doi: 10.1111/j.1472-8206.2007.00473.

REVIEW Clinical pharmacology in the geriatric

ARTICLE
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 ABSTRACT
adverse drug reactions,
clinical pharmacology, Geriatric patients are a subset of older people with multiple comorbidities that usually
evidence-based medicine, have significant functional implications. Geriatric patients have impaired homeo-
geriatric medicine stasis 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
Received 23 May 2006;
revised 1 August 2006;
patients requires an understanding of the efficacy of the medication in frail older
accepted 7 December 2006 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,
*Correspondence and reprints:
application of the evidence to frail older people through an understanding of changes
shilmer@med.usyd.edu.au
in pharmacokinetics and pharmacodynamics, and attention to medication manage-
ment 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 and clinical pharmacology in order to
geriatric medicine grew exponentially at the end of the guide prescribing in older people.
last century, reflecting the dramatic increase in medica-
tion usage and the ageing population. The interplay
COMPREHENSIVE ASSESSMENT –
between these specialties is critical for modern prescri-
A KEYSTONE OF GERIATRIC MEDICINE
bing because older people are the major users of
medications and their responses to medications are Regulatory bodies usually consider older people to be
highly variable [1,2]. those over 65 years of age and as such this definition
The basic concepts of modern pharmacokinetics and includes an extremely diverse group of people. Geriatric
pharmacodynamics were developed in the first half of the patients are a subset of frail older people with multiple
20th century. By the 1970s it was widely recognized comorbidities that usually have significant functional
that disease states and extremes of age introduce implications. Frailty is a poorly defined but increasingly
considerable variability in both pharmacokinetic and studied condition characterized by high susceptibility to
pharmacodynamic responses [3]. Even so, there is still a disease, impending decline in physical function and high
very limited evidence base underpinning geriatric pre- risk of death [5]. The frailty syndrome includes an
scribing and the complexities of geriatric pharmacology excessive reduction of lean body mass, a reduction
often appear to be underappreciated both in the design of in walking performance and mobility, and poor endur-
clinical trials and prescribing of medications [2,4]. In this ance associated with a perception of exhaustion and
review, we attempt to draw together the principles of fatigue [5].

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218 S. N. Hilmer et al.

Clinicians should develop comprehensive care plans – were achieved in older people. In the absence of such
including decisions on medication use – for frail older evidence, extrapolation of clinical trial data from young-
patients by integrating comprehensive information on all er patients or an understanding of disease processes
factors that can affect health status: disability, cognition, might be of some value in determining efficacy and
comorbidities, social role, psychological state and the safety;
availability of services and carers. This multidimensional 2. Determine the likelihood of adverse drug events in
approach is supported by clinical trials demonstrating that older subjects. In general adverse drug reaction data are
Comprehensive Geriatric Assessment has positive effects poorly described by clinical trials and especially so in
on health, functional status and mortality both in the subgroups of older patients. Thus the clinician usually
acute hospital setting [6] and in the community [7]. will need to rely on data from post-marketing surveil-
Comprehensive geriatric assessment captures the com- lance. Allowance should be made for the increased
plexity of problems that characterize frail older persons [8]. prevalence of adverse drug reactions in older people,
which is exacerbated as patients receive multiple medi-
cations for the management of different medical condi-
GENERAL PRINCIPLES OF PRESCRIBING
tions;
TO GERIATRIC PATIENTS
3. Discuss the harm:benefit analysis with the patient.
Comprehensive geriatric assessment and the recognition Patient autonomy is an important medical ethical
of frailty can assist the clinician in designing effective, principle often underemphasized in prescribing guide-
multidisciplinary management plans. Broad functional lines. Participation of older patients in treatment deci-
outcomes are usually the major therapeutic goal of such sions including medicines presents challenges, not the
treatment plans in geriatric patients, rather than the least of which may be a divergence between the goals of
specific disease-based outcomes typically investigated in the patient and the prescriber [9];
clinical trials. This approach also facilitates assessment of 4. Decide on the dose regime. There are many age-
the risk and benefit of prescribing a medication for a related changes in the disposition of and response to
particular condition in the context of comorbidity and medications. However, clinical trial evidence for any
disability, predicts likely changes in pharmacokinetics requirement for dose adjustment is limited. Furthermore,
and pharmacodynamics, and gives information on what selection of dose form may be an important issue to
assistance the patient may require to adhere to the achieve optimal drug delivery in a convenient manner;
optimal medication regime [4]. 5. Monitor the patient very carefully. The paucity of
Appropriate medical management requires a consid- clinical trial data in frail older patients and the marked
eration of all possible treatment options for a patient increase in the prevalence of adverse drug reactions
based on the available evidence including non-pharma- necessitate close monitoring of the patient. Functional
cological management options. In Australia, the Quality and quality of life outcomes may be more relevant to the
Use of Medicines Framework has identified three key older patient than individual primary disease outcomes
steps in prescribing: (1) decide what the best treatment is investigated in clinical trials.
(i.e. use non-pharmacological management options
first); (2) select medicines wisely (based on the suitability
EVIDENCE FOR EFFICACY IN
of the patient); and (3) use medicines based on the best
GERIATRIC PATIENTS
evidence (the right dose and duration) (http://www.
health.gov.au/internet/wcms/publishing.nsf/Content/ Older adults’ definition of successful ageing is multi-
nmp-quality.htm). In addition in geriatric patients, dimensional, encompassing physical, functional, psycho-
prescribing requires a detailed knowledge of the deficits logical and social health [10]. Ideally, therapeutics
in the evidence base and an appreciation of age-related should aim to meet these goals, but outcomes in clinical
changes in drug disposition, pharmacodynamic res- trials rarely address such a wide spectrum of issues.
ponses and the high prevalence of adverse drug reac- Furthermore endpoints that are relevant to older people
tions. The following steps broadly guide prescribing in such as independence, falls, cognitive impairment and
geriatric patients [4]: physical function are difficult to measure in clinical trials
1. Determine the evidence for efficacy in older subjects. and rarely assessed as adverse drug reactions.
This requires an analysis of clinical trial data with a Physical function is an important outcome for older
focus on whether optimal and meaningful outcomes people, and has been shown to predict disability, nursing

