261 21
22
23
24
25
26
27
28
WAGSTAFF, D. J. and STREET, J. C.
(1971).
GINTER, E. (1973). Cholesterol: Vitamin C controls its transformation to bile acids, Science, 179, 702. TURLEY, S. D., WEST, C. E. and HORTON, B. J. (1976). The role of ascorbic acid in the regulation of cholesterol metabolism and in the , 1. pathogenesis of atherosclerosis. Atherosclerosis, 24 PATEL, J. M. and PAWAR, S. S. (1974). Riboflavin and drug metabolism in adult male and female rats, Biochem. Pharmac., 23, 1467. BECKING, G. C. (1973). Vitamin A status and hepatic drug metabolism in the rat, Canad. J. Phys. Pharmac., 51, 6. COLBY, H. D., KRAMER, R. E., GREINER, J. W., ROBINSON, D. A., KRAUSSE, R. F. and CANADY, W. J. (1975). Hepatic drug metabolism in retinol-deficient rats, Biochem. Pharmac., 24, 1644. SPORN, M. B., DUNLOP, N. M., NEWTON, D. L. and SMITH, J. M. (1976). Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids), Fed. Proc., 35, 1332. GENTA, V. M., KAUFMAN, D. G., HARRIS, C. C., SMITH, J. M., SPORN, M. B. and SAFFIOTI, V. (1974). Vitamin A deficiency enhances
binding
of
benzo(a)pyrene
Nature
Ascorbic acid defi-
ciency and induction of hepatic microsomal hydroxylative enzymes by organochlorine pesticides. Toxicol. Appl. Pharmacol., 19, 10.
to tracheal
epithelial DNA,
29
(Lond), 247, 48. CARPENTER, M. P. (1972). Vitamin E and microsomal hydroxylations, Ann. N.Y.
drug
Acad. Sci., 203, 81. HAUSWIRTH, J. W. and NAIR, P. P. (1975). Effects of different vitamin E-deficient basal diets on hepatic catalase and microsomal 5 in rats, Am. J. Clin. Nut., 28, 1087. cytochromes P-450 and b 31 WALKER, B. E., KELLEHER, J., DIXON, M. F. and LOSOWSKY, M. S. (1974). Vitamin E protection of the liver from paracetamol in the rat, Clin. Sci. Mol. Med., 47, 449. 32 BECKING, G. C. (1972). Influence of dietary iron levels on hepatic in vitro in the rat, Biochem. Phardrug metabolism in vivo and mac., 21, 1585. 33 HOENSCH, H., Woo, C. H. and SCHMID, R. (1975). Cytochrome P-450 and drug metabolism in intestinal villous and crypt cells of rat: effect of dietary iron. Biochem. Biophys. Res. Comm., 65, 399. 34 DINGELL, J. V., JOINER, P. D. and HURWITZ, L. (1966). Impairment of hepatic drug metabolism in calcium deficiency, Biochem. Pharmacol., 15 , 971. 35 BECKING, G. C. and MORRISON, A. B. (1970). Role of dietary magnesium in the metabolism of drugs by NADPH-dependent rat liver microsomal enzymes, Biochem. Pharmacol., 19, 2639. 30
SOME ADVERSE EFFECTS OF DRUGS ON NUTRITION JOHN W. T. DICKERSON, BSC, PH.D., F.I.BIOL., F.I.F.S.T., F.R.S.H. Professor o f Human Nutrition, Department o f Biochemistry,
University of Surrey ADVERSE REACTIONS to drugs are a serious in modern medicine. Such a reaction has been defined by the World Health Organization’ as one which is ’noxious, unintended and occurs at doses normally used in man for prophylaxis, diagnosis and therapy’. These reactions may be of various kinds and occur at the site of entry, in transit or at storage sites or at the site of action. They may result from the administration of a single drug or be the result of interactions between two or more drugs administered at the same time. Examples of each of these kinds of reactions involving nutrients can be found and will emerge during the course of this presentation. The effects of drugs on nutrition should be seen as one facet of the problem of adverse reactions. The importance of this problem is underlined by the fact that we have become a Nation of drug-takers. A number of factors combine to produce this situation. The relatively low cost to the consumer of drugs readily, and in some cases perhaps too readily prescribed, under the National Health Service (N.H.S.) is one factor. Another factor is the ease with which certain drugs, such as aspirin, can be obtained over the counter without prescription. The annual consumption of aspirin tablets in Britain was estimated some years ago’ at 4,000 million and there are more than 300 prescriptions containing aspirin on the market. In the context of our present discussion, alcohol must also be considered a drug and anybody over the age of eighteen can purchase unlimited quantities of this, and, of course, individuals of any age can consume it in their own homes. As far as drugs supplied by the N.H.S. are concerned total values are not readily available for all,
hazard
but a few
examples will indicate the size of the problem. Prescriptions for tranquillisers alone supplied through the N.H.S. in 1974 totalled £11,100,000 whilst the cost of appetite suppressants used in the treatment of obesity rose from £2,478,926 in 1973 to £3,582,000 in 1974. In 1975 anti-diarrhoeal drugs cost £2,070,000 and expectorants and cough suppressants £11,552,000. Not all drugs interact with nutrition and many of those that do depend on this interaction for their therapeutic effect. These effects have been reviewed elsewhere.3The present discussion will be limited to some adverse effects of drugs, and those that are likely to occur in elderly people are of special interest, for in these people they may further exacerbate an existing tendency to malnutrition. APPETITE SUPPRESSANTS ANORECTIC DRUGS (Table I) are prescribed to help overweight patients to lose weight and often to help them adhere to a reducing dietary regimen, although it TABLE I
Appetite suppressants
Downloaded from rsh.sagepub.com at UCSF LIBRARY & CKM on April 9, 2015
262 TABLE III
Figure
1
Appetite suppressant drugs
is commonly found that repeated administration may be associated with disappearance of the anorectic effect.4 One of these drugs, amphetamine (Fig. 1), has pleasant euphoric side-effects and patients become addicted to it. This drug inhibits the enzyme monoamine oxidase (MAO) which inactivates, amongst other substances, sympathomimetic amines that occur naturally in some foods. Antidepressant drugs, such as
iproniazid
or
tranylcypromine
are
more
powerful
inhibitors of this enzyme and may be taken by obese individuals who are often depressed, particularly if they are trying to lose weight. If patients taking these drugs then eat foods containing sympathomimetic amines, such as tyramine (Table II), they develop a headache, nausea, and hypertension and may even die. These unpleasant side-effects result from the entry of the amine into the circulation and its distribution to the tissues where it exerts its undesirable vaso-constrictor action. Further serious complications may arise because individuals who develop a headache are likely to take aspirin or an aspirin-containing preparation which can cause profound hypoglycaemia. All patients taking antidepressant drugs should be warned not to consume foods containing large amounts of tyramine. Fenfluramine (Fig. 1) is safer to use as an appetite suppressant than amphetamine since it has less sideeffects. Unlike amphetamine, it has a sedative action so that there is no need to take an antidepressant drug with it. TABLE II
Toxic reactions to inhibitors (MAOI).
