Both malnutrition and polypharmacy (polypragmasia) are very frequently occurring phenomena in contemporary medicine, which significantly influence the quality of life and mortality, particularly in the older age groups. As increasing age is often associated with a greater disease burden, there is increased and very often excessive administration of drugs. Malnutrition develops either independently not only as a result of disease but also as a consequence of ageing, related to sarcopenia, decreased physical activity and loss of appetite.
The relationship between polypharmacy and malnutrition is based on a number of mechanisms. Long-term abuse of multiple drugs results in anorexia, generally as minor or more serious impairment of the digestive tract, although conversely malnutrition very often results in deteriorated biological availability of drugs and changes in their pharmacokinetics and pharmacodynamics. This gives rise to a vicious circle, wherein polypharmacy, particularly in excess, degrades the nutritional status, and the degraded nutritional status demands increased doses of drugs with the increased occurrence of undesirable side-effects. These relations are shown in Fig. 1.
Polypharmacy is widespread in many European and non-European countries, thus increasing the costs of treatment, and the increased doses of drugs increase the risk to patients and often diminish the quality of life. According to a large European study , the countries with the highest occurrence of polypharmacy include the Czech Republic and Finland, whereas the lowest prevalence of polypharmacy is found in Norway and the Netherlands. The occurrence of malnutrition in both in-patients and out-patients and its dependence on polymorbidity and age are well known, but the interrelation of polypharmacy and malnutrition has been far less investigated, although there have been a few studies dealing with this relationship [2▪▪,3,4▪▪,5].
OCCURRENCE OF MALNUTRITION AND ITS RELATION TO POLYPHARMACY
The highest occurrence of malnutrition is related to polymorbidity, higher age and the length of duration of chronic disease. As both polypharmacy and malnutrition are frequently connected in a complex manner with these conditions, it is difficult to quantify exactly the contribution of polypharmacy to malnutrition. An important fact is that malnutrition is frequent not only in patients prior to admission to hospital but it also develops in hospital as a result of iatrogeny and polypharmacy. The diseases and conditions most frequently implicated in the development of malnutrition include the following groups:
1. patients of higher age groups, in particular 80 years and older (50% of cases);
2. patients with chronic respiratory diseases (45%);
3. patients with digestive tract diseases (80%);
4. patients with tumours (85%);
5. patients at risk (65%, with the highest share in kwashiorkor-type malnutrition); and
6. several neurodegenerative diseases, chronic infections and psychiatric diseases.
The above-mentioned groups of diseases are frequently associated with long-term therapy using multiple drugs. The risk and presence of malnutrition are currently best diagnosed by the screening examination MUST – Malnutrition Universal Screening Tool .
In the elderly, the system of evaluation of nutritional status by means of Mini Nutritional Assessment (MNA) is still in use, and is based on anthropometric data, diet screening, clinical examination and subjective evaluation of well-being by the patient .
Depletion of plasma proteins resulting from malnutrition is of particular importance for the relationship with pharmacokinetics in drugs of hydrophilic character. Low levels of plasma proteins result in a relative increase in the free fraction of the drug in plasma, which determines the availability of the drug and thus its pharmacological activity, but on the contrary, marked depletion of plasma proteins also results in rapid elimination and catabolism of the drug. Acceleration of turnover of the drug, its increased catabolism and elimination, thus, frequently result in a necessary increase in single-dose quantity and frequency of administration, or addition of more drugs.
DEFINITION OF POLYPHARMACY AND CLINICAL CONSEQUENCES
Polypharmacy is usually defined as a condition in which the patient is treated with multiple drugs, the threshold being usually considered as more than four drugs. This is the usual interpretation of polypharmacy in the literature, and in routine practice, it is also called polypragmasia, particularly in the German-speaking countries. The use of multiple drugs does not however have to be a negative phenomenon, as it is often interpreted, and therefore, the definition of polypharmacy is sometimes supplemented by the feature that it is a drug-administration problem if there is no reason for administration. This is nevertheless not the only problem of defining polypharmacy. Jyrkkä et al.[2▪▪] introduced the term ‘excessive polypharmacy’, when the patient takes more than nine drugs.
Veehof et al. report not only the number of drugs but also the duration of their administration. They define polypharmacy as a condition in which two or more drugs are administered for a minimal period of 240 days. Werder and Preskorn  state that there are several definitions, and that in the case of exposure of the patient to two to four drugs, this is called minor polypharmacy and in the case of five and more drugs simultaneously, major polypharmacy.
