Clinical pharmacology in the geriatric patient

doi: 10.1111/j.1472-8206.2007.00473.x REVIEW ARTICLE Clinical pharmacology in the geriatric patient Sarah N. Hilmera*, Andrew J. McLachlanb,c, David ...
Author: Lorraine Joseph
0 downloads 2 Views 496KB Size
doi: 10.1111/j.1472-8206.2007.00473.x REVIEW ARTICLE

Clinical pharmacology in the geriatric patient Sarah N. Hilmera*, Andrew J. McLachlanb,c, David G. Le Couteurb a

Departments of Clinical Pharmacology and Aged Care and Rehabilitation Medicine, Royal North Shore Hospital and the University of Sydney, St Leonards, NSW 2065, Australia b Centre for Education and Research on Ageing (CERA) Concord RG Hospital and the University of Sydney, Concord, NSW 2139, Australia c Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia

Keywords adverse drug reactions, clinical pharmacology, evidence-based medicine, geriatric medicine

Received 23 May 2006; revised 1 August 2006; accepted 7 December 2006

*Correspondence and reprints: [email protected]

ABSTRACT

Geriatric patients are a subset of older people with multiple comorbidities that usually have significant functional implications. Geriatric patients have impaired homeostasis and wide inter-individual variability. Comprehensive geriatric assessment captures the complexity of the problems that characterize frail older patients and can be used to guide management, including prescribing. Prescribing for geriatric patients requires an understanding of the efficacy of the medication in frail older people, assessment of the risk of adverse drug events, discussion of the harm:benefit ratio with the patient, a decision about the dose regime and careful monitoring of the patient’s response. This requires evaluation of evidence from clinical trials, application of the evidence to frail older people through an understanding of changes in pharmacokinetics and pharmacodynamics, and attention to medication management issues. Given that most disease occurs in older people, and that older people are the major recipients of drug therapy in the Western world, increased research and a better evidence base is essential to guide clinicians who manage geriatric patients.

The demand for expertise in clinical pharmacology and geriatric medicine grew exponentially at the end of the last century, reflecting the dramatic increase in medication usage and the ageing population. The interplay between these specialties is critical for modern prescribing because older people are the major users of medications and their responses to medications are highly variable [1,2]. The basic concepts of modern pharmacokinetics and pharmacodynamics were developed in the first half of the 20th century. By the 1970s it was widely recognized that disease states and extremes of age introduce considerable variability in both pharmacokinetic and pharmacodynamic responses [3]. Even so, there is still a very limited evidence base underpinning geriatric prescribing and the complexities of geriatric pharmacology often appear to be underappreciated both in the design of clinical trials and prescribing of medications [2,4]. In this review, we attempt to draw together the principles of

geriatric medicine and clinical pharmacology in order to guide prescribing in older people. COMPREHENSIVE ASSESSMENT – A KEYSTONE OF GERIATRIC MEDICINE Regulatory bodies usually consider older people to be those over 65 years of age and as such this definition includes an extremely diverse group of people. Geriatric patients are a subset of frail older people with multiple comorbidities that usually have significant functional implications. Frailty is a poorly defined but increasingly studied condition characterized by high susceptibility to disease, impending decline in physical function and high risk of death [5]. The frailty syndrome includes an excessive reduction of lean body mass, a reduction in walking performance and mobility, and poor endurance associated with a perception of exhaustion and fatigue [5].

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

217

S. N. Hilmer et al.

218

Clinicians should develop comprehensive care plans – including decisions on medication use – for frail older patients by integrating comprehensive information on all factors that can affect health status: disability, cognition, comorbidities, social role, psychological state and the availability of services and carers. This multidimensional approach is supported by clinical trials demonstrating that Comprehensive Geriatric Assessment has positive effects on health, functional status and mortality both in the acute hospital setting [6] and in the community [7]. Comprehensive geriatric assessment captures the complexity of problems that characterize frail older persons [8]. GENERAL PRINCIPLES OF PRESCRIBING TO GERIATRIC PATIENTS Comprehensive geriatric assessment and the recognition of frailty can assist the clinician in designing effective, multidisciplinary management plans. Broad functional outcomes are usually the major therapeutic goal of such treatment plans in geriatric patients, rather than the specific disease-based outcomes typically investigated in clinical trials. This approach also facilitates assessment of the risk and benefit of prescribing a medication for a particular condition in the context of comorbidity and disability, predicts likely changes in pharmacokinetics and pharmacodynamics, and gives information on what assistance the patient may require to adhere to the optimal medication regime [4]. Appropriate medical management requires a consideration of all possible treatment options for a patient based on the available evidence including non-pharmacological management options. In Australia, the Quality Use of Medicines Framework has identified three key steps in prescribing: (1) decide what the best treatment is (i.e. use non-pharmacological management options first); (2) select medicines wisely (based on the suitability of the patient); and (3) use medicines based on the best evidence (the right dose and duration) (http://www. health.gov.au/internet/wcms/publishing.nsf/Content/ nmp-quality.htm). In addition in geriatric patients, prescribing requires a detailed knowledge of the deficits in the evidence base and an appreciation of age-related changes in drug disposition, pharmacodynamic responses and the high prevalence of adverse drug reactions. The following steps broadly guide prescribing in geriatric patients [4]: 1. Determine the evidence for efficacy in older subjects. This requires an analysis of clinical trial data with a focus on whether optimal and meaningful outcomes

were achieved in older people. In the absence of such evidence, extrapolation of clinical trial data from younger patients or an understanding of disease processes might be of some value in determining efficacy and safety; 2. Determine the likelihood of adverse drug events in older subjects. In general adverse drug reaction data are poorly described by clinical trials and especially so in subgroups of older patients. Thus the clinician usually will need to rely on data from post-marketing surveillance. Allowance should be made for the increased prevalence of adverse drug reactions in older people, which is exacerbated as patients receive multiple medications for the management of different medical conditions; 3. Discuss the harm:benefit analysis with the patient. Patient autonomy is an important medical ethical principle often underemphasized in prescribing guidelines. Participation of older patients in treatment decisions including medicines presents challenges, not the least of which may be a divergence between the goals of the patient and the prescriber [9]; 4. Decide on the dose regime. There are many agerelated changes in the disposition of and response to medications. However, clinical trial evidence for any requirement for dose adjustment is limited. Furthermore, selection of dose form may be an important issue to achieve optimal drug delivery in a convenient manner; 5. Monitor the patient very carefully. The paucity of clinical trial data in frail older patients and the marked increase in the prevalence of adverse drug reactions necessitate close monitoring of the patient. Functional and quality of life outcomes may be more relevant to the older patient than individual primary disease outcomes investigated in clinical trials. EVIDENCE FOR EFFICACY IN GERIATRIC PATIENTS Older adults’ definition of successful ageing is multidimensional, encompassing physical, functional, psychological and social health [10]. Ideally, therapeutics should aim to meet these goals, but outcomes in clinical trials rarely address such a wide spectrum of issues. Furthermore endpoints that are relevant to older people such as independence, falls, cognitive impairment and physical function are difficult to measure in clinical trials and rarely assessed as adverse drug reactions. Physical function is an important outcome for older people, and has been shown to predict disability, nursing

