Practical Therapeutics

Drugs 16: 358-382 (1978)

AD IS Press 1978

Drug Use in the Elderly:

A Review of Problems and Special Considerations

Robert E. Vestal
Department of Medicine. University of Washington School of Medicine. Seattle, and
the Medical Service, Veterans Administration Hospital, Boise, Idaho

Summary With the recognition that the aged cons tillite an increasing proportion of our patient popula-
tion. attention is being directed toward understanding the epidemiology. pharmacology and
toxicology of drug use in the elder(l'. As a group. elderly patients have more iI/ness and inel'it-
ably take more medications tl1an younger patiellls. Although not unique to geriatric medicine.
medication errors and lack of comprehension Ilf treatment plans are prevalent. These factors
undoubted(v contribute to the increased incidence of adverse drug reactions in the elder(I.
It is possible that age difference.~ in pharmacokinetics may contribute importalllly 10 the ap-
parent increased 'sensitivity' of older persons to both the therapeutic and toxic effects of some
drrtgs. For most drugs studied. such pharmacokinetic d(fferences are generally consistellf with
age differences in body composition. protein binding. renal function and tissue pe~fusion. Aging
is associated with a dc'Crease in lean bod.!' mass and total body water. a decrease in serum
albumin cOllcentration. a decline in glomerrtlar and tubular function in the kidney. and
dimini.~hed cardiac Oil/put. lh'er blood flo ..... alld cerebral blood flow. Although some evidence
suggests that I1epalic metaboli.ml of drrtgs is impaired with aging. it is increasing(I' clear that
apparellf ~ffects of al?e on antipyrine metabolism may be more related to age differences in
other factors. SUell a.~ diet and smoking. than to age per se. For antipyrine. a model compound
for the study of hepatic microsomal drug metabolising enzyme acthity inman. biologicall'aria-
tion seem.~ to be much more imp0r/alll than any single nOli-genetic variable presenlly inl'eslil?-
ated. Thefew amilahle studie.~ slIggest litlle effect of age Oil drrtg absorptioll. hlll more infor-
matioll is lIeeded.
III addition to cOI/.~idering the epidemiology of drllg lise and the altered physiology in the
elderly. tlris rel'iell' attempts to provide an (/I'eniell' of what is known about the relationship I!f
advanced age and the pharmacokinetic,~ WId pharmacodynamics (!f represelltatil'e compollnds
from sel'eral grollps of drug~. A Ithollgh the response to isoprenaline (isoproterenol) and
propranolol is impaired in tire elder(l. most studies seem to bear out the long held clillical im-
pression that the elderly are generaN\' more sensitive to drugs than younger individuals.
Final(l'. sel'eral general principles (If drug use in a patielll I!f allY age are restated as
guidelines for geriatric pharmacotherapy. Wort/,y of special consideratioll are ways of promot-
ing compliallce with prescribed therapy.
 Drug Use in the Elderly 359

The increasing proportion of geriatric patients in 1. Epidemiological Aspects q{ Drug Use

