Update Article

Drug Therapy in Elderly

S Sandhiya*, C Adithan**

Abstract
Population aging is considered as the most serious problem in developed countries and is going to be a threat for
developing countries. Aging is associated with various physiological changes and multiple diseases like diabetes,
hypertension, arthritis etc. which alter the pharmacological response to a drug. Moreover, elderly people are more
sensitive to frequently used drugs like NSAIDs, benzodiazepines, opioids etc. All these factors alter the drug response
resulting in adverse drug reactions (ADRs) and hospitalization, consuming 40% of health service expenditure in
developed countries. Hence it is mandatory for physicians to be aware of normal age related physiological and
pharmacological changes taking place in old people. This will help to avoid irrational prescribing, minimize ADRs
and maximize benefits of drugs in elderly patients. Above all educating the old patients and their care providers
regarding the importance and proper use of drugs to their well being is necessary to improve adherence. Hence
setting therapeutic guidelines for treating elderly patients will enhance their quality of life.

Introduction
L ife span of humans has increased in the recent years
due to social, economical and health care improvement.
Medical society has identified persons aged over 65 as
elderly while those above 75 as geriatric population. By 2050
the worldwide elderly population is expected to reach 1.4
billion which means that one out of ten people will be more
than 65 years of age. Currently population aging is most
serious in Europe and Japan. China is expected to have an
increase in the proportion of elderly people by next century.
The present elderly population in India is over 77 million,
constituting 7.7% of the total population and is expected
to rise to 100 million by 2013.1
Aging is associated with progressive decline in
physiological functions as well as multiple diseases like
diabetes, hypertension, arthritis and amnesia. These age
Fig. 1 : Factors causing ADR in elderly.
related changes associated with reduced income and
loneliness further worsen their health. 2,3 This results in the age related alterations in pharmacological response,
polypharmacy and increased incidence of adverse drug precautions to be taken to avoid ADRs and principles of
reactions (ADRs) as shown in Fig. 1. It has been found that prescribing drugs for elderly patients.
35% of ambulatory older patients experience an ADR of
which 29% require health care services. Thus 40% health Pharmacological changes in elderly
service expenditure is spent on elderly in developed Age related physiological and pathological changes play
countries.4,5 Hence it is mandatory for physicians to be aware a major role in altering the pharmacological actions of a
of normal age related physiological and pharmacological drug. The age related physiological alterations in various
changes taking place in old people. This will help to avoid organs and their consequences are shown in Table 1 and
irrational prescribing, minimize ADRs and maximize 2. Of these changes impaired hepatic and renal functions
benefits of drugs in elderly patients. This review deals with play a significant role in decreasing absorption, distribution,
metabolism and excretion of drugs. These pharmacokinetic
changes alter free drug concentration which is a major
*Senior Resident; **Director - Professor and Head; Department of
Pharmacology, JIPMER, Puducherry - 605 006, India.
determinant of a drugs potency and duration of action.
Apart from these changes, aging is also associated with
JAPI VOL. 56 JULY 2008 www.japi.org 525
 Table 1 : Age related physiological changes and their consequences on drug therapy in geriatric population.4
System Age related physiological changes Consequences
General Increased body fat Vd of lipid soluble drugs is increased requiring higher
Decreased total body water dose eg. diazepam.
Vd of water soluble drugs is decreased requiring low
dose eg. aminoglycosides, digoxin.
Gastrointestinal tract Decreased gastric acidity Absorption of basic drugs is enhanced eg. propranolol.
Decreased gastrointestinal motility Absorption of acidic drugs is decreased eg. barbiturates.
Decreased hepatic and splanchnic Decreased absorption of drugs.
blood flow Decreased metabolism of drugs. eg. lignocaine.
Renal Decreased renal blood flow, glomerular Renal clearance is decreased and hence drugs excreted
filtration rate and tubular secretion through kidney should be used cautiously eg.
aminoglycosides, digoxin, lithium.
Musculoskeletal Decreased muscle mass Resulting in functional impairment and fracture
Decreased bone density requiring treatment, hospitalization, etc.