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

Clinical pharmacology in the geriatric patient

home admission and mortality [11]. Benzodiazepine exposure in community dwelling older people has been associated with poorer self-reported functional status [12] and greater decline in objective physical performance tests over 4 years [13]. Potentially inappropriate medication use in older people is currently guided predominantly by expert consensus statements such as the recently updated Beers criteria [14]. However, this exposure does not correlate with decline in self-reported functional status in community dwelling older people [15] or with health outcomes in hospitalized older people [16]. In some studies, angiotensin-converting enzyme (ACE) inhibitors, 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors and testosterone have been associated with delayed functional decline in older people [17]. However, ACE inhibitors have also been associated with impaired balance, a risk factor for falls [18], HMG CoA reductase inhibitors with myopathy [19], disability [20] and a trend towards increased falls [21], and testosterone with behavioural changes [22]. Treatment of hypertension with antihypertensive medications has been inconsistently associated with prevention of cognitive decline in older people [23–25]. One of the most difficult aspects of interpreting current clinical trials relates to analysing the data obtained in older subgroups. For example the majority of people with heart failure are over the age of 75 years. Yet in this specific subgroup there is no statistically significant effect on outcomes with beta blockers [26] or ACE inhibitors [27]. On one hand, this may be a statistical quirk related to power and subgroup analysis. On the other hand, it is quite plausible that these drugs have no effect in geriatric patients because of changes in comorbidity, life expectancy, disease pathogenesis and pharmacological responses. Similarly, there are well-performed, large trials indicating that bisphosphonates might be ineffective in preventing hip fractures in women over the age of 80 years [28]. Such issues can only be resolved by conducting randomized clinical trials in geriatric subjects, despite the technical difficulties in performing trials in older people. Published trials performed in the very old are rare [29], but have been increasing in recent times [30]. Even when clinical data show statistically significant efficacy in older people, the results still have to be interpreted for clinical relevance. Cholinesterase inhibitors are widely recommended for the symptomatic treatment of moderately severe Alzheimer’s disease and the trials were performed in older patients. Clinically

219

perceptible improvement was measured in clinical trials using the CIBIC-Plus scale and was increased in treated subjects (OR 1.56, 95% CI 1.32–1.85). From the clinician’s point of view, if he or she treated 100 subjects with Alzheimer’s dementia, 24 would improve but in 17 of these patients the improvement would be secondary to the placebo effect. However, 15 subjects (over and above the placebo response) would report side-effects particularly nausea, abdominal pain and diarrhoea and 10 additional subjects would withdraw from therapy because of adverse reactions [31]. Furthermore, recent trials showed an increase in mortality with galantamine therapy in mild cognitive impairment [32]. Understandably, whether such drugs are useful in clinical practice is fiercely debated. ADVERSE DRUG REACTIONS The prevalence of adverse drug reactions is increased in older people [33–41], and reactions are generally more severe [33,41]. It has been reported that adverse drug reactions are the fourth to sixth greatest cause of death [42]. Between 5% and 10% of hospital admissions amongst older people are related to adverse drug reactions [43–46] and for every dollar spent on medications in nursing facilities for older people, $1.33 is subsequently required for the treatment of drug-related morbidity and mortality [47]. The rates of hospital admissions for adverse drug reactions amongst older people, particularly reactions to cardiovascular medications, have been steadily increasing over the last decade [48]. Even so ageing may not be an independent risk factor for adverse drug reactions but merely a marker for comorbidity, altered pharmacokinetics and the use of multiple medications [36,46,49]. Of all the factors that are most consistently associated with adverse drug reactions, polypharmacy has been considered the most important [33] and indeed, some studies that have used multivariate analysis report that the association between old age and adverse drug reactions is the result of the confounding association between age and polypharmacy [36]. However, it is clear that age-related changes in pharmacodynamics and pharmacokinetics contribute the risk of adverse medicine events [33,40]. Most adverse drug reactions causing admission of older people to hospital are classified as type A reactions and hence are predictable and potentially preventable [40]. In a review and meta-analysis of hospitalizations caused by adverse drug reactions it was concluded that

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

S. N. Hilmer et al.

220

older people are four times more likely to be admitted to hospital as a result of an adverse drug reaction (16.6% vs. 4.1%) and are more likely to have preventable adverse drug reactions (88% vs. 24%). In another study of people over 75 years, 30.4% of admissions were secondary to adverse drug reactions of which one half were considered preventable [50]. However, it is also clear that ageing itself is associated with increased risk of adverse drug reactions to specific classes of drugs that may be independent of polypharmacy and altered pharmacology [34]. The association between old age and non-steroidal anti-inflammatory drug (NSAID)-induced adverse effects has become a major issue recently, particularly with the introduction and widespread use of cyclooxygenase-2 selective NSAID agents. The incidence of upper gastrointestinal haemorrhage or perforation increases substantially with old age in subjects taking NSAIDs [51]. In subjects over 70 years of age, the number needed to harm each year to produce an upper gastrointestinal haemorrhage or perforation is approximately 50 [51]. In addition, older people exposed to NSAIDs have a 1.7-fold increased chance of subsequent antihypertensive therapy [52,53] and an increased prevalence of renal impairment [54]. Even rare and probably idiosyncratic adverse reactions, such as interstitial nephritis and hepatitis associated with H2-receptor antagonists are primarily an issue for older people [55]. The association between falls and medication use has been substantiated by epidemiological and observational studies [56–59]. A systematic review examining the relationship between psychotropic drugs and falls in older people, found that the odds ratio for one or more falls was 1.73 (95% CI 1.52–1.97) for exposure to any psychotropic medication, and there was little difference between the different classes of psychotropic agents with respect to risk [59]. In this regard the newer generation psychotropic drugs have not lived up to expectations related to falls in older people. Selective serotonin inhibitors and newer generation antipyschotic agents appear to have at least an equivalent propensity to falls and fractures in older people as do the older tricyclic antidepressants [60] and first-generation antipsychotic agents [61]. The association between some medications and falls may be partially explained by increased mobility of patients receiving these therapies. The significant problem of hip fracture has been associated with the use of barbiturates [62], benzodiazepines [63], tricyclic antidepressants [64], antipsychotics [64] and selective serotonin reuptake inhibitors [60] in elderly patients. In

a systematic review, we estimated that the risk of hip fracture was increased by 50–110% in older subjects receiving benzodiazepines and that up to 10% of hip fractures were directly attributable to benzodiazepine usage [65]. Lower limb muscle weakness has been associated with an OR of 1.76 (95% CI 1.31–2.37) for any fall and 3.06 (95% CI 1.41–5.04) for recurrent falls [66]. However, while not well described, the risk of falls does not appear to be significantly increased by exposure to medications associated with myopathy, such as HMG CoA inhibitors and corticosteroids [21]. The inconsistent association between the number of medications that the patient is exposed to and falls risk will be discussed under polypharmacy. Confusion is frequently secondary to exposure to medications in older people. In the hospital setting, medications have been reported to be the cause of delirium in 11–30% of cases [67]. Benzodiazepine exposure in community dwelling older people has been associated with memory impairment [68]. Exposure to anticholinergic medications and high serum anticholinergic activity, a measure of peripheral blood anticholinergic burden, have been associated with decreased Mini-Mental State Examination scores in community dwelling older people [69], with non-progressive mild cognitive impairment [70] and with the presence of delirium in older medical inpatients [71]. Polypharmacy, defined as the use of five or more medications, occurs in 20–40% of older people [72–74] and has been linked to poor health outcomes [75]. The risk factors for polypharmacy include old age, comorbidity, recent hospitalization, female gender, depression, number of treating doctors [76] and practitioner characteristics [76]. In addition to using multiple prescribed medications, older people are also major users of complementary and alternative medicines and may not report these without prompting [77–79]. A longitudinal series of surveys of the use of complementary and alternative medicines conducted in South Australia [80] found that 37% of people over the age of 65 years regularly used such medicines. Older people are at great risk of adverse effects and herb–drug interactions when using complementary and alternative medicines [81]. About a third of older patients are at risk of interactions between complementary and alternative medicines and their prescription medicines [77,82] especially some of the herbal medicines promoted for use in the elderly [81,83]. Part of the risk of polypharmacy may be the unintentional practice of prescribing additional drugs for the