most clinical practices has stimulated considerable in- in the Elder~l'
terest in the factors influencing drug treatment of the
elderly. The growing literature on the effects of aging I . I Demographic Considerations
on pharmacokinetics (the time course of absorption,
In developed countries, trends show that the pro-
distribution and elimination of drugs from the body)
portion of elderly in the population has been rising
has been the subject of several excellent reviews
steadily over the past several decades. This is due to a
(Triggs and Nation, 1975; Crooks et aI., 1976;
combination of falling birth rate and medical,
Richey and Bender, 1977).
economic and social factors which favour prolonged
Somewhat less investigative attention has been
life. About II % of the American population, more
devoted to clinical aspects of drug response (pharma-
than 23 million people, are now over 65 years of age.
codynamics) in the elderly (Bender, 1964; Holloway,
It is projected that by the year 2030 nearly 52 million
1974; O'MaIley et aI., 1976). Relatively limited data
people will be over age 65 and will constitute up to
are available which carefully quantify the influence of
I 7 % of the population. According to recent statistics
aging on drug 'sensitivity'. However, most clinicians
(Gibson et al.. 1977), in fiscal year 1976 the aged
have the impression that the aged are more sensitive
spent about 25 % of the national total of $US 11.2
to both the therapeutic and the toxic effects of many
billion for drugs and drug sundries. On the average,
drugs.
each elderly person spent over $100 that year for
The purpose of this review is to consider
prescribed and non-prescribed drugs. If current
epidemiological, physiological. pharmacokinetic and
trends continue we may expect that by the year 2030
pharmacodynamic aspects of drug use in the elderly
expenditures for drugs by the elderly in the United
and to suggest some general principles of geriatric
States may constitute over 40 % of the national total.
prescribing.
In the United Kingdom, where the elderly represent
As will become evident, although statistically valid
only 12 % of the population, they are responsible for
age differences or correlations with age can be
approximately 30 % of national health expenditure on
demonstrated, biological variation may preclude
drug prescriptions (O'Malley et aI., 1976). Some seg-
clinically useful generalisations regarding the effects
ments of health care delivery systems in developed
of age (Vestal et aI., 1975; Houghton et aI., 1975).
countries may bear a disproportionate burden of the
This is a problem for many clinical studies in
health care needs of the aged. Thus, in the United
geriatrics because the elderly in many ways are a
States, the Veterans Administration anticipates that
more heterogeneous group than the young and the
between 1970 and the turn of the century the propor-
distinction between physiological and chronological
tion of adult males aged 65 years or older who are
aging is very difficult to determine with precision. It
veterans will increase from 26 % to 59 %. In 1970,
should also be emphasised that all currently available
there were 2.2 million and by the year 2000 there
studies are cross sectional rather than longitudinal in
will be 7. I million aged veterans who are eligible for
design and can only provide information about age
care at V A Hospitals (National Academy of Sciences,
differences in pharmacokinetics rather than changes
1977). Such figures emphasise that the needs of
with aging (Rowe, 1977).
Nevertheless, a clinician who has some familiar- geriatric patients will constitute an increasingly im-
portant aspect of medical care for the future.
ity with the differences in physiology and pharma-
cology associated with aging will be better prepar-
1.2 Multiple Disease States in the Geriatric Patient
ed to rationally individualise treatment and critic-
ally evaluate the responses to drugs in his elderly Geriatric patients take more medications because
patients. they have more diseases than younger and middle
 Drug Use in the Elderly
aged patients. Multiple diseases are the rule rather
than the exception in the elderly patient. Superim-
posed upon old injuries, prior illness and past opera-
tions may be a variety of chronic disorders, such as
cataracts, pernicious anaemia, osteoarthritis, osteo-
porosis, atherosclerosis and diabetes. Malignancy,
stroke, Parkinson's disease, dementia and fracture of
the femur all have an increased incidence in the
elderly. In 200 consecutive cases admitted to the
Aberdeen Geriatric Unit in Scotland, 78 % of patients
had at least 4 major disease processes, 38 % had 6 or
greater and 13 % had 8 or more (Wilson et aI., 1962).
Complications of chronic illness in the elderly in-
clude thromboembolism, dehydration, urinary tract
infection, pressure sores, hypostatic pneumonia and
immobility contractu res. There were I 93 untoward
reactions caused by hospitalisation in 146 of 500 con-
secutive patients aged 65 or older in a study by
Reichel (J 965). Nearly 32 % were related to accidents
and trauma, such as falling from bed, and 28 % were
reactions to medications. Intercurrent disease pro-
cesses developing during hospitalisation numbered 44
cases of which pulmonary embolism and infarction
accounted for 36 % and aspiration pneumonia 34 %.
It should be noted that the elderly often manifest
an altered response to disease. Infection is often
associated with mild tachycardia and mental confu-
sion or other nonspecific symptoms. Fever, leu-
cocytosis, lymphadenopathy and lymphangitis may
be minimal or absent. The elderly seem to be less sen-
sitive to pain and more stoical. Pain may be more
readily forgotten because of the mental impairment
suffered by some elderly patients. Angina is often
atypical or poorly described and the painless myocar-
dial infarction is more common than the typical pre-
sentation in younger patients. Pathy (J 967) found
that chest pain was the major presenting sign of
myocardial infarction in only I 9 % of cases. A sud-
den change in intellectual function is the most com-
mon presenting symptom or sign of physical illness
in any geriatric unit and must not be attributed to
'senility'. Causes include congestive heart failure,
carcinomatosis, stroke, metabolic disorders and
medications.
360
1.3 Medication Compliance in the Elderly
It is well known that many patients have difficulty
taking medications as prescribed by their clinicians.
One review of over 50 studies found that complete
failure to take medication occurred in between 25 and
50 % of all outpatients (Blackwell, 1972). Geriatric
patients are an important subset of the outpatient
population and as such are also subject to errors in
self administration of medications. Based on careful
review of drug histories in 178 chronically ill, am-
bulatory patients aged 60 or older in the General
Medical Clinic at New York Hospital, Schwartz et al.
(J 962) found that 59 % made one or more medication
errors and 26 % made potentially serious errors. Er-
ror prone patients were more likely to make multiple
mistakes than single mistakes. The average number
of errors was 2.6 errors per error making patient.
The most frequent error was omission of medication,
followed by lack of knowledge about medications, use
of medications not prescribed by a clinician, and er-
rors of dosage, sequence or timing. Almost identical
data were obtained by similar techniques in a Seattle
area clinic (Neely and Patrick, 1968). In a study of
geriatric patients 10 days after hospitalisation, Parkin
et al. (J 976) found that 66 of 130 patients deviated
from the drug regimen prescribed at discharge. In
that study, noncomprehension or lack of a clear un-
derstanding of a regimen (in 46 patients) was actually
a greater problem than noncompliance or failure to
follow instructions (in 20 patients).
While medication errors are prevalent among
elderly patients, studies using objective measures of
compliance indicate that they are not necessarily more
prone to noncompliance than younger patients (Zaki
et aI., 1968; Porter, 1969; Weintraub et aI., 1973).
For example, Weintraub and his associates (J 973)
used serum digoxin concentration as an objective
measure of compliance in 101 outpatients. Patient
compliance was ascertained subjectively by asking
patients how often they missed taking digoxin. Based
on patient response, compliant patients had a mean
serum digoxin concentration of 1.2ng/ml and non-
compliant patients had a mean of 0.7ng/ml
 Drug Use in the Bderfy
(p < 0.00 I). However, that study showed no differ-
ence in either the percentage of compliant patients or
in the serum digoxin concentration at equivalent
doses between elderly patients aged 60 and over and
younger patients. Nevertheless, it seems reasonable to
attempt some type of intervention aimed at reducing
medication errors by geriatric patients, particularly
since this is a group who use medications extensively
and do seem to be at increased risk for adverse effects
from drugs (O'Malley et aI., 1976). In a relatively
small series, Malahy (1966) found no beneficial effect
from patient instruction and drug labelling, but a
larger study by Wandless and Davie (J 977) is more
encouraging and showed that patients given a tear off
calendar or a tablet identification card as memory
aids, made fewer errors as determined by tablet
counts than those given only standard instructions.
Other studies also suggest the use of a mechanical aid
to influence compliance, as for antituberculosis ther-
apy (Moulding et aI., 1967). Further effort should be
made to discover ways of improving compliance with
therapeutic regimens by geriatric patients.
1.4 Adverse Drug Reactions in the Elderly
The extensive use of drugs by geriatric patients
probably accounts at least in part for a higher inci-
dence of adverse drug reactions in the elderly than in
the young. Adverse drug reactions are most frequent
in patients taking many drugs and in patients with ab-
normal renal function, infections or previous drug
reactions (Smith et al., 1966). In a study of 714
hospitalised patients at the Johns Hopkins Hospital,
Seidl and his associates (1966) found that 24 % of
patients over the age of 80 had adverse drug reac-
tions, compared with 11.8 % in patients 41 to 50
years old. An even larger study in Belfast showed the
overall incidence of adverse drug reactions to be
10.2 % in 1160 consecutive patients, but 15.4 % in
patients over age 60 and 20.3 % over age 70 (Hur-
witz, 1969). Although these studies were conducted
in a hospital setting, adverse drug reactions leading to
hospital admissions have been documented in outpa-
361
tients as well. Of 236 consecutive patients admitted to
an Australian psychogeriatric unit, 37 (16 %) were
suffering the direct effect of psychotherapeutic
medications (Learoyd, 1972): 7 patients were ex-
cessively sedated or confused, 14 patients had dis-
inhibition reactions with restlessness, agitation,
paranoia and aggression, and 16 patients had psychic
disturbances associated with respiratory depression,
hypotensive syncope, urinary retention and gastroin-
testinal ileus. Many of the latter group had falls and 3
suffered fractures. All improved and were discharged
from the hospital when their medication was signifi-
cantly reduced or stopped. Investigators at the
University of Florida Hospital found that 3 % of
6063 consecutive admissions were necessitated by
drug induced illness (Caranasos et aI., 1974).41 % of
these 177 patients were over age 60. Adverse drug
reactions, medication errors. and inappropriate or ir-
rational therapy are also being recognised in-
creasingly by clinical pharmacists conducting studies
and working in extended care facilities (Cheung and
Kayne. 1975; Bergman. 1975).
2. Physiological and Environmental Aspects of
Geriatric Pharmacology
Important and sometimes subtle physiological and
psychological changes occur with 'normal' aging. in-
dependent of the more overt diseases which are pre-
valent in the elderly. These changes might reasonably
be expected to alter drug responsiveness as a result of
changes in disposition and particularly elimination of
drugs and/ or changes in organ or receptor sensitivity
(table O. It is generally acknowledged that older
patients are more susceptible to both the therapeutic
and toxic effects of many drugs (e.g. O'Malley et aI.,
1976). At the present time. only a few drugs have
been carefully studied in the elderly and except for
drugs predominantly excreted by the kidney it is not
yet possible to generalise on the type or magnitude of
changes. While most pharmacokinetic studies in the
elderly have been conducted after single dose ad-
ministration. for many drugs more clinically useful
 Drug Use in the Elderly 362

Table I. Summary of factors affecting drug disposition and Nation, 1975; Crooks et aI., 1976; Richey and
response in the elderly Bender, 1977). However, apparent age differences in
drug metabolism are probably multifactorial (Vestal
Effect Altered physiology Clinical
importance et al., 1975).

Absorp- Elevated gastric pH Not sufficiently

tion Reduced GI blood flow studied
? Reduced number 2.1 Drug Absorption
of absorbing cells
? Reduced GI motility A number of physiological alterations associated
Distri- Body composition with older age might be expected to affect drug ab-
bution Reduced total Higher concentration
sorption from the gastrointestinal tract (Bender,
body water of drugs distributed
Reduced lean body in body fluids 1968). For example, elevated gastric pH could alter
mass/kg body weight ? Longer duration of the ionisation and solubility of some drugs and the
Increased body fat action of fat soluble
reduction in intestinal blood flow might be expected
drugs
Protein binding to lessen the rate and extent of drug absorption. A
Reduced serum Higher free fraction of reduction in the number of absorbing cells, a delay in
albumin highly protein bound
gastric emptying and decreased gastrointestinal
drugs
motility are other possible age differences which
Elimin- Hepatic metabolism
ation ? Reduced enzyme Apparently slower
might affect absorption of some drugs. Available evi-
activity biotransformation dence suggests an effect of increasing age on active
Reduced hepatic mass of some drugs transport systems in the gastrointestinal tract.
Reduced hepatic Influenced by envir-
blood flow onmental factors (e.g.
Reduced absorption of iron, thiamine, calcium and
nutrition and smoking) galactose have been demonstrated. Most drugs are ab-
Renal excretion sorbed by passive diffusion and would not be influ-
Reduced glomerular Slower excretion of enced by such changes. Although higher plasma
filtration rate some drugs levels in elderly than in younger patients have been
Reduced renal
plasma flow found after oral administration of several drugs, these
Altered tubular differences can be explained by a decreased elimina-
function
tion rate or an alteration in drug distribution in the
Re- Multiple disease states More variation in dose elderly rather than a difference in drug absorption
sponse Multiple drug use response
(Crooks et al., 1976). The available data are limited
common Adverse drug
Altered receptor sen- reactions common and additional studies are necessary before firm con-
sitivity clusions can be made.
Organ specific age
differences