Cardiovascular system Increased blood pressure Cardiovascular complications requiring treatment,
hospitalization, etc.
Central nervous system Brain atrophy Results in forgetfulness, depression, Parkinsons,
Decreased brain catecholamine synthesis insomnia etc. requiring therapy.
Decreased dopaminergic synthesis
Decreased sleep (stage 4)
Genitourinary Vaginal / urethral mucosal atrophy Bacteriuria, increased residual urine volume requiring
Prostate enlargement hormonal or drug therapy.
Endocrine Decreased BMR Resulting in Diabetes mellitus which needs life long
Vulnerable to stress treatment.
Glucose intolerance
Vd volume of distribution; BMR basal metabolic rate.

Table 2 : Age related pharmacokinetic changes in the elderly.4
Pharmacokinetic parameter Age related changes
Absorption Nil
Distribution of First generation antihistamines
Lipid soluble drugs Increased
Water soluble drugs Decreased
Acidic drugs Increased
Basic drugs Decreased
Metabolism sedative effect.
Phase I Decreased
Phase II Nil
Excretion Decreased
pharmacodynamic changes like altered organ response
to drugs. These changes are vital as they contribute to the
variations in drug response.4
Pharmacodynamic changes
The end organ response to a drug is increased in elderly
resulting in toxicity at normal therapeutic doses. The
enhanced sensitivity is seen with commonly used drugs
like NSAIDs, opioids, benzodiazepines, antipsychotics and
antiparkinsonian drugs.4 Some of the commonly used drugs
and their adverse effects in elderly patients are shown in
Table 3. Hence care should be taken to reduce the dose while
prescribing these drugs in elderly. Since, pharmacokinetic
changes are more important than pharmacodynamic
changes while deciding the treatment, this review gives
more details about these parameters.
Pharmacokinetic changes
Absorption
Table 3 : Commonly used drugs and their adverse effects in
elderly.4
Drugs Adverse effects
Promethazine, Strong anticholinergic and
Hydroxyzine sedative effect.
Low potent antipsychotics
Chlorpromazine Strong anticholinergic and
Prochlorperazine Extrapyramidal and orthostatic
adverse events.
Long acting benzodiazepines
Nitrazepam Long half life resulting in
prolonged sedation,
Flunitrazepam causing falls and fractures.
Analgesics
Pethidine Causes convulsions and renal
failure.
Propoxyphene
Combination of NSAID with
Warfarin Increases GI bleeding.
ACE inhibitor Renal failure.
SSRI Increases GI bleeding.
Diuretics Reduces the effect of diuretics.
ACE- angiotensin converting enzyme; SSRI selective serotonin
reuptake inhibitor
Oral absorption of drug is altered in elderly due to
fall in gastric pH, delayed gastric emptying, reduced
gastrointestinal (GI) blood flow and motility. The
consequences of these changes are shown in Table 1 and 2.
However, absorption of a drug does not change significantly
with age as other pharmacokinetic parameters.4
Distribution

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 Drug distribution in the body depends on body
composition, plasma protein binding and blood flow to
the organs. Aging is associated with reduced total body
water and increase in total body fat. This physiological
change results in decreased volume of distribution (Vd)
of water soluble drugs like digoxin (Table 2). Thus elderly
patients with congestive heart failure require lesser
loading and maintenance doses of digoxin. Volume of
distribution (Vd) of lipid soluble drugs like diazepam and
nitrazepam is increased and hence the dose needs to be
increased. However, lorazepam is an exception among the
benzodiazepines as it has small volume of distribution.4-7
One of the important determinants of Vd is relative binding
of drugs to plasma proteins like albumin and 1 acid
glycoprotein. With aging, the concentration of albumin
which binds to acidic drugs decreases. This is especially
important for drugs like phenytoin with high albumin
binding. In a patient with normal renal function, 92% of
phenytoin is bound to plasma protein and only 8% is in free
form. This free form increases to 16% in renal impairment
thus producing ADRs.8 However, 1 acid glycoprotein
which binds to basic drugs increases with aging and
binding of basic drugs like antidepressants, antipsychotics,
blockers, increase resulting in decreased free drug level
and reduced action. Hence, theoretically speaking the dose
of acidic drugs like phenytoin and barbiturates needs to
be decreased as the free form available for action is more
resulting in toxicity. Similarly the dose of basic drugs like
blockers should be increased as the free form of the drug
is less resulting in therapeutic failure (Table 2). Surprisingly,
clinically significant change with alteration in plasma
protein binding has not been reported so far.