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

Clinical pharmacology in the geriatric patient

adverse effects of other drugs – ‘prescribing cascade’ [84] or ‘double-dipping’ [85]. For example, the odds ratio for starting antihypertensive treatment for recent users of NSAIDs compared with non-users was 1.66 (95% CI 1.54–1.80) and the risk was dose-dependent [52]. In older patients, the risk of commencing levodopa was increased in subjects taking metoclopramide (odds ratio 3.09, 95% CI 2.25–4.26) [86]. The harm associated with polypharmacy includes increased risks of adverse drug reactions, drug interactions, increased costs and errors in patient adherence to therapy. The prevalence of adverse drug reactions increases with the number of prescribed drugs. The risk of a definite adverse drug reaction is increased in subjects of any age taking four or more medications (odds ratio 2.94, 95% CI 2.38–3.6) [36] and the prevalence of any adverse drug reaction in hospital inpatients was 18.6% for those taking one to five drugs compared with 81.4% among those on six or more medications [37]. The risk of falling and of recurrent falls was doubled in those subjects taking four or more medications [58]. However, a recent study reported that falls are associated with increasing numbers of chronic diseases rather than with polypharmacy [87]. Some of the hazards attributed to polypharmacy may be related to the underlying comorbidities for which the medications are prescribed. It is important to determine the potential benefits of polypharmacy in particular settings before dismissing it as entirely inappropriate. Clinical trials tend to exclude subjects with comorbidity and polypharmacy. If subjects with multiple conditions are studied, often the intervention and outcome focus on a single disorder. For example, there is good evidence for the benefit of polypharmacy from clinical trials in subjects with diabetes mellitus. The use of antihyperlipidemic agents, antihypertensives, antiplatelet agents and ACE inhibitors have all been shown to have considerable mortality benefits in these diabetic patients [88,89]. MEDICATION WITHDRAWAL There is evidence for the benefit of reducing exposure to some classes of medications in older people. In a randomized placebo-controlled trial of withdrawal of psychotropic medications in older subjects taking, on average, 5–6.5 medications each, it was found that there was a 76% reduction in falls over 44 weeks (odds ratio 0.34, 95% CI 0.16–0.74) [90]. There have been at least four trials investigating the effect of withdrawal of antihypertensive medications in older people. Overall,

221

40% of subjects remain normotensive, particularly if weight loss and salt restriction are implemented [91]. One study of 333 elderly (70–84 years) hypertensive patients found that antihypertensive therapy could be withdrawn for up to 5 years in 20% of subjects. During the state of ‘no treatment’ subjects had lower total mortality risk than the matched general population of the treated group [92]. Patient satisfaction is often increased when polypharmacy is reduced [93,94]. In a retrospective study of drug withdrawal in older subjects, 238 medications were ceased in 124 subjects for a variety of clinician-based reasons. There were no clinical consequences for nearly three quarters of the medications that had been ceased [95]. However, the risk of postoperative complications was increased in a retrospective analysis of subjects who had medications withdrawn in the peri-operative period [96]. Medication withdrawal is difficult to implement. Prescriber feedback and pharmacist-led medication reviews have been tried [97,98]. General practitioners have also been encouraged to withdraw medications in their older patients with polypharmacy [97]. Most drugs can be stopped without major withdrawal effects but it should be noted that acute withdrawal of benzodiazepines [99] and anticonvulsants can be associated with seizures, beta-blockers with tachycardia and exacerbation of ischaemic heart disease, antidepressants with a well defined withdrawal syndrome [100] and levodopa with neuroleptic malignant syndrome [101]. Although there is little evidence supporting the approach to medication withdrawal, in general a stepwise approach is recommended, with weaning of psychotropic and cardiovascular medications. Research by geriatricians and clinical pharmacologists is needed to develop more sophisticated evidence-based prescribing guidelines than simply counting drugs, to ascertain which medications at what doses improve relevant functional outcomes, which are detrimental, and which can be safely withdrawn. MEDICATION MANAGEMENT IN GERIATRIC PATIENTS Continuity of prescribing Obtaining an accurate medication history and reviewing all of a patient’s medications is an essential component of geriatric assessment. Geriatric patients have multiple comorbidities and thus may have their medications prescribed by several doctors. These patients are also

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

S. N. Hilmer et al.

222

frequent users of acute hospitals where medications may be reviewed and altered. Medication histories obtained from older people are often inaccurate and reconciliation of the history from multiple sources is required [102]. Trials of interventions to improve the transfer of medication information from the hospital to the community, such as medication cards [103] or a pharmacist to coordinate medication-management [104] have provided some benefits but results remain disappointing. Pharmacist-led home review of medications has also been studied [98]. While the role of electronic data management is currently being investigated, at present the most useful and accurate record of patients’ medications is the ‘plastic bag’ containing all of their medications [102]. Adherence Typical adherence rates for prescribed medications are about 50% [105] and do not vary significantly with age [106]. Adherence to medications is difficult to measure, poorly recognized, and complex [107]. Barriers to compliance that are common in older people include chronic conditions, polypharmacy, complex regimens, a higher prevalence of adverse drug reactions, unaffordable drug costs, cognitive impairment, visual impairment, manual dexterity problems and dysphagia [106,108]. Dysphagia often results in the need to crush (or reformulate) solid oral doses, which is not appropriate for all dose forms, especially modified release formulations, and new formulations appropriate for older people with swallowing disorders will need to be developed [109–112]. Strategies to improve adherence, which are often multi-factorial and complex, have generally only provided minimal benefit [113]. Monitoring The ageing process, especially frailty, diminishes homeostatic responses and the capacity to deal effectively with any physiological perturbation, including initiation of a new medication and changes in dose regimes [2]. Therefore, it is imperative that such subjects are closely monitored both for evidence of efficacy (the medication should be ceased if it is ineffective) or adverse drug reactions. Adverse drug reactions present with a wide variety of symptoms and are the ‘great imitators’ of medicine in the 21st century. Medications need to be reviewed regularly in response to rapid changes in clinical status including hospitalization, new diseases, mediation load and transition into a palliative phase.

AGE-RELATED CHANGES IN PHARMACOKINETICS Once a decision has been made to prescribe a medication to an older person, a dosage regime needs to be constructed. This is often based upon consideration of age-related changes in pharmacokinetics, although it must be conceded that there are few clinical trials that have addressed the effects of altering dose on safety and efficacy outcomes. Furthermore, it has been argued that interindividual variability in pharmacokinetics (from all causes) may be far greater than age-related variability [114]. There are many age-related changes in the processes of drug absorption from the gastrointestinal tract, plasma protein binding and drug distribution; however, the implications for drug dosage are minimal [2]. The hepatic metabolism of many drugs is reduced in elderly patients [115]. The extent is variable between drug groups but usually represents a 30–50% reduction in clearance of drugs cleared by phase I hepatic metabolism [115,116]. This appears to be secondary to age-related changes in hepatic blood flow, liver mass and the hepatic endothelium rather than ageing changes in drug metabolizing enzymes or their expression [2,114,117,118]. Age-related reductions in hepatic clearance increase the bioavailability of drugs with a significant first pass effect and reduce the clearance of hepatically metabolized drugs, probably increasing the risk of type A dose-related adverse drug reactions. However, there will also be a decrease in the activation of some pro-drugs, causing reduced or delayed efficacy in elderly patients. Phase II metabolism via conjugation pathways appears to be maintained in healthy older people but reduced with frailty. Conjugation of paracetamol [119] is reduced in frail but not fit older people. Similarly, esterase activity is reduced in frail but not fit older people [120]. Hepatic transporters have recently been recognized as important determinants of drug disposition, for both uptake and biliary excretion. Variability in the expression and/or function of these transporters has been described with genetic polymorphisms and disease. There are no studies on the expression of transporters in aged human livers, but there is evidence that hepatic expression of P-glycoprotein is increased in old rats, which, if functional, should result in increased biliary excretion [121]. While most drug metabolism occurs in the liver, enzymes in the wall of the gastrointestinal tract, such as

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

Clinical pharmacology in the geriatric patient

CYP450 contribute to the pre-systemic metabolism of a number of drugs. Age-related changes in the expression of these enzymes in the gastrointestinal tract are not well described. Data from animal studies provide some evidence that CYP3A expression is maintained in the intestinal mucosa of old rats [122]. It has been accepted that there is a marked age-related reduction in creatinine clearance in older people, even in the presence of normal serum creatinine concentrations. The Cockcroft Gault equation [123] is often used to estimate the creatinine clearance in older people in order to adjust the maintenance dose of renally excreted drugs that have narrow therapeutic indices, such as aminoglycosides, digoxin and lithium. However, the Cockcroft Gault equation was derived from men being investigated for renal disease. A review of recent studies of healthy older people has shown that in the absence of renal disease, glomerular filtration rate is reasonably maintained into old age [2]. Practitioners have recently started to estimate renal function using the Modification of Diet in Renal Disease equation, which also includes age, and shows a better correlation with accurately measured glomerular filtration rate than creatinine clearance [124]. However, it has not been validated in extremes of age or for adjusting doses of renally excreted drugs [125]. The few studies on the effects of healthy ageing on lithium, gentamicin [126] and digoxin [127] pharmacokinetics have not shown any dramatic reduction in renal clearance independent of changes in renal function. While many studies have identified an effect of age on the clearance of such drugs in patients [128], this is likely to reflect the high prevalence of renal disease in older people, as well as the high prevalence of polypharmacy and potential drug interactions affecting renal excretion. Rather than relying on generalizations about ageing changes in liver and renal function to define dosage, regulatory authorities now require pharmacokinetic data from older people. In many cases, such data include only relatively ‘young’ old people (e.g. older than 65 years) so that data on the very elderly or frail patient, where altered kinetics are likely to have a major impact, are not available. AGE-RELATED CHANGES IN PHARMACODYNAMICS Age-related changes in effector system function result in age-related changes in pharmacodynamics. End-organ response is affected by physiological changes that occur