2.2 Drug Distribution

As a group, elderly patients tend to be somewhat

information will be obtained from studies carried out
under continuous multiple dose conditions. Some
pharmacokinetic age differences have been docu-
mented and tend to be consistent with age related
changes in body composition, protein binding, hepatic
drug metabolism, and renal excretion (Triggs and
smaller than younger patients. Standard drug doses
might be expected to result in higher blood and tissue
levels. Body composition is an important determinant
of drug distribution and differs with age. Total body
water, both in absolute terms (Shock et aI., 1963) and
as a percentage of body weight (Edelman and Leib-
 Drug Use in the Elderly
man, 19 59: Vestal et aI., 1975), have been shown to
be reduced by 10 to 15 % between ages 20 and 80. It
should be noted, however, that body composition
data may be dependent upon the population under in-
vestigation and studies by the same group of in-
vestigators in 2 different populations gave differing
results (Shock et aI., 1963; Norris et aI., 1963). Lean
body mass in proportion to body weight also is
diminished with age (Forbes and Reina, 1970;
Novak, 1972). This seems to be due to a relative in-
crease in body fat with age. Comparing the age
groups 18 to 25 and 65 to 85 years, Novak (\ 972)
found that body fat increased from 18 to 36 % of
body weight in men and from 33 to 45 % in women.
In the very elderly, even fat tends to be reduced
(Norris et aI., 1963).
The effect of these changes in total body water and
body fat is a reduction in the proportion of actual lean
body mass per unit of total body weight. Longitudinal
data in a small group of subjects support this
generalisation (Forbes and Reina, 1970). Thus, one
might predict that drugs that are distributed mainly in
body water or lean body mass might have higher
blood levels in the elderly, particularly if the dose is
based on total body weight or surface area. This is
true for ethanol which distributes in body water
(Vestal et al., 1977). Higher peak ethanol levels were
observed in older subjects without a difference in
rates of metabolism. Although confirmatory studies
are not available, alterations in body fat may result in
accumulation and prolongation of action of highly
lipid soluble drugs.
Since free drug concentration is an important
determinant of drug distribution and elimination,
alterations in the binding of drugs to plasma proteins,
red blood cells and other body tissues may be impor-
tant causes of altered pharmacokinetics' in aged
patients. Serum albumin is reduced in old age (W ood-
ford- Williams et aI., 1964; Cammarata et aI., 1967).
One study compared serum protein concentrations in
50 young normal adults (average age 27 years) with
90 elderly subjects ranging in age from 65 to 103
years. There was essentially no difference in total
serum protein. However, young subjects had a mean
363
albumin concentration of 4.7g/dl as compared with
3.8g/ dl in the elderly subjects. This 19 % reduction
was accompanied by an increase in the globulin frac-
tion (Cammarata et aI., 1967). Data suggests that
disease and immobility may be more important than
age per se (Woodford-Williams et at., 1964). A dis-
turbance of the normal metabolic response to
the stimulus of a reduced albumin pool seems to be
present in some elderly individuals (Misera et al.,
1975).
Many drugs are bound to albumin in the plasma.
The albumin concentration, the number of available
binding sites and the binding affinity, or tightness of
binding, will be important determinants of the free or
unbound plasma drug concentration. The less
albumin available for drug binding, the more free
drug that is available for diffusion into body tissues
where sites of action may be located, or in the case of
the liver and kidney, where drug elimination can take
place. For many of the drugs studied there are no ap-
parent age differences in albumin binding (Crooks et
aI., 1976; Richey and Bender, 1977). The 2 available
studies of warfarin binding give conflicting results
(Hayes et al., 1975a; Shepherd et aI., 1977). How-
ever, for pethidine/meperidine (Mather et aI., 1975),
phenytoin (Hayes et aI., I 975b), phenylbutazone
(Wallace et al., 1976), carbenoxolone (Hayes and
Langman, 1975) and tolbutamide (Miller et aI.,
1978), plasma albumin binding has been shown to
decrease as a function of age. Because of reduced
albumin levels in some elderly patients, they may be
more susceptible to the effects of multiple drug ther-
apy on drug binding (Wallace et aI., 1976).
The binding of drugs by red cells has also been in-
vestigated. Chan et al. (1975) demonstrated that red
cell binding of pethidine in young patients was greater
than that in elderly patients. However, interpretation
of these results is clouded by technical considerations
(Wilkinson and Schenker, 1976), and except for
chlormethiazole (Nation et aI., I 977b) thus far age
related differences in the proportion of erythrocyte
bound drug have not been shown for other drugs.
However, only a small number of drugs have been
studied.
 Drug Use in the Elderly
2.3 Drug Elimination
Removal of drugs from the body occurs prin-
cipally by two routes: (I) liver metabolism to less ac-
tive or inactive metabolites which are usually excreted
by the kidney, and (2) excretion of unchanged drug by
the kidney. Both of these processes may be altered in
the elderly.
2.3.1 Hepatic Metabolism
Studies in experimental animals have shown
reduced activity of liver microsomal drug metabolis-
ing enzymes (Kato and Takanaka, 1968), and altera-
tions in liver microsomal enzyme induction (Adel-
man, 1971). There are no similar direct studies of the
effects of age on liver drug metabolising enzyme ac-
tivity in man. From autopsy studies it is known that
liver mass bears a relatively constant relationship to
body weight (2.5 %) until middle age, when it
becomes relatively and progressively smaller with age
(1.6 % of body weight by the tenth decade of life)
[Geokas and Haverback, 1969]. Regional blood flow
to the liver also decreases with advancing age. Esti-
mates of the decline in liver blood flow range from
0.3 to 1.5 % per year based on indirect measurements
(Geokas and Haverback, 1969). Thus, in a person
aged 65 the hepatic blood flow is reduced by 40 to
45 % compared with a person aged 25. This decline
in liver blood flow is partially the result of the decline
in cardiac output which occurs with aging (Bender,
1965). For drugs with high hepatic extraction ratios,
such as lignocaine (lidocaine) and propranolol whose
metabolism is highly dependent upon liver blood
flow, one might predict an effect of age on hepatic
drug clearance (Nies et aI., 1976).
Some evidence suggests that in man the aging pro-
cess may result in alteration of the intrinsic metabolic
capacity of the liver for some drugs. Several studies
with antipyrine, for example, have consistently
Fig. 1. Decline in metabolic clearance of antipyrine with age in 307 healthy males (top panel). Multiple regression analysis of
several factors which might influence antipyrine metabolism demonstrated significant effects of cigarette smoking and age. but
85 % of the variance in clearance was unexplained (bottom panel) [after Vestal et al.: Clinical Pharmacology and Therapeutics 18:
425-432. 1975; by permission of author and editod
364
reported a prolonged half-life and reduced metabolic
clearance in older subjects (O'Malley et al., 1971; lid-
dell et al., 1975; Vestal et aI., 1975). Antipyrine is a
useful model compound because it is only minimally
protein bound and is extensively metabolised by the
liver prior to excretion. Preliminary data also sug-
gests that reduced antipyrine metabolism correlates
with a reduction in liver volume in elderly subjects
(Rasmussen et aI., 1976). The largest available study
of antipyrine metabolism, however, showed that in-
terindividual variation (6-fold) exceeded the effect of
age and only 3 % of the variance in metabolic
clearance could be expiained by age alone (fig. I;
Vestal et aI., 1975). Most of this wide interindividual
variation in drug metabolism is undoubtedly due to a
variety of genetic and environmental factors. Thus,
age itself probably has only a minor influence on rates
of metabolism of antipyrine in adult man.
Other drugs have been less extensively studied but
in many cases alterations in plasma clearance and
elimination half-life can be explained by other phar-
macokinetic considerations such as age differences in
volumes of distribution and protein binding (Crooks
et aI., 1976). A recent study comparing the effects of
age on the oxidation of acetanilide and the acetylation
of isoniazid found a significant prolongation of the
plasma half-life of acetanilide in the elderly subjects
but no age difference in the half-life of isoniazid
(Farah et aI., 1977). Whatever the mechanisms of the
effect of aging on hepatic drug metabolism, this study
emphasises that non-microsomal enzyme pathways
of biotransformation may be unaffected. This seems
to be true for the oxidation of ethanol by alcohol
dehydrogenase, an enzyme present in the soluble frac-
tion of liver cell homogenates (Vestal et al., 1977).
2.3.2 Renal Excretion
Studies of the effect of aging on renal physiology
indicate that both glomerular and tubular functions
Drug Use in the Eklerlv 365

