Gender and Polypharmacotherapy in the Elderly: A Clinical Challenge
Polypharmacotherapy is a major concern in the elderly and especially in older women after the age of 80. It results from the intake of prescription and non-prescription drugs, being often a problem of evidence-based therapy. Besides the fact that women live longer than men and outnumber them, reasons for polypharmacy in women are diverse and include a different attitude towards intake of drugs between men and women, the propensity of women to rather see a physician and talk about their problems, the load of family responsibility as women are the main caregivers within a family, the influence of physician sex on patient care, the level of education, social deprivation and self-rated health. Women are more often prescribed potentially inappropriate medication and more often become victims of adverse drug reactions. This is not only due to the number and quality of drugs prescribed but also to differences in pharmacokinetics and - dynamics which make them more vulnerable to drug exposure. Thus, inappropriate prescribing contributes to hospitalization, poor quality of life, costs, compliance issues and poor outcomes. More preclinical and clinical studies with elderly patients and especially elderly women are needed to study the underlying mechanisms of the pharmacologic differences and obtain more insight into the difference in risk between men and women. Attention to prescribing of medications, consistent review of medication lists, and reevaluation of indications and outcomes of prescribing are essential to ensure that drugs are used appropriately in elderly women, polypharmacy is minimized and safety for patients is maximized.
1.1 Definition and Incidence of Polypharmacy
The term “polypharmacy” or “polypharmacotherapy” ranges from the use of a large number of medications to the use of potentially inappropriate medications (PIMs) or medication duplication (Maggiore et al. 2010). It can refer to perceptions of prescribers or consumers and may or may not include non-prescription medication like over-the-counter remedies or herbal/supplementary agent use (Maggiore et al. 2010; Junius-Walker et al. 2006). Thus, the definition of polypharmacy is vague. European studies defined polypharmacy according to the number of medications taken, whereas the studies conducted in the USA defined polypharmacy according to whether a medication was clinically indicated (Fulton and Allen 2005). Clients may have several diagnoses and comorbidities, necessitating the use of multiple medications; therefore, a definition of polypharmacy based upon the number of medications may be inappropriate (Fulton and Allen 2005; Viktil et al. 2007). There is no consensus or commonly used cut-off point referring to the number of drugs anyway (Hajjar et al. 2007). One of the most commonly used definitions is the concurrent use of five or more drugs (Haider et al. 2009). In the Kuopio 75+ Study, “polypharmacy” was defined as the use of six to nine drugs whereas the concomitant use of ten or more drugs was referred to as “excessive polypharmacy” (Jyrkka et al. 2009). Whichever level is the basis of the definition, polypharmacy stands out as a marked risk factor for developing drug related problems (Viktil et al. 2007).
Prescribing for elderly persons with several chronic diseases is a balance between limiting the number of drugs and using all drugs that may be beneficial (Colley and Lucas 1993; Rochon and Gurwitz 1999). According to current guidelines, a patient with diabetes, hypertension, heart failure and atrial fibrillation requires a minimum of six different drugs. Redefining thresholds (e.g., for blood pressure and cholesterol) and marketing of new drugs (most of them without adequate testing in the older population) also promote polypharmacy, thus making polypharmacy a problem of evidence-based medicine and medical progress (Schuler et al. 2008).
Besides multiple diseases and advanced age, additional patient-related risk factors for polypharmacy were low level of self-rated health, living in an institution, number of visits to a primary care provider per year and being female (Chen et al. 2001; Fulton and Allen 2005; Jyrkka et al. 2009). On average, each German person of the 17 million people aged 65 years or more was prescribed 1,303 defined daily doses (DDD)/year in 2010, but women used 3% more than men (1,320 versus 1,281 DDD) (Thürmann et al. 2012).
2 Polypharmacy and Women
2.1 International Studies Confirm that Women Consume more Medication than Men
In Sweden, women ≥65 years treated in primary care had more non-fatal diagnoses and used an average of 4.8 prescription medications whereas men consumed an average of 3.8 (Jörgensen et al. 2001). Linjakumpu et al. (2002) also found that in Finland community-dwelling women aged 64 years or over used more prescription medications than men, with 81% of women using medications compared to 74% of men in 1990. Until 1998, drug consumption even increased with 93% of women using medications compared to 82% of men. These changes were most prominent among persons aged 85 years or over.