223

with increasing age in the absence of pathology. Of particular interest to pharmacologists are the age-related changes in calcium channels and beta-adrenergic receptors, with implications for the clinical use of their agonists and antagonists [1]. For example, the betaadrenergic response decreases with increasing age, and controlling for plasma concentration, the bradycardic response to labetolol is decreased in older people [129]. Older people have been shown to be more sensitive to sedating effects of some medications due to changes in both pharmacokinetics and pharmacodynamics, e.g. they lose consciousness at a dose and lower plasma concentration of propofol at the effector site than younger people [130] and have increased sensitivity to sedation with benzodiazepines such as triazolam [131]. Age-related changes in the autonomic nervous system predispose older people to postural hypotension [132], which may be further exacerbated by medications with anticholinergic effects and antihypertensives [133]. APPLICATION OF PRINCIPLES OF GERIATRIC PHARMACOLOGY TO SPECIFIC PHARMACOTHERAPIES Treatment of cardiac failure with beta blockers Appropriate treatment of cardiac failure in geriatric patients highlights the hazards of extrapolating evidence from younger adults to geriatric patients. For example, there is substantial clinical trial evidence for the use of beta-blockers in patients with cardiac failure receiving an ACE inhibitor and a recent subgroup analysis of the clinical trials for metoprolol concluded ‘the time has come to overcome the barriers that physicians perceive to beta-blocker treatment and to provide it to the large number of elderly patients with heart failure’. However, in subjects over 75 years (n ¼ 490) the relative risk for primary outcome of hospitalization and all cause mortality was not statistically significant [0.79 (95% CI 0.55–1.14)] nor was total mortality [0.71 (95% CI 0.42–1.19)] [134]. Similarly in the SENIORS study it was concluded that nebivolol is ‘an effective and well tolerated treatment for heart failure in the elderly’ yet the relative risk for the primary outcome (hospitalization and all cause mortality) in the older cohort aged more than 75.2 years was not significant [0.92 (95% CI 0.72– 1.12)] [135]. There are many possible reasons for the lack of benefit of beta-blockers in older people with heart failure. Outcomes like hospitalization and mortality are less likely to be influenced by management of a single

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

S. N. Hilmer et al.

224

disease, such as heart failure, in an older person with more comorbidities than a younger person. Pharmacodynamically, with both increasing age and heart failure, there is decreasing responsiveness of beta receptors, with different changes in the second messenger mechanisms [136], and this could contribute to lack of effect of betablockers in patients with both old age and heart failure. With increasing age, diastolic failure accounts for a higher proportion of the population with heart failure [137] and even in younger people, the evidence for betablockers in heart failure is predominantly in patients with systolic failure. Interestingly, caloric restriction, which delays the ageing process, has been shown to reduce the incidence diastolic heart failure [138]. This suggests that management of cardiac failure in older people may require interventions directed at the ageing process, rather than blanket application of interventions that have only been shown to be efficacious in youngand middle-aged adults. Cancer chemotherapy The incidence of most cancers increases with age and prescription of chemotherapy in the geriatric patient requires consideration of the principles of both medical ethics and geriatric pharmacology. There is limited evidence from clinical trials to support the use of chemotherapy in older subjects with cancer, particularly those with comorbidities. Older people are more prone to toxicity from chemotherapeutic agents, due to age-related changes in both pharmacokinetics and pharmacodynamics [8,139]. A comprehensive geriatric assessment approach, including identification of the frailty syndrome, may assist oncologists in identification of older patients who are likely to develop severe toxicity and severe side effects in response to aggressive treatment [8]. Paracetamol for chronic pain Chronic pain is common in older people and tends to be musculoskeletal [140]. A study of adults aged 65 years and older living in retirement facilities in the USA with persistent pain found that 61% had used paracetamol and management with paracetamol was rated more than moderately helpful in 40% of cases [141]. Studies of pain relief in older people must consider both age-related differences in pain perception and reporting, which are not yet well defined [142], and meaningful outcomes for older people, such as mobility. Unintentional overdose with paracetamol is accounts for approximately half of the cases of acute liver failure

from paracetamol toxicity and cases associated with chronic paracetamol use occur more often in older patients [143]. The increased risk of paracetamol toxicity from chronic use in older people is partly explained by the reduced hepatic clearance. The 30–40% reduction in liver weight in normal ageing must be accounted for in dose calculations. Recognition of frailty is critical, as paracetamol conjugation per unit volume of liver is normal in healthy older people but reduced in the frail [119]. Fasting may also enhance paracetamol hepatotoxicity [144] and malnutrition is common in geriatric patients, affecting up to 15% of community-dwelling older people [145], 23–62% of hospitalized patients in acute wards [146], 50% of older patients in subacute wards [147] and up to 85% of nursing home residents [148]. Toxicology studies in rats do not show an increase in paracetamol hepatotoxicity with increasing age [149]. The clinical increased risk of paracetamol hepatotoxicity in older people is likely to be related to dosing that does not account for decreased liver volume with age, and to frailty and malnutrition. Warfarin for stroke prevention in atrial fibrillation The use of warfarin in geriatric patients with atrial fibrillation requires careful analysis of the potential benefits and risks for the individual. On meta-analysis of clinical trials, the benefits of warfarin are well established [150]. Both atrial fibrillation and stroke increase with age, and the association between stroke and atrial fibrillation is maintained in older people [151]. Therefore, the benefits of warfarin for stroke prevention are potentially greater in older people with atrial fibrillation. However, SPAF II [152], a randomized controlled trial to compare aspirin and warfarin for atrial fibrillation specifically in patients over 75 years, found the rate of all stroke (ischaemic or haemorrhagic) with residual deficit was 4.3% per year with aspirin and 4.6% per year with warfarin (RR 1.1). Furthermore, the outcome of anticoagulation in older patients with atrial fibrillation in terms of quality adjusted life years is either negligible or negative [153,154]. Patients aged over 75 years who are prescribed warfarin for atrial fibrillation have a significantly greater risk of major haemorrhage than those less than 75 years [152]. For those over 75 years, the annual rate of major haemorrhage was 4.2% for patients in a randomized trial [152] and 10.0% for frail older people in an observational study [155]. Some of the high risk of haemorrhage with warfarin in geriatric patients may be related to difficulty maintaining optimal levels of anticoagulation

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

Clinical pharmacology in the geriatric patient

[156]. Achieving therapeutic anticoagulation is challenged in older people by compliance with dosing and monitoring requirements, particularly in those with cognitive impairment, increased risk of drug–drug interactions with increased prevalence of polypharmacy, increased inter-individual variability, increased hospitalizations [157] and irregular food and alcohol intake. However, major bleeds occur at lower international normalized ratios with increasing age [158]. The increased risk of haemorrhage in older people may be related to vascular rigidity and endothelial dysfunction, despite an increase in coagulation system proteins and platelet activation with increasing age [159]. Older people have a higher prevalence of gastrointestinal pathology, predisposing them to gastrointestinal bleeding, and are at increased risk of falls, which can cause severe injury in the presence of anticoagulation, particularly from intracerebral bleeds [160]. Warfarin has also recently been associated with osteoporotic fractures [161], which are a functionally important adverse event in older people. The decision on whether to prescribe warfarin for stroke prevention in an individual geriatric patient with atrial fibrillation depends on the complexity of the individual. A multidisciplinary intervention to optimize antithrombotic use in older patients with atrial fibrillation that captured patient complexity [162] found that the intervention was associated with fewer patients receiving warfarin, after having been assessed inappropriate candidates. Prescribing biases may be introduced by clinical experience. While a prescriber’s experience of an adverse bleeding event in a patient on warfarin for atrial fibrillation will decrease subsequent prescribing of warfarin, treating a patient who has a stroke while not anticoagulated does not increase warfarin prescribing for subsequent patients [163]. The prescriber needs to calculate the risks and benefits of anticoagulation for the individual geriatric patient, discuss these with the patient, whose preferences may differ widely from clinical practice guidelines [164], when possible obtain informed consent for the decision, and review the decision frequently. CONCLUSIONS Most disease occurs in older people, particularly geriatric patients and the frail elderly. These older patients have the greatest potential to benefit from medications, however, observational studies indicate an increased prevalence of adverse drug reactions and some clinical