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Clinical pharmacology in the geriatric patient 219

home admission and mortality [11]. Benzodiazepine perceptible improvement was measured in clinical trials
exposure in community dwelling older people has been using the CIBIC-Plus scale and was increased in treated
associated with poorer self-reported functional status subjects (OR 1.56, 95% CI 1.32–1.85). From the
[12] and greater decline in objective physical perform- clinician’s point of view, if he or she treated 100 subjects
ance tests over 4 years [13]. Potentially inappropriate with Alzheimer’s dementia, 24 would improve but in 17
medication use in older people is currently guided of these patients the improvement would be secondary to
predominantly by expert consensus statements such as the placebo effect. However, 15 subjects (over and above
the recently updated Beers criteria [14]. However, this the placebo response) would report side-effects partic-
exposure does not correlate with decline in self-reported ularly nausea, abdominal pain and diarrhoea and 10
functional status in community dwelling older people additional subjects would withdraw from therapy
[15] or with health outcomes in hospitalized older people because of adverse reactions [31]. Furthermore, recent
[16]. trials showed an increase in mortality with galantamine
In some studies, angiotensin-converting enzyme therapy in mild cognitive impairment [32]. Understand-
(ACE) inhibitors, 3-hydroxy-3-methylglutaryl (HMG) ably, whether such drugs are useful in clinical practice is
CoA reductase inhibitors and testosterone have been fiercely debated.
associated with delayed functional decline in older people
[17]. However, ACE inhibitors have also been associated
ADVERSE DRUG REACTIONS
with impaired balance, a risk factor for falls [18], HMG
CoA reductase inhibitors with myopathy [19], disability The prevalence of adverse drug reactions is increased in
[20] and a trend towards increased falls [21], and older people [33–41], and reactions are generally more
testosterone with behavioural changes [22]. Treatment severe [33,41]. It has been reported that adverse drug
of hypertension with antihypertensive medications has reactions are the fourth to sixth greatest cause of death
been inconsistently associated with prevention of cogni- [42]. Between 5% and 10% of hospital admissions
tive decline in older people [23–25]. amongst older people are related to adverse drug
One of the most difficult aspects of interpreting current reactions [43–46] and for every dollar spent on medi-
clinical trials relates to analysing the data obtained in cations in nursing facilities for older people, $1.33 is
older subgroups. For example the majority of people with subsequently required for the treatment of drug-related
heart failure are over the age of 75 years. Yet in this morbidity and mortality [47]. The rates of hospital
specific subgroup there is no statistically significant effect admissions for adverse drug reactions amongst older
on outcomes with beta blockers [26] or ACE inhibitors people, particularly reactions to cardiovascular medica-
[27]. On one hand, this may be a statistical quirk related tions, have been steadily increasing over the last decade
to power and subgroup analysis. On the other hand, it is [48].
quite plausible that these drugs have no effect in geriatric Even so ageing may not be an independent risk factor
patients because of changes in comorbidity, life expect- for adverse drug reactions but merely a marker for
ancy, disease pathogenesis and pharmacological res- comorbidity, altered pharmacokinetics and the use of
ponses. Similarly, there are well-performed, large trials multiple medications [36,46,49]. Of all the factors that
indicating that bisphosphonates might be ineffective in are most consistently associated with adverse drug
preventing hip fractures in women over the age of reactions, polypharmacy has been considered the most
80 years [28]. Such issues can only be resolved by important [33] and indeed, some studies that have used
conducting randomized clinical trials in geriatric sub- multivariate analysis report that the association between
jects, despite the technical difficulties in performing trials old age and adverse drug reactions is the result of the
in older people. Published trials performed in the very old confounding association between age and polypharmacy
are rare [29], but have been increasing in recent times [36]. However, it is clear that age-related changes in
[30]. pharmacodynamics and pharmacokinetics contribute
Even when clinical data show statistically significant the risk of adverse medicine events [33,40].
efficacy in older people, the results still have to be Most adverse drug reactions causing admission of
interpreted for clinical relevance. Cholinesterase inhibi- older people to hospital are classified as type A reactions
tors are widely recommended for the symptomatic and hence are predictable and potentially preventable
treatment of moderately severe Alzheimer’s disease and [40]. In a review and meta-analysis of hospitalizations
the trials were performed in older patients. Clinically caused by adverse drug reactions it was concluded that