Among the ambulatory adult population of the USA, the rate of prescription medication was similar in men and women aged 65 years or older but differed in men and women younger than 65 years of age where women used much more drugs than men. Between 45 and 64 years of age, 90% of females used at least one prescription drug, 44% used five to ten, and 14% took at least ten different prescription drugs per week versus 83, 30, and 6%, respectively, in men (Patterns of Medication Use in the United States, 2006).
2.2 Is there any Reason Why Women are Rather Exposed to Polypharmacy?
Women constitute the majority of old people because women life longer than men. Currently, women outnumber men by about 70 million among those aged 60 years or over worldwide. Among those aged 80 years or over, women are nearly twice as numerous as men, and among centenarians women are between 4 and 5 times as numerous as men (United Nations 2009). In Germany, women >65 years represent 23% of the population, whereas the rate of men is 18% (Thürmann et al. 2012).
Furthermore, consulting rates differ between men and women. Between the ages of 15 and 64 years, consulting rates for British women exceeded that for men in general practice (Martin et al. 1998). German women also attended primary care providers more often than men (68 versus 53%) (Zok 2006). Since consulting a physician is a risk factor for polypharmacy, this can be another reason why women are more endangered.
Non-prescription drugs are often used simultaneously with prescription drugs. According to an evaluation in Germany, six non-prescription drugs are consumed on average in addition to eight prescribed drugs per year (Zok 2006). Women use self-medication more frequently than men (58 versus 41%), the rate increasing with income, education and being (or feeling) sick (Zok 2006). Therefore, there must be a factor beyond age, polymorbidity and consulting rates. It seems that women have a different attitude towards drug intake and that their expectations concerning drug therapy are more positive. This is a field that requires further research.
A prediction model for polypharmacy also concluded that educational level accounted for the most variation in polypharmacy in individuals aged 65 and older. Women, on average, consumed more prescription medications than men, though gender differences were non-significant. Older, more educated women may be most likely to engage in polypharmaceutical consumption, suggesting a greater likelihood of an adverse drug event (Perry and Turner 2001). The so-called gender-paradox describes a discrepancy between morbidity and mortality among women: Although women’s self-rated health is generally poorer than that of men, they have more preventive check-ups and visits to doctors and use more medication, they still live longer than men (Schwabe and Paffrath 2008).
Thus, the scientific literature, the public press, and numerous authors recognize the existence of differences between the sexes and the greater numbers of women than men at older ages, but with the exception of sex-specific conditions or diseases like osteoporosis or depression, the approach to medication therapy in the elderly has not traditionally included sex-specific considerations (Schwartz 2007). Contributing factors may be: (a) the misconception that as sex hormones diminish at older ages, pharmacokinetic or pharmacodynamic differences between the sexes are less at older ages, and (b) the lack of significant numbers of older women enrolled in premarketing pharmacokinetic or pharmacodynamic studies or in randomized clinical trials of common disorders in older populations (Schwartz 2007).
3 Consequences of Polypharmacy
Polypharmacy is a potential risk factor for medication problems. The most common results of polypharmacy are inappropriate medication, increased adverse drug reactions (ADRs), drug–drug interactions, medication errors such as administration of an inappropriate dose of medicine or giving the wrong drug, hospitalization, poor quality of life, and higher costs (Haider et al. 2007; Jyrkka et al. 2009; Hajjar et al. 2007; Shi et al. 2008). Furthermore, the more drugs an elderly person uses, the greater the likelihood of lower adherence to the medication regimen and poorer health outcomes (Barat et al. 2001; Sorensen et al. 2005). Polypharmacy has also been reported to increase the risk of falls (Baranzini et al. 2009; Sommeregger et al. 2010). However, there is evidence that fall risk is associated with the use of polypharmacy regimens that include at least one established fall risk-increasing drug such as psychotropic medication, antiarrhythmics or antiparkinson drugs rather than with polypharmacy per se (Baranzini et al. 2009).
