Drug safety in elderly [621375]

Drug safety in elderly

Europe's elderly population has been estimated to be steadily increasing over the
next few years. The reality in our country is no different from what is estimated at
European level[1,2]. Demographic studies estimate that the proportion of the population
aged 65 or over will double from 15% to 30% by 2060 [1].
The International Conference on Harmonization considers that the elderly is a
special group. Char acteristics such as the presence of comorbidities, poly -medication and
drug pharmacokinetics and pharmacodynamics influenced by age are factors that lead to
an increased susceptibility to adverse reactions [2].

Pharmacokinetic and pharmacodynamic changes i n the elderly
Aging is associated with general changes that influence the passage of drugs in the
organism. These changes may lead to increased half -life for different molecules that could
also mean increased risk of toxicity and adverse reactions [3].
All pharmacokinetic stages are influenced by age. Drug absorbtion is influenced by the
reduction of gastric and intestinal persitalism or swallowing diffyculties. The elderly have
a reduced volume of distribution and increased serum concentrations for hy drophilic
drugs (e.g gentamycin, alcohol) while increasing lipid proportion in the body is associated
with increased half -life for lipophilic drugs (ex diazepam, amitriptyline). [3]
With age, the organs responsible for the metabolism of most drugs (liver and
kidneys) go through physiologically changes. Reducing liver size by 25 -35% and liver
irrigation by up to 40% [4] would suggest a modified liver function, however analyzes
show that liver function is often maintained [3,4]. Recent studies have highlight ed the
gradual deterioration of renal function with age could reach up to 40% [3]. Reducing renal
function with age greatly affects drugs metabolised primarily in the kidney (ex digoxin,
diuretics, penicillins). Hypertension and ischemic cardiopathy – the most common
conditions in the elderly affect glomerular filtration [3]. It was observed that phase I
metabolism is more affected by age compared to phase II.[3.5]

Comorbidity

Comorbidity refers to the concomitant existence of two or more diseases. A
systematic review of 41 studies aimed to assessing the level of comorbidity, found that
between 55 and 98% of the study population aged 65 or over suffers from comorbidities
[6]. Increased prevalence of comorbidities was observed in females and patients with low
socio -economic situation[6,7]. A study conducted by Fettuci et al concluded that patients
most often suffered from hypertension (HTA) 61.9%, ischemic cardiomyopathy – 31.2%,
pain – 23.6% and renal chronic disease – 18.5%.[27] Other disorders such as d epression,
diabetes, constipation and thyroid disease were also present with a lower frequency in
this population.[7]
Co-morbidity often involves poly -medication and increased risk of drug

interactions and adverse events to which this population is expos ed to[6]. Most therapeutic
guidelines are the results of clinical trials conducted in patients with only one pathology,
from which elderly with poly -pathology are excluded. Extrapolation of the results
obtained in such studies to the majority of the popula tion makes it difficult to predict the
adverse events that may occur in patients with co -morbidity and poly medication. [7]
Prescription based on therapeutic protocols that treat each individual disorder
systematically disadvantages people with multiple h ealth problems. Such a approach
promotes insufficiently coordinated therapy, which is not adapted to the individuality of
each patient, resulting in ineffective and potentially harmful treatment. Geriatric societies
are proposing to develop therapeutic pr otocols that also take into account poly -pathology
patients [6].

Poly-pharmacy
Poly-pharmacy is defined as the use of at least five drugs a day. The level of poly –
medication has been studied for long by scientists, while the results being variant. Nobil i
et al. reported the rate of poly -medication at 52% among Italian elderly hospitalized with
an average of 4.9 drugs (N 1332, mean age 79.4 years) at admission [8]. The poly –
medication rate increased to 67% on discharge, with an average of 6 drugs. In Aus tria ,
Schuler et al. reported a rate of poly -medication at 58% and an average consumption of
7.5 drugs per day (N 543, median age 82 years) [9].
The most common over the counter (OTC) drugs consumed by adults and especially
the elderly were analgesics (a spirin, acetaminophen and ibuprofen), combinations of cold
medicines (diphenhydramine and pseudoephedrine), vitamins and minerals
(multivitamins, vitamins E and C, calcium ) and herbal products (Panax ginseng extract,
Ginkgo biloba extract, sunflower) anta cids and laxatives [10,11].
A US study on the use of prescription drugs reported that in 2002 the most common
prescription drug among elderly ambulatory patients were conjugated estrogens,
levotiroxine, hydrochlorothiazide, atorvastatin and lisinopril. The same study reported
that the most common classes of ambulatory prescription drugs over a period of one year
were cardiovascular, antibiotic, diuretic, analgesic, hypolipidemic and antisecretory
agents. This result is to be expected because medicines refle ct treatment for the most
common conditions.[12]
There are many consequences of poly pharmacy. In addition to increasing direct
treatment costs, patients have a higher risk of adverse drug reactions, drug interactions,
non-adherence, decreased functional status, and various geriatric syndromes [13]. The
number of adverse drug reactions (ADR) for all age groups has increased in recent years,
with an estimate cost of 4.3 million in 2005 [13]. Poly -pharmacy increases the risk of
ADR from 13% (for two drugs) t o 58% (for five drugs) or event up to 82%(for seven
drugs). The most common drug classes associated with RA were cardiovascular drugs,
diuretics, anticoagulants, non -steroidal anti -inflammatory drugs, antibiotics and anti –
diabetics [14].
Potential drug i nteractions are common. In a prospective, randomized, controlled,

longitudinal, multicentred European study of 1,601 elderly people living in the community,
46% had a drug interaction[15]. This result is consistent with other studies indicating the
prevale nce of potential drug -drug interactions between 35% and 60% in elderly [15]. The
drug interaction risk increases with the number of drugs and may be close to 100% in
patients using eight or more drugs.
The prevalence of drug -disease interactions is report ed to be 15% to 40% in elderly
patients. Researchers noted that the most common interactions were aspirin in patients
with peptic ulcer, calcium channel blockers and heart failure, and beta blockers in diabetes
[16]. The risk of interactions between diseas e and drug has been shown to increase with
the number of drugs used and the number of co -morbidities [14].

