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Journal of Nutritional & Environmental MedicineMay 2007; 16(2): 149–166 MARGARET MOSS, MA (CANTAB), UCTD (MANCHESTER), DIPION, CBIOL,MIBIOL, Director of the Nutrition and Allergy Clinic 11 Mauldeth Close, Heaton Mersey, Stockport, Cheshire SK4 3NP AbstractPurpose: To collate evidence on nutrient deficiencies caused by drugs.
Design: Search of Medline and other databases, and published literature.
Materials and methods: Medline, Scirus and Google Scholar databases, journal articles and books.
Results: There is evidence that many drugs, medicinal or recreational, produce deficiencies invitamins, minerals, fatty acids and/or amino acids. Some drugs cause multiple deficiencies. They mayreduce conversion of vitamins to their active forms, or inhibit the production of importantmetabolites. By killing beneficial bacteria in the gut, they may cause vitamin deficiency. They mayreduce absorption, or cause excretion of nutrients.
Conclusions: Many drugs have been identified, which appear to cause deficiencies in essential nutrientsand their metabolites. Nutrients could be prescribed with drugs, to limit the damage done, providedthat this does not undermine the action of the drugs. Further research is needed to confirm theresults of those studies that have been carried out, and to find out about nutrient depletion from newdrugs.
Key words: drug–nutrient interaction, drug–vitamin interaction, drug–mineral interaction, nutrientdeficiency, vitamin deficiency, mineral deficiency, coenzyme Q10 deficiency Nutrients are amino acids, vitamins, elements and essential fatty acids that are required bythe body in order to carry out its normal functions. Drugs act by bypassing the normalprocesses, and thus often cause side effects. Often drugs act as anti-nutrients, by causingdeficiency in essential substances, or by interfering with their functions. People who arealready deficient, or whose nutritional status is marginal are likely to be more susceptible toside effects of drugs. However, some drugs increase the levels of certain nutrients.
Drugs may affect nutritional status in different ways. They can alter intake, absorption, metabolism, utilisation or excretion [1,2]. Many people take several drugs at a time, and noone knows what the interactions of all these drugs are. These drugs may be medicinal, orrecreational. Research on drug–nutrient interactions is very limited. I shall list here some ofthe information that has been reported so far, on possible deficiencies in nutrients, gutbacteria and hormones caused by drugs. Further research is needed in some cases, to checkthe findings. Research trials may produce conflicting information. Sometimes the research Correspondence: Margaret Moss, MA (Cantab), UCTD (Manchester), DipION, CBiol, MIBiol, Director of the Nutrition andAllergy Clinic, 11 Mauldeth Close, Heaton Mersey, Stockport, Cheshire SK4 3NP.
ISSN 1359-0847 print/ISSN 1364-6907 online # 2007 Informa UK LtdDOI: 10.1080/13590840701352740 has been carried out into only one drug in a group, and we can only suspect that others havethe same effect. Some individuals are more susceptible to loss of nutrients than others, andthey are more likely to suffer from side effects. Research that has only been carried out onlaboratory animals needs to be followed by studies on humans.
Prescription of drugs should be based on cost–benefit considerations. There are occasions where the side effects of a drug are acceptable, because of the gravity of thedisease, and the lack of any other means of combating it effectively. However, there is nopoint in taking a drug if the expected side effects are worse than the disease or if the diseasecan be treated effectively without side effects. Short courses of drugs are usually less of athreat than long-term courses. Often illness is caused by nutrient deficiency, and unless thedeficiency is treated, there may be more serious consequences later on. Using drugs tocover up deficiency symptoms can therefore be dangerous.
In some cases, side effects of drugs may be reduced by taking a supplement of a relevant nutrient. However, in other cases this is not recommended, as it may make the drug useless.
For example, carbamazapine and phenobarbitone appear to lower folic acid levels [3], butgiving too much folic acid may inactivate the drug [4].
Drugs have a generic name, and sometimes several other names given by different manufacturers. One manufacturer may use different names in different countries. This canmake it difficult to check on drug–nutrient interactions.
It may be thought that people living in affluent countries are not subject to nutrient deficiencies. However, a combination of genetic diversity in nutrient requirements, unwisefood selection or preparation, intensive exercise, infection, and the use of anti-nutrientdrugs may lead to deficiency symptoms.
A search was carried out of the literature on drug-nutrient interactions, using books and theMedline, Scirus and Google Scholar databases, to collect information on anti-nutrientdrugs. ‘Drug–nutrient interactions’, ‘Drug–vitamin interactions’, and ‘Drug–mineralinteractions’ were used as general search terms. Specific searches, for example for‘Statin, coenzyme Q10’, or ‘Seelig, magnesium deficiency’ were also used.