225

trials have failed to establish therapeutic benefits seen in younger adult subjects. Thus the decision to prescribe medications to geriatric patients requires individual analysis of harm and benefit rather than broad application of prescribing guidelines. To do this the clinician must have a thorough knowledge of the magnitude of the reported risks and benefits of the medications. Much of geriatric medicine is concerned with the recognition and management of adverse drug reactions and frequently the major intervention is withdrawal of medications rather than the prescription of new medications. This practice may generate short-term gains in terms of function but the long-term consequences of medication withdrawal have not been investigated extensively. Age-related changes in pharmacokinetics and pharmacodynamics, polypharmacy and numerous comorbidities further contribute to the complexity of drug therapy. Given that older people are the major recipients of drug therapy in the Western world, increased research and a better evidence base is an imperative to guide clinicians who manage geriatric patients and frail older people. ACKNOWLEDGEMENTS This review was supported by grants from National Health and Medical Research Council of Australia, Healthy Ageing Research Programme of the NHMRC, Ageing and Alzheimer’s Research Foundation, Geoff and Elaine Penney Ageing Research Unit. REFERENCES 1 Abernethy D.R. Altered pharmacodynamics of cardiovascular drugs and their relation to altered pharmacokinetics in elderly patients. Clin. Geriatr. Med. (1990) 6 285–292. 2 McLean A.J., Le Couteur D.G. Aging biology and geriatric clinical pharmacology. Pharmacol. Rev. (2004) 56 163– 184. 3 Hochhaus G., Barrett J.S., Derendorf H. Evolution of pharmacokinetics and pharmacokinetic/dynamic correlations during the 20th century. J. Clin. Pharmacol. (2000) 40 908– 917. 4 Le Couteur D.G., Naganathan V., Cogger V.C., Cumming R.G., McLean A.J. Pharmacotherapy in the elderly: clinical issues and perspectives. In: Kohli K., Gupta M., Tejwani S. (Eds), Contemporary perspectives on clinical therapeutics, Elsevier, Amsterdam, 2006, pp. 709–722. 5 Fried L.P., Tangen C.M., Walston J. et al. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. (2001) 56 M146–M156.

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

S. N. Hilmer et al.

226

6 Reuben D.B., Borok G.M., Wolde-Tsadik G., Ershoff D.H., Fishman L.K., Ambrosini V.L. et al. A randomized trial of comprehensive geriatric assessment in the care of hospitalized patients. N. Engl. J. Med. (1995) 332 1345–1350. 7 Reuben D.B., Frank J.C., Hirsch S.H., McGuigan K.A., Maly R.C. A randomized clinical trial of outpatient comprehensive geriatric assessment coupled with an intervention to increase adherence to recommendations. J. Am. Geriatr. Soc. (1999) 47 269–276. 8 Ferrucci L., Guralnik J.M., Cavazzini C., Bandinelli S., Lauretani F., Bartali B. et al. The frailty syndrome: a critical issue in geriatric oncology. Crit. Rev. Oncol. Hematol. (2003) 46 127– 137. 9 Belcher V.N., Fried T.R., Agostini J.V., Tinetti M.E. Views of older adults on patient participation in medication-related decision making. J. Gen. Intern. Med. (2006) 21 298–303. 10 Phelan E.A., Anderson L.A., LaCroix A.Z., Larson E.B. Older adults’ views of ‘‘successful aging’’ – how do they compare with researchers’ definitions? J. Am. Geriatr. Soc. (2004) 52 211–216. 11 Guralnik J.M., Simonsick E.M., Ferrucci L., Glynn R.J., Berkman L.F., Blazer D.G. et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J. Gerontol. (1994) 49 M85–M94. 12 Ried L.D., Johnson R.E., Gettman D.A. Benzodiazepine exposure and functional status in older people. J. Am. Geriatr. Soc. (1998) 46 71–76. 13 Gray S.L., Penninx B.W., Blough D.K., Artz M.B., Guralnik J.M., Wallace R.B., et al. Benzodiazepine use and physical performance in community-dwelling older women. J. Am. Geriatr. Soc. (2003) 51 1563–1570. 14 Beers M.H. Explicit criteria for determining potentially inappropriate medication use by the elderly. An update. Arch. Intern. Med. (1997) 157 1531–1536. 15 Hanlon J.T., Fillenbaum G.G., Kuchibhatla M., Artz M.B., Boult C., Gross C.R. et al. Impact of inappropriate drug use on mortality and functional status in representative community dwelling elders. Med. Care (2002) 40 166–176. 16 Onder G., Landi F., Liperoti R., Fialova D., Gambassi G., Bernabei R. Impact of inappropriate drug use among hospitalized older adults. Eur. J. Clin. Pharmacol. (2005) 61 453–459. 17 Savo A., Maiorano P.M., Onder G., Bernabei R. Pharmacoepidemiology and disability in older adults: can medications slow the age-related decline in physical function? Expert Opin. Pharmacother. (2004) 5 407–413. 18 Agostini J.V., Han L., Tinetti M.E. The relationship between number of medications and weight loss or impaired balance in older adults. J. Am. Geriatr. Soc. (2004) 52 1719–1723. 19 Thompson P.D., Clarkson P., Karas R.H. Statin-associated myopathy. JAMA (2003) 289 1681–1690. 20 Dobkin B.H. Underappreciated statin-induced myopathic weakness causes disability. Neurorehabil. Neural. Repair (2005) 19 259–263. 21 Pasco J.A., Kotowicz M.A., Henry M.J., Sanders K.M., Nicholson G.C. Falls and 3-hydroxy-3-methylglutaryl

22 23

24 25

26

27

28

29

30

31 32

33

34

35

36

37

coenzyme a reductase inhibitors. Arch. Intern. Med. (2002) 162 2381. Lunenfeld B. Androgen therapy in the aging male. World J. Urol. (2003) 21 292–305. Forette F., Seux M.L., Staessen J.A., Thijs L., Birkenhager W.H., Babarskiene M.R. et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet (1998) 352 1347– 1351. Spence J.D. Preventing dementia by treating hypertension and preventing stroke. Hypertension (2004) 44 20–21. Anson O., Paran E. Hypertension and cognitive functioning among the elderly: an overview. Am. J. Ther. (2005) 12 359– 365. Le Couteur D.G., Bailey L., Naganathan V. Beta-blockers and heart failure in older people. Eur. Heart J. (2006) 27 887– 888. Flather M.D., Yusuf S., Kober L., Pfeffer M., Hall A., Murray G., et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet (2000) 355 1575– 1581. McClung M.R., Geusens P., Miller P.D., Zippel H., Bensen W.G., Roux C. et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N. Engl. J. Med. (2001) 344 333–340. Nair B.R. Evidence based medicine for older people: available, accessible, acceptable, adaptable? Aust. J. Ageing (2002) 21 58–60. Le Quintrec J.L., Bussy C., Golmard J.L., Herve C., Baulon A., Piette F. Randomized controlled drug trials on very elderly subjects: descriptive and methodological analysis of trials published between 1990 and 2002 and comparison with trials on adults. J. Gerontol. A Biol. Sci. Med. Sci. (2005) 60 340–344. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst. Rev. (2006) CD005593. Loy C., Schneider L. Galantamine for Alzheimer’s disease and mild cognitive impairment. Cochrane Database Syst. Rev. (2006) CD001747. Walker J., Wynne H. Review: the frequency and severity of adverse drug reactions in elderly people. Age Ageing (1994) 23 255–259. Beyth R.J., Shorr R.I. Epidemiology of adverse drug reactions in the elderly by drug class. Drugs Aging (1999) 14 231–239. Bordet R., Gautier S., Le Louet H., Dupuis B., Caron J. Analysis of the direct cost of adverse drug reactions in hospitalised patients. Eur. J. Clin. Pharmacol. (2001) 56 935–941. Carbonin P., Pahor M., Bernabei R., Sgadari A. Is age an independent risk factor of adverse drug reactions in hospitalized medical patients? J. Am. Geriatr. Soc. (1991) 39 1093– 1099. Hurwitz N. Predisposing factors in adverse reactions to drugs. Br. Med. J. (1969) 1 536–539.