It has already been said that polypharmacy is connected with suboptimal or unsuitable drug prescription and may sometimes result in the so-called drug-related problem (DRP). Polypharmacy is often solved in elderly patients, and it is often realized that they have been prescribed unsuitable drugs, which may be aggravating their condition and in addition increasing pharmacotherapy; the most famous lists of unsuitable drugs are the Beers and STOPP criteria. STOPP is an acronym from Screening Tool of Older Persons’ Potentially inappropriate prescription. Many authors have shown that avoidance of these drugs could theoretically decrease the occurrence of polypharmacy.
However, some authors have begun to realize that the use of drugs from these lists is not necessarily a negative phenomenon in every senior, and even analogically that exposure to a larger number of drugs can be advantageous for the patient. That is why the standard definition of polypharmacy as a negative phenomenon in pharmacotherapy on the basis of the number of drugs may be misleading for many physicians and patients. For instance, in polymorbid patients, it is highly probable that the patient will take several drugs and the evaluators of pharmacotherapy will be of different opinions whether it is a rational approach to treatment or not. The definition of polypharmacy is therefore sometimes specified as the condition under which it is impossible to find the reason for administration. Elsewhere, it is reported that the characteristic of polypharmacy is the exposure to two or more drugs for one diagnosis. Nevertheless, in some diagnoses, for example arterial hypertension, it is recommended to use rationally combined drugs. It has been shown that the patient is more often exposed to more drugs particularly in diseases which are serious, or in which the results of mortality studies demonstrate effectiveness in a larger number of pharmacological groups (e.g. polypharmacy is often described in the diseases affecting the coronary blood bed, sudden vascular cerebral events, chronic obstructive pulmonary disease and diabetes mellitus) [10▪▪,11]. Moss and Crane  have found in a study of polypharmacy that women aged over 65 years and after myocardial infarction used one to 15 drugs with the median of four drugs, four groups of drugs (anticoagulants, statins, beta-blockers and inhibitors of angiotensin-converting enzyme) being recommended as necessary for secondary prevention. That is why a larger number may be beneficial for the patient [13▪]. It is thus necessary to individually evaluate the proportionality of drug administration. Nevertheless, polypharmacy is often detrimental to the patient.
CAUSES OF POLYPHARMACY
The reasons for administration of an excessive number of drugs, and thus sometimes the state of polypharmacy, vary, which are listed as follows:
1. Both patient and physician think that the prescription will support the quality of care;
2. ‘Health tourism’: if the philosophy ad 1 is accepted by several physicians and the patient consults them independently of each other, there is a great risk of exposure to many drugs;
4. Where there is an expectation of the occurrence of a disease in a patient (particularly in the elderly), interpretation of the undesirable effects of administered drugs as manifestations of such disease, with subsequent additional pharmacotherapy (so-called prescription cascade);
5. Where the therapeutic goal is not achieved, failure to search for and detect noncompliance (not only of pharmacotherapy but also recommended lifestyle) results in prescription of another drug or more drugs;
6. Due to the existence of many generic drugs on the market, the patient/therapist does not realize that a drug with the same active dose has already been prescribed, thus creating duplication;
7. Insufficient transfer of information about pharmacotherapy, especially when transferring the patient between therapists, and above all when transferring the patient from out-patient to the hospital sphere and vice versa;
8. Insufficient understanding of consumers (and patients) about pharmacotherapy and its risks;
9. Inadequate systematic healthcare, where the goal of treatment has not been declared and the therapy not analyzed (its benefits, risks), that is absence of or nonadherence to a so-called medication management programme (MMP) and in the elderly specifically the comprehensive geriatric assessment (CGA);
10. Lack of more detailed information about the mechanisms of administered drugs and insufficient involvement of pharmacists and clinical pharmacologists in therapeutic teams; and
11. Easy availability of over-the-counter drugs, drugs available via Internet pharmacies and ‘green medicine’. Exposure of patients to drugs for self-medication is difficult to ascertain in the population, and therefore, it is not directly a criterion in the definitions of polypharmacy, but it may exacerbate the consequences of polypharmacy.