Metabolism
Age related attenuation of liver functions due to reduced
hepatic mass and blood flow decreases drug metabolizing
capacity. This has been proved with a compound called
antipyrine, which is totally metabolized by hepatic
enzymes. In elderly people antipyrine shows prolonged
half life and decreased metabolic clearance, implying
reduced metabolizing capacity of liver.9,10 Altered drug
metabolism can also be attributed to other factors like
co-administration of drugs, associated illness, smoking,
genetic factors and environmental factors.11 Drugs undergo
two types of metabolism in the liver namely phase I which
includes reactions like oxidation, hydroxylation etc and
phase II mainly involving conjugation reactions. The main
purpose of these phases is to make the drug water soluble
and eliminate it from the body. Drugs like chlordiazepoxide
and diazepam which undergo oxidative metabolism (Phase
I) exhibit decreased clearance and increased half life in
elderly patients. While drugs like oxazepam, lorazepam and
temazepam which are eliminated by conjugation (Phase II)
reactions do not show alteration in clearance.12 This clearly
shows that only phase I metabolism is affected in the elderly
without significant change in phase II metabolism.
Excretion
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The most important age related change is reduced renal
clearance seen in about two thirds of elderly patients.13,14
Drugs that are mainly excreted via kidney have a prolonged
half life in patients with reduced renal function resulting
in drug toxicity at therapeutic doses. However, the decrease
in renal function as measured by creatinine clearance is not
associated with an equal rise in serum creatinine level. This
may be a consequence of declined muscle mass with age.
Hence a rough correction can be made by using Cockcroft
Gault formula13,15 which is applicable to patients between
40- 80 yrs of age.
Cockcroft Gault formula:
CLCr (ml/min) = (140 age in yrs) x weight in kg
72 x serum creatinine in mg/dl
This is a population estimate and hence may not be
applicable to a particular patient. In one third of the elderly
with normal renal functions, a dose correction based on
this formula will be too low. However, a low initial dose is
desirable if the physician is not sure of the patients renal
status. Moreover, dose reduction is mandatory only for drugs
or their active metabolites which are excreted primarily
through kidney. For example the usual maintenance dose
of digoxin in normal elderly patient is 125 g while in renal
failure it has to be reduced to 62.5 g.
Nomogram is another approach for evaluation of
endogenous creatinine clearance from age, body weight
and serum creatinine. This helps in determining the dose
and dosing interval of drugs like aminoglycosides and
vancomycin which are mainly excreted through kidney in
elderly with impaired renal function.16-18 In the schematic
nomogram shown in Fig. 2, the right hand ordinate indicates
the elimination clearance of drug measured in young adults
of normal renal function and left hand ordinate indicates
expected elimination clearance of drug in a functionally
anephric patient assuming that some of administered
dose is eliminated by non renal routes. The dotted line
connecting these points from the creatinine clearance in
abcissa can be used to estimate drug elimination clearance
in an individual patient.
Adverse drug reactions in the elderly
Drug related adverse effects have profound economic
consequences on elderly patients as well as on health
care system. Thirty percent of hospital admissions in
elderly people are drug related problems like depression,
constipation, falls, immobility, confusion and hip fracture.5,19
ADRs are considered the fourth leading cause of death in
United States next to heart disease, cancer and stroke.20
However, the incidence is underestimated as adverse drug
reactions mimic disease states and are less likely recognized
by physicians and elderly patients themselves.21
Adverse reactions occurring in the elderly may be a
result of intrinsic or extrinsic factors. Intrinsic factors are
mainly patient related and include age related physiological
changes, altered pharmacological parameters, impaired
organ functions, female sex, drug interactions, small body
size, severity of the disease, presence of multiple diseases
and polypharmacy. Extrinsic factors are physician related
and depends on prescribing pattern and medication
management.