Non-adherence
Complex drug regimens may lead to non -adherence in the elderly. Studies in elderly
living in community have reported adherence rates to drug therapy between 43% and 95%
[14]. High variability can be attributed to different definitions of adhrence, and to the
method by which adherence was measured. The number of drugs has been shown to be a
stronger predictor of non -adherence versus agin g, with higher rates of non -adherence as
the number of drugs increases [16].
Elderly in Romania have access to medicines based on prescriptions issued by general
practitioner or specialists. Patients also have access to non -prescription medicines and
vario us natural products. While prescription drugs are subject of a monitoring system,
non-prescription drugs and natural products are not recorded in any database and are more
difficult to track, making it difficult to analyze prescriptions. [17]

Adverse rea ctions in the elderly patient
At first glance, we would be tempted to say that the risk of adverse reactions is
correlated with age [18]. Studies have yielded contradictory results in this respect, but a
common agreement has been reached that says the eld erly is more prone to adverse
reactions due to associated risk factors not to age. [19]

Nature of side effects in the elderly
An adverse event can be defined as any unwanted response that occurs while use of
a drug in therapeutic doses for diagnostic, pr ophylactic or curative purposes. Adverse
reactions are most commonly divided into Class A and Class B ADRs. [18]
Class A adverse reactions are those that result from the pharmacological effect of the drug
and are more rarely encountered at therapeutic dose s of the drug. The intensity of these
side effects is dose -dependent [18,20]. Type B side effects are less common side effects,
but are more severe compared to type A. This type of RA is caused by immunological
reactions (eg anaphylactic shock) and is asso ciated with increased levels of mortality and
morbidity.[20]. The literature talks about two other types of ADR: type C associated with
long-term use and type D – delayed reactions (eg carcinogenicity)[20]
More than 80% of the RA leading to hospital admiss ions are type A ADR. Antibiotics,

anticoagulants, digoxin, diuretics, hypoglycaemic agents, antineoplastic agents and non –
steroidal anti -inflammatory drugs account for 60% of in admissions ADR and 70% of
ADRs occurring during hospitalization.[21]
It has b een observed that type A ADR is more common in the elderly and type B
reactions are uncommon in this population[20]. However, some important and
occasionally severe B -type toxicity (eg antibiotic -associated hepatotoxicity) appear to be
more common in the e lderly than in the younger patients. [22]

Avoiding side effects
Since most ADR in the elderly are predictable and therefore can be avoided,
effective communication between patient, physician and pharmacist is vital. Physicians
should carefully check the prescribed medication with the patient so that they understand
the risks they are exposed to and the most common ADRs and interactions to be avoided.
This regular review process should continue, whether the elderly patient is hospitalized,
living in a nurs ing home or in the community [13].
Whenever possible, the prescribing physician should choose the drug with the
highest therapeutic index, provided that the efficacy is comparable to that of the narrower
therapeutic index. Avoid combinations that show syn ergistic toxic effects is
recommended (eg, two anticholinergic substances). Doses should be carefully adjusted
especially for low therapeutic agents, starting with a low initial dose and regular
monitoring the response to treatment. The number of prescrip tion drugs should be kept to
a minimum, and the number of people involved in patient care also. These measures have
shown that to be associate with a lower risk of ADR and increased patient compliance[13].

Criteria for reducing RA
Physiological changes, e specially those pathological, occurring in the elderly population
influence the therapeutic response of this category to different treatments and highlight a
greater risk of prescribing problems.[24] Inappropriate prescribing is a phenomenon that
refers to the use of certain drugs in conditions where the patient is exposed to a higher risk
than the benefit obtained. The literature talks about three inadequate prescribing situations:
prescription drugs with an increased risk of side effects and drug -drug int eractions for this
population, suppressive drugs. [25]
The literature suggests three inadequate prescriptions (PIs): PI of drugs with an increased
risk of side effects or drug interactions in the elderly, under -prescribing – refers to the
absence of drugs for which it has been shown to be effective in preventive or curative
indications in the elderly and over -prescribing refers to the use of therapies that do not
have therapeutic benefits. Such inadequate prescriptions can be identified in the
therapeutic p lan of each patient using explicit criteria listed in the literature. These criteria
contain lists of active substances that are recommended to be avoided or used with caution
in the elderly or medication that is recommended to be introduced into therapy. In
literature there are various validated instruments containing such criteria in one form or
another[25]. In the following, some of these criteria will be addressed.

Beers Criteria
The Beers criteria were drafted by the American Geriatric Society and firs t appeared in
1991 to identify potential inadequate drug prescriptions among institutionalized patients.
In the years 1997, 2003 and 2012, the list of criteria was revised and adapted to non –
institutionalized people. The fourth revised edition (2