foods during therapy
with monoamine oxidase
ORAL CONTRACEPTIVES HORMONES PLAY a major role in controlling the body’s metabolism. It is therefore not surprising that the ingestion of combinations of oestrogen and progcstagen as contraceptive agents should be associated BB 11 h metabolic changes (Table III). Deaths due to thmmbosis have occurred in women taking these preparations, and recently there has been a report of 21 cases of small bowel ischaemia in women receiving 0.05 mg/d of oestrogen. It is not known to wheat extent these complications may be due to the metabolic changes summarized in Table III. However, raised blood lipid concentrations are recognised as possible risk factors in vascular disease (for references, see Lee and Dickerson6) and others78 have suggested that low ascorbic acid status may also be involved. The cffects of oral contraceptives on blood lipids could, in fact, be considered as perhaps the most disturbing feature of their use. Indeed, it seems necessary to evaluate all the metabolic changes induced by these agents in the light of the fact that they are now readily available to young women and are being prescribed for teenage girls as a treatment for dysmenorrhoea. The lower concentrations of plasma triglycerides and cholesterol in pre-menopausal women correlate with a significantly smaller risk of sudden death from ischaemic heart disease. However, the increase in plasma triglycerides and cholesterol that occurs in women taking oral contraceptives9 reduces the sex differential between men and women of similar ages. Experiments in rats have indicated that the incorporation of sunflower oil into the diet mitigated the changes in blood lipids caused by oral contraceptives, particularly when the diet was also low in cholesterol.10 Disturbances of tryptophan metabolism were amongst the first biochemical abnormalities to be described in women taking the combination type oral contraceptives. These abnormalities may be observed in about 80 per cent of women receiving the ’pill’. Their pattern is similar to that found in individuals who have a nutritional deficiency of vitamin B6 and indicates a reduced availability of pyridoxal phosphate. However, most women have normal tissue levels of pyridoxal phosphate as demonstrated by normal erythrocyte aminotransferase activity and plasma levels of pyridoxal phosphate. But in 15-20 per cent of women taking the ’pill’ clear evidence of sub-clinical pyridoxal phosphate deficiency has been found.&dquo; This recent work suggests that there is a link via the effects on tryptophan metabolism, between vitamin B6 deficiency and the impaired glucose tolerance induced by the
agents. Oral contraceptives reduce the concentration in the blood of a number of vitamins in addition to B6. Thus, values for folic acid, vitamin B12, ascorbic acid and riboflavin have all been reported to be lower in women
Downloaded from rsh.sagepub.com at UCSF LIBRARY & CKM on April 9, 2015
263 the ’pill’ than in controls, and it seems that the oestrogen component of the pill is again responsible. As
taking far
as folic acid and ascorbic acid are concerned the reductions in concentration are probably brought about, at least in part, by a common mechanism, for oestrogen induces the secretion of cortisol by the adrenal and this in turn induces the activity of the mixed function oxidase system in the liver, which requires both folic acid and ascorbic acid as co-factors. However, there is some evidence that oral contraceptives accelerate the breakdown of ascorbic acid and cause a change in tissue distribution of the vitamin. 12 There is a risk that the reduction in the levels of ascorbic acid, and also of folic acid, by oral contraceptives, may be further exacerbated by taking other drugs such as aspirin or anticonvulsants respectively (vida infra). Blood ascorbic acid levels are also reduced by smoking. Thus it is possible to visualize in some women a situation developing in which a state of sub-clinical ascorbic acid deficiency does develop. This may well affect function in subtle ways that are only apparent on careful assessment, but which nevertheless may represent a reduction in the ability to work. There is evidence, for instance, that brain function is reduced when the deficiency of ascorbic acid is insufficient to produce overt scurvy. 13 In this study five healthy prisoner volunteers were given a diet that was deficient in ascorbic acid. Changes were found in measures of personality which corresponded to the ’neurotic triad’ of hysteria, depression and hypochondriasis. These changes preceded decreased psychomotor performance associated with decreased arousal and motivation. Drug induced riboflavin deficiency has been reported in experimental animals. However, biochemical evidence of deficiency without clinical manifestation has been reported in Thai women on oral contraceptives,14 and this interaction could be important in those parts of the world where riboflavin deficiency is common and where oral contraceptives are being increasingly used. The metabolic consequences of taking oral contraceptives cannot be ignored by any responsible doctor. They are not the harmless agents that previous reports might have led one to believe, and in the light of the fact that their long term effects are almost unknown, it might be prudent to consider that they should only he made available after due consideration of risk and benefit in individual women.