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10 20 30 40 50 60 70 80 90 100
Age (years)
 Drug Use in the Elderly
are affected. Glomerular filtration rate (GFR), as
measured by insulin or creatinine clearance (fig. 2),
may faU as much as 50 % with an average decline of
about 35 % between ages 20 and 90 (Rowe et al..
I 976a), Renal plasma flow declines approximately
1.9% peryear(Bender, 1965). Bothurineconcentrat-
ing ability during water deprivation (Rowe et aI.,
1976b) and renal sodium conservation (Epstein and
Hollenberg, 1976) decline with age. Data also suggest
a heightened sensitivity to hyperosmolality in the
elderly (Helderman et aI., 1978). Although in young
persons, GFR must fall to about 30ml per minute
before elevations in serum creatinine and blood urea
values are detected. In the older patient with reduced
lean body mass, the production of creatinine is also
reduced and GFR must fall to an even greater extent
before serum levels of creatinine rise above the nor-
mal range. Thus, unlike intrinsic hepatic drug meta-
bolism for which the effects of old age are less certain
and probably less important than the wide interin-
dividual variation, diminished renal function is com-
mon and easily measured in the elderly.
The extent of impairment may vary from in-
dividual to individual but a simple clinical test of
renal function, such as the creatinine clearance, can be
used along with plasma level determinations in ad-
justing doses and dosage schedUles of drugs which are
primarily excreted by the kidney. Drugs so excreted
by the kidney which show age related changes in the
rate of elimination include penicillin, dihydrostrep-
tomycin, tetracycline, kanamycin, digoxin, practolol,
sulphamethizole and phenobarbitone (Crooks et aI.,
1976; Richey and Bender, 1977).
2.3.3 Nutritional and Environmental Factors
There is ample evidence in the literature to support
the importance of dietary composition as an environ-
mental determinant of drug metabolism and drug
toxicity (Campbell and Hayes, 1974). However. most
studies have been conducted in experimental animals.
In man a low carbohydrate-high protein diet was
associated with a shortened half-life for antipyrine
and theophylline compared with a high carbohydrate-
low protein diet (Kappas et aI., 1976). A number of
366
factors may lead to nutritional deficiencies in the
elderly. These include a general decline in bodily
health, difficulty in obtaining and preparing food, the
restricted economic circumstances resulting from
retirement, loneliness and social isolation, depression
following loss of spouse and friends, and ignorance
about good nutrition. Several studies, particularly in
the United Kingdom, have documented protein and
vitamin deficiencies in house bound elderly as com-
pared with more active people of equivalent age.
Although overt protein malnutrition is relatively un-
common, signs of vitamin deficiency must be
carefully sought. Nutritional factors such as these
may contribute substantially to age differences in
drug metabolism (Smithard and Langman, 1977).
Cigarette smoking appears to have an important
influence on drug metabolism (Vestal et al.. 1975;
Hart et aI., 1976). For antipyrine, the association of
cigarette smoking and enhanced antipyrine metabol-
ism appeared to be limited to young and middle aged
subjects (Vestal et aI., 1975). Preliminary data from a
smaller study have confirmed this observation and
show little or no effect of smoking on the metabolism
of propranolol in elderly as compared with young
subjects (Wood et aI., 1978). Stevenson and his
associates (J 977) showed a significant increase in
plasma clearance of antipyrine and quinine in young
subjects following dichloralphenazone treatment, but
no significant alteration in the elderly group. Taken
together. the data for cigarette smoking and the data
following dichloralphenazone treatment suggest that
elderly patients show a reduced enzyme induction re-
sponse. Additional studies are needed to confirm
these observations and elucidate the mechanism.
3. Alterations in Drug Disposition and Drug
Response in the Elderly
The effects of age on pharmacokinetics are of in-
terest primarily because they may provide insight into
the mechanisms of altered drug response in the
elderly. This area of research in geriatric clinical phar-
macology has received relatively less attention than
pharmacokinetics, but increasingly attempts are being
 Drug Use in the Elderly 367

2001-

1801-
.....
"E
....
M
160~

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. '~" ..:...
'" .....
.' ". \.....
-\./.: ~::.~~. ":'~'"
'.'.~.\"':.' t:..
~. '.:t. .. " .
J. :'. '., "
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E . ~ . \' " .. lit .. V;.~.f . ;;: .
:~:. \.:. t...::
: .~.'" .~. ft:"', \~~ " .
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.5 ....... .
<:.' ':'.~ :.:.....~:. :: ...... ,:- {."'. ;~
to.

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u ., t
f :

.
~
m 801- ,
u
~
'.
'E 601-
.~

l3 40
2u 30 4U 50 60 70 80 90
Age (years)

Fig, 2, Cross sectional analysis of true creatinine clearance in 548 normal subjects (r = - 0.54, slope = - 0.80 and intercept at
age zero = 165.6). These values are equivalent to values by the automated total chromogen method when multiplied by 0.80
(after Rowe et al.: Journal of Gerontology 31: 155-163, 1976a; by permission of author and editor).

made to examine drug response in the elderly as well
as drug disposition.
3.1 Cardiovascular and Respiratory Drugs
3.1.1 Cardiac Glycnsides
A major cause of adverse drug reactions in most
studies is digitalis intoxication. Elderly patients are
frequently affiicted by cardiovascular disease requir-
ing the use of digitalis preparations often in combina-
tion with diuretics. There is no good evidence, how-
ever, that the elderly are inherently more sensitive to
the therapeutic and toxic effect of digitalis. Cham-
berlain et al. (1970) measured plasma digoxin con-
centrations in I 16 patients with atrial fibrillation on
long term oral treatment. The mean plasma con-
centrations in both the young group (aged 32 to 59)
and the old group (aged 60 to 84) were identical
(1.5ng/mO. All patients had well controlled ventricu-
lar rates between 60 and 80 beats per minute with
slightly greater variance in the elderly, The plasma
levels in the older age group were attained with a
mean dose ofO,32mg per day compared with 0.42mg
per day in the younger group, but this was explained
by the reduced renal function in the aged patients.
The half-life of digoxin has been shown to increase
as much as 40 % in the elderly with a decline in
creatinine clearance (Ewy et aI., 1969). In the small
elderly patient with reduced lean body mass and im-
paired renal function both the loading dose and main-
tenance dose should be reduced empirically. How-
ever, plasma digoxin levels correlate with symptoms
of toxicity and should be used to achieve optimum
maintenance dosage. The clinician should be alert to
symptoms suggesting digitalis intoxication such as
fatigue, anorexia, visual complaints, nausea and psy-
chic disturbances such as bad dreams, restlessness,
nervousness, agitation, listlessness, drowsiness, faint-
ing and pseudohallucinations, as well as more overt
signs of toxicity such as rhythm disturbances (Lely
and van Enter, 1972). It should be remembered that
not all patients taking digitalis need maintenance
 Drug Use in the Elderly 368

therapy. One study showed that almost 75 % of
elderly patients in sinus -rhythm on maintenance
digoxin therapy could be safely withdrawn from
treatment (Dan, 1970). A recent report on the use of
digoxin in a group of elderly patients revealed that
only about one-third were receiving an ideal dose and
withdrawal of the drug or revision of dosage where
appropriate resulted in clinical benefit (Whiting et al.,
1978).
3. /.2 Diuretics
It is generally recognised that the elderly are more
susceptible to the complications of diuretic therapy.
The main complications include hypokalaemia with
associated digitalis toxicity, impaired glucose
tolerance, hyperuricaemia and occasionally symp-
tomatic gout, hypovolaemia with hypotension,
dehydration with pre-renal azotaemia, acid-base im-
balance, hyponatraemia, and both urinary inconti-
nence and urinary retention. Thus, diuretics are also a
common cause of adverse drug reactions. In I study.
6 % of adverse reactions were related to diuretics
(Caranasos et aI., 1974) and in a study of three ex-
tended care facilities, diuretics were involved in over
20% of adverse drug reactions (Cheung and Kayne.
1975). At present. there are no pharmacokinetic or
pharmacodynamic studies to explain an enhanced
clinical response. Reduced dietary potassium (Dall et
al.. 1971) and a propensity to orthostatic changes in
blood pressure (Caird et al., 1973). may predispose
the elderly to the side effects of diuretics. Additional
studies are needed in the area of the effects of age on
the clinical pharmacology of diuretics.
3. /.3 ~-A drenoceptor Blockers and
Antiarrhythmic Drugs
Evidence is accumulating that there may be funda-
mental age differences in the pharmacology of the
autonomic nervous system. Although there is con-
flicting evidence (de Champlain and Cousineau.
1977). some recent studies indicate that plasma
noradrenaline (norepinephrine) levels correlate
positively with age (Lake et aI., 1977; Sever et al ..
1977). In addition, the number of ~-adrenoceptors

900

I
'"

"': ..~.
.~

700
E'
_

I
a.
0>

E

:g ~
:l-
500
0..2
.00
>'"
mo.