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220 S. N. Hilmer et al.

older people are four times more likely to be admitted to a systematic review, we estimated that the risk of hip
hospital as a result of an adverse drug reaction (16.6% fracture was increased by 50–110% in older subjects
vs. 4.1%) and are more likely to have preventable receiving benzodiazepines and that up to 10% of hip
adverse drug reactions (88% vs. 24%). In another study fractures were directly attributable to benzodiazepine
of people over 75 years, 30.4% of admissions were usage [65]. Lower limb muscle weakness has been
secondary to adverse drug reactions of which one half associated with an OR of 1.76 (95% CI 1.31–2.37) for
were considered preventable [50]. any fall and 3.06 (95% CI 1.41–5.04) for recurrent falls
However, it is also clear that ageing itself is associated [66]. However, while not well described, the risk of falls
with increased risk of adverse drug reactions to specific does not appear to be significantly increased by exposure
classes of drugs that may be independent of polyphar- to medications associated with myopathy, such as HMG
macy and altered pharmacology [34]. The association CoA inhibitors and corticosteroids [21]. The inconsistent
between old age and non-steroidal anti-inflammatory association between the number of medications that the
drug (NSAID)-induced adverse effects has become a patient is exposed to and falls risk will be discussed under
major issue recently, particularly with the introduction polypharmacy.
and widespread use of cyclooxygenase-2 selective NSAID Confusion is frequently secondary to exposure to
agents. The incidence of upper gastrointestinal haemor- medications in older people. In the hospital setting,
rhage or perforation increases substantially with old age medications have been reported to be the cause of
in subjects taking NSAIDs [51]. In subjects over 70 years delirium in 11–30% of cases [67]. Benzodiazepine
of age, the number needed to harm each year to produce exposure in community dwelling older people has been
an upper gastrointestinal haemorrhage or perforation is associated with memory impairment [68]. Exposure to
approximately 50 [51]. In addition, older people exposed anticholinergic medications and high serum anticholin-
to NSAIDs have a 1.7-fold increased chance of sub- ergic activity, a measure of peripheral blood anticho-
sequent antihypertensive therapy [52,53] and an linergic burden, have been associated with decreased
increased prevalence of renal impairment [54]. Even Mini-Mental State Examination scores in community
rare and probably idiosyncratic adverse reactions, such dwelling older people [69], with non-progressive mild
as interstitial nephritis and hepatitis associated with cognitive impairment [70] and with the presence of
H2-receptor antagonists are primarily an issue for older delirium in older medical inpatients [71].
people [55]. Polypharmacy, defined as the use of five or more
The association between falls and medication use has medications, occurs in 20–40% of older people [72–74]
been substantiated by epidemiological and observational and has been linked to poor health outcomes [75]. The
studies [56–59]. A systematic review examining the risk factors for polypharmacy include old age, comor-
relationship between psychotropic drugs and falls in bidity, recent hospitalization, female gender, depres-
older people, found that the odds ratio for one or more sion, number of treating doctors [76] and practitioner
falls was 1.73 (95% CI 1.52–1.97) for exposure to any characteristics [76].
psychotropic medication, and there was little difference In addition to using multiple prescribed medications,
between the different classes of psychotropic agents with older people are also major users of complementary and
respect to risk [59]. In this regard the newer generation alternative medicines and may not report these without
psychotropic drugs have not lived up to expectations prompting [77–79]. A longitudinal series of surveys of
related to falls in older people. Selective serotonin the use of complementary and alternative medicines
inhibitors and newer generation antipyschotic agents conducted in South Australia [80] found that 37% of
appear to have at least an equivalent propensity to falls people over the age of 65 years regularly used such
and fractures in older people as do the older tricyclic medicines. Older people are at great risk of adverse effects
antidepressants [60] and first-generation antipsychotic and herb–drug interactions when using complementary
agents [61]. The association between some medications and alternative medicines [81]. About a third of older
and falls may be partially explained by increased mobility patients are at risk of interactions between complement-
of patients receiving these therapies. The significant ary and alternative medicines and their prescription
problem of hip fracture has been associated with the use medicines [77,82] especially some of the herbal medi-
of barbiturates [62], benzodiazepines [63], tricyclic cines promoted for use in the elderly [81,83].
antidepressants [64], antipsychotics [64] and selective Part of the risk of polypharmacy may be the uninten-
serotonin reuptake inhibitors [60] in elderly patients. In tional practice of prescribing additional drugs for the