ANTICONVULSANTS EPILEPSY OCCURS in 1 in 200 of the population.&dquo; It usually manifests itself in infancy or adolescence and consequent life-long treatment with one, or a combination, of anticonvulsant drugs (Fig. 2) of which
phenytoin (epanutin, dilantin) and phenobarbitone are the most commonly used, gives time for nutritional side-effects to become evident. Megaloblastic anaemia due to folic acid deficiency was first described in patients receiving long term treatment with anticonvulsant drugs in 1952, and rickets was first described in children receiving these drugs in 1968. Frank megaloblastic anaemia is, in fact, not common in patients on anticonvulsant therapy whereas low
and red cell concentrations of the vitamin are found in about 40 per cent of such patients. A number of suggestions have been made about the mechanism whereby the reduction in blood levels of the vitamin is brought about. However, recent work in our laboratory supports the suggestion that it arises because of competition for folic acid as a co-enzyme by the raised levels of hepatic drug-metabolizing enzymes induced by serum
Figure
3
Vicious circle
Downloaded from rsh.sagepub.com at UCSF LIBRARY & CKM on April 9, 2015
of drug toxicity ciency
induced
by folic
acid
defi-
264 the drug.’6 An estimate of the dietary intake of folic acid by the patients gave a value of 49~g per day. This value, together with that obtained from other dietary studies&dquo; suggests that the intake of folic acid in British psychiatric hospitals is considerably lower than the 100~g per day recommended by Chanarin.18 Giving folic acid supplements to epileptic patients has been reported to exacerbate the clinical condition and to necessitate increase of drug levels in order to control the seizures. It seems that a balance between drug dosage and folic acid intake must be worked out such that the epilepsy is controlled on the lowest drug intake commensurate with normal blood folic acid levels. Failure to recognise the risk of folic acid deficiency in these patients could result in increased toxicity of the drug as the folic acid levels are depleted and the development of a vicious circle (Fig. 3) in which on a given drug intake the drug level in the body would eventually rise due to failure of the detoxicating mechanisms. Our findings suggest that this sequence of changes will occur when any drug which acts as an enzyme-inducer is given over a sufficient period of time. Epidemiological evidence suggests that the incidence of congenital malformations is higher in the offspring of women receiving anticonvulsant drugs than in the general population. Experiments on rats receiving a low folate intake suggest that the malformations are due to interaction of the drugs with folic acid.’9 Rickets or osteomalacia may occur in patients receiving long term treatment with high doses of anticonvulsants and was first reported from Germany in 1968. It seems that the hepatic drug-metabolizing enzymes divert vitamin D from its normal pathway to the 25-hydroxymetabolite to other hydroxylated and less active metabolites. Patients with ’anticonvulsant rickets’ have low circulating levels of 25hydroxycholecalciferol in the plasma. 20 Indeed, these workers found some evidence of vitamin D resistance in their patients, and it has been suggested that patients taking anti-convulsants may require about 14~g vitamin D orally to prevent osteomalacia 21 and children on combination anti-convulsant therapy may need as much as 35Ag per day. 21 ALCOHOL AS REMARKED earlier, alcohol must be considered as a drug. Small amounts stimulate appetite and are useful for this purpose during convalescence. It is also a source of energy, providing 29.7 kJ (7 kcals)/g and because of this alcoholics eat little normal food and may develop multiple vitamin deficiencies. Alcohol specifically interferes with the absorption of thiamin and folic acid from the small intestine. Long-standing thiamin deficiency in malnourished alcoholics may lead to a neurological and psychiatric disease, the Wernicke-Korsakoff syndrome, which is associated with irreversible changes in brain structure. Alcohol also has a toxic effect on the bone marrow but this is reversible. Folate deficiency is common in alcoholics and occurs particularly in spiritdrinkers. Some kinds of beer are, in fact, good sources of folic acid.23 Probably the most important, and potentially the most dangerous effect of alcohol is that it induces hypoglycaemia. This effect, as seen in malnourished or fasting subjects has been known for a long time but is comparatively rare when we consider the degree of alcohol abuse, furthermore it tends to occur only in chronic alcoholics. 21 Our colleague, Professor Vincent Marks, has recently drawn attention to a much com-
problem which may occur in perfectly normal healthy individuals. It seems that alcohol, equivalent to three double gin and tonics, or to a few pints of beer, when taken together with foods that rapidly yield glucose such as biscuits, sliced bread or bread rolls, may potentiate the insulin-releasing properties of the glucose. The result of this is that some hours after taking such a ’lunch’ a sense of undue fatigue, with lack of concentration and impairment ofjudgement may occur. It is not difficult to imagine that these effects may have serious consequences if they arise when a person is driving a car. Another potentially dangerous effect of alcohol is that it potentiates the effects of other drugs such as barbiturates, tranquillisers and antihistamines. The medical complications of alcoholism are summarised in Figure 4. moner
Figure 4 Medical complications of alcoholism 25
ASCORBIC ACID A NUMBER OF drugs lower the concentration of ascorbic acid in the blood. Clinical scurvy has been described in a patient with rheumatoid arthritis treated with prednisonet6 and high doses of aspirin, also used in the treatment of this condition, deplete the tissues of the vitamin.&dquo; Others28 have shown that aspirin prevents ascorbic acid entering leucocytes. Ascorbic acid has received considerable popularity as a panacea in the prevention or treatment of a number of conditions notably the common cold, bladder cancer and pain due to skeletal metastases. However, it is not the harmless substance that is commonly imagined and its use in gram, i.e. pharmacological, quantities is not without risk.29 Some people may metabolize abnormally large amounts of ascorbic acid to oxalate and thus be at risk of developing renal stones due to the insolubility of calcium oxalate. Another potential hazard is that it may induce a relative deficiency of available sulphate in the body by virtue of the fact that it combines with sulphate to form ascorbic acid sulphate. The importance of this reaction is two-fold. The main dietary sources of sulphate in the
are the sulphur-containing amino acid, methionine and cyst(e)ine and the availability of these will therefore be reduced .21 Furthermore, combinations of drugs with sulphate and subsequent excretion of the sulphate complex is one way in which they are detoxicated. Administration of large amounts of ascorbic acid leads to a reduction in the excretion of such complexes3° and in this way could lead to an accumulation of the drug in the body. Incidentally, another vitamin currently being taken in pharmacological amounts, vitamin E, reduces the availability of vitamin K and can cause serious haemor-
body
Downloaded from rsh.sagepub.com at UCSF LIBRARY & CKM on April 9, 2015
265
rhage
if taken in combination with drugs such are also anti-vitamin K agents.