-Q)

~~
u
300


~
Q)'C
a.>

"'.!:
-'0
o I
E:r: 100
.... "
20 40 60 80 100
Age (years)

Fig. 3. Correlation of ~-adrenoceptor concentrations with age (r = - 0.64, p < 0.(01) estimated from maximum specific
binding of (-)3H-dihydroalprenolol to crude mononuclear cell membranes of subjects aged 24 to 81 years (after Schocken and
Roth: Nature 267: 856-858, 1977; by permission of author and editor).
 Drug Use in the Elderly 369

(fig. 3) in membrane fractions of lymphocytes correl-
ates negatively with age, without apparent alteration
in receptor affinity (Schocken and Roth, 1977). Resis-
tance to the chronotropic response of the heart to
isoprenaline (isoproterenol) has also been shown to
correlate positively with age (fig. 4) [London et al..
1976; Vestal et aI., 1978].
Conway et al. (t 97 t) showed that propranolol
reduces the heart rate and cardiac output during exer-
cise. but to a lesser extent in older subjects aged 50 to
65 years than in younger subjects aged 20 to 35. It
was concluded that the sympathetic drive to the heart
elicited by the stimulus of exercise declines with age.
There is recent evidence, however, that the sensitivity
to propranolol itself in elderly subjects is reduced.
Utilising dose response curves to isoprenaline before
and after a continuous infusion of propranolol. it is
40
0
2O~
10
00
0
0
o 00
5-1
0
possible to obtain an estimate of the apparent affinity
constant of propranolol binding to the ~-adrenocep
tor. This apparent affinity constant is a measure of
sensitivity to propranolol (McDevitt et aI., 1976) and
correlated inversely with age (Vestal et aI., 1978).
These clinical findings are in contrast to the il1 I'ifro
receptor studies which suggest a difference in receptor
number rather than affinity. Further studies are
needed to confirm these observations and to explore
the reasons for this apparent discrepancy.
Pharmacokinetic age related differences have also
been reported for ~-blocking agents. Thus, Castleden
et al. (1975) found a 4-fold increase in plasma
propranolol levels after a single 40mg oral dose in a
group of elderly as compared with a group of young
subjects. It was proposed that the higher plasma
levels in the elderly were the result of reduced hepatic
extraction and metabolism, in particular a reduced
hepatic first-pass effect. A subsequent study has
shown the presence of age related pharmacokinetic
differences during continuous repeat dose conditions,
but they were of lesser magnitude and appeared to be
explainable on the basis of a reduced effect of cigarette
smoking in the aged subjects (Wood et al.. 1978).
Practolol also appears to be eliminated more slowly in
the elderly, probably a consequence of the diminished
renal function (Castleden et aI., 1975). It is possible
that these pharmacokinetic age related differences for
propranolol may contribute to the higher incidence of

0 o propranolol toxicity (such as bradycardia, pulmonary

3

2
0
oedema and hypotension) in patients 60 years or older
.: 0\
~
o 00 (Greenblatt and Koch-W eser, 1973), but it is more
e.
0 likely that the elderly are predisposed to toxicity
~
'0 .'. 0

r = 0.42 because of more extensive cardiovascular disease,
~ P < 0.001 diminished renal function with azotaemia, and use of
<5 0.5

multiple cardiovascular drug therapy.
r I I I I I
10 20 30 40 50 60 Toxicity to lignocaine has also been reported to be
Age (years) twice as common among elderly patients (4 % less
than age 50 and 8 % age 70 or older) [Pfeifer et aI.,
1976]. Again this probably reflects the tendency of
Fig. 4. Correlation between age and the dose of adverse drug reactions to occur more commonly in
isoprenaline (isoproterenol) which increased the resting heart
patients with more serious underlying disease. includ-
rate by 25 beats per minute in 80 normal and hypertensive
patients (after London et al.: Journal of Qinical Pharmacology ing congestive heart failure. The pharmacokinetics of
16: 174-182, 1976; by permission of author and editor). lignocaine have been examined in healthy young and
 Drug Use in the Elderly 370

aged subjects (Nation et al., I 977a). The elderly sub-
jects were found to have significantly longer elimina-
tion half-lives compared with younger individuals,
but without a change in plasma clearance. However,
the drug appeared to distribute differently in the aged
as reflected by significantly increased apparent
volumes of distribution in the elderly. This means
that at equivalent doses, steady state plasma levels
should not be higher in elderly than in young patients
in the absence of congestive heart failure or liver
disease, which because of a decrease in hepatic blood
flow, have been shown to impair hepatic clearance of
this drug (Thomson et al.. 1973).
Total plasma clearance of quinidine. has recently
been reported to be significantly less in elderly sub-
jects than in young individuals, due in part at least to
reduced renal clearance (Ochs et al.. 1977). There are
no studies specifically investigating antiarrhythmic
efficacy as a function of age in man.
tention to orthostatic hypotension as well as diuretic
induced hypokalaemia.
3.1.5 AllliclJOKulal1/s
Elderly individuals are more sensitive to the
effects of both heparin (]jck et al., 1968) and warfarin
(fig. 5) [O'Malley et al.. 1977]. No information is
available regarding the disposition of heparin in older
patients. The increased risk of haemorrhagic com-
plications may in part be due to diminished mechani-
cal haemostatic response in the presence of degenera-
tive vascular disease. With warfarin, at concentra-
tions much above therapeutic plasma levels. a
decrease in the binding capacity of elderly people for
warfarin was demonstrated. which correlated with a
fall in plasma albumin concentration <Hayes et aJ..
1975a). At therapeutic concentrations no effect of age

3.1.4 AIUih,1'per/ensil'(! AKell/s

0,6
Postural hypotension is common in the elderly, g
largely because of an impaired baroreceptor response ~ 5
o
(Gribbon et aI., 1971) and a reduction in peripheral '0

venous tone (Caird et aI., 1973). These factors com- ~4

'C
plicate the use of antihypertensive medications as well . 3
as diuretics in elderly patients since the dose must be '"
't:

titrated even more cautiously than in younger patients '"

~ 2
to avoid severe orthostasis and syncope.
Older patients also seem clinically to be very sensi-
16
tive to the antihypertensive and the central nervous
system depressant effects of methyldopa and other 14
agents with similar properties (Dollery and
Harington. 1962). The use of reserpine is to be dis- *
~ 12
Q)

