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Akreditasi IDI 3 SKP

Principles of Drug Use in the Elderly

Arini Setiawati
Dept. of Pharmacology and Therapeutics, Faculty of Medicine,
University of Indonesia, Jakarta, Indonesia

ABSTRACT
There is a multitude of problems in prescribing drugs for elderly (> 60 years) patients caused by pharmacokinetic changes, pharmacodynamic
changes, and drug-disease interactions. Special precautions should be given, particularly to several commonly prescribed drugs among
elderly.

Key words: pharmacodynamic changes, pharmacokinetic changes, drug-disease interactions

ABSTRAK
Terdapat beberapa masalah yang harus diperhatikan pada penggunaan obat di kalangan lanjut usia mengingat telah terjadinya perubahan
farmakokinetik, farmakodinamik, dan interaksi obat-penyakit. Beberapa hal perlu diperhatikan secara khusus, terutama untuk obat-obat yang
sering digunakan oleh para lanjut usia. Arini Setiawati. Prinsip-Prinsip Penggunaan Obat di Kalangan Lanjut Usia.

Kata kunci: perubahan farmakokinetik, perubahan farmakodinamik, interaksi obat-penyakit

INTRODUCTION 1. Oral absorption 4. Drug distribution

There is a multitude of problems in prescrib-
ing drugs for elderly (> 60 years) patients.
1. In normal aging, physiologic functions de-
crease, causing a decline in the homeostatic
reserve. Changes in physiologic function also
alter pharmacokinetic and pharmacodynamic
profiles of certain drugs, while lowered ho-
meostatic reserve alters drug response. Both
changes in pharmacologic profile and drug
response will cause an increase in adverse
drug events in the elderly.
2. Elderly patients have multiple diseases,
requiring multiple medications, which cause
a lot more drug-drug interactions.
3. Atypical disease presentation in elderly
patients causes wrong diagnosis, leading to
wrong medication.
4. Adverse drug events in the elderly may be
misinterpreted as a new medical problem, for
which another drug is given, this may cause
additional adverse event, requiring another
drug, and a prescribing cascade is developed.
PHARMACOKINETIC CHANGES
There are several pharmacokinetic changes
that occur in the elderly:
In the elderly, gastric acid secretion decreases,
the resulting increase in gastric pH causes de-
crease in dissolution and absorption of several
substances (i.e: ketoconazole, itraconazole,
and iron). Other changes are lower intestinal
absorption area (around 20-30%), lower gas-
trointestinal blood flow (estimated 40%) and
lower gastrointestinal motility. Lower active
transport causes lower absorption of several
substrates that need active transport mecha-
nism such as calcium, iron, vitamin B1, vitamin
B12, I-dopa.
2. Transdermal absorption
In the elderly, hydration and lipid content of
stratum corneum become less, causing lower
percutaneous absorption and lowering the
bioavalibility of relatively hydrophilic com-
pounds e.g. hydrocortisone, aspirin, caffeine,
and benzoic acid.
3. First pass metabolism
Hepatic blood flow decreases, thus it may
increase the bioavailibility of certain drugs
with high HE (hepatic extraction) such as
labetalol, metoprolol, propranolol, CCBs, and
morphine.
There are several factors involved in drug dis-
tribution changes in the elderly:
The elderly tends to have less total body
water, causing less volume of distribution of
some water soluble drugs (e.g. ethanol, ci-
metidine, gentamicin), leading to increase in
plasma concentration.
Less lean body mass leads to lower vol-
ume of distribution of digoxin from 25% up
to 50%, causing higher plasma concentration,
and thus loading dose needs to be lowered.
Increasing total body fat (18%-36% for
male, 33%-45% for female) may affect volume
of distribution of some fat soluble drugs (such
as thiopental, diazepam, chlordiazepoxide,
and clobazam). These changes lead to longer
elimination half life.
5. Plasma protein binding
The elderly have less (6-20%) plasma alb
umin. It will decrease protein binding of acidic
drugs with high protein binding e.g. phenylb-
utazone, salicylate, phenytoin, warfarin, valp-
roic acid, naproxen), leading to increase in free
(active) drug concentration (> 50 100%).
While plasma albumin becomes less,
plasma 1-acid glycoprotein in the elderly in-