CONCLUSIONS DRUGS MAY interfere with nutrition in a variety of ways some of which are desirable and others undesirable. Undesirable effects may result from the administration of a single drug, particularly if it is given over a long period, or more often as a result of the interaction of two or more drugs given simultaneously. Doctors need to be increasingly aware of such interactions some of which may be caused by substances like alcohol which may not often be considered as a drug, or by aspirin which can be readily obtained over the counter from a Pharmacy. There is a need for these adverse effects to be more widely known and I have done no more than hint at a few of them. The elderly are particularly vulnerable and the effects of drugs on nutrition may well be responsible for some of the adverse effects of drugs seen in old people. Drugnutrient interactions are therefore important in the context of both curative and preventive medicine.
as
warfarin,3’ which
CYTOTOXIC DRUGS THESE DRUGS are used in the treatment of certain forms of cancer. Some of them owe their effects on tumours to the fact that they are anti-metabolites. Methotrexate, for instance, competes for folic acid and thus decreases the availability of this vitamin for tumour growth. However, other drugs of this kind appear to cause an incidental reduction in the availability of vitamins. We32 have been studying the effects of 5-fluorouracil on thiamin status following the observation that patients receiving the drug showed biochemical evidence of thiamin deficiency. It appears that this deficiency may occur in the face of an adequate thiamin intake due to a reduction in the phosphorylation of thiamin to its active co-enzyme, thiamin pyrophosphate. A synergistic effect between drugs and nutrients may also occur. Thus, vitamin A has been shown to enhance the antitumour activity of cyclophosphamide in experimental animals.33 DRUG-NUTRIENT INTERACTION IN THE ELDERLY THERE ARE various factors that may contribute to the high incidence of adverse reactions to drugs in old people. Multiple pathology often leads to multiple pharmacy with the increased risk of interactions between drugs and increased toxicity of drugs due to a decreased ability to metabolize them. This situation is further aggravated in some cases by the direct toxic effects of the drugs on a deteriorated renal function. Superimposed on this is the fact that illness in the elderly pre-disposes them to nutritional deficiencies34 which may be induced by the drugs and also further exacerbate their toxicity. Some drugs that are commonly prescribed by doctors for old people, or which they may obtain for themselves, are shown in Table IV. Some of these have already been discussed. Some oral hypoglycaemic agents used in the control of adult-onset diabetes, such as sulphonylureas may cause serious or fatal hypoglycaemia in elderly malnourished patients. Their action may be potentiated by other drugs such as phenylbutazone and warfarin which displace the sulphonylureas from binding sites on plasma proteins. Their hypoglycaemic action is also potentiated by aspirin and alcohol both of which may so easily be taken with the drugs unless the patients are specifically warned. Potassium deficiency has been claimed to be a cause of mental depression35 and muscle weakness36 in the elderly. The body is depleted of both potassium and sodium by thiazide diuretics and these drugs should not be given without potassium supplements. Iron-deficiency anaemia is common amongst old people. Sometimes it is due to the inadequate consumption of foods that contain readily available iron. The possibility that it may be due to protracted small losses from the gastro-intestinal tract should not be overlooked and this kind of loss may be exacerbated by aspirin. In one study&dquo; blood losses in 144 patients
receiving aspirin were
or
aspirin-containing preparations
estimated with 51Cr labelled red cells
to average
day. When aspirin is used infrequently as an analgesic, losses of this magnitude may not be serious, but Alka-Seltzer tablets (aspirin and sodium bicarbonate) may be used regularly by old people for indigestion and in this case any accompanying blood about 5 ml per
losses could lead to anaemia.
TABLE IV Nutritional interactions with
drugs commonly given to elderly patients
,
REFERENCES 1 WORLD HEALTH ORGANIZATION (1969). International drug monitoring, World Health Organization Technical Report, Series No. 425, Geneva. 2 WADE, O. L. (1970). Adverse reactions to drugs, London: Heinemann Medical. 3 DICKERSON, J. W. T. (1978). The interrelationships of nutrition and drugs, Ch.14 in ’Nutrition in the Clinical Management of Disease’. Eds. J. W. T. Dickerson and H. A. Lee, London: Edward Arnold. 4 KIRBY, M. J. and TURNER, P. (1976). Do anorectic drugs produce weight loss by appetite suppression? Lancet, 1, 566.