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Clinical pharmacology in the geriatric patient 221

adverse effects of other drugs – ‘prescribing cascade’ [84] 40% of subjects remain normotensive, particularly if
or ‘double-dipping’ [85]. For example, the odds ratio for weight loss and salt restriction are implemented [91].
starting antihypertensive treatment for recent users of One study of 333 elderly (70–84 years) hypertensive
NSAIDs compared with non-users was 1.66 (95% CI patients found that antihypertensive therapy could be
1.54–1.80) and the risk was dose-dependent [52]. In withdrawn for up to 5 years in 20% of subjects. During
older patients, the risk of commencing levodopa was the state of ‘no treatment’ subjects had lower total
increased in subjects taking metoclopramide (odds ratio mortality risk than the matched general population of
3.09, 95% CI 2.25–4.26) [86]. the treated group [92].
The harm associated with polypharmacy includes Patient satisfaction is often increased when polyphar-
increased risks of adverse drug reactions, drug inter- macy is reduced [93,94]. In a retrospective study of drug
actions, increased costs and errors in patient adherence withdrawal in older subjects, 238 medications were
to therapy. The prevalence of adverse drug reactions ceased in 124 subjects for a variety of clinician-based
increases with the number of prescribed drugs. The risk reasons. There were no clinical consequences for nearly
of a definite adverse drug reaction is increased in subjects three quarters of the medications that had been ceased
of any age taking four or more medications (odds ratio [95]. However, the risk of postoperative complications
2.94, 95% CI 2.38–3.6) [36] and the prevalence of any was increased in a retrospective analysis of subjects who
adverse drug reaction in hospital inpatients was 18.6% had medications withdrawn in the peri-operative period
for those taking one to five drugs compared with 81.4% [96].
among those on six or more medications [37]. The risk of Medication withdrawal is difficult to implement. Pre-
falling and of recurrent falls was doubled in those scriber feedback and pharmacist-led medication reviews
subjects taking four or more medications [58]. However, have been tried [97,98]. General practitioners have also
a recent study reported that falls are associated with been encouraged to withdraw medications in their older
increasing numbers of chronic diseases rather than with patients with polypharmacy [97]. Most drugs can be
polypharmacy [87]. Some of the hazards attributed to stopped without major withdrawal effects but it should
polypharmacy may be related to the underlying comor- be noted that acute withdrawal of benzodiazepines [99]
bidities for which the medications are prescribed. and anticonvulsants can be associated with seizures,
It is important to determine the potential benefits of beta-blockers with tachycardia and exacerbation of
polypharmacy in particular settings before dismissing it ischaemic heart disease, antidepressants with a well
as entirely inappropriate. Clinical trials tend to exclude defined withdrawal syndrome [100] and levodopa with
subjects with comorbidity and polypharmacy. If subjects neuroleptic malignant syndrome [101].
with multiple conditions are studied, often the inter- Although there is little evidence supporting the
vention and outcome focus on a single disorder. For approach to medication withdrawal, in general a step-
example, there is good evidence for the benefit of wise approach is recommended, with weaning of psycho-
polypharmacy from clinical trials in subjects with tropic and cardiovascular medications. Research by
diabetes mellitus. The use of antihyperlipidemic agents, geriatricians and clinical pharmacologists is needed to
antihypertensives, antiplatelet agents and ACE inhibitors develop more sophisticated evidence-based prescribing
have all been shown to have considerable mortality guidelines than simply counting drugs, to ascertain
benefits in these diabetic patients [88,89]. which medications at what doses improve relevant
functional outcomes, which are detrimental, and which
can be safely withdrawn.
MEDICATION WITHDRAWAL
There is evidence for the benefit of reducing exposure
MEDICATION MANAGEMENT IN
to some classes of medications in older people. In a
GERIATRIC PATIENTS
randomized placebo-controlled trial of withdrawal of
psychotropic medications in older subjects taking, on Continuity of prescribing
average, 5–6.5 medications each, it was found that there Obtaining an accurate medication history and reviewing
was a 76% reduction in falls over 44 weeks (odds ratio all of a patient’s medications is an essential component of
0.34, 95% CI 0.16–0.74) [90]. There have been at least geriatric assessment. Geriatric patients have multiple
four trials investigating the effect of withdrawal of comorbidities and thus may have their medications
antihypertensive medications in older people. Overall, prescribed by several doctors. These patients are also