'5
couraged because of its tendency to cause gastric ~ 10
ulceration and an insidious form of psychic depres- e
sion. Certainly. the injudicious use of antihyperten- ~ 8' 30 40 50 60 70 80
sive therapy in the elderly must be avoided since the
Age (years)
complications can be serious (Jackson et al.. 1976),
but the available data indicate that elevated diastolic
and systolic blood pressures are both important risk Fig. 5. The mean ( SEM) daily dose of warfarin adminis-
tered and the prothrombin time as a percentage of control for
factors for cardiovascular disease in individuals over
patients (n = 177) in the age groups shown (after O'Malley et
age 65 as well as in those less than 65 (Dyer et aI., al.: British Journal of Oinical Pharmacology 4: 309-314, 1977;
1977). Treatment should be cautious with careful at- by permission of author and editor!.
 Drug Use in the Elderly
was observed, nor were any other pharmacokinetic
age related differences demonstrated (Shepherd et al..
197n However. at similar plasma warfarin con-
centrations there was greater inhibition of vitamin K-
dependent clotting factor synthesis in the elderly, but
without a difference in the rate of clotting factor
degradation. Possible explanations offered for these
interesting observations were that the elderly have a
decreased affinity for vitamin K and are relatively
deficient in vitamin K due to reduced dietary intake,
defective absorption or altered pharmacokinetics of
the vitamin itself (Shepherd et al.. 1977).
3.1.6 Brollcillidila/ors
Although only 3 of the normal subjects were over
age 60, Piafsky et al. (\ 977a) observed no apparent
effect of age on either the elimination half-life or ap-
parent volume of distribution at steady state of
theophylline. They did, however, observe a signifi-
cant impairment of plasma clearance of theophylline
in patients with congestive heart failure or in another
study in patients with hepatic cirrhosis (Piafsky et al..
1977b). A recently published nomogram for the clini-
cal use of intravenous infusions of theophylline in-
cludes age as a variable and the data presented indi-
cate that the maintenance rate should be reduced by
approximately 25 % in the elderly to maintain plasma
levels in the therapeutic range Ousko et aI., 197n
Based on pharmacokinetic data obtained in 10 elderly
patients (aged 60 to 77) with apparently normal
hepatic, renal and cardiopulmonary function,
Nielsen-Kudsk et al. (I 978) calculated that following
a loading dose of5.6mg/kg intravenous doses of 0.35
and 0.53mg/kg per h were required to maintain
steady-state plasma concentrations of 10 and
15mg/ mL respectively. These data are consistent
with the observations of Jusko et al. (I 977). There is
no clear evidence that the elderly are more susceptible
to the toxic effects of theophylline than are younger
patients. While there are case reports in the literature
of seizures in elderly patients receiving theophylline
(Zwillich et aI., 1975), in most instances elevated
plasma levels were present. Certainly, it is likely that
because of increased prevalence of cardiovascular
371
disease, the elderly will be more sensitive to the toxic
arrhythmias induced by theophylline.
3.2 Drugs Acting on the Central Nervous System
Most clinicians will agree that the elderly patient
tends to be clinically mote sensitive to drugs which
act on the central nervous system. Physiological ex-
planation for this observation includes a gradual loss
of neurons from the cerebral cortex, accumulation of
lipofuscin pigment in brain cells, complex endocrine
changes and a decline in cerebral blood flow in in-
dividuals with atherosclerosis. Older subjects may
have cerebral blood flows as much as 20 % less per
100 grams of brain tissue than younger subjects
(Bender, 1965).
Data on skin sensitivity to pain are conflicting but
tend to suggest that the elderly are less sensitive to
cutaneous pain. In terms of deep pain, they seem to be
less sensitive and more prone to show a therapeutic
response when a placebo is substituted for an effective
analgesic.
3.2.1 Analgesics
Age has been shown to be the most important
variable in determining the degree of pain relief
afforded following administration of a potent
analgesic (Bellville et al., 1971). Under double-blind
conditions, nurse conducted interviews revealed a
progressive age related increase in relief of pain inten-
sity in 71 2 patients receiving 10mg of morphine
sulphate and 20mg of pentazocine (fig. 6). There were
no differences in the frequency of side effects with
age. Available data suggest that this increased re-
sponsiveness is most likely related to age related dif-
ferences in pain perception. Pharmacokinetic age rel-
ated differences have been reported following intra-
venous administration of morphine 10mg per 70kg
body weight. Serum levels at 2 minutes correlated
directly with patient age and averaged 70% higher in
the older age group (Berkowitz et al., 1975). The
serum half-life, however, was independent of age.
Plasma binding of pethidine (meperidine) also correl-
 Drug Use in the Elderly 372

ated negatively with age (Mather et aI., 1975) - see frank psychosis. For this reason, barbiturates proba-
also section 2.2. Age related changes such as these bly have little role in geriatric therapy. Traeger et al.
may contribute to the enhanced effect of analgesics in (t 974) showed the half-life of phenobarbitone to in-
the elderly. Whether the reduced clearance of crease from 71 hours in a young age group to 107
paracetamol (acetaminophen) in the elderly has clini- hours in subjects over age 70. Oral amylobarbitone
cal importance remains to be determined (Briant et has also been shown to give higher plasma levels in
aI., 1976). an elderly patient group Orvine et aI., 1974). There
was also a marked reduction in excretion of the 3-hy-
3.2.2 Sedative-Hypnotic and Anxio{ytic Agents droxy metabolite. These pharmacokinetic differences
The increased sensitivity and paradoxical response were attributed to impaired metabolism in the older
of the aged to barbiturates is well known (Bender. subjects, but an effect of age on renal excretion cannot
1964). In a significant proportion of elderly patients. be excluded.
the response may vary from mild restlessness to A prolonged half-life with both a reduced
clearance and volume of distribution has been found
in elderly subjects given intravenous chlormethiazole
(Nation et aI., 1976). After oral administration peak
11 Morphine
o Pentazocine plasma levels were markedly elevated in elderly sub-
jects compared with young, probably due to decreased
10 presystemic elimination of the drug by the liver (Na-
tion et aI., I 977b). Plasma and red cell binding of
9 chlormethiazole were significantly reduced in the
aged. These findings suggest that older patients would
be predisposed to adverse effects from standard doses
8
of this drug.
Considerable information is accumulating on the
1l 7 pharmacokinetics and pharmacodynamics of the ben-
c:
~ zodiazepine group of compounds in the elderly.
~ 6 Studies by Klotz et al. (t 975) demonstrated a 4- to 5-
~
.~ fold increase in the plasma half-life of diazepam .
Analysis revealed, however, that this was the result
.~ 5
of a markedly increased volume of distribution in
c:
.~
elderly subjects compared with young rather than an
E
::>
4 alteration in total plasma clearance. This means that
CJ)

c: although it may take longer for diazepam to achieve

III
::1: 3 steady state, accumulation to excessive plasma levels
is unlikely. Reanalysis of data originally reported by
Mean age (years) Andreasen et al. (1976) on the pharmacokinetics of
diazepam in normal subjects (age 26 to 49) and
Fig. 6. Correlation of an estimate of pain relief (mean sum patients with cirrhosis (age 23 to 68) has further
pain intensity difference) with age group after 10mg morphine emphasised that age, sex and body size should be in-
(slope = 0.039, p <0.001) and 20mg pentazocine
cluded as independent variables in pharmacokinetic
(slope = 0.052, p < 0.001) administered intramuscularly to
712 patients for acute postoperative pain (after Bellville et al.: studies (Greenblatt et aI., 1978). Stepwise multiple
Journal of the American Medical Association 217: 1835-1841. regression indicated that age and liver disease were
1971; by permission of author and editor). equally important determinants of elimination half-
 Drug Use in the Elderly 373

life and together accounted for 34 % of the variance
in half-life. Age and sex collectively accounted for
33 % of the variance in the volume of distribution.
However. confirming previous studies (Klotz et al..
1975). liver disease was the single most important
determinant of weight-corrected diazepam clearance.
Reidenberg et al. (1978) have recently shown negative
correlations between age and titrated dose and bet-
ween age and resultant plasma levels of diazepam in
patients receiving this drug as sedation for elective
cardioversion. These data clearly indicate an increased
sensitivity of the elderly nervous system to the
depressant effects of diazepam. This study confirms
previous findings suggesting increased clinical depres-
sion of the central nervous system by diazepam and
chlordiazepoxide in relation to age (Boston Collabora-
tive Drug Surveillance Program. 1973).
Greater impairment of psychomotor performance
has also been reported in the elderly than in young
subjects following a 10mg oral dose of nitrazepam
(Castleden et al.. 1977). No pharmacokinetic differ-
ences between the 2 groups could be demonstrated.
Although prolongation of the half-life of lorazepam
has been shown in I study in elderly subjects
(Kyriakopoulos, 1976), Wilkinson (t 977) recently
reported no difference in his study between young
and old groups. A 2- to 3-fold prolongation in the
elimination half-life of chlordiazepoxide from 9-12
hours to 17-30 hours has. however. been observed.
This was due to a proportional difference in the
systemic clearance of the drug. in the absence of any
alteration in plasma binding or drug distribution in I
study (Wilkinson. 1977), and to a difference in both
the clearance and distribution volume in another
study (Shader et al.. 1977). Oxazepam elimination. on
the other hand. appears to be unaffected by age. Thus.
despite structural similarities there appears to be no
consistent pattern by which aging affects disposition
of the benzodiazepines. These drugs are now widely
accepted to be the antianxiety drugs of choice.