Continued
Downloaded from rsh.sagepub.com at UCSF LIBRARY & CKM on April 9, 2015
on
page 274
22
23
24
25
26
27
28
WAGSTAFF, D. J. and STREET, J. C.
(1971).
GINTER, E. (1973). Cholesterol: Vitamin C controls its transformation to bile acids, Science, 179, 702. TURLEY, S. D., WEST, C. E. and HORTON, B. J. (1976). The role of ascorbic acid in the regulation of cholesterol metabolism and in the , 1. pathogenesis of atherosclerosis. Atherosclerosis, 24 PATEL, J. M. and PAWAR, S. S. (1974). Riboflavin and drug metabolism in adult male and female rats, Biochem. Pharmac., 23, 1467. BECKING, G. C. (1973). Vitamin A status and hepatic drug metabolism in the rat, Canad. J. Phys. Pharmac., 51, 6. COLBY, H. D., KRAMER, R. E., GREINER, J. W., ROBINSON, D. A., KRAUSSE, R. F. and CANADY, W. J. (1975). Hepatic drug metabolism in retinol-deficient rats, Biochem. Pharmac., 24, 1644. SPORN, M. B., DUNLOP, N. M., NEWTON, D. L. and SMITH, J. M. (1976). Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids), Fed. Proc., 35, 1332. GENTA, V. M., KAUFMAN, D. G., HARRIS, C. C., SMITH, J. M., SPORN, M. B. and SAFFIOTI, V. (1974). Vitamin A deficiency enhances
binding
of
benzo(a)pyrene
Nature
Ascorbic acid defi-
ciency and induction of hepatic microsomal hydroxylative enzymes by organochlorine pesticides. Toxicol. Appl. Pharmacol., 19, 10.
to tracheal
epithelial DNA,
29
(Lond), 247, 48. CARPENTER, M. P. (1972). Vitamin E and microsomal hydroxylations, Ann. N.Y.
drug
Acad. Sci., 203, 81. HAUSWIRTH, J. W. and NAIR, P. P. (1975). Effects of different vitamin E-deficient basal diets on hepatic catalase and microsomal 5 in rats, Am. J. Clin. Nut., 28, 1087. cytochromes P-450 and b 31 WALKER, B. E., KELLEHER, J., DIXON, M. F. and LOSOWSKY, M. S. (1974). Vitamin E protection of the liver from paracetamol in the rat, Clin. Sci. Mol. Med., 47, 449. 32 BECKING, G. C. (1972). Influence of dietary iron levels on hepatic in vitro in the rat, Biochem. Phardrug metabolism in vivo and mac., 21, 1585. 33 HOENSCH, H., Woo, C. H. and SCHMID, R. (1975). Cytochrome P-450 and drug metabolism in intestinal villous and crypt cells of rat: effect of dietary iron. Biochem. Biophys. Res. Comm., 65, 399. 34 DINGELL, J. V., JOINER, P. D. and HURWITZ, L. (1966). Impairment of hepatic drug metabolism in calcium deficiency, Biochem. Pharmacol., 15 , 971. 35 BECKING, G. C. and MORRISON, A. B. (1970). Role of dietary magnesium in the metabolism of drugs by NADPH-dependent rat liver microsomal enzymes, Biochem. Pharmacol., 19, 2639. 30
SOME ADVERSE EFFECTS OF DRUGS ON NUTRITION JOHN W. T. DICKERSON, BSC, PH.D., F.I.BIOL., F.I.F.S.T., F.R.S.H. Professor o f Human Nutrition, Department o f Biochemistry,
University of Surrey ADVERSE REACTIONS to drugs are a serious in modern medicine. Such a reaction has been defined by the World Health Organization’ as one which is ’noxious, unintended and occurs at doses normally used in man for prophylaxis, diagnosis and therapy’. These reactions may be of various kinds and occur at the site of entry, in transit or at storage sites or at the site of action. They may result from the administration of a single drug or be the result of interactions between two or more drugs administered at the same time. Examples of each of these kinds of reactions involving nutrients can be found and will emerge during the course of this presentation. The effects of drugs on nutrition should be seen as one facet of the problem of adverse reactions. The importance of this problem is underlined by the fact that we have become a Nation of drug-takers. A number of factors combine to produce this situation. The relatively low cost to the consumer of drugs readily, and in some cases perhaps too readily prescribed, under the National Health Service (N.H.S.) is one factor. Another factor is the ease with which certain drugs, such as aspirin, can be obtained over the counter without prescription. The annual consumption of aspirin tablets in Britain was estimated some years ago’ at 4,000 million and there are more than 300 prescriptions containing aspirin on the market. In the context of our present discussion, alcohol must also be considered a drug and anybody over the age of eighteen can purchase unlimited quantities of this, and, of course, individuals of any age can consume it in their own homes. As far as drugs supplied by the N.H.S. are concerned total values are not readily available for all,
hazard
but a few
examples will indicate the size of the problem. Prescriptions for tranquillisers alone supplied through the N.H.S. in 1974 totalled £11,100,000 whilst the cost of appetite suppressants used in the treatment of obesity rose from £2,478,926 in 1973 to £3,582,000 in 1974. In 1975 anti-diarrhoeal drugs cost £2,070,000 and expectorants and cough suppressants £11,552,000. Not all drugs interact with nutrition and many of those that do depend on this interaction for their therapeutic effect. These effects have been reviewed elsewhere.3The present discussion will be limited to some adverse effects of drugs, and those that are likely to occur in elderly people are of special interest, for in these people they may further exacerbate an existing tendency to malnutrition. APPETITE SUPPRESSANTS ANORECTIC DRUGS (Table I) are prescribed to help overweight patients to lose weight and often to help them adhere to a reducing dietary regimen, although it TABLE I
Appetite suppressants
Downloaded from rsh.sagepub.com at UCSF LIBRARY & CKM on April 9, 2015
262 TABLE III
Figure
1
Appetite suppressant drugs
is commonly found that repeated administration may be associated with disappearance of the anorectic effect.4 One of these drugs, amphetamine (Fig. 1), has pleasant euphoric side-effects and patients become addicted to it. This drug inhibits the enzyme monoamine oxidase (MAO) which inactivates, amongst other substances, sympathomimetic amines that occur naturally in some foods. Antidepressant drugs, such as
iproniazid
or
tranylcypromine
are
more
powerful