Drug usage and frequency of ADR in the elderly
ADR in old people depends on the number of diseases
and the drugs used to treat them. More the number of
drugs prescribed higher the chance of drug interactions
and adverse drug reactions. Approximately 40 percent
of elderly people use at least five medications per week
and 12 percent use minimum ten medications per week.20
Positive relationship has been found between number of
drugs taken and the incidence of adverse reactions. Studies
have shown that 85-95 % of ambulatory elderly take at
least one medication with an average of three to four.22-
23
Drugs commonly associated with ADRs are sedatives,
antihypertensives, antiparkinsonian, antipsychotics,
Fig. 2 : Schematic diagram showing estimation of individual drug
clearance using a nomogram.
Endogenous creatinine clearance (CLCr) either calculated or measured
can be used to find out the individual patients drug clearance. This
information can be used to adjust dose and dosing interval.
NSAIDS, steroids and theophylline.24,25 Hence, a complete
drug history including over the counter medications is
mandatory prior to prescribing.
In the absence of precise clinical information, consensus
criteria can be used for safe prescribing in elderly patients.
One of the most widely used consensus criteria for drug
use in elderly patients was proposed by Beers et al in
1991.26,27 This criteria educates clinicians regarding the
drugs or classes of drugs to be avoided in elderly in
nursing home as shown in Table 4. These drugs were either
lacking in efficacy or pose high risk to patients while safer
alternatives are available. In 1997, the criteria were updated
and applied to all elderly patients.27 The Beers criteria for
ambulatory and nursing populations older than 65 years
had been revised and updated again in 2002.28 Some of
the drugs to be avoided in elderly people according to
Beers criteria are given in Table 4. Beers criteria should be
viewed as an important component of the clinical decision
making process to ensure best possible outcomes for
elderly patients.29 However, aging and drug therapy are
individualized process, hence patient specific parameters
must be given preference while prescribing.
Precautions to be taken in elderly people to avoid adverse
drug reactions:
1. Ensure that the symptom deserving medical treatment
is not an adverse effect of another drug.
2. Drug therapy should be considered only if non-
pharmacologic measure fails or if benefit outweighs
risk.

Table 4 : Some of the inappropriate drugs to be avoided in elderly according to Beers criteria26
Drugs Statement
1. Sedative - hypnotics
a. Long acting benzodiazepines eg. Chlordiazepoxide, diazepam, flurazepam All drugs should be avoided
b. Short acting benzodiazepines eg. oxazepam, triazolam, alprazolam Night use > 4 wks to be avoided
c. Short acting barbiturates eg. Pentobarbital, secobarbital All use should be avoided
2. Antidepressants : Amitriptyline All use should be avoided
3. Antipsychotics
Haloperidol Doses > 3 mg/d should be avoided;
patients with known psychotic disorders may
require higher doses
Thioridazine Doses > 30 mg/day should be avoided
4. Antihypertensives
Hydrochlorothiazide Doses > 50 mg/day should be avoided
Propranolol All use should be avoided except if used to
control violent behaviours
5. NSAIDs : Indomethacin, phenylbutazone All use should be avoided
6. Analgesics : Propoxyphene, Pentazocine All use should be avoided
7. Dementia treatment : Cyclandelate, Isoxsuprine All use should be avoided
8. Platelet inhibitors : Dipyridamole All use should be avoided
9. Histamine blockers : Ranitidine Doses > 300 mg/day and therapy beyond 12
wks should be avoided
10. Antibiotics : Oral antibiotics Therapy > 4 wks should be avoided except for
osteomyelitis, prostatitis, tuberculosis,
endocarditis
11. Decongestants : Oxymetazoline, phenylephrine, pseudoephedrine Daily use for > 2wks should be avoided
12. Iron Doses > 325 mg/day should be avoided
13. Muscle relaxants : Carisoprodol All use should be avoided
14. GI antispasmodics : Dicyclomine All use should be avoided
GI - gastrointestinal; NSAIDs Non steroidal anti inflammatory drugs

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3. Number of drugs and dosage form should be kept as
convenient as possible.