40 , 16/ 41
~
Average daily dose

Less than 15mg

32 i
D 15- 29.99mg

~ 30mg or more
24 '-

'"c
.2
U
.,[I!'" 16

'"Ci;
>
~q)
o~ 8
> "';::

"c '"Co
~o
*
cr
[I!
LL._
0
<40 40-49 50-59 60 - 69 ~70
Age (years)

Fig. 7. Frequency of adverse reactions to flurazepam in relation to age and average daily dose (after Greenblatt et al.: Clinical
Pharmacology and Therapeutics 21: 355-361,1977; by permission of author and editorl.
 Drug Use in the Elderly
The elderly (fig. 7) are more susceptible to the tox-
ic effects of flurazepam (most drowsiness. confusion
or ataxia) and for this reason a low initial dose (15mg)
is preferable (Greenblatt et al.. 1977). Another exam-
ple is ethanol. When controlled for equivalent levels.
healthy elderly subjects receiving ethanol demon-
strated greater impairment of reaction time. memory
and auditory attention than younger subjects
(Robertson-Tchabo et al.. 1975).
3.2.3 Tri(l'c1ic AlIlidepressallls
Elderly patients are prone to adverse effects from
tricyclic antidepressants. These include cardiotoxicity.
orthostatic hypotension. confusional states and urin-
ary retention. Aggravation of glaucoma and dryness
of mouth are other aggravating side effects also rel-
ated to the atropine-like properties of these drugs.
They should therefore be used with caution and
proper attention given to the increased possibility of
adverse reactions. Of interest is a recent report that
plasma levels of imipramine and desmethylimipra-
mine (desipramine) showed significant positive age
correlations (Nies et al.. 1977). The plasma half-life
of both compounds correlated positively with age but
only that of desmethylimipramine was statistically
significant. Steady state plasma levels of amitriptyline
also correlated significantly with age but not with the
metabolite nortriptyline. Thus. it would appear that
elderly patients achieve higher plasma levels of tri-
cyclic antidepressants than younger patients when
given equivalent doses. This is an important area for
further investigation to confirm and elucidate the
mechanism of these age related differences.
3.2.4 Antipsychotic Drugs
As with the tricyclic antidepressants. the anti-
psychotic drugs have prominent sedative. car-
diovascular and anticholinergic side effects. Ex-
trapyramidal side effects are also common in the
elderly. The peak incidence of akathisia occurs bet-
ween the ages of 40 and 50 and that of akinetic
Parkinsonism around 80 years. Choreiform side
effects from long term phenothiazine medication are
374
5 times more frequent in an aged than in a young
population (Salzman et al.. 1976). It is important
therefore to establish a diagnosis before using these
agents. and when an indication is present. to use them
carefully. It is also important to be certain that un-
derlying medical illness has not caused or exacerbated
psychiatric symptoms. Raskind and his associates
(J 976). working with a geriatric crisis prevention
team. found undiagnosed medical illnesses. such as
hyperthyroidism. congestive heart failure. hy-
ponatraemia and diabetes. in 25 % of patients. Drugs
were also a common cause of cognitive dysfunction.
paranoia and depression.
3.2.5 Allti-Parkinsonian Drugs
The elderly patient with Parkinson's disease tends
to be quite sensitive to anticholinergic and anti-
histamine drugs used for treatment. Early signs of in-
tolerance include mild confusion. nightmares and in-
creased forgetfulness. Often. it is the evening dose
that precipitates the signs of toxicity. Other anti-
cholinergic side effects such as urinary hesitancy and
retention. constipation and obstipation with faecal
impaction are also prominent. Paradoxical behaviour
alterations may be observed with levodopa. Emo-
tional status may be depressed or elated. cognitive
perception may be normal or markedly impaired.
Signs of dementia may be aggravated. with increased
paranoid or agitated behaviour (Holloway. 1974).
3.2.6 Allticolll'lI/sants
While with phenytoin. an age related increase in
plasma levels has been observed, the marked interin-
dividual variation indicates that genetic differences
and the effect of saturation (dose dependent) elimina-
tion kinetics are probably much more important
determinants of steady state serum phenytoin con-
centration than are age, weight. height or sex
(Houghton et aI., 1975). Total plasma clearance of
phenytoin has been shown to increase with age as a
result of decreased plasma binding. secondary to an
age dependent decline in plasma albumin (Hooper et
aI., 1974; Hayes et al.. I 975b). The possible clinical
 Drug Use in the Elderly
significance of these findings in terms of drug sen-
sitivity has yet to be defined.
3.3 Agents Acting on the Endocrine System
The physiological effects of age on the endocrine
system have been recently reviewed in detail (Greger-
man and Bierman, 1974; Andres and Tobin, 1977).
3.3.1 H.I'poJdl'cGefl1ic Agellts
Although glucose tolerance deteriorates with ad-
vancing age, the precise explanation is unknown. An
analysis of insulin kinetics has shown no differences
with age in the parameters of a 3 compartment
insulin system (Andres and Tobin, 1977). Neither the
metabolic clearance rate for insulin nor the delivery
rate of insulin to the systemic circulation under basal
conditions was influenced by age. No apparent differ-
ences in insulin sensitivity with age were present in
these studies. Insulin therapy in the elderly is essen-
tially the same as for younger diabetic patients, but
age adjusted criteria should be invoked when making
the diagnosis of diabetes in the older patient. Ag-
gressive treatment of diabetes in the elderly is usually
not justified and may be hazardous.
A delayed and less profound fall in blood glucose
concentration has been recognised in older subjects in
response to intravenous tolbutamide (Swerdloff et aI.,
1967). These changes may be due to impairment of
endogenous insulin release in response to tolbutamide
or to age related differences in the pharmacokinetics
of intravenous tolbutamide. Miller et al. (J 977) have
reported that total plasma clearance and volume of
distribution were positively correlated with age.
These parameters both correlated with the fraction of
tolbutamide unbound to plasma protein, which was
itself positively correlated with age. As reported by
Sotaniemi and Huhti (J 974), no age differences in
plasma half-life of tolbutamide were observed.
Whether these pharmacokinetic changes account for
the alteration in tolbutamide response or contribute to
the severe hypoglycaemic reactions which can occur
in elderly patients taking oral hypoglycaemic agents
375
(Gardner et aI., 1963) remains to be established. In
view of the difficulty in administration of insulin in
the elderly and the controversy in some centres sur-
rounding the use of oral antidiabetic agents, dietary
control is to be preferred. The majority of elderly
patients with diabetes can be controlled satisfactorily
on diet alone.
3.3.2 Thyroid Gild Antithyroid Drllgs
Studies in man have shown a progressive decrease
in the rate of thyroxine (T-4) disposal with advancing
age (Gregerman and Bierman, 1974). Since the total
plasma T-4 is unchanged, the homeostatic response to
this progressive slowing in the rate of cellular
degradation of the hormone is a decreased rate of
secretion. Triiodothyronine (T-3) concentration
decreases by 25 to 40 % in older subjects. The thera-
peutic implication of these physiological changes is
that somewhat lower than standard doses may suffice
for thyroid replacement therapy.
Almost no information is available concerning age
related alterations in response to drugs used for the
treatment of hyperthyroidism and there is no phar-
macokinetic data on antithyroid drugs in geriatric
patients. Although the clinical response to
methimazole was as prompt in old as in young
patients, there was a tendency for the percentage of
recoveries to decrease with age (McGavick et at..
1955).
3.3.3 Corticosteroids
The effect of aging on the hypothalamic-pituitary-
adrenal axis has been tentatively summarised by
Andres and Tobin (J 977). Available evidence to date
indicates that basal levels of ACTH and glucocor-
ticoids are unchanged with age, that the disposal of
corticoid is reduced with age and that the sensitivity
of the adrenal gland to ACTH is reduced. The impor-
tance of these physiological changes for glucocor-
ticoid therapy have not been investigated.
3.3.40estrogens
Postmenopausal oestrogen replacement therapy
has been advocated to prevent the development of
 Drug Use in the Elderly
osteoporosis. There are presently few well controlled
studies available indicating that exogenous oestrogens
are effective for prevention or treatment of osteo-
porosis and atherosclerosis in older women with a
surgically induced or natural menopause. In view of
the possibility that oestrogens may increase the risk
of cancer of the uterus and breast, many consider it
unwise to use this hormone for long term prophylaxis
or treatment (Weiss, 1975).
3.4 Non-Steroidal Anti-Inflammatory Agents
A slightly longer half-life of indomethacin has
been reported in elderly subjects but this was not
statistically different from the young group. The
elderly had higher serum levels of indomethacin and
excreted less unchanged drug than did the younger
control group, but additional data are needed to deter-
mine whether these changes are due to age related
alterations in drug elimination (Traeger et aI., 1973).
Although albumin binding of phenylbutazone is
decreased in the elderly (Wallace et ai., 1976), data
for phenylbutazone elimination rate do not show a
consistent difference between young and old subjects