4 Use of Potentially Inappropriate Medication
For the last decades, panels of experts in geriatric medicine and pharmacology developed lists of drugs that are considered as potentially inappropriate in the elderly because of their risk of causing an adverse effect outweighing the potential benefit. The first publications of drugs “to avoid in the elderly” were led by Marc Beers and colleagues (Beers 1997).
A number of studies of community-dwelling elders have found that older women were more likely than men to receive drugs “to avoid in the elderly” (Bierman et al. 2007; Zhan et al. 2001; Goulding 2004; Howard et al. 2004; Schuler et al. 2008; Johnell et al. 2009; Thürmann et al. 2012).
Zhan et al. (2001) stratified a subset of 33 drugs from the Beers drug list into three categories: (1) drugs that should always be avoided, (2) drugs that are rarely appropriate, and (3) drugs that have some indications but are often misused. An analysis of rates of potentially inappropriate medication (PIM) use among persons aged >65 enrolled in US managed care plans in 2000–2001 indicated that 6% of elderly females used at least 1 of 11 drugs classified as “should always be avoided,” compared with 4% of men. For medications classified as “rarely appropriate,” 16% of women received these drugs compared with 11% of men. Medications with “some indications but which are often misused” were used by 19% of women and 14% of men (Gurwitz 2005).
In a population of veterans aged >65 years, again women were more likely than men to have received PIMs in all three categories: always avoid, rarely appropriate, and some indications before and after adjustment for demographic characteristics, number of unique medications and characteristics of care (Bierman et al. 2007). There were higher rates of use of analgesic, psychotropic, and anticholinergic medications that should be avoided among women compared with men. For both men and women, those using more medications were more likely to have been prescribed an inappropriate medication (Bierman et al. 2007).
5 Which Medication and Why?
Numerous studies have documented the greater use of psychotropic drugs by women relative to men (Simoni-Wastila 1998; Goulding 2004; Thürmann et al. 2012). As the prevalence of mental illness, patient’s and physician’s age, self-rated psychological well-being and physician specialty are associated with psychotropic drug prescription in men and women, reasons for women’s greater use are not readily apparent. Simoni-Wastila (1998) found that the probability of receiving any psychotropic drug is 55% greater in office visits by women than men. Gender differences in coping with and expressing distress, willingness to seek medical care, perceptions of illness and physician prescribing bias might be some explanations (Lagro-Janssen 2008; Cafferata and Meyers 1990). Family responsibilities, but also marital separation, divorce, or widowhood and the presence of family stressors such as an ill spouse are correlated with the likelihood of obtaining a psychotropic drug prescription (Cafferata and Meyers 1990). However, women do not receive more of all types of psychotropics; rather, general practice office visits (in contrast to psychiatric visits) by women are more likely than men’s visits to result in an anxiolytic or antidepressant prescription (Simoni-Wastila 1998).
Among ambulatory care visits with pain relievers prescribed, women’s visits were more likely than men’s to involve inappropriate pain relievers (Goulding 2004).
Some authors believe that women are more likely than men to report pain or depressive symptoms and therefore are more likely than men to be diagnosed and then treated for these conditions. Physicians are used to prescribing the older and inappropriate drugs in antidepressants, antianxiety agents, sedatives/hypnotics and pain relievers and may not be aware of their risks. Furthermore, older drugs tend to be less expensive and cost may play a role, thus leading to the high percentage of PIM in elderly women (Goulding 2004). However, if providers are more likely to attribute somatic complaints in women to mental health conditions, then sex bias in clinical decision making may contribute to these differences, and this would need to be addressed (Bierman et al. 2007; Lagro-Janssen 2008). Indeed, some studies suggest that the interaction between physician and patient gender may influence the amounts and types of treatments provided by physicians (Lagro-Janssen 2008). The fact that sedative and antidepressant drugs are prescribed twice as often in women suggests that polypharmacy in elderly women might also be a consequence of social deprivation (Bierman et al. 2007). Because of higher survivorship and lower propensities to remarry, older women are more likely than older men to live alone. Globally, an estimated 19% of women aged 60 years or over live alone, whereas just 8% of men in that age group do so (United Nations 2009).