Many drugs were identified, which are thought to act as anti-nutrients (Table I).
Deficiencies may be caused in many nutrients. Elements may be affected, includingcalcium, chlorine, copper, iron, magnesium, manganese, nitrogen, phosphorus, potassium,selenium, sodium and zinc. Vitamins A, B1, B2, B3, B6, B12, C, D, E and K, folic acid andbiotin may also be affected, as well as carotene and coenzyme Q10. Amino acids involvedmay include L-carnitine, L-leucine, and the sulphur amino acids. Fat and carbohydrate arealso mentioned in the literature, as well as beneficial gut bacteria. Hormones may beinvolved, including DHEA (dehydroepiandrosterone) and melatonin.
A nutritional approach aims at finding out which biochemical systems are failing to workproperly, and rectifying them. This is a very different process from the use of drugs or evenherbs, which do not usually enhance an existing biochemical pathway. They are more likelyto divert the body down a new pathway, which was not part of its design. This can lead to Table I. Drugs that may reduce the absorption or activity of nutrients or normal body constituents.
5-Fluorouracil (5-FU, Efudex, Fluoroplex) Glyburide (Glibenclamide, Diabeta, Micronase) Isoniazid (INH, Laniazid, Rifamate, Rimactane) Lansoprazole (Prevacid, proton pump inhibitor) Losartan (Cozaar, angiotensin-II receptor Non-steroidal anti-inflammatory analgesics Omeprazole (Prilosec – proton pump inhibitor) Selective Serotonin Reuptake Inhibitors (SSRIs) Sulfasalazine (Azulfidine – sulphonamide) Tetracyclines (Achromycin, Sumycin – antibiotic) Potassium Theophylline (Slo-Bid, Slo-phyllin, Theo-dur) Ventolin (Albuterol/Salbutamol/Proventil) side effects, sometimes because of causing nutrient deficiencies. Nutrients also interact witheach other, often cooperatively, but sometimes in competition with each other.
Research already carried out suggests that deficiencies are caused by large numbers of drugs. This is not likely to be a popular topic for sponsoring research. So we probably knowonly a small proportion of these interactions.
Diuretics are commonly used drugs, which can cause deficiency of magnesium, potassium and vitamin B1. There is evidence that magnesium protects against potassiumdeficiency, vitamin B1 deactivation, hypertension, intravascular coagulation, diabetes,congestive heart failure, hyperlipidaemia, atherosclerosis, arrhythmia, myocardial infarc-tion, preeclampsia, asthma, kidney and liver damage, migraine, multiple sclerosis,glaucoma, Alzheimer’s disease, recurrent bacterial infection of cavities, fungal infection,premenstrual syndrome, hypochlorhydria, behavioural disorders, osteoporosis, moodswings, dental caries, hearing loss, cramps, muscle weakness, impotence, aggression,cancer, and iron accumulation. A person presenting with what may be temporaryhypertension may find that the drug prescribed makes the condition permanent, as well asleading to other disastrous consequences [113–126]. Hypertension could be treated withmagnesium, taurine and coenzyme Q10, salt reduction and the avoidance of liquorice.
Alternatively, diuretics could be used together with magnesium and potassium.
A healthy person, with total cholesterol within the reference range, and an excellent HDL:LDL ratio may be advised to take a statin (HMG-CoA reductase inhibitor) drug, orchoose to buy one over the counter. These drugs cause deficiency of coenzyme Q10, anutrient which has been found to protect the heart against stress, and in particular,oxidative stress [127–128]. Coenzyme Q10 levels tend to drop with age. There is evidencethat coenzyme Q10 protects against arrhythmia and heart failure, and that deficiency cancause ataxia [129–133]. It may reduce the pro-inflammatory cytokines, TNF-alpha and IL-6 [134], increase exercise capacity [130] or reduce high blood pressure [130]. It has beensuggested that coenzyme Q10 be administered before cardiac surgery [135]. It may betaken together with statin drugs, without making them ineffective [136]. The bioavailabilityof coenzyme Q10 supplements may depend on their form [137]. As alternatives to statins,cholesterol may be reduced with sterols in macadamia nuts and oil, glycation of cholesterolcould be reduced by avoiding milk, fruit juice and sugar [138], and anti-oxidants could be used to reduce oxidation of glycated cholesterol [139]. Nicotinic acid, magnesium,chromium, lecithin and L-carnitine could be used to improve the total cholesterol:highdensity lipoprotein ratio [140–144].