4. Potential drug interactions should be weighed before
including a new drug in the regimen.
Treatment options for some commonly seen
diseases
Insomnia
The prevalence of sleep disorders increases with age.
Older people tend to sleep earlier in the evening but also
wake up earlier. Some of them have fragmented sleep due
to repeated awakenings. This may be primary or secondary
to coexistent illness or medications. Pain due to arthritis
constitutes one of the most common causes of insomnia
in this population. Similarly nocturia due to diabetes or
prostatic disease is also a cause of sleep disturbances
and daytime fatigue. In these cases, treatment should
be targeted at the underlying disease to improve sleep
efficiency and unnecessary use of hypnotics should be
avoided. Moreover, simple measures like avoidance of
beverages in the night, voiding the bladder before going to
bed and shifting to a dark, quiet room may help the patient
in getting sleep.
However, if treatment for insomnia is needed, sedative
hypnotics like benzodiazepines can be used. Care should be
taken to avoid long acting drugs like diazepam, flurazepam
and chlordiazepoxide as they cause drowsiness, confusion,
slurred speech, unsteady gait, falls and day time sleep. These
effects seem to be less with short acting benzodiazepines
like triazolam and oxazepam which may be effective for
sleep onset problems.16,26 In patients with early-morning
awakening, an intermediate agent such as temazepam
may be more useful. Similarly non-benzodiazepine drugs
like zolpidem, zaleplon, zopiclone and eszopiclone which
have little disruption on normal sleep architecture can also
be used.30
Arthritis
NSAIDs like aspirin are frequently prescribed in elderly
for diseases like rheumatoid arthritis, osteoarthritis, etc. GI
bleeding associated with such treatment is more common
in elderly patients. Selective COX-2 inhibitors seemed
to be promising candidates for long-term treatment
of chronic diseases, like arthritis due to their reduced
incidence of gastrointestinal adverse effects. However,
some of these agents have been withdrawn due to their
side effects like myocardial infarction and stroke. Hence,
non pharmacological measures like weight reduction,
warmth, exercise, use of a walking stick, etc. should be
tried first for diseases like osteoarthritis, rheumatoid
arthritis, soft tissue lesions and back pain. In case of pain,
analgesics like paracetamol or ibuprofen can be used.
If pain relief is inadequate with either drug an opioid
analgesic can be added.16 According to the Working Group
on Pain Management, an international multidisciplinary
panel, paracetamol is considered as baseline drug for the
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treatment of moderate-to-severe musculoskeletal pain
and for greater analgesia addition of a weak opioid is
recommended.31,32
Edema
Mild oedema can be treated by non-pharmacological
measures like elevation of legs, supportive stockings and
active life style. If treatment with diuretics is needed it has to
be restricted for fewer days. Diuretics prescribed irrationally
for a longer duration may lead to postural hypotension
and falls.16
Other drugs
Drug induced bleeding is commonly seen in elderly
and hence drugs like co-trimoxazole should be avoided
unless there is no other alternative. Similarly the dose of
anticoagulant like warfarin needs to be decreased as it
causes serious bleeding in them.16 Moreover neuroprotective
agents used in elderly people for stroke have not shown any
beneficial effects in the long run. Hence by avoiding these
drugs adherence can be improved.
Adherence
Cognitive changes like forgetting to take pills at the
right time, economic stresses due to decreased income,
increased expenses due to illness, loss of spouse, physical
disabilities etc can reduce adherence in elderly people. This
can be improved by reducing the number and frequency
of drug administration as it is easy to remember. Dosage
schedule at night time is preferred for antipsychotic drugs to
reduce adverse reactions like drowsiness, sedation, postural
hypotension, etc. Similarly, diuretics are to be prescribed in
the morning time as they may disturb sleep given during
night time. Further drugs packed in readily openable
containers and labeled in large print are needed for elderly
patients with arthritis and poor vision. Big size tablets and
capsules should be avoided as elderly patients may have
difficulty in swallowing. Effervescent tablets and liquid
formulations like syrups are preferred in old people. If many
drugs are to be used together they should have distinct
colour and shape to avoid confusion to the patient.4
Above all educating the elderly patients regarding the
use and administration of drugs and the importance of
drugs to their well being is necessary to improve adherence.