(O'Malley et aI., 1971; Triggs et aI., 1975). One study
showed a slightly prolonged half-life while a second
study showed a somewhat shortened half-life. How-
ever, a significant decrease in the clearance of
phenylbutazone from 86ml per hour to 65ml per
hour has been reported (Crooks et al., 1976). The dis-
crepancy between the earlier studies may result from
differences in phenylbutazone dosage and size of the
study groups.
Except for a report that salicylate binding is un-
changed in the elderly (Wallace et ai., 1976), there is
no information on pharmacokinetic changes with age
for salicylates. Salicylates are, however, a major cause
of adverse drug reactions, particularly gastrointestinal
bleeding (Caranasos et al., 1974). Little information
is available on the sensitivity of the elderly to the
effects of other non-steroidal anti-inflammatory
agents but side effects may limit tolerance of some
agents in the elderly. In a group of 20 elderly patients
376
Table II. Principles of geriatric prescribing
1. Strive for a diagnosis prior to treatment.
2. Take a careful drug history.
3. Know the pharmacology of drugs prescribed.
4. Titrate the dose with patient response.
5. Use smaller doses in the elderly.
6. Simplify the therapeutic regimen.
7. Regularly review the drugs in the treatment plan and dis-
continue those not needed.
8. Remember that drugs may cause illness.
(10 with osteoarthritis, 9 with rheumatoid arthritis,
and I with ankylosing spondylitis) treated with in-
domethacin, there was definite improvement in only
20 % and slight improvement in 50 % . The incidence
of side effects (nausea, vomiting, diarrhoea, gastroin-
testinal bleeding, abdominal pain, headache, and
dizziness) was 55 % and required stopping the drug in
5 patients (Brocklehurst and Humphreys, 1965).
Many of these patients received maximum doses ex-
ceeding 100mg. While a trial of indomethacin may be
warranted, the elderly patient in particular should be
observed carefully for troublesome side effects. These
may be minimised by giving the drug with meals or
antacids. Unfortunately, antacids may reduce the
bioavailability of indomethacin (Galeazzi. 1977). A
single night time dose may provide adequate relief of
morning stiffness with an absence of central effects.
4. Basic Principles alGeriatric
Prescribing
With some minor modifications. the principles of
geriatric prescribing (table II) are essentially the same
as would be applied to any patient. old or young. and
have been reviewed by others <Hall. 1973; Freeman,
1974; Holloway; 1974; O'Malley et al.. 1976).
 Drug Use in the Elderly
J) Slril'efiJr a DiaRllOsis Prior 10 Trl!all11l!/Il
For some patients. symptomatiC therapy may be
all that can be offered. but whenever possible specific
treatment is preferable. I f the patient's symptoms are
due to malnutrition. ill fitting dentures. social
deprivation. inability to pay for previously ordered
medications. abuse or misuse of medications. addi-
tional drug therapy is only likely to complicate the
situation.
2) Takl! a Carl!ful DrllR HislOfY
This is fundamental to all good medical practice.
but it is especially important in dealing with the
elderly patient who usually will have multiple
problems and be taking multiple medications.
It is not unusual for a patient to receive 2 or more
drugs of the same type or with similar side effects -
perhaps prescribed by the same or different clinicians.
For example. antidepressants. antipsychotic agents.
antihistamines. and non-prescription 'cold' remedies
and sedative preparations all have anticholinergic pro-
perties. Their effects may be additive, producing un-
wanted toxicity such as dry mouth, blurred vision,
constipation. urinary retention and a variety of
neuropsychiatric symptoms.
Since cigarette smoking, alcohol use and caffeine
may modify the response to some drugs, it is impor-
tant to ask the patient about these habits. It is also im-
portant to know whether the patient uses aspirin,
sleep aids, laxatives, unusual quantities of vitamins or
other non-prescription medications. It is also advisa-
ble to maintain a problem oriented medication list or
some other systematic record to assist in following
the patient's treatment programme.
3) KilOII' IiiI.' Pharmacology (If Ihl! Drugs Prl!scribed
Use a few drugs well rather than many drugs
poorly. One's ability to use a drug rationally will be
enhanced by an understanding of its route of elimina-
tion. half-life. protein binding properties and propen-
sity for interactions with other drugs, along with a
knowledge of its major pharmacological actions, side
effects and toxicity. Such knowledge arms the clini-
cian with the best defence against serious drug reac-
tions - the ability to anticipate and recognise early
signs of drug toxicity. It also permits the rational ad-
377
justment of drug dosage when confronted by complex
medical problems. some of which might influence
drug disposition.
4) Tilrale DruK DosaKe wilh Paliel/l Respol/Se
Try to identify signs or symptoms that can be
assessed serially for effectiveness of drug therapy. In-
crease drug dosage gradually until the desired thera-
peutic end point is reached or unwanted toxicity is
present or anticipated. For the treatment of hyperten-
sion. control of blood pressure is the obvious thera-
peutic end point. However, side effects or drug tox-
icity may require that dosage be limited and an addi-
tional drug added in order to achieve satisfactory
blood pressure control. In the treatment of depres-
sion. this approach is more difficult but nevertheless
possible by means of a selective mental status
examination.
Judicious monitoring of plasma levels may be
useful guides to therapy with some drugs. The patient
shOUld be regularly questioned for the presence of un-
wanted side effects. particularly during the initial
stages of treatment and when changes in treatment or
disease status occur. If a drug causes more symptoms
than it alleviates. it should not be used.
5) u.w: Smaller Doses ill Ihe Elder(l'
It is better to give too little drug to the older
patient than to risk giving too much. The usual dose
for some patients will be too large for others. Dosage,
route and frequency of drug therapy will be deter-
mined clinically - based on the urgency of the
patient's condition, body size and weight and the
therapeutic index and pharmacological properties of
the drug. Obviously. penicillin dosage has much
wider limits than digoxin dosage. In general, caution
is a virtue in geriatric therapy.
6) Sill7plif.i' Ihe Therapeutic Regimen
Complex drug regimens may be easily
mismanaged by the elderly patient with a deteriorat-
ing memory or impaired vision. In order to promote
comprehension and compliance the following steps
are suggested (table III).
a) Explain the treatment plan to both the patient
and a friend or relative and give concise written direc-
tions.
 Drug Use in the Elderly
Table III. Techniques to enhance geriatric compliance
1. Give instructions to both patient and a relative or friend.
2. Encourage the use of a medication calendar or diary.
3. Select a dosage form appropriate for the patient.
4. Label drug containers clearly.
5. Encourage the return or destruction of old medications.
b) Suggest the use of a diary or calendar to record
daily drug administration.
c) Choose a dosage form that is appropriate for the
patient. An elixir may be more suitable than tablets
for a patient who has difficulty swallowing.
d) Label the drug container clearly and when ap-
propriate specify standard containers. The arthritic
patient will have difficulty opening safety caps.
e) Encourage the return or destruction of old.
unused medications. The accumulation of old medica-
tions from prior treatment programmes will only
serve to confuse the patient. He may inadvertently
mix new medications with old. or take drugs at high-
er or lower dosage than newly prescribed.
7) Reglllar~1' Review the Drugs in the Treatment
Plan and Discontinue Those Not Needed
Review the indications for each drug in a patient's
treatment plan at least once every 3 to 6 months.
Medications given for specific indications may be
continued long after the problem has been resolved.
This is particularly true when patients are seen by a
number of clinicians over a period of time.
8) Remember That Drugs May Cause Illness
Drugs may be a possible explanation for unusual
symptoms which may disappear when the suspected
offender is removed from the treatment programme.
Try to avoid substituting prescriptions for taking ade-
quate medical and social histories. Often the relation-
ship of the clinician with his patient is more impor-
tant than the drugs he prescribes. Favourable patient
morale can be promoted by emphasising clinical im-
provement or success in therapy. even if the change is
small. The patient needs to be a partner in this treat-
378
ment programme and needs encouragement to learn
to adjust to and live with his disease or disability.
Geriatric patients. like most other patients. greatly
appreciate a clinician who is sincerely interested in
their emotional and social. as well as medical. well-
being.
Acknowledgments
The author wishes to thank Dr George N. Aagaard and
Dr David G. Shand for their review of the manuscript and
helpful suggestions. Technical assistance of Mr Frank
Kreipe. the assistance of our librarians. Miss Maryann
Duggan and Mrs Bonnie Hirsch. and our secretaries. Mrs
Marjorie Locklear and Mrs Mim Carpenter. is gratefully
acknowledged.
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Author's address: Dr Rohert E. Vestal. Medical Service.
Veterans Administration Hospital. Boise. Idaho 83702 (USA).