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

Clinical pharmacology in the geriatric patient

38 Kellaway G.S., McCrae E. Intensive monitoring for adverse drug effects in patients discharged from acute medical wards. N. Z. Med. J. (1973) 78 525–528. 39 Pouyanne P., Haramburu F., Imbs J.L., Begaud B. Admissions to hospital caused by adverse drug reactions: cross sectional incidence study. French Pharmacovigilance Centres. BMJ (2000) 320 1036. 40 Routledge P.A., O’Mahony M.S., Woodhouse K.W. Adverse drug reactions in elderly patients. Br. J. Clin. Pharmacol. (2004) 57 121–126. 41 Atkin P.A., Veitch P.C., Veitch E.M., Ogle S.J. The epidemiology of serious adverse drug reactions among the elderly. Drugs Aging (1999) 14 141–152. 42 Lazarou J., Pomeranz B.H., Corey P.N. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA (1998) 279 1200–1205. 43 Mjorndal T., Boman M.D., Hagg S., Backstrom M., Wiholm B.E., Wahlin A. et al. Adverse drug reactions as a cause for admissions to a department of internal medicine. Pharmacoepidemiol. Drug Saf. (2002) 11 65–72. 44 Mannesse C.K., Derkx F.H., de Ridder M.A., Man in ‘t Veld A.J., van der Cammen T.J. Contribution of adverse drug reactions to hospital admission of older patients. Age Ageing (2000) 29 35–39. 45 Einarson T.R. Drug-related hospital admissions. Ann. Pharmacother. (1993) 27 832–840. 46 Atkin P.A., Shenfield G.M. Medication-related adverse reactions and the elderly: a literature review. Adverse Drug React. Toxicol. Rev. (1995) 14 175–191. 47 Bootman J.L., Harrison D.L., Cox E. The health care cost of drug-related morbidity and mortality in nursing facilities. Arch. Intern. Med. (1997) 157 2089–2096. 48 Burgess C.L., Holman C.D., Satti A.G. Adverse drug reactions in older Australians, 1981–2002. Med. J. Aust. (2005) 182 267–270. 49 Gurwitz J.H., Avorn J. The ambiguous relation between aging and adverse drug reactions. Ann. Intern. Med. (1991) 114 956–966. 50 Chan M., Nicklason F., Vial J.H. Adverse drug events as a cause of hospital admission in the elderly. Intern. Med. J. (2001) 31 199–205. 51 Hernandez-Diaz S., Rodriguez L.A. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch. Intern. Med. (2000) 160 2093–2099. 52 Gurwitz J.H., Avorn J., Bohn R.L., Glynn R.J., Monane M., Mogun H. Initiation of antihypertensive treatment during nonsteroidal anti-inflammatory drug therapy. JAMA (1994) 272 781–786. 53 Johnson A.G. NSAIDs and blood pressure. Clinical importance for older patients. Drugs Aging (1998) 12 17–27. 54 Henry D., Page J., Whyte I., Nanra R., Hall C. Consumption of non-steroidal anti-inflammatory drugs and the development of functional renal impairment in elderly subjects.

227

55

56 57 58

59

60

61

62 63

64

65

66

67 68

69

70

71

Results of a case-control study. Br. J. Clin. Pharmacol. (1997) 44 85–90. Fisher A.A., Le Couteur D.G. Nephrotoxicity and hepatotoxicity of histamine H2 receptor antagonists. Drug Saf. (2001) 24 39–57. Cumming R.G., Nevitt M.C., Cummings S.R. Epidemiology of hip fractures. Epidemiol. Rev. (1997) 19 244–257. Cumming R.G. Epidemiology of medication-related falls and fractures in the elderly. Drugs Aging (1998) 12 43–53. Leipzig R.M., Cumming R.G., Tinetti M.E. Drugs and falls in older people: a systematic review and meta-analysis: II. Cardiac and analgesic drugs. J. Am. Geriatr. Soc. (1999) 47 40–50. Leipzig R.M., Cumming R.G., Tinetti M.E. Drugs and falls in older people: a systematic review and meta-analysis: I. Psychotropic drugs. J. Am. Geriatr. Soc. (1999) 47 30–39. Liu B., Anderson G., Mittmann N., To T., Axcell T., Shear N. Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people. Lancet (1998) 351 1303–1307. Hien le T.T., Cumming R.G., Cameron I.D., Chen J.S., Lord S.R., March L.M. et al. Atypical antipsychotic medications and risk of falls in residents of aged care facilities. J. Am. Geriatr. Soc. (2005) 53 1290–1295. Macdonald J.B., Macdonald E.T. Barbiturates and fractures. Br. Med. J. (1977) 2 891. Ray W.A., Griffin M.R., Downey W. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA (1989) 262 3303–3307. Ray W.A., Griffin M.R., Schaffner W., Baugh D.K., Melton L.J. III. Psychotropic drug use and the risk of hip fracture. N. Engl. J. Med. (1987) 316 363–369. Cumming R.G., Le Couteur D.G. Benzodiazepines and risk of hip fractures in older people: a review of the evidence. CNS Drugs (2003) 17 825–837. Moreland J.D., Richardson J.A., Goldsmith C.H., Clase C.M. Muscle weakness and falls in older adults: a systematic review and meta-analysis. J. Am. Geriatr. Soc. (2004) 52 1121– 1129. Moore A.R., O’Keeffe S.T. Drug-induced cognitive impairment in the elderly. Drugs Aging (1999) 15 15–28. Hanlon J.T., Horner R.D., Schmader K.E., Fillenbaum G.G., Lewis I.K., Wall W.E. Jr et al. Benzodiazepine use and cognitive function among community-dwelling elderly. Clin. Pharmacol. Ther. (1998) 64 684–692. Mulsant B.H., Pollock B.G., Kirshner M., Shen C., Dodge H., Ganguli M. Serum anticholinergic activity in a communitybased sample of older adults: relationship with cognitive performance. Arch. Gen. Psychiatry (2003) 60 198–203. Ancelin M.L., Artero S., Portet F., Dupuy A.M., Touchon J., Ritchie K. Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study. BMJ (2006) 332 455–459. Flacker J.M., Cummings V., Mach J.R. Jr, Bettin K., Kiely D.K., Wei J. The association of serum anticholinergic activity with

