Anna Giulia Cattaneo, M.D.
University of Insubria, DBSF, via J-H. Dunant, 3 - 21100 Varese.
The problem of treating old people with drugs is a major
challenge both for the complexity, and for the social cost
of the treatment. Elderly is a main cause of poverty in developed
countries, and many individuals reaching the retirement age
must cope with their increased physical frailty, added to
substantial reduction of financial resources. These facts
are frequently superimposed to a background of depression
and lack of inner drive, decreased ability of self care, abandonment
or incapability to understand from the family, and need for
multiple drugs intake associated with reduced tolerance to
many of them. Attempts of auto-medication and unauthorized
discontinuation of the right therapy, and sometimes overmedication
and medical malpractice have the obvious consequence of increased
morbidity and possibly serious side effects.
In this Editorial a summary of most important factors leading
to a poor compliance with drug therapy in the oldest subjects
is presented. The pharmacokinetics of an antiarrhythmic agent
is presented, as an example.
Factors affecting the safety of drug therapy in aged individuals.
The severity of the impact of aging on the quality of life
in older individuals is mainly determined not only by the
patient himself and the entity of aging process, but even
by the taking care (physicians, nurses, family members, others).
The patient could experience:
1. Increased morbidity when age increases, leading to
increased need for drug therapy and reduced autonomy.
2. Abandonment, poor ability of self-care (impaired motility
and economical support, visual or intellectual decline) leading
to frequent misuse of therapy.
3. Increased depression, leading to reduce determination
in following therapeutic protocols and even in seeking help
for physical disabilities.
The care taking (professional, or a family member) must face
difficulties, like those listed below:
1. Impaired ability to eat and swallow medicines, complain
for gastric discomfort, leading to difficulties in
correctly following the therapeutic schedules.
2. Reduced muscle mass, leading to difficulties in
administering parenteral therapy
3. Unapparent or confusing symptoms, hostile or poorly co-operative
habit of the old subject, leading to delay in reporting
possible side reaction of drugs to the physician.
The physician must be an expert manager of the frail body
of elderly patients, and be aware that:
1. Multiple drug assumption required for multi-systemic affecting
diseases lead to increased risk of adverse side reactions
2. More frequent occasions for use and misuse of antimicrobial
agents lead to enhanced infective episodes with resistant
3. Symptoms unapparent or misunderstood lead to poorly
diagnosed side reaction of drugs or of counteracting diseases.
4. Altered physiology and reduced renal, hepatic and cardiovascular
function lead to altered clearance and distribution
of drugs into body compartment.
5. Erroneous eating habits and aging of metabolic organs lead
to malabsorption, low content of protein in plasma, reduced
(or relatively augmented, in comparison with muscles) fat
body pads and altered body compartments, in a word erratic
Prevention of malpractice and poor compliance.
Post marketing pharmacovigilance is the main preventive measure
in this field. It can be extended to the aged population of
a town, a region or a country, or be limited to representative
samples, sized according to the epidemiological protocols.
Data should be inserted into a national database, as recently
auspicated by the Italian Group for Pharmaco-epidemiology
in the Aged (Gruppo Italiano di Farmacoepidemiologia dell'Anziano,
GIFA), and discussed in the 49° Congress of the Italian
Society of Geriatrics and Gerontology (SIGG),
held in November, 3rd - 7 th, 2004.
Large populations can be analysed in this way, and a great
number of data can be collected and validated using adequate
statistical tools. Patient's symptoms, before, during and
after drug therapy, compliance with therapy itself, type and
timing of drug assumed can be evaluated by questionnaires
in addition to supervision. Mental and physical condition,
economical an social status of individuals entered in the
study can be evaluated in the same way. A new field of interest,
increasingly important, is pharmacogenetics, which could be
improved by the creation of databases of genetic profile of
populations: genotypes related to abnormal drug sensitivity,
or associated with diseases and other clinical conditions
could be taken into account. However, at the present state
of practical knowledge, these kind of data seem to be a target
for a not near future, at least when general screening of
the old population is taken into account. The existence in
the sampled population of sub samples (women vs. men, subjects
living at home vs. those living in nursing homes, and others)
should be evident if the study has been well planned. This
classification can simplify the result analysis, and help
to adopt effective preventive measures against complaint,
side effects and jatrogenic diseases.
