Expert answer:hematologic, Women and men’s health, Pediatric
Solved by verified expert:discussion 1 is due by the time given, more time to be given for discussion 2 and 3Format 2 pages or more each, please as detailed as can be with references, no need for cover pageDiscussion 1 -Select one of the following hematologic disorders: anemia, hemophilia, cancer, sickle cell anemia, thalassemia, thrombolytic disorders, or white blood cell disorders. Consider the types of drugs that would be prescribed to patients to treat symptoms associated with this disorder.Select one of the following factors: genetics, gender, ethnicity, age, or behavior. Reflect on how this factor might impact the effects of prescribed drugs, as well as any measures you might take to help reduce negative side effects.With these thoughts in mind:Post a description of the hematologic disorder you selected including types of drugs that would be prescribed to patients to treat associated symptoms. Then, explain how the factor you selected might impact the effects of prescribed drugs, as well as any measures you might take to help reduce negative side effects.Discussion 2Consider the following scenario:As an advanced practice nurse at a community health clinic, you often treat female (and sometimes male patients) with hormone deficiencies. One of your patients requests that you prescribe supplemental hormones. This poses the questions: How will you determine what kind of treatment to suggest? What patient factors should you consider? Are supplemental hormones the best option for the patient, or would they benefit from alternative treatments?To prepare:Review Chapter 56 of the Arcangelo and Peterson text, as well as the Holloway and Makinen and Huhtaniemi articles in the Learning Resources.Review the provided scenario and reflect on whether or not you would support hormone replacement therapy.Locate and review additional articles about research on hormone replacement therapy for women and/or men. Consider the strengths and limitations of hormone replacement therapy.Based on your research of the strengths and limitations, again reflect on whether or not you would support hormone replacement therapy.Consider whether you would prescribe supplemental hormones or recommend alternative treatments to patients with hormone deficiencies.With these thoughts in mind:Post a description of the strengths and limitations of hormone replacement therapy. Based on these strengths and limitations, explain why you would or why you would not support hormone replacement therapy. Explain whether you would prescribe supplemental hormones or recommend alternative treatments to patients with hormone deficiencies and why.Discussion 3The unapproved use of approved drugs, also called off-label use, with children is quite common. This is because pediatric dosage guidelines are typically unavailable since very few drugs have been specifically researched and tested with children.When treating children, prescribers often adjust dosages approved for adults to accommodate a child’s weight. However, children are not just “smaller” adults. Adults and children process and respond to drugs differently in their absorption, distribution, metabolism, and excretion. Children even respond differently during stages from infancy to adolescence. This poses potential safety concerns when prescribing drugs to pediatric patients. As an advanced practice nurse, you have to be aware of safety implications of the off-label use of drugs with this patient group.To prepare:Review the Bazzano et al. and Mayhew articles in the Learning Resources. Reflect on situations in which children should be prescribed drugs for off-label use.Think about strategies to make the off-label use and dosage of drugs safer for children from infancy to adolescence. Consider specific off-label drugs that you think require extra care and attention when used in pediatrics.With these thoughts in mind:Post an explanation of circumstances under which children should be prescribed drugs for off-label use. Then, describe strategies to make the off-label use and dosage of drugs safer for children from infancy to adolescence. Include descriptions and names of off-label drugs that require extra care and attention when used in pediatrics.
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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:
shilmer@med.usyd.edu.au
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 antihypert …
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