It is also essential to discuss these things with a close
relative, friend, neighbour or any other care giver. Moreover
to be vigilant patients or their relatives should be asked to
bring the drug containers during follow up visits. If the drug
is found to be outdated or not needed in the future it can
be discarded after clearly explaining to the patient.4
Difficulties in setting therapeutic guidelines
for elderly patients
Since the elderly population is on the rise, understanding
age related physiological and pharmacological changes,
avoiding polypharmacy and regular review of all drug
treatment will help in rational prescription. Setting
objectives and guidelines may reduce unwanted adverse
reactions due to inappropriate or over prescribing in elderly
patients (Fig. 3). Some of the following points can be taken
into account to reduce ADRs.
a. Need for the treatment
Non pharmacological measures should be considered
as far as possible before starting treatment for diseases like
obesity, mild hypertension and atherosclerosis. They can be
controlled by altered life style, regular walking, reduced salt
intake, cessation of smoking and alcohol consumption.
b. Choosing the appropriate drug
If the patient needs treatment, most efficacious drug
with less ADR targeting the cause than symptom should
be selected. The associated illness like renal failure, hepatic
failure, cardiac failure, diabetes mellitus and hypertension
should be also be taken into consideration. Avoiding drugs
like blockers in hypertensive patients with history of
asthma or reducing dose of digoxin in elderly with renal
failure can prevent unwanted ADR induced diseases.
c. Formulation
Prescribing drugs in the form of syrups, suspensions and
effervescent tablets can improve adherence in elderly as
they find it easy to swallow. Similarly care should be taken
not to give drugs in child-resistant containers as patients
with debilitating diseases may find it difficult to open.
d. Maintaining record and periodic review
Maintaining a drug record will help to check adherence,
possible drug interactions, ADR and the economic burden
of the patient. Patients receiving long term therapy should
be reviewed carefully to assess the need for the drug.
Depending on the disease condition the drug can be either
stopped or changed.
Difficulties in setting guidelines
Older generation represent a high proportion of the
Fig. 3 : Principles of prescribing in elderly.4,16
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population receiving drugs like NSAIDs for rheumatoid
arthritis and osteoarthritis.33 Moreover, 80% of deaths due to
acute myocardial infarction occur in people above 65 yrs of
age.34,35 Hence drugs used for these conditions will provide
information regarding ADRs only if used in this population.
However, for safety concern this special population is
usually not involved in clinical trials. This limits the ability
to generalize study findings in the elderly population
which experiences multiple diseases.36,37 Of these, diseases
like diabetes mellitus and hypertension are chronic and
are not always effectively treated with drugs. Moreover,
physiological changes and the resulting pharmacokinetic
variations differ among elderly individuals. These factors
make therapeutic decision making or setting guidelines for
an individual elderly patient more complex.
Summary
Drug therapy in older patients varies from that of adults
due to altered physiological functions, associated illness,
age related disability, loneliness and stress. The success of
a drug therapy in elderly, depends on considering these
factors in addition to correct diagnosis, treatment plan,
prescription, patient education and dose adherence.
Care should be taken to avoid iatrogenic diseases in this
population by avoiding inappropriate prescribing. For
appropriate and rational prescription in elderly patients the
following factors should be taken into account
age related pharmacokinetic and pharmacodynamic
changes
socioeconomic, cultural and psychological factors
multiple diseases and altered presentation of illness
decreased vision, cognitive and hearing impairment
polypharmacy and increased susceptibility to ADRs
Above all adding quality life to years should be the major
concern of a physician than mere addition of years to life.
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