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

S. N. Hilmer et al.

228

72

73

74

75

76

77

78

79

80

81

82

83

84

85 86

delirium in elderly medical patients. Am. J. Geriatr. Psychiatry (1998) 6 31–41. Anderson G., Kerluke K. Distribution of prescription drug exposures in the elderly: description and implications. J. Clin. Epidemiol. (1996) 49 929–935. Jorgensen T., Johansson S., Kennerfalk A., Wallander M.A., Svardsudd K. Prescription drug use, diagnoses, and healthcare utilization among the elderly. Ann. Pharmacother. (2001) 35 1004–1009. Kennerfalk A., Ruigomez A., Wallander M.A., Wilhelmsen L., Johansson S. Geriatric drug therapy and healthcare utilization in the United kingdom. Ann. Pharmacother. (2002) 36 797– 803. Sorensen L., Stokes J.A., Purdie D.M., Woodward M., Roberts M.S. Medication management at home: medication-related risk factors associated with poor health outcomes. Age Ageing (2005) 34 626–632. Simons L.A., Tett S., Simons J., Lauchlan R., McCallum J., Friedlander Y. et al. Multiple medication use in the elderly. Use of prescription and non-prescription drugs in an Australian community setting. Med. J. Aust. (1992) 157 242–246. Cohen R.J., Ek K., Pan C.X. Complementary and alternative medicine (CAM) use by older adults: a comparison of selfreport and physician chart documentation. J. Gerontol. A Biol. Sci. Med. Sci. (2002) 57 M223–M227. Flaherty J.H., Takahashi R. The use of complementary and alternative medical therapies among older persons around the world. Clin. Geriatr. Med. (2004) 20 179–200. Bressler R. Herb–drug interactions: interactions between Ginkgo biloba and prescription medications. Geriatrics (2005) 60 30–33. MacLennan A.H., Wilson D.H., Taylor A.W. Prevalence and cost of alternative medicine in Australia. Lancet (1996) 347 569–573. Hoblyn J.C., Brooks J.O. III. Herbal supplements in older adults. Consider interactions and adverse events that may result from supplement use. Geriatrics (2005) 60 22–23. Dergal J.M., Gold J.L., Laxer D.A., Lee M.S., Binns M.A., Lanctot K.L. et al. Potential interactions between herbal medicines and conventional drug therapies used by older adults attending a memory clinic. Drugs Aging (2002) 19 879–886. Jiang X., Williams K.M., Liauw W.S., Ammit A.J., Roufogalis B.D., Duke C.C. et al. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br. J. Clin. Pharmacol. (2005) 59 425–432. Rochon P.A., Gurwitz J.H. Optimising drug treatment for elderly people: the prescribing cascade. BMJ (1997) 315 1096–1099. Carlson J.E. Perils of polypharmacy: 10 steps to prudent prescribing. Geriatrics (1996) 51 26–30, 35. Avorn J., Bohn R.L., Mogun H., Gurwitz J.H., Monane M., Everitt D. et al. Neuroleptic drug exposure and treatment of parkinsonism in the elderly: a case-control study. Am. J. Med. (1995) 99 48–54.

87 Lawlor D.A., Patel R., Ebrahim S. Association between falls in elderly women and chronic diseases and drug use: cross sectional study. BMJ (2003) 327 712–717. 88 Adler A.I. Cardiovascular risk reduction in diabetes: underemphasised and overdue. Messages from major trials. Clin. Med. (2001) 1 472–477. 89 Kassab E., McFarlane S.I., Sower J.R. Vascular complications in diabetes and their prevention. Vasc. Med. (2001) 6 249– 255. 90 Campbell A.J., Robertson M.C., Gardner M.M., Norton R.N., Buchner D.M. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial. J. Am. Geriatr. Soc. (1999) 47 850–853. 91 Froom J., Trilling J. Reducing antihypertensive medication use in nursing home patients. Arch. Fam. Med. (2000) 9 378– 383. 92 Ekbom T., Lindholm L.H., Oden A., Dahlof B., Hansson L., Wester P.O. et al. A 5-year prospective, observational study of the withdrawal of antihypertensive treatment in elderly people. J. Intern. Med. (1994) 235 581–588. 93 Straand J., Sandvik H. Stopping long-term drug therapy in general practice. How well do physicians and patients agree? Fam. Pract. (2001) 18 597–601. 94 Matsuura M. Patient satisfaction with polypharmacy reduction in chronic epileptics. Psychiatry Clin. Neurosci. (2000) 54 249–253. 95 Graves T., Hanlon J.T., Schmader K.E., Landsman P.B., Samsa G.P., Pieper C.F. et al. Adverse events after discontinuing medications in elderly outpatients. Arch. Intern. Med. (1997) 157 2205–2210. 96 Kennedy J.M., van Rij A.M., Spears G.F., Pettigrew R.A., Tucker I.G. Polypharmacy in a general surgical unit and consequences of drug withdrawal. Br. J. Clin. Pharmacol. (2000) 49 353–362. 97 Woodward M. Deprescribing: achieving better health outcomes for older people through reducing medications. J. Pharm. Pract. Res. (2003) 33 323–328. 98 Sorensen L., Stokes J.A., Purdie D.M., Woodward M., Elliott R., Roberts M.S. Medication reviews in the community: results of a randomized, controlled effectiveness trial. Br. J. Clin. Pharmacol. (2004) 58 648–664. 99 Bogunovic O.J., Greenfield S.F. Practical geriatrics: use of benzodiazepines among elderly patients. Psychiatr. Serv. (2004) 55 233–235. 100 Mottram P., Wilson K., Strobl J. Antidepressants for depressed elderly. Cochrane Database Syst. Rev. (2006), CD003491. 101 Friedman J.H., Feinberg S.S., Feldman R.G. A neuroleptic malignantlike syndrome due to levodopa therapy withdrawal. JAMA (1985) 254 2792–2795. 102 Atkin P.A., Stringer R.S., Duffy J.B., Elion C., Ferraris C.S., Misrachi S.R. et al. The influence of information provided by patients on the accuracy of medication records. Med. J. Aust. (1998) 169 85–88. 103 Atkin P.A., Finnegan T.P., Ogle S.J., Shenfield G.M. Are medication record cards useful? Med. J. Aust. (1995) 162 300–301.

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

Clinical pharmacology in the geriatric patient

104 Crotty M., Rowett D., Spurling L., Giles L.C., Phillips P.A. Does the addition of a pharmacist transition coordinator improve evidence-based medication management and health outcomes in older adults moving from the hospital to a long-term care facility? Results of a randomized, controlled trial. Am. J. Geriatr. Pharmacother. (2004) 2 257–264. 105 Sackett D.L., Snow J.C. Compliance in health care. Johns Hopkins University Press, Baltimore, 1979. 106 Hughes C.M. Medication non-adherence in the elderly: how big is the problem? Drugs Aging (2004) 21 793–811. 107 Osterberg L., Blaschke T. Adherence to medication. N. Engl. J. Med. (2005) 353 487–497. 108 Atkin P.A., Finnegan T.P., Ogle S.J., Shenfield G.M. Functional ability of patients to manage medication packaging: a survey of geriatric inpatients. Age Ageing (1994) 23 113–116. 109 Fawell N.G., Cookson T.L., Scranton S.S. Relationship between tablet splitting and compliance, drug acquisition cost, and patient acceptance. Am. J. Health Syst. Pharm. (1999) 56 2542–2545. 110 Marriott J.L., Nation R.L. Splitting tablets. Aust. Prescr. (2002) 25 133–135. 111 Wright D. Medication administration in nursing homes. Nurs. Stand. (2002) 16 33–38. 112 Carnaby-Mann G., Crary M. Pill swallowing by adults with dysphagia. Arch. Otolaryngol. Head Neck Surg. (2005) 131 970–975. 113 Haynes R., Yao X., Degani A., Kripalani S., Garg A., McDonald H. et al. Interventions to enhance medication adherence. Cochrane Database Syst. Rev. (2005), CD000011. 114 Schmucker D.L. Age-related changes in liver structure and function: implications for disease? Exp. Gerontol. (2005) 40 650–659. 115 Le Couteur D.G., McLean A.J. The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis. Clin. Pharmacokinet. (1998) 34 359–373. 116 Schmucker D.L. Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging (2001) 18 837–851. 117 Le Couteur D.G., Fraser R., Hilmer S., Rivory L.P., McLean A.J. The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance. Clin. Pharmacokinet. (2005) 44 187–200. 118 Cotreau M.M., von Moltke L.L., Greenblatt D.J. The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin. Pharmacokinet. (2005) 44 33–60. 119 Wynne H.A., Cope L.H., Herd B., Rawlins M.D., James O.F., Woodhouse K.W. The association of age and frailty with paracetamol conjugation in man. Age Ageing (1990) 19 419–424. 120 Summerbell J., Wynne H., Hankey C.R., Williams F.M. The effect of age and frailty upon blood esterase activities and their response to dietary supplementation. Br. J. Clin. Pharmacol. (1993) 36 399–404. 121 Warrington J.S., Greenblatt D.J., von Moltke L.L. The effect of age on P-glycoprotein expression and function in the Fischer344 rat. J. Pharmacol. Exp. Ther. (2004) 309 730–736.