WHO has online published the guidelines
for efficaciously report drug side effects (file .pdf, 288
kb). The need to develop post marketing pharmacovigilance
services active in this area should be of great interest.
b. Admission to results
The possibility to have free access to evidences on drug toxicity
and counteracting effects of drugs in old population, from
the local or national databases could be of importance for
the practitioner that must cope with a rare, or not before
experienced side effect of drug in an aged patient, perhaps
unable to correctly report his distress. The online access
to rapid and clear review, eventually organised as an alphabetic
list of compounds, or as a net of causes of toxic signs and
symptoms, is in my opinion a powerful mean to counteract malpractice
or at least drugs misuse, especially when the state of knowledge
is regularly updated by non-profit organisms.
A comprehensive search motor is furnished form the Food
and Drug Administration (FDA). Another useful tool
is maintained in a self-claimed non-for-profit web site (The
Drug Monitor). The site offers free accession to a
calculator for several variables (like the anion gap, the
glomerular filtrate, etc.) involved in drug clearance: corrections
for age, gender and body features are included. A similar
tool, devoted to problems concerning aging and maintained
by public institution or scientific societies, should be very
c. Improved training in geriatrics in medical schools
The world population is aging: the WHO and other organisms
strongly advocates that all future medical doctors should
be well trained in care of the older persons, that will represent
an increasing part of their patients in daily practice. Documents
on global survey on geriatrics in medical curriculum are freely
accessible at the web site of the American
Geriatrics Society and of WHO
(document .pdf, 630 kb, published in 2002). The first institute
auspicate special training in geriatrics for medical specialists.
On the basis of aging process in the world population, with
special focus on developing countries, the WHO predicts that
an epidemiological transition should be expected, and strongly
advocates that future doctors will be trained at the best
in care of older persons. Results from a worldwide study (TeGeME,
carried out in 2000) are presented: an inter-countries comparison
index (GERIND) has been calculated on the basis of a set of
qualitative and quantitative characteristics of rules and
facilities for teaching and practicing geriatrics in medical
schools. The analysis of 34 participants (Italy was not included)
permits to divide countries into three groups: A) high proportion
of older persons among the population and insufficient geriatric
education; B) low, but steadily rising older population segment
and insufficient geriatric education; C) high segment of older
persons among the population and good training of medical
students in geriatric medicine. Predictions for 2025 are done:
no substantial variation of the quality of teaching should
be expected, in association with a shift on the left (older
ages in population) in all groups.
Geriatrics must be considered as a discipline requiring multidisciplinary
approach: the need to have good knowledge and skills in medical
disciplines, as well as in psychiatry and surgical practice,
is mandatory to avoid the feeling of disorientation that could
disturb the beginner at its first contact with patients suffering
from loss of consciousness, memory, and presenting the physical
sequels of aging. Pharmacovigilance and pharmacokinetics must
be familiar to the physician involved in this kind of care.