Deficiencies that may be caused by drugs can have diverse effects. Riboflavin (vitamin B2) deficiency may be caused by adriamycin, amitriptylene, anticonvulsants, boron,chlorpromazine, ethanol, and oral contraceptives. Riboflavin is needed for electrontransport, which is part of energy production [145–146]. It is also needed for production ofsulphate, which is used in detoxification of amines and phenols [147]. Amitriptyleneprescribed for a person with ME may intensify the exhaustion, unless riboflavin issupplemented. People with ME often have poor sulphate conjugation [147], andamitriptylene is likely to make this worse. Riboflavin is also needed to activate vitaminB6 [148–149]. People may have fits because of lack of activated vitamin B6 [150–152].
Anticonvulsants may worsen this, unless riboflavin is supplemented.
Vitamin D deficiency may be caused by many drugs (Table II), and excessive vitamin A.
Epileptics in Sweden, who may have little exposure to sunlight, and whose food is fortifiedwith much vitamin A [153], may have their risk of osteoporosis increased by takingphenytoin.
Polypharmacy may cause increased problems. Magnesium deficiency may cause anxiety [154], hypertension [119,155] and osteoporosis [156–157]. The patient may be prescribeddrugs for each of these results of magnesium deficiency, resulting in a variety of furtherdeficiencies. These may lead to further symptoms and the provision of more drugs.
Lifestyle may affect responses to drugs. Alcohol is detoxified mainly by alcohol dehydrogenase, followed by aldehyde dehydrogenase, and oxidase. High alcoholconsumption also requires cytochrome P450 2E1 [158]. An alcoholic may have five timesthe normal CYP2E1 [158]. When drinking heavily, processing of other chemicals byCYP2E1 may be competitively inhibited. However, if admitted to hospital, and unable toobtain alcohol, he/she may cope very well with medicinal drugs, as the CYP2E1 is stillavailable to process them [158]. A teetotaller may have a worse reaction to the same drugs.
People who are ill are likely to have nutritional deficiencies that contributed to the illness.
Their responses to drugs will be affected by their genes, their food intake, their use of other Table II. Drugs which may cause vitamin D deficiency.
drugs, recreational or medicinal, their age and gender, and the stresses to which they aresubject.
Diets vary greatly in nutritional content. People who are already deficient will be more susceptible to the effects of drugs. Those already on drugs causing the same deficiencies,will be more at risk and those with genetic problems causing deficiency will also be at risk.
People may have atypical forms of enzymes, which are less effective. An example ofbiochemical individuality involves the three siblings who consumed much chicken liverpaˆte´. One died of vitamin A toxicity, one was very ill, and the third was apparentlyunaffected [159]. Stresses, like pregnancy, grief, infection, surgery, and excessive exercisecontribute to deficiencies. Nutrients are lost in chronic or acute diarrhoea, or excessivesweating.
In order to avoid causing nutrient deficiencies when treating or trying to prevent disease, the following strategies could be considered:a. Use non-drug treatments when these are available and effective; for example, supplementing nutrients that are already deficient and making changes to diet andexercise.
b. Manufacture drugs together with relevant nutrients where this is possible, so as to avoid c. Prescribe nutrients together with drugs, in separate containers, to avoid causing deficiency; for example, probiotics could be prescribed at a different time of day fromantibiotics.
d. Prescribe smaller quantities of drugs, together with nutrient supplements, where they e. Label drugs clearly, and provide information in drug handbooks, so that the person prescribing them knows what deficiencies are likely to be produced, whether therelevant nutrients may be supplemented, and whether there is a level of supplementa-tion that would inactivate the drug.
Require drug companies to fund research on deficiencies caused by their products.
g. Require medical schools to teach nutrition in greater depth, and to emphasize the nutritional deficiencies which may be caused by drugs.
Many drugs (including some commonly used, some used in combinations, and someavailable over the counter) cause deficiencies in nutrients, which can compromise health.
The value of a drug treatment can be weighed against the consequences of deficiencies thatmay be caused. Drugs could be prescribed together with relevant nutritional supplements,where the supplements do not prevent the drug from working [160]. More research needsto be done, to identify deficiencies caused by drugs, in order to protect the public. Thisresearch could be taught to medical students and to doctors as part of their continuingprofessional development.
It is sometimes assumed that people whose diet provides recommended amounts of all the nutrients will not have deficiencies. Many people in affluent countries take one or moredrugs for long periods of time, and may well have deficiencies in specific nutrients, orcombinations of nutrients. Such deficiencies can lead to life-threatening conditions.
Those whose diets are deficient in essential nutrients, from lack of knowledge, cooking skills, money or inclination, may well experience side effects from drugs, when betternourished individuals do not.
I thank the nutritionist, Jan Robertson, with whom I have had lengthy discussions on howto prescribe nutrient supplements safely to patients already taking drugs.
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