inhibitors of this enzyme and may be taken by obese individuals who are often depressed, particularly if they are trying to lose weight. If patients taking these drugs then eat foods containing sympathomimetic amines, such as tyramine (Table II), they develop a headache, nausea, and hypertension and may even die. These unpleasant side-effects result from the entry of the amine into the circulation and its distribution to the tissues where it exerts its undesirable vaso-constrictor action. Further serious complications may arise because individuals who develop a headache are likely to take aspirin or an aspirin-containing preparation which can cause profound hypoglycaemia. All patients taking antidepressant drugs should be warned not to consume foods containing large amounts of tyramine. Fenfluramine (Fig. 1) is safer to use as an appetite suppressant than amphetamine since it has less sideeffects. Unlike amphetamine, it has a sedative action so that there is no need to take an antidepressant drug with it. TABLE II
Toxic reactions to inhibitors (MAOI).
foods during therapy
with monoamine oxidase
ORAL CONTRACEPTIVES HORMONES PLAY a major role in controlling the body’s metabolism. It is therefore not surprising that the ingestion of combinations of oestrogen and progcstagen as contraceptive agents should be associated BB 11 h metabolic changes (Table III). Deaths due to thmmbosis have occurred in women taking these preparations, and recently there has been a report of 21 cases of small bowel ischaemia in women receiving 0.05 mg/d of oestrogen. It is not known to wheat extent these complications may be due to the metabolic changes summarized in Table III. However, raised blood lipid concentrations are recognised as possible risk factors in vascular disease (for references, see Lee and Dickerson6) and others78 have suggested that low ascorbic acid status may also be involved. The cffects of oral contraceptives on blood lipids could, in fact, be considered as perhaps the most disturbing feature of their use. Indeed, it seems necessary to evaluate all the metabolic changes induced by these agents in the light of the fact that they are now readily available to young women and are being prescribed for teenage girls as a treatment for dysmenorrhoea. The lower concentrations of plasma triglycerides and cholesterol in pre-menopausal women correlate with a significantly smaller risk of sudden death from ischaemic heart disease. However, the increase in plasma triglycerides and cholesterol that occurs in women taking oral contraceptives9 reduces the sex differential between men and women of similar ages. Experiments in rats have indicated that the incorporation of sunflower oil into the diet mitigated the changes in blood lipids caused by oral contraceptives, particularly when the diet was also low in cholesterol.10 Disturbances of tryptophan metabolism were amongst the first biochemical abnormalities to be described in women taking the combination type oral contraceptives. These abnormalities may be observed in about 80 per cent of women receiving the ’pill’. Their pattern is similar to that found in individuals who have a nutritional deficiency of vitamin B6 and indicates a reduced availability of pyridoxal phosphate. However, most women have normal tissue levels of pyridoxal phosphate as demonstrated by normal erythrocyte aminotransferase activity and plasma levels of pyridoxal phosphate. But in 15-20 per cent of women taking the ’pill’ clear evidence of sub-clinical pyridoxal phosphate deficiency has been found.&dquo; This recent work suggests that there is a link via the effects on tryptophan metabolism, between vitamin B6 deficiency and the impaired glucose tolerance induced by the
agents. Oral contraceptives reduce the concentration in the blood of a number of vitamins in addition to B6. Thus, values for folic acid, vitamin B12, ascorbic acid and riboflavin have all been reported to be lower in women
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263 the ’pill’ than in controls, and it seems that the oestrogen component of the pill is again responsible. As
taking far
as folic acid and ascorbic acid are concerned the reductions in concentration are probably brought about, at least in part, by a common mechanism, for oestrogen induces the secretion of cortisol by the adrenal and this in turn induces the activity of the mixed function oxidase system in the liver, which requires both folic acid and ascorbic acid as co-factors. However, there is some evidence that oral contraceptives accelerate the breakdown of ascorbic acid and cause a change in tissue distribution of the vitamin. 12 There is a risk that the reduction in the levels of ascorbic acid, and also of folic acid, by oral contraceptives, may be further exacerbated by taking other drugs such as aspirin or anticonvulsants respectively (vida infra). Blood ascorbic acid levels are also reduced by smoking. Thus it is possible to visualize in some women a situation developing in which a state of sub-clinical ascorbic acid deficiency does develop. This may well affect function in subtle ways that are only apparent on careful assessment, but which nevertheless may represent a reduction in the ability to work. There is evidence, for instance, that brain function is reduced when the deficiency of ascorbic acid is insufficient to produce overt scurvy. 13 In this study five healthy prisoner volunteers were given a diet that was deficient in ascorbic acid. Changes were found in measures of personality which corresponded to the ’neurotic triad’ of hysteria, depression and hypochondriasis. These changes preceded decreased psychomotor performance associated with decreased arousal and motivation. Drug induced riboflavin deficiency has been reported in experimental animals. However, biochemical evidence of deficiency without clinical manifestation has been reported in Thai women on oral contraceptives,14 and this interaction could be important in those parts of the world where riboflavin deficiency is common and where oral contraceptives are being increasingly used. The metabolic consequences of taking oral contraceptives cannot be ignored by any responsible doctor. They are not the harmless agents that previous reports might have led one to believe, and in the light of the fact that their long term effects are almost unknown, it might be prudent to consider that they should only he made available after due consideration of risk and benefit in individual women.