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222 S. N. Hilmer et al.

frequent users of acute hospitals where medications may

AGE-RELATED CHANGES IN
be reviewed and altered. Medication histories obtained
PHARMACOKINETICS
from older people are often inaccurate and reconciliation
of the history from multiple sources is required [102]. Once a decision has been made to prescribe a medication
Trials of interventions to improve the transfer of medi- to an older person, a dosage regime needs to be construc-
cation information from the hospital to the community, ted. This is often based upon consideration of age-related
such as medication cards [103] or a pharmacist to co- changes in pharmacokinetics, although it must be
ordinate medication-management [104] have provided conceded that there are few clinical trials that have
some benefits but results remain disappointing. Pharma- addressed the effects of altering dose on safety and efficacy
cist-led home review of medications has also been outcomes. Furthermore, it has been argued that inter-
studied [98]. While the role of electronic data manage- individual variability in pharmacokinetics (from all cau-
ment is currently being investigated, at present the ses) may be far greater than age-related variability [114].
most useful and accurate record of patients’ medications There are many age-related changes in the processes
is the ‘plastic bag’ containing all of their medications of drug absorption from the gastrointestinal tract,
[102]. plasma protein binding and drug distribution; however,
the implications for drug dosage are minimal [2].
Adherence The hepatic metabolism of many drugs is reduced in
Typical adherence rates for prescribed medications are elderly patients [115]. The extent is variable between
about 50% [105] and do not vary significantly with age drug groups but usually represents a 30–50% reduction
[106]. Adherence to medications is difficult to measure, in clearance of drugs cleared by phase I hepatic
poorly recognized, and complex [107]. Barriers to metabolism [115,116]. This appears to be secondary to
compliance that are common in older people include age-related changes in hepatic blood flow, liver mass and
chronic conditions, polypharmacy, complex regimens, a the hepatic endothelium rather than ageing changes
higher prevalence of adverse drug reactions, unafford- in drug metabolizing enzymes or their expression
able drug costs, cognitive impairment, visual impair- [2,114,117,118]. Age-related reductions in hepatic
ment, manual dexterity problems and dysphagia clearance increase the bioavailability of drugs with a
[106,108]. Dysphagia often results in the need to crush significant first pass effect and reduce the clearance of
(or reformulate) solid oral doses, which is not appropri- hepatically metabolized drugs, probably increasing the
ate for all dose forms, especially modified release formu- risk of type A dose-related adverse drug reactions.
lations, and new formulations appropriate for older However, there will also be a decrease in the activation
people with swallowing disorders will need to be devel- of some pro-drugs, causing reduced or delayed efficacy in
oped [109–112]. Strategies to improve adherence, which elderly patients.
are often multi-factorial and complex, have generally Phase II metabolism via conjugation pathways ap-
only provided minimal benefit [113]. pears to be maintained in healthy older people but
reduced with frailty. Conjugation of paracetamol [119] is
Monitoring reduced in frail but not fit older people. Similarly,
The ageing process, especially frailty, diminishes esterase activity is reduced in frail but not fit older
homeostatic responses and the capacity to deal effect- people [120].
ively with any physiological perturbation, including Hepatic transporters have recently been recognized as
initiation of a new medication and changes in dose important determinants of drug disposition, for both
regimes [2]. Therefore, it is imperative that such uptake and biliary excretion. Variability in the expres-
subjects are closely monitored both for evidence of sion and/or function of these transporters has been
efficacy (the medication should be ceased if it is described with genetic polymorphisms and disease. There
ineffective) or adverse drug reactions. Adverse drug are no studies on the expression of transporters in aged
reactions present with a wide variety of symptoms and human livers, but there is evidence that hepatic expres-
are the ‘great imitators’ of medicine in the 21st sion of P-glycoprotein is increased in old rats, which, if
century. Medications need to be reviewed regularly in functional, should result in increased biliary excretion
response to rapid changes in clinical status including [121].
hospitalization, new diseases, mediation load and While most drug metabolism occurs in the liver,
transition into a palliative phase. enzymes in the wall of the gastrointestinal tract, such as