In a study of very old people (≥85 years), significant gender disparities in the prescription of several other drugs, such as diuretics, nitroglycerin and oral antihyperglycemic drugs, were observed. In most cases, women were prescribed more drugs than men in general. There was a strong association between female sex and the prescriptions of thiazide diuretics, potassium-sparing diuretics and diuretics as a whole. On the other hand, men more often had undergone coronary artery surgery. These disparities could only in part be explained by differences in diagnoses and symptoms (Brännström et al. 2011).
In an Austrian inpatient study, again some drugs were significantly more often prescribed for women: diuretics, betablockers, antidepressant and antipsychotic, benzodiazepines and levothyroxine, whereas allopurinol was more common in men (Schuler et al. 2008).
6 Women and Adverse Drug Reactions
Women are perceived to be more prone to drug-related problems than men, especially at an age of ≥65 years (Martin et al. 1998; Drici and Clement 2001; Zopf et al. 2008; Krähenbühl-Melcher et al. 2007; Hofer-Dueckelmann et al. 2011; Rodenburg et al. 2010). In a study evaluating polypharmacy and inappropriate prescribing in elderly internal-medicine patients (≥75 years) in Austria, 18% of elderly patients suffered from an adverse drug event in which women were much more frequently affected. Indeed, female gender was an independent predictor of adverse drug events (Schuler et al. 2008). Polypharmacy is another risk factor for ADRs and thus has been shown to predict hospital readmission related to ADRs. ADRs are often aggravated by another drug with the same side effects due to pharmacodynamic interactions (Jyrkka et al. 2009). Van der Hooft studied ADR-related hospitalizations in the Netherlands in 2001. The proportion of females with ADR-related hospitalizations varied between the different age categories, increasing with increasing age from 50.5% in the age group 65–79 years to 66.6% in the highest age group (80 years and older) (van der Hooft et al. 2006).
A 1.5- to 1.7-fold higher ADR rate for the female gender cannot be explained by age or number of prescriptions only (Rodenburg et al. 2010; Zopf et al. 2008). There seems to exist an increased vulnerability to drug toxicity with advancing age and female sex (Martin et al. 1998).
Such a propensity may result from gender-associated differences in drug exposure as well as from possible differences in the way the adverse event is perceived (Drici and Clement 2001; Zopf et al. 2008). A pharmacological explanation for the increase in ADR rates in females may be differences in pharmacokinetics and—dynamics such as lower body size and weight in females with consequent changes in apparent volume of distribution (Martin et al. 1998). Other possible explanations are differences in body composition like muscle mass, organ blood flow and organ function, activity of receptors or physiological (menopause, pregnancy, menstruation) aspects (Beierle et al. 1999).
Indeed, sex differences in the incidence of ADRs and pharmacatoxicity have been reported for several classes of drugs and specifically for several cardiovascular preparations. Given the high incidence of cardiovascular conditions and thus the broad use of these drugs in the general population, these reports have to be considered of relevance to public health (Oertelt-Prigione and Regitz-Zagrosek 2009). For example, two-thirds of the cases of drug-induced tachycardia occur in women. Therefore, this ADR represents a perfect example of gender differences impairing women’s health. Estrogens facilitate bradycardia-induced prolongation of the QT interval and the emergence of arrhythmia with antipsychotics, antihistamines, antiarrhythmics or antibiotic treatment whereas androgens shorten the QT interval and blunt the QT response to drugs (Drici and Clement 2001; Zopf et al. 2008).
Earlier studies suggest that women present more commonly with gastrointestinal and cutaneous allergic drug reactions (Martin et al. 1998).