ANTICONVULSANTS EPILEPSY OCCURS in 1 in 200 of the population.&dquo; It usually manifests itself in infancy or adolescence and consequent life-long treatment with one, or a combination, of anticonvulsant drugs (Fig. 2) of which
phenytoin (epanutin, dilantin) and phenobarbitone are the most commonly used, gives time for nutritional side-effects to become evident. Megaloblastic anaemia due to folic acid deficiency was first described in patients receiving long term treatment with anticonvulsant drugs in 1952, and rickets was first described in children receiving these drugs in 1968. Frank megaloblastic anaemia is, in fact, not common in patients on anticonvulsant therapy whereas low
and red cell concentrations of the vitamin are found in about 40 per cent of such patients. A number of suggestions have been made about the mechanism whereby the reduction in blood levels of the vitamin is brought about. However, recent work in our laboratory supports the suggestion that it arises because of competition for folic acid as a co-enzyme by the raised levels of hepatic drug-metabolizing enzymes induced by serum
Figure
3
Vicious circle
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of drug toxicity ciency
induced
by folic
acid
defi-
264 the drug.’6 An estimate of the dietary intake of folic acid by the patients gave a value of 49~g per day. This value, together with that obtained from other dietary studies&dquo; suggests that the intake of folic acid in British psychiatric hospitals is considerably lower than the 100~g per day recommended by Chanarin.18 Giving folic acid supplements to epileptic patients has been reported to exacerbate the clinical condition and to necessitate increase of drug levels in order to control the seizures. It seems that a balance between drug dosage and folic acid intake must be worked out such that the epilepsy is controlled on the lowest drug intake commensurate with normal blood folic acid levels. Failure to recognise the risk of folic acid deficiency in these patients could result in increased toxicity of the drug as the folic acid levels are depleted and the development of a vicious circle (Fig. 3) in which on a given drug intake the drug level in the body would eventually rise due to failure of the detoxicating mechanisms. Our findings suggest that this sequence of changes will occur when any drug which acts as an enzyme-inducer is given over a sufficient period of time. Epidemiological evidence suggests that the incidence of congenital malformations is higher in the offspring of women receiving anticonvulsant drugs than in the general population. Experiments on rats receiving a low folate intake suggest that the malformations are due to interaction of the drugs with folic acid.’9 Rickets or osteomalacia may occur in patients receiving long term treatment with high doses of anticonvulsants and was first reported from Germany in 1968. It seems that the hepatic drug-metabolizing enzymes divert vitamin D from its normal pathway to the 25-hydroxymetabolite to other hydroxylated and less active metabolites. Patients with ’anticonvulsant rickets’ have low circulating levels of 25hydroxycholecalciferol in the plasma. 20 Indeed, these workers found some evidence of vitamin D resistance in their patients, and it has been suggested that patients taking anti-convulsants may require about 14~g vitamin D orally to prevent osteomalacia 21 and children on combination anti-convulsant therapy may need as much as 35Ag per day. 21 ALCOHOL AS REMARKED earlier, alcohol must be considered as a drug. Small amounts stimulate appetite and are useful for this purpose during convalescence. It is also a source of energy, providing 29.7 kJ (7 kcals)/g and because of this alcoholics eat little normal food and may develop multiple vitamin deficiencies. Alcohol specifically interferes with the absorption of thiamin and folic acid from the small intestine. Long-standing thiamin deficiency in malnourished alcoholics may lead to a neurological and psychiatric disease, the Wernicke-Korsakoff syndrome, which is associated with irreversible changes in brain structure. Alcohol also has a toxic effect on the bone marrow but this is reversible. Folate deficiency is common in alcoholics and occurs particularly in spiritdrinkers. Some kinds of beer are, in fact, good sources of folic acid.23 Probably the most important, and potentially the most dangerous effect of alcohol is that it induces hypoglycaemia. This effect, as seen in malnourished or fasting subjects has been known for a long time but is comparatively rare when we consider the degree of alcohol abuse, furthermore it tends to occur only in chronic alcoholics. 21 Our colleague, Professor Vincent Marks, has recently drawn attention to a much com-
problem which may occur in perfectly normal healthy individuals. It seems that alcohol, equivalent to three double gin and tonics, or to a few pints of beer, when taken together with foods that rapidly yield glucose such as biscuits, sliced bread or bread rolls, may potentiate the insulin-releasing properties of the glucose. The result of this is that some hours after taking such a ’lunch’ a sense of undue fatigue, with lack of concentration and impairment ofjudgement may occur. It is not difficult to imagine that these effects may have serious consequences if they arise when a person is driving a car. Another potentially dangerous effect of alcohol is that it potentiates the effects of other drugs such as barbiturates, tranquillisers and antihistamines. The medical complications of alcoholism are summarised in Figure 4. moner
Figure 4 Medical complications of alcoholism 25
ASCORBIC ACID A NUMBER OF drugs lower the concentration of ascorbic acid in the blood. Clinical scurvy has been described in a patient with rheumatoid arthritis treated with prednisonet6 and high doses of aspirin, also used in the treatment of this condition, deplete the tissues of the vitamin.&dquo; Others28 have shown that aspirin prevents ascorbic acid entering leucocytes. Ascorbic acid has received considerable popularity as a panacea in the prevention or treatment of a number of conditions notably the common cold, bladder cancer and pain due to skeletal metastases. However, it is not the harmless substance that is commonly imagined and its use in gram, i.e. pharmacological, quantities is not without risk.29 Some people may metabolize abnormally large amounts of ascorbic acid to oxalate and thus be at risk of developing renal stones due to the insolubility of calcium oxalate. Another potential hazard is that it may induce a relative deficiency of available sulphate in the body by virtue of the fact that it combines with sulphate to form ascorbic acid sulphate. The importance of this reaction is two-fold. The main dietary sources of sulphate in the
are the sulphur-containing amino acid, methionine and cyst(e)ine and the availability of these will therefore be reduced .21 Furthermore, combinations of drugs with sulphate and subsequent excretion of the sulphate complex is one way in which they are detoxicated. Administration of large amounts of ascorbic acid leads to a reduction in the excretion of such complexes3° and in this way could lead to an accumulation of the drug in the body. Incidentally, another vitamin currently being taken in pharmacological amounts, vitamin E, reduces the availability of vitamin K and can cause serious haemor-
body
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265
rhage
if taken in combination with drugs such are also anti-vitamin K agents.