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Clinical pharmacology in the geriatric patient 223

CYP450 contribute to the pre-systemic metabolism of a with increasing age in the absence of pathology. Of
number of drugs. Age-related changes in the expression particular interest to pharmacologists are the age-related
of these enzymes in the gastrointestinal tract are not changes in calcium channels and beta-adrenergic recep-
well described. Data from animal studies provide some tors, with implications for the clinical use of their
evidence that CYP3A expression is maintained in the agonists and antagonists [1]. For example, the beta-
intestinal mucosa of old rats [122]. adrenergic response decreases with increasing age, and
It has been accepted that there is a marked age-related controlling for plasma concentration, the bradycardic
reduction in creatinine clearance in older people, even in response to labetolol is decreased in older people [129].
the presence of normal serum creatinine concentrations. Older people have been shown to be more sensitive to
The Cockcroft Gault equation [123] is often used to sedating effects of some medications due to changes in
estimate the creatinine clearance in older people in order both pharmacokinetics and pharmacodynamics, e.g.
to adjust the maintenance dose of renally excreted drugs they lose consciousness at a dose and lower plasma
that have narrow therapeutic indices, such as amino- concentration of propofol at the effector site than
glycosides, digoxin and lithium. However, the Cockcroft younger people [130] and have increased sensitivity to
Gault equation was derived from men being investigated sedation with benzodiazepines such as triazolam [131].
for renal disease. A review of recent studies of healthy Age-related changes in the autonomic nervous system
older people has shown that in the absence of renal predispose older people to postural hypotension [132],
disease, glomerular filtration rate is reasonably main- which may be further exacerbated by medications with
tained into old age [2]. Practitioners have recently anticholinergic effects and antihypertensives [133].
started to estimate renal function using the Modification
of Diet in Renal Disease equation, which also includes
APPLICATION OF PRINCIPLES OF
age, and shows a better correlation with accurately
GERIATRIC PHARMACOLOGY TO
measured glomerular filtration rate than creatinine
SPECIFIC PHARMACOTHERAPIES
clearance [124]. However, it has not been validated in
extremes of age or for adjusting doses of renally excreted Treatment of cardiac failure with beta blockers
drugs [125]. The few studies on the effects of healthy Appropriate treatment of cardiac failure in geriatric
ageing on lithium, gentamicin [126] and digoxin [127] patients highlights the hazards of extrapolating evidence
pharmacokinetics have not shown any dramatic reduc- from younger adults to geriatric patients. For example,
tion in renal clearance independent of changes in renal there is substantial clinical trial evidence for the use of
function. While many studies have identified an effect of beta-blockers in patients with cardiac failure receiving
age on the clearance of such drugs in patients [128], this an ACE inhibitor and a recent subgroup analysis of the
is likely to reflect the high prevalence of renal disease in clinical trials for metoprolol concluded ‘the time has
older people, as well as the high prevalence of polyphar- come to overcome the barriers that physicians perceive
macy and potential drug interactions affecting renal to beta-blocker treatment and to provide it to the large
excretion. number of elderly patients with heart failure’. However,
Rather than relying on generalizations about ageing in subjects over 75 years (n ¼ 490) the relative risk for
changes in liver and renal function to define dosage, primary outcome of hospitalization and all cause mor-
regulatory authorities now require pharmacokinetic tality was not statistically significant [0.79 (95% CI
data from older people. In many cases, such data include 0.55–1.14)] nor was total mortality [0.71 (95% CI
only relatively ‘young’ old people (e.g. older than 0.42–1.19)] [134]. Similarly in the SENIORS study it
65 years) so that data on the very elderly or frail patient, was concluded that nebivolol is ‘an effective and well
where altered kinetics are likely to have a major impact, tolerated treatment for heart failure in the elderly’ yet
are not available. 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–
AGE-RELATED CHANGES IN
1.12)] [135].
PHARMACODYNAMICS
There are many possible reasons for the lack of benefit
Age-related changes in effector system function result in of beta-blockers in older people with heart failure.
age-related changes in pharmacodynamics. End-organ Outcomes like hospitalization and mortality are less
response is affected by physiological changes that occur likely to be influenced by management of a single