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 CONTINUING MEDICAL EDUCATION
creases. This will lead to higher protein bind-
ing of basic drugs with high protein binding
(e.g. lidocaine, propranalol, and imipramine),
and cause decrease in free (active) drug con-
centration.
6. Hepatic metabolism
Along with aging process, the elderly are
less sensitive to induction of these enzymes:
CYP1A2, CYP2C9, CYP2C19, CYP3A3/4.
Low liver mass (liver weight decreases by
20-50% and liver volume decreases by 25%)
leads to decrease in total amount of drug me-
tabolizing enzymes.
Low liver blood flow (decreases by 35%)
leads to lower liver perfusion (decreases by
10-15%), and decreases in the amount of drug
metabolized by liver enzymes.
Decreased liver enzymes will affect drugs
metabolized by liver enzymes (phase I & phase
II) with high and low hepatic extraction, lead-
ing to lower clearance and longer elimination
half life of these drugs (e.g. CCBs, warfarin,
theophylline, benzodiazepines, barbiturates,
quinidine). Avoid using barbiturates and long
acting benzodiazepines for elderly, due to the
prolonged duration of action, and use short
acting benzodiazepines instead.
7. Renal excretion
In general, elderly patients may undergo 3
kidney physiological changes: low renal mass
(decreases by 25%-30%), low renal blood flow
(1%/year decline after 40 years old), and low
glomerular filtration rate (decreases by 35%).
These 3 changes will affect certain drugs
which are eliminated by renal excretion (such
as ACEIs, digoxin, metformin, cimetidine, ra-
nitidine, aminoglycosides, furosemide, HCT,
lithium, atenolol), causing lower clearance
rate, and prolonged elimination half life.
For drugs with narrow therapeutic index such
as digoxin, aminoglycosides, lithium, cisplatin,
bleomycin, and melphalan, dosage adjust-
ment (DM) based on ClCr is needed.
To estimate ClCr, Cockcroft & Gault equation
may be used:
For ClCr < 25 mL/min: if the calculated dose
ClCr = 2.2 x Toxic dose
For ClCr > 100 mL/min: if the calculated dose
ClCr = 0.5 0.8 x Subtherapeutic dose
888
This formula is for rough estimation only. For po-
tentially toxic drug, it must be followed by close
monitoring of serum drug concentration.
PHARMACODYNAMIC CHANGES
There are several physiologic changes which
lead to pharmacodynamic changes of certain
drugs in the elderly patients.
Decrease in -receptor response. Studies
showed that these changes lead to less tachy-
cardia in response to isoproterenol and less
bradycardia in response to propranolol. No
change in -receptor response was observed.
Low baroreceptor activity may increase
risk of postural hypotension in response to
antihypertensive agents.
Low diuretic response decreases diuresis
effect of furosemide.
High sensitivity to benzodiazepine in-
creases sedation effect of certain drugs such
as diazepam, temazepam, clonazepam, and
nitrazepam.
High brain sensitivity to narcotics increas-
es analgesic effect of fentanyl, alfentanyl, and
morphine.
High sensitivity to warfarin increases an-
ticoagulant effect of warfarin. No change in
heparin sensitivity was reported.
High sensitivity to CCBs increases antihy-
pertensive effect of verapamil and diltiazem.
High sensitivity to anticholinergics may
increase adverse reactions of anticholinergics:
dementia, constipation, urinary retention, and
faster heart rate.
There are some commonly prescribed drugs
in the elderly:
1. Analgesics & NSAIDs
Due to the low clearance of morphine and
meperidine in the elderly, analgesic effect in-
creases, therefore titrate to the lower doses.
Hepatic metabolism of acetaminophen is re-
duced in the elderly, but dosage adjustment
is uncommon.
Use of NSAIDs may increase risk of hyper-
kalemia, renal failure, and death from GI hem-
orrhage, therefore close monitoring is needed
in NSAIDs administration.
2. Anticoagulants
Anticoagulant effects of warfarin increase in the
elderly, therefore titrate the dose based on INR.
While concomitant use of warfarin with cime-
tidine increases plasma concentration of war-
farin, concomitant use with phenylbutazone
increases the free concentration of warfarin.
No change in heparin sensitivity in the elderly
is reported. Titrate the dose to therapeutic ef-
fect.
3. Cardiovascular drugs
Diuretics
Diuretics are most effective in patients with low
renin hypertension. The elderly have low renin
activity, therefore diuretics can be used in low
dosage which will decrease the adverse drug re-
actions, including postural hypotension. Avoid
using diuretics in patients with hypokalemia
(its prevalence increases in the elderly).
-blockers
The clearance decreases, but the response
also decreases, thus adjust the dose based on
BP and heart rate.
CCBs (Calcium Channel Blockers)
In the elderly, plasma concentrations of CCBs
may be higher, therefore smaller dose ad-
ministration may be more appropriate. Long
acting CCBs have been shown to be more
effective in the elderly, but avoid the use of
short-acting nifedipine, since its usage may
increase risk of CV mortality.
ACEIs
In the elderly, decreased renal clearance of
ACEIs leads to higher plasma concentrations,
also cardiovascular reflexes decreased in the
elderly. Based on these factors, it is recom-
mended to lower initial dose of ACEIs to avoid
risk of first dose hypotension.
-blockers
To avoid risk of first dose hypotension, it is bet-
ter to reduce initial dose of -blockers. Long-
acting -blockers have 2 known benefits: re-
duced hypotension risk and more convenient
for the patient.
Digoxin
Elderly may have lower Vd of digoxin, there-
fore loading dose of digoxin may need to be
reduced. Due to the low glomerular filtration
rate, maintenance dose of digoxin may need
to be reduced too.