CONCLUSIONS DRUGS MAY interfere with nutrition in a variety of ways some of which are desirable and others undesirable. Undesirable effects may result from the administration of a single drug, particularly if it is given over a long period, or more often as a result of the interaction of two or more drugs given simultaneously. Doctors need to be increasingly aware of such interactions some of which may be caused by substances like alcohol which may not often be considered as a drug, or by aspirin which can be readily obtained over the counter from a Pharmacy. There is a need for these adverse effects to be more widely known and I have done no more than hint at a few of them. The elderly are particularly vulnerable and the effects of drugs on nutrition may well be responsible for some of the adverse effects of drugs seen in old people. Drugnutrient interactions are therefore important in the context of both curative and preventive medicine.
as
warfarin,3’ which
CYTOTOXIC DRUGS THESE DRUGS are used in the treatment of certain forms of cancer. Some of them owe their effects on tumours to the fact that they are anti-metabolites. Methotrexate, for instance, competes for folic acid and thus decreases the availability of this vitamin for tumour growth. However, other drugs of this kind appear to cause an incidental reduction in the availability of vitamins. We32 have been studying the effects of 5-fluorouracil on thiamin status following the observation that patients receiving the drug showed biochemical evidence of thiamin deficiency. It appears that this deficiency may occur in the face of an adequate thiamin intake due to a reduction in the phosphorylation of thiamin to its active co-enzyme, thiamin pyrophosphate. A synergistic effect between drugs and nutrients may also occur. Thus, vitamin A has been shown to enhance the antitumour activity of cyclophosphamide in experimental animals.33 DRUG-NUTRIENT INTERACTION IN THE ELDERLY THERE ARE various factors that may contribute to the high incidence of adverse reactions to drugs in old people. Multiple pathology often leads to multiple pharmacy with the increased risk of interactions between drugs and increased toxicity of drugs due to a decreased ability to metabolize them. This situation is further aggravated in some cases by the direct toxic effects of the drugs on a deteriorated renal function. Superimposed on this is the fact that illness in the elderly pre-disposes them to nutritional deficiencies34 which may be induced by the drugs and also further exacerbate their toxicity. Some drugs that are commonly prescribed by doctors for old people, or which they may obtain for themselves, are shown in Table IV. Some of these have already been discussed. Some oral hypoglycaemic agents used in the control of adult-onset diabetes, such as sulphonylureas may cause serious or fatal hypoglycaemia in elderly malnourished patients. Their action may be potentiated by other drugs such as phenylbutazone and warfarin which displace the sulphonylureas from binding sites on plasma proteins. Their hypoglycaemic action is also potentiated by aspirin and alcohol both of which may so easily be taken with the drugs unless the patients are specifically warned. Potassium deficiency has been claimed to be a cause of mental depression35 and muscle weakness36 in the elderly. The body is depleted of both potassium and sodium by thiazide diuretics and these drugs should not be given without potassium supplements. Iron-deficiency anaemia is common amongst old people. Sometimes it is due to the inadequate consumption of foods that contain readily available iron. The possibility that it may be due to protracted small losses from the gastro-intestinal tract should not be overlooked and this kind of loss may be exacerbated by aspirin. In one study&dquo; blood losses in 144 patients
receiving aspirin were
or
aspirin-containing preparations
estimated with 51Cr labelled red cells
to average
day. When aspirin is used infrequently as an analgesic, losses of this magnitude may not be serious, but Alka-Seltzer tablets (aspirin and sodium bicarbonate) may be used regularly by old people for indigestion and in this case any accompanying blood about 5 ml per
losses could lead to anaemia.
TABLE IV Nutritional interactions with
drugs commonly given to elderly patients
,
REFERENCES 1 WORLD HEALTH ORGANIZATION (1969). International drug monitoring, World Health Organization Technical Report, Series No. 425, Geneva. 2 WADE, O. L. (1970). Adverse reactions to drugs, London: Heinemann Medical. 3 DICKERSON, J. W. T. (1978). The interrelationships of nutrition and drugs, Ch.14 in ’Nutrition in the Clinical Management of Disease’. Eds. J. W. T. Dickerson and H. A. Lee, London: Edward Arnold. 4 KIRBY, M. J. and TURNER, P. (1976). Do anorectic drugs produce weight loss by appetite suppression? Lancet, 1, 566.
Continued
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on
page 274