Organ systems involved in ADEs (Hofer-Dueckelmann et al. 2011)
Involved organ system
Acute renal failure
Dose-related ADRs (52%) were the dominant type in female subjects (Martin et al. 1998; Zopf et al. 2008). Patients weighing 50 kg or less (n = 155) received milligram-per-kilogram doses of three study drugs that were 31–46% higher than the group mean and 70–88% higher than patients weighing more than 90 kg (Campion et al. 1987). In another study, again patients with polypharmacy and low body weight had a significantly higher risk for wrong dosage (31 versus 13%, p <0.0005, OR 3.05) (Schuler et al. 2008). Intravascular volumes, organ volumes, and muscle volumes are usually smaller in older individuals than younger individuals, and the smallest volumes of distribution encountered in clinical practice will usually be seen in older Caucasian or Asian women. The impact of a reduced volume of drug distribution is most evident when a loading or intravenous bolus dose of a medication is given, and for those drugs that have a narrow toxic to therapeutic ratio. Weight adjustment for loading doses of digoxin, lidocaine and other type I antiarrhythmic drugs, type III antiarrhythmic drugs, aminoglycoside antibiotics, chemotherapy regimens, and for unfractionated heparin is routinely recommended. The difference in body weight is thought by some to be the most important gender difference that affects drug concentrations (Schwartz 2007).
As cytochrome P 450 activity varies between men and women, it is recommended to reduce the doses of CYP 450 2D6 substrates like carvedilol, metoprolol or paroxetin by approximately 20% in older patients and by another 10–20% in women compared with men as women are more susceptible to ADRs. Renal clearance will be lower in women than in men, and lowest in older women. Thus, routine estimation of glomerular filtration or creatinine clearance is recommended to guide dosing of renally cleared medications to reduce adverse events in both the acute and chronic care setting (Schwartz 2007). Because of slower clearance of cardiotonic glycosides in women, drug effects may be greater if doses have not been adjusted (Rodenburg et al. 2010).
7 Women and Clinical Trials
Many of the evidence-based therapies include drugs that have not been tested in the older population or in women at all since they are underrepresented in clinical trials (Lee et al. 2001; Gurwitz 2005). Although the authorities emphasized the importance of including more women in clinical trials as early as 1986, women are still underrepresented in clinical research nowadays (Kim et al. 2010).
A study examining trial enrollment of women and elderly persons in published randomized controlled trials of acute coronary syndromes during 1966–2000 found that both women and elderly persons remained highly underrepresented in the published literature, much of the sex disparity being a byproduct of underenrollment of elderly persons (Lee et al. 2001). The universal extension of trial results from a younger, mostly male population to women and elderly patients of both sexes may be inappropriate. In a post hoc subgroup analysis of the Digitalis Investigation Group Trial assessing sex-based differences in the effects of digoxin therapy, digoxin was associated with an increased risk of death from any cause among women, but not men, with heart failure and depressed left ventricular systolic dysfunction (Rathore et al. 2002). Drug-related risks are not always apparent until a drug is used in large numbers of elderly patients, many of whom are older, more likely to be female, and have more comorbidities than the participants in clinical trials (Gurwitz 2005). On the other hand, the paucity of information regarding the safety and efficacy of therapies in women and elderly persons may lead some physicians to withhold evidence-based drugs and interventions in these subgroups and rather prescribe old and PIM, although some drugs might be safe if used in an appropriate way (Lee et al. 2001). Concern about the burden of trial participation can make it more difficult to recruit a diverse population to participate in clinical trials, however, it is ethically clear that investigators have a duty to make special efforts to recruit a population of subjects that adequately reflects the population who will be exposed to the therapy that is the subject of the trial (Morse et al. 2004). Phase IV trials and registries are required to detect safety problems in this vulnerable subpopulation to alter these patterns of exclusion from clinical trials to ensure evidence-based care to all patients.
Polypharmacy is a complex and worrying phenomenon that leads to medical problems especially in the elderly. Female gender appears to be a potential risk factor for polypharmacy. Older women are more likely to be prescribed PIM and to suffer from ADRs as they have an increased vulnerability to drug toxicity. To ensure evidence-based care to all patients, efforts are necessary to increase the representation of elderly female and male participants in preclinical and clinical trials and registries and to address drug safety issues more rigorously.
Take Home Messages
Polypharmacy is common in the elderly, female gender being a risk factor for it.
Polypharmacy in elderly women results in higher rates of PIM and ADRs.
Reasons for ADRs are higher vulnerability due to differences in pharmacology in elderly women.
More research is needed in elderly women to ensure safe medication therapy independent of age and gender.
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