Antiarrhythmics
Elderly tend to have low clearance and low
therapeutic index of antiarrhythmics, which in-
crease the toxicity, therefore close monitoring
of antiarrhythmic concentration is needed.
Postural hypotension is one of the most com-
mon problem in the administration of cardio-
vascular drugs to the elderly. It is estimated
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that 20% of persons > 65 years and 30% of
persons > 75 years experience postural hy-
potension. Known iatrogenic causes of pos-
tural hypotension are -blockers, ACEIs, ARBs,
adrenergic neuron blockers, diuretics, nitrates,
TCADs, and antipsychotics.
Choices of antihypertensive agent for the el-
derly are diuretics (low renin) and CCBs (effi-
cacy correlates with age).
4. Psychotropic drugs
Antipsychotics
Antipsychotics usage in the elderly tends to
give variable responses, and because the el-
derly are vulnerable to adverse effects of this
class of drug, it is recommended to give low
initial dose, then titrate upward. Haloperidol is
associated with less cardiovascular and anti-
cholinergic adverse effects.
TCADs
TCADs metabolism is lower in the elderly,
leads to higher risk of adverse effects of these
drugs. It is recommended to give lower initial
dose at bedtime.
Antidepressants
Antidepressants for the elderly: SSRIs are rela-
tively safer than TCADs, e.g. sertraline seems to
be the better choice because it is least com-
plicated than other antideppressants.
Hypnotics
Hypnotics use is recommended only for few
weeks, then it should be tapered off because
rebound may occur.
Barbiturates are not recommended for the
elderly due to their prolonged duration of ac-
tion will lead to higher risk of adverse events.
Benzodiazepines cause excessive CNS depres-
sion (sedation & confusion) which may lead to
falls and trauma, including hip fracture. Short-
and medium-acting benzodiazepines (e. g.
triazolam, oxazepam, temazepam, lorazepam)
are best because causing less adverse events.
Other things that need to be known are
that elderly may have low clearance of drugs,
but have higher CNS sensitivity, therefore start
with low initial dose and titrate up slowly.
Other than drugs mentioned above, be cautious
when giving drugs with anticholinergic activity
(such as anticholinergics, antihistamines H1,
antiarrhythmics, TCADs, phenothiazines and
other antipsychotics, opiate analgesics), since
these drugs have central anticholinergic effects,
which will cause cognitive impairment in the
elderly. Many drugs commonly prescribed for
the elderly (e. g. antihypertensives [-blockers,
reserpine], benzodiazepines, I-dopa, digitalis,
steroids, phenothiazines, indomethacine) may
also cause depression. Pattern of drug side ef-
fects may change with aging process, espe-
cially for CNS side effects. For example, in case of
patient with advanced cancer: patients with age
less than 66 years old tend to have higher risk
of oversedation, but patients older than 66 years
old may have higher risk of delirium.
DRUG-DISEASE INTERACTIONS
Elderly, other than undergo physiological
changes, may also develop diseases related to
aging, which may interact with drug adminis-
tration. Some cases below are few examples
of drug-disease interactions:
Chronic heart failure or chronic liver dys-
function will decrease hepatic blood flow,
leading to increased concentration of drugs
with high hepatic extraction (e.g. lidocaine, imi-
pramine), resulting in increased drug toxicity.
Patients with benign prostate hyperplasia
who receive anticholinergics will experience
higher urinary retention, and if they receive
decongestants (-agonists), they will have
lower urinary flow.
Elderly with chronic obstructive pulmo-
nary disease (COPD) who received -blockers
will suffer from bronchoconstriction, and if
they receive narcotic analgesics they will ex-
perience respiratory depression.
Elderly with dementia who receive one of
these drugs: anticholinergics, antidepressants,
opiates, benzodiazepines, levodopa will suffer
from delirium.
There are many other diseases that may inter-
act with drug administration, such as peptic
ulcer, chronic renal insufficiency, diabetes,
hypertension. Therefore it is very important to
know the patients medical history completely
before prescribing any medication.
Other than drug-disease interaction, there are
several food that may interact with certain
drugs. For example; charcoal grilled meat and
cruciferous vegetables may increase theo-
phylline, caffeine, and paracetamol metabo-
lism. Other example is naringin (in grapefruit
juice) that may block the metabolism of CY-
P3A4 substrates (e. g. cyclosporin, nifedipine,
felodipine), increasing the oral bioavailibility
of these drugs.
SUMMARY
In summary, there are 10 principles of drug
therapy in the elderly:
1. Record a complete history of drug use (in-
cluding OTC drugs), habits and diet.
2. Make an accurate diagnosis (beware of
drug-induced disease).
3. Evaluate the need for drug therapy
4. Be familiar with the pharmacological of
the drug prescribed, the age related altera-
tions, and the interactions with existing dis-
ease and drug.
5. In general, use smaller initial doses (START
LOW)
6. Titrate drug dosage to therapeutic re-
sponse. Wait at least 3 half-life before increas-
ing dose (GO SLOW).
7. Simplify the therapeutic regimen (reduce
number of drugs, take at the same time of
each day, once or twice daily).
8. Encourage treatment adherence. Provide
suitable preparation and container.
9. Be alert to the possibility of drug reactions
and interactions with disease states and other
drugs.
10. Regularly review treatment plan, and dis-
continue drugs that are no longer needed.

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