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224 S. N. Hilmer et al.

disease, such as heart failure, in an older person with from paracetamol toxicity and cases associated with
more comorbidities than a younger person. Pharmaco- chronic paracetamol use occur more often in older
dynamically, with both increasing age and heart failure, patients [143]. The increased risk of paracetamol toxicity
there is decreasing responsiveness of beta receptors, with from chronic use in older people is partly explained by
different changes in the second messenger mechanisms the reduced hepatic clearance. The 30–40% reduction in
[136], and this could contribute to lack of effect of beta- liver weight in normal ageing must be accounted for
blockers in patients with both old age and heart failure. in dose calculations. Recognition of frailty is critical, as
With increasing age, diastolic failure accounts for a paracetamol conjugation per unit volume of liver is
higher proportion of the population with heart failure normal in healthy older people but reduced in the frail
[137] and even in younger people, the evidence for beta- [119]. Fasting may also enhance paracetamol hepato-
blockers in heart failure is predominantly in patients toxicity [144] and malnutrition is common in geriatric
with systolic failure. Interestingly, caloric restriction, patients, affecting up to 15% of community-dwelling
which delays the ageing process, has been shown to older people [145], 23–62% of hospitalized patients in
reduce the incidence diastolic heart failure [138]. This acute wards [146], 50% of older patients in subacute
suggests that management of cardiac failure in older wards [147] and up to 85% of nursing home residents
people may require interventions directed at the ageing [148]. Toxicology studies in rats do not show an increase
process, rather than blanket application of interventions in paracetamol hepatotoxicity with increasing age [149].
that have only been shown to be efficacious in young- The clinical increased risk of paracetamol hepatotoxicity
and middle-aged adults. in older people is likely to be related to dosing that does
not account for decreased liver volume with age, and to
Cancer chemotherapy frailty and malnutrition.
The incidence of most cancers increases with age and
prescription of chemotherapy in the geriatric patient Warfarin for stroke prevention in atrial fibrillation
requires consideration of the principles of both medical The use of warfarin in geriatric patients with atrial
ethics and geriatric pharmacology. There is limited fibrillation requires careful analysis of the potential
evidence from clinical trials to support the use of benefits and risks for the individual. On meta-analysis
chemotherapy in older subjects with cancer, particularly of clinical trials, the benefits of warfarin are well
those with comorbidities. Older people are more prone established [150]. Both atrial fibrillation and stroke
to toxicity from chemotherapeutic agents, due to increase with age, and the association between stroke
age-related changes in both pharmacokinetics and and atrial fibrillation is maintained in older people
pharmacodynamics [8,139]. A comprehensive geriatric [151]. Therefore, the benefits of warfarin for stroke pre-
assessment approach, including identification of the vention are potentially greater in older people with atrial
frailty syndrome, may assist oncologists in identification fibrillation. However, SPAF II [152], a randomized
of older patients who are likely to develop severe toxicity controlled trial to compare aspirin and warfarin for
and severe side effects in response to aggressive treat- atrial fibrillation specifically in patients over 75 years,
ment [8]. found the rate of all stroke (ischaemic or haemorrhagic)
with residual deficit was 4.3% per year with aspirin and
Paracetamol for chronic pain 4.6% per year with warfarin (RR 1.1). Furthermore, the
Chronic pain is common in older people and tends to be outcome of anticoagulation in older patients with atrial
musculoskeletal [140]. A study of adults aged 65 years fibrillation in terms of quality adjusted life years is either
and older living in retirement facilities in the USA with negligible or negative [153,154].
persistent pain found that 61% had used paracetamol Patients aged over 75 years who are prescribed
and management with paracetamol was rated more than warfarin for atrial fibrillation have a significantly greater
moderately helpful in 40% of cases [141]. Studies of pain risk of major haemorrhage than those less than 75 years
relief in older people must consider both age-related [152]. For those over 75 years, the annual rate of major
differences in pain perception and reporting, which are haemorrhage was 4.2% for patients in a randomized trial
not yet well defined [142], and meaningful outcomes for [152] and 10.0% for frail older people in an observa-
older people, such as mobility. tional study [155]. Some of the high risk of haemorrhage
Unintentional overdose with paracetamol is accounts with warfarin in geriatric patients may be related to
for approximately half of the cases of acute liver failure 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 225