CONSEQUENCES OF POLYPHARMACY
However, it must be admitted that polypharmacy does not necessarily significantly shorten life and we have no direct evidence for it yet, though as we have stated, there are up to 10 causes for hospitalization due to drugs. Drug-related problems (DRPs) are logically more frequent in polypharmacy. Nevertheless, randomized studies comparing the use or nonuse of MMP or CGA, especially involving clinical pharmacists, not only usually reveal that it is suitable to reduce the number of drugs but also that such intervention never significantly changes the outcome of treatment of disease, but does serve to save the financial means of the patient and the health insurance system.
These analyses and our own experience reveal not only the necessity to reduce therapy but that the lack of a drug or underdosing should also be identified as DRP.
Consequences of polypharmacy may be:
1. increased probability of drug interactions, and the specific risk of duplications, whether it be administration of the same active ingredient in two or more preparations (this has been encountered both in our research and our practice) or administration of two drugs;
2. higher risk of undesirable effects not only due to possible occurrence of drug interactions but also greater probability of contraindications;
3. increased costs of treatment due to the larger number of drugs as well as higher costs for solution of the resulting drug problems;
4. polypharmacy decreases drug compliance; and
5. it may influence the nutritional condition of the patient.
It can generally be said that in the patient with polypharmacy, there is an increased risk of occurrence of DRP. Results from several studies [6,14,15] have documented that about 6% of patients are admitted to hospitals due to the occurrence of DRP.
GENERAL INFLUENCE OF DRUGS ON THE NUTRITIONAL STATUS
Drugs may cause a disorder in the intake of food and may exert direct or indirect metabolic effects and thus influence the nutritional status. There are more than 250 drugs, which may impact on the intake, absorption, metabolism and excretion of nutrients. Pharmacotherapy is probably most frequently accompanied by dyspepsia, which may itself cause a disorder in nutrition. Drug-induced dyspepsia is however difficult to determine, as it is difficult to separate any drug cause of malnutrition from the effect of disease or other cause. Dyspepsia spontaneously occurs in many patients for a variety of reasons (disease, dietary mistakes, emotional states, etc.). This is why dyspepsia is considered to be a consequence of pharmacotherapy but is disregarded when monitoring the undesirable effects of drugs . The mechanisms by which drugs may influence the nutritional status are summarized in Table 1. Other side-effects of drugs adversely affecting nutritional status are anorexia (acetylcholinesterase inhibitors, antibiotics, digoxin, hypnotics), early satiety (anticholinergics, sympathomimetics), reduced feeding ability (sedatives, opiates), dysphagia (NSAIDs), constipation (opiates, diuretics) and diarrhoea (laxatives, antibiotics) . These side-effects often aggravate the already present subclinical nutritional deficiencies or low energy intake, especially in the elderly. Also, early identification of depression is important in screening for possible malnutrition [2▪▪].
EFFECT OF POLYPHARMACY ON THE NUTRITIONAL STATUS
There are few records on polypharmacy that would clearly indicate a causal relationship between this state and the nutritional status. It is, however, probable that a combination of drugs has a greater influence on the nutritional status, and that only occasionally a combination of drugs may improve food intake or limit the influence of the drugs on the nutritional status as described in Table 1. Polypharmacy and malnutrition may influence each other (see Fig. 1), and for the time being, the interaction between a larger number of drugs and nutritional status is not fully appreciated. The effects of polypharmacy on nutrition are estimated from the fact that problems with nutrition occur mainly in elderly patients, a group which is also more frequently subject to polypharmacy. However, it is difficult to separate where a limited food intake is due to a concrete disease and where it is a manifestation of DRP (Fig. 2). Nevertheless, it is known that about 65% of hospitalized patients have a worse nutritional status than their healthy contemporaries. A worsened nutritional status may adversely influence the process of treatment.
Polypharmacy is a global problem that occurs frequently and everywhere regardless of the type of health service and continent. The relationship of drugs to nutrition is thus very diverse and we continue to uncover new pieces of knowledge. The difficulty with investigation of the relationship between nutrition and drugs is that any disorder in food intake may be due to many different causes, and not many studies could analyze those different aspects of malnutrition and drug effects together.
This study was supported by the project (Ministry of Health, Czech Republic) for conceptual development of research organization 00179906.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 111–112).
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An outstanding review describing the scarce evidence about the association of polypharmacy with malnutrition.
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