A brief discussion of recent trials
Recent studies underline old and new fundamentals in pharmacologically
care for older patients. The most important among them can
be shortly summarized as follows:
1. Reach an accurate diagnosis before starting treatment
2. Attempt to correct or ameliorate symptoms with adequate
modifications of live stile (drinking alcohols, smoking, eating
habits, exercise, adequate fluid intake) to avoid or minimize
3. Evaluate the integrity of most important district for pharmacokinetics/dynamics
(kidney and liver function, plasma carriers of drugs, mainly
albumin and other proteins, body mass index and body surface,
evaluation of subcutaneous fat pad, muscle mass and the entity
of eventual dehydration or oedema)
4. Record accurately all drug used by the subjects, keeping
in mind the possibility of auto medication even with agents
not considered as active drugs by subjects (like herbal preparations)
5. Evaluate the real adherence to the therapy
6. Maintain an accurate and actual knowledge of all the possible
counteracting effects and of their underlying causes
Older subjects are at risk of overmedications: it is generally
better to avoid prescribing antiobesity drugs, analeptics,
vasodilators, drugs claimed to improve mental, physical or
sexual fitness. The most frequently used drugs in the elderly
seems to be sedatives/hypnotics, diuretics, cardiac therapy
agents, and minor analgesics and antipyretics: remember that
sedatives and diuretics can enhance the risk of nocturnal
falls, aspirin and glucocorticoids agents seems to be associated
with increased risk for developing dementia in particular
genotypes, involving apoE epsilon4 allele, and cardiac glycosides
can cause complex side effects, involving the CNS (also with
behavioural modifications) in addition to the cardiovascular
Pharmacokinetics of antiarrhythmic drugs: the case of
In a study involving 300 subjects treated with antiarrhythmic
drugs, 40% of patients showing drug-induced side effects were
treated with disopyramide (Vigreux P et al, Terapie, 1995,
This molecule, while not widely used, appears to be interesting
for the purposes of this paper, because its complex pharmacokinetics
is altered in aging and in age-related pathologic conditions,
because it is not a drug at risk of auto prescription, and
because its administration schedule is relatively simple (oral
administration, once or twice daily).
The metabolic fate of disopyramide follows a hepatic pathway
of dealkilation, controlled by inducible enzymes. The pathway
is stereo selective: the drug in pharmaceutical preparations
is a mix of two isomers, only one of which is easily metabolised
for unclear reasons.
It is uncertain if the major metabolite retain some antiarrhythmic
effect and/or enhanced side-effects in humans, however it
competes with the parent molecule for the saturable (non-linear)
binding to plasma protein, namely to a1 -acid glycoprotein.
This is an acute-phase reactant, increased in aging, IMA,
CRF and renal transplant recipients.
The excretion is 80% urinary (mainly as active, free drug),
both by glomerular filtration and tubular secretion, and 15%
faecal (ca.1/3 as active drug). Total clearance is a function
of total drug concentration; renal clearance is a function
of free (unbound) drug concentration (30% from tubular excretion).
Measured parameters during long-term therapy:
1. Oral absorption >90%
2. Vd at the steady state (l/Kg, range) = ca 0,5 (total);
ca 1,5 (free drug)
3. Total concentration in plasma: range: 2 -8 mg/l
(after 400 - 600 mg/day)
4. Plasma to tissues or fluids concentration: 1: 7
up to 1: 15 in fat, liver, spleen; 1: 0,3 in brain; 1: 0,8-1.51
5. Metabolite concentration: up to 30 % of active drug.
6. t1/2 = 5-9 hours.
Factors related to the aging that can alter pharmacokinetics:
Aging, alone or associated to cardiac ischemia,
- Increases: binding to protein and the level of the binding
protein (by 50%), volume of distribution (Vd) (x 2), steady-state
concentration of the free drug in plasma (by 25%), half-life
- Decreases total clearance (by 30%)
Other conditions more frequent in aged individuals and able
to modify the kinetics of this drug are renal and liver failure,
Acute Myocardial Infarct (AMI) (only in acute phase, not in
convalescent state), Congestive Hearth Failure (CHF), and
chronic inflammatory diseases. These conditions act on absorption,
binding to protein, metabolism, clearance and half-life, distribution
volume and absorption, often with a random effect.
Multiple drug assumption can lead to multiple effects
on liver metabolism (rifampicin, phenytoin) and to competitive
binding with a1 -acid glycoprotein.
Better training in geriatrics in medical schools, both for
specialists and for general physicians, wider access to well
planned and updated tools both for pharmacovigilance and pharmacokinetics,
and improved personal skills seems to be highly recommended.
Final targets of these efforts will be a better compliance
with therapy, improved wellness and reduced wasting of economical
resources due to approximate or inadequate treatments.
When keeping in mind that the older patients represent an
increasing part of the near future patients in daily clinical
practice, all over the world, the importance of the cited
aspects appears to be self-imposing.
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