[156]. Achieving therapeutic anticoagulation is chal- trials have failed to establish therapeutic benefits seen in
lenged in older people by compliance with dosing and younger adult subjects. Thus the decision to prescribe
monitoring requirements, particularly in those with medications to geriatric patients requires individual
cognitive impairment, increased risk of drug–drug inter- analysis of harm and benefit rather than broad applica-
actions with increased prevalence of polypharmacy, tion of prescribing guidelines. To do this the clinician
increased inter-individual variability, increased hospital- must have a thorough knowledge of the magnitude of
izations [157] and irregular food and alcohol intake. the reported risks and benefits of the medications.
However, major bleeds occur at lower international Much of geriatric medicine is concerned with the
normalized ratios with increasing age [158]. The recognition and management of adverse drug reactions
increased risk of haemorrhage in older people may be and frequently the major intervention is withdrawal of
related to vascular rigidity and endothelial dysfunction, medications rather than the prescription of new medi-
despite an increase in coagulation system proteins and cations. This practice may generate short-term gains in
platelet activation with increasing age [159]. Older terms of function but the long-term consequences of
people have a higher prevalence of gastrointestinal medication withdrawal have not been investigated
pathology, predisposing them to gastrointestinal bleed- extensively.
ing, and are at increased risk of falls, which can cause Age-related changes in pharmacokinetics and phar-
severe injury in the presence of anticoagulation, partic- macodynamics, polypharmacy and numerous comorbi-
ularly from intracerebral bleeds [160]. dities further contribute to the complexity of drug
Warfarin has also recently been associated with therapy.
osteoporotic fractures [161], which are a functionally Given that older people are the major recipients of drug
important adverse event in older people. therapy in the Western world, increased research and a
The decision on whether to prescribe warfarin for better evidence base is an imperative to guide clinicians
stroke prevention in an individual geriatric patient with who manage geriatric patients and frail older people.
atrial fibrillation depends on the complexity of the
individual. A multidisciplinary intervention to optimize
ACKNOWLEDGEMENTS
antithrombotic use in older patients with atrial fibrilla-
tion that captured patient complexity [162] found that This review was supported by grants from National
the intervention was associated with fewer patients Health and Medical Research Council of Australia,
receiving warfarin, after having been assessed inappro- Healthy Ageing Research Programme of the NHMRC,
priate candidates. Prescribing biases may be introduced Ageing and Alzheimer’s Research Foundation, Geoff and
by clinical experience. While a prescriber’s experience of Elaine Penney Ageing Research Unit.
an adverse bleeding event in a patient on warfarin for
atrial fibrillation will decrease subsequent prescribing of
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