tissue sensitivity to drugs is one that is largely unexplored. As mentioned above, isoniazid toxicity may be enhanced in the elderly because of vitamin B6 deficiency. In addition, foods contain natural and synthetic antioxidants (tocopherol, butylated hydroxytoluene, butylated hydroxyanisole) which play a protective role by scavenging free radicals produced by drugs (89). It is conceivable that age-assoclated changes in dietary patterns might affect the intake of these substances and influence drug toxicity. Conclusions The extent to which aging affects drug-induced nutrient depletio~ Js undetermined. It is important, however, that nutritional allowances for the elderly take into account the increased prevalence of chronic illnesses and the extensive use of drugs in older persons. Drug-induced nutritional deficiencies should be avoided by supplementing the diets of geriatric patients with the appropriate nutrients. Finally, there is a need to investigate the role of nutritional factors in modifying age-associated changes in drug disposition and drug toxicity. References I. 2. 3. 4. 5. 6. 7. 8. 9.
E.L. SCHNEIDER, E.M. VINING, E.C. HADLEY and S.A. FARNHAM, N. Eng. J. Med. 314 157-160 (1986). J.N. HATHCOCK, Drug-Nutrient Interact. 4 217-234 (1985). D.A. ROE, Continuing Educ. 8 5 174-181 (T985). D.A. ROE, Drug-Nutrient Interact. 4 117-135 (1985). P. WELLING, Drug-Nutrient Interact. 4 173-207 (1985). M.G. KOVAR, Public Hlth. Rep. 92 9-I~ (1977). J.G. OUSLANDER, Ann. Int. Med. 95 711-722 (1981). D.J. GREENBLATT, E.M. SELLERS and R.I. SHADER, N. Eng. J. Med. 306 1081-1088 (1982). R.F. VESTAL, J. Am. Geriatr. Soc. 30 191-200 (1982).
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28. 29. 30. 31. 32.
33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50.
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