229

122 Warrington J.S., Greenblatt D.J., von Moltke L.L. Age-related differences in CYP3A expression and activity in the rat liver, intestine, and kidney. J. Pharmacol. Exp. Ther. (2004) 309 720–729. 123 Cockcroft D.W., Gault M.H. Prediction of creatinine clearance from serum creatinine. Nephron (1976) 16 31–41. 124 Levey A.S., Bosch J.P., Lewis J.B., Greene T., Rogers N., Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann. Intern. Med. (1999) 130 461–470. 125 Mathew T.H. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: a position statement. Med. J. Aust. (2005) 183 138–141. 126 Morike K., Schwab M., Klotz U. Use of aminoglycosides in elderly patients. Pharmacokinetic and clinical considerations. Drugs Aging (1997) 10 259–277. 127 Miura T., Kojima R., Sugiura Y., Mizutani M., Takatsu F., Suzuki Y. Effect of aging on the incidence of digoxin toxicity. Ann. Pharmacother. (2000) 34 427–432. 128 Triggs E., Charles B. Pharmacokinetics and therapeutic drug monitoring of gentamicin in the elderly. Clin. Pharmacokinet. (1999) 37 331–341. 129 Abernethy D.R., Schwartz J.B., Plachetka J.R., Todd E.L., Egan J.M. Comparison in young and elderly patients of pharmacodynamics and disposition of labetalol in systemic hypertension. Am. J. Cardiol. (1987) 60 697–702. 130 Schnider T.W., Minto C.F., Shafer S.L., Gambus P.L., Andresen C., Goodale D.B. et al. The influence of age on propofol pharmacodynamics. Anesthesiology (1999) 90 1502–1516. 131 Greenblatt D.J., Harmatz J.S., von Moltke L.L., Wright C.E., Shader R.I. Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate. Clin. Pharmacol. Ther. (2004) 76 467–479. 132 Shi X., Wray D.W., Formes K.J., Wang H.W., Hayes P.M., AH O.Y. et al. Orthostatic hypotension in aging humans. Am. J. Physiol. Heart Circ. Physiol. (2000) 279 H1548–H1554. 133 Verhaeverbeke I., Mets T. Drug-induced orthostatic hypotension in the elderly: avoiding its onset. Drug Saf. (1997) 17 105–118. 134 Deedwania P.C., Gottlieb S., Ghali J.K., Waagstein F., Wikstrand J.C. Efficacy, safety and tolerability of beta-adrenergic blockade with metoprolol CR/XL in elderly patients with heart failure. Eur. Heart J. (2004) 25 1300–1309. 135 Flather M.D., Shibata M.C., Coats A.J., Van Veldhuisen D.J., Parkhomenko A., Borbola J. et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur. Heart J. (2005) 26 215–225. 136 Brodde O.E., Leineweber K. Autonomic receptor systems in the failing and aging human heart: similarities and differences. Eur. J. Pharmacol. (2004) 500 167–176. 137 Owan T.E., Redfield M.M. Epidemiology of diastolic heart failure. Prog. Cardiovasc. Dis. (2005) 47 320–332. 138 Meyer T.E., Kovacs S.J., Ehsani A.A., Klein S., Holloszy J.O., Fontana L. Long-term caloric restriction ameliorates the

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

S. N. Hilmer et al.

230

139

140 141

142

143

144

145

146

147

148

149 150

151

152

decline in diastolic function in humans. J. Am. Coll. Cardiol. (2006) 47 398–402. Wasil T., Lichtman S.M. Clinical pharmacology issues relevant to the dosing and toxicity of chemotherapy drugs in the elderly. Oncologist (2005) 10 602–612. Helme R.D., Gibson S.J. The epidemiology of pain in elderly people. Clin. Geriatr. Med. (2001) 17 417–431. Kemp C.A., Ersek M., Turner J.A. A descriptive study of older adults with persistent pain: use and perceived effectiveness of pain management strategies. BMC Geriatr. (2005) 5 12. Gibson S.J., Helme R.D. Age-related differences in pain perception and report. Clin. Geriatr. Med. (2001) 17 433– 456. Larson A.M., Polson J., Fontana R.J., Davern T.J., Lalani E., Hynan L.S. et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology (2005) 42 1364–1372. Whitcomb D.C., Block G.D. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA (1994) 272 1845–1850. Mion L.C., McDowell J.A., Heaney L.K. Nutritional assessment of the elderly in the ambulatory care setting. Nurse Pract. Forum (1994) 5 46–51. Zador D.A., Truswell A.S. Nutritional status on admission to a general surgical ward in a Sydney hospital. Aust. N. Z. J. Med. (1987) 17 234–240. Visvanathan R., Penhall R., Chapman I. Nutritional screening of older people in a sub-acute care facility in Australia and its relation to discharge outcomes. Age Ageing (2004) 33 260– 265. Shaver H.J., Loper J.A., Lutes R.A. Nutritional status of nursing home patients. J. Parenter. Enteral. Nutr. (1980) 4 367–370. Rikans L.E., Moore D.R. Acetaminophen hepatotoxicity in aging rats. Drug Chem. Toxicol. (1988) 11 237–247. Hart R.G., Benavente O., McBride R., Pearce L.A. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann. Intern. Med. (1999) 131 492–501. Wolf P.A., Abbott R.D., Kannel W.B. Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch. Intern. Med. (1987) 147 1561–1564. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet (1994) 343 687–691.

153 Man-Son-Hing M., Laupacis A. Balancing the risks of stroke and upper gastrointestinal tract bleeding in older patients with atrial fibrillation. Arch. Intern. Med. (2002) 162 541–550. 154 Desbiens N.A. Deciding on anticoagulating the oldest old with atrial fibrillation: insights from cost-effectiveness analysis. J. Am. Geriatr. Soc. (2002) 50 863–869. 155 Johnson C.E., Lim W.K., Workman B.S. People aged over 75 in atrial fibrillation on warfarin: the rate of major hemorrhage and stroke in more than 500 patient-years of follow-up. J. Am. Geriatr. Soc. (2005) 53 655–659. 156 Fihn S.D., Callahan C.M., Martin D.C., McDonell M.B., Henikoff J.G., White R.H. The risk for and severity of bleeding complications in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics. Ann. Intern. Med. (1996) 124 970–979. 157 van Walraven C., Austin P.C., Oake N., Wells P., Mamdani M., Forster A.J. The effect of hospitalization on oral anticoagulation control: a population-based study. Thromb. Res. (2007) 119 705–714. 158 Wittkowsky A.K., Whitely K.S., Devine E.B., Nutescu E. Effect of age on international normalized ratio at the time of major bleeding in patients treated with warfarin. Pharmacotherapy. (2004) 24 600–605. 159 Franchini M. Hemostasis and aging. Crit. Rev. Oncol. Hematol. (2006) 60 144–151. 160 Gage B.F., Birman-Deych E., Kerzner R., Radford M.J., Nilasena D.S., Rich M.W. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am. J. Med. (2005) 118 612–617. 161 Gage B.F., Birman-Deych E., Radford M.J., Nilasena D.S., Binder E.F. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch. Intern. Med. (2006) 166 241–246. 162 Bajorek B.V., Krass I., Ogle S.J., Duguid M.J., Shenfield G.M. Optimizing the use of antithrombotic therapy for atrial fibrillation in older people: a pharmacist-led multidisciplinary intervention. J. Am. Geriatr. Soc. (2005) 53 1912–1920. 163 Choudhry N.K., Anderson G.M., Laupacis A., Ross-Degnan D., Normand S.L., Soumerai S.B. Impact of adverse events on prescribing warfarin in patients with atrial fibrillation: matched pair analysis. BMJ (2006) 332 141–145. 164 Man-Son-Hing M., Gage B.F., Montgomery A.A., Howitt A., Thomson R., Devereaux P.J., et al. Preference-based antithrombotic therapy in atrial fibrillation: implications for clinical decision making. Med. Decis. Making (2005) 25 548– 559.

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd. Fundamental & Clinical Pharmacology 21 (2007) 217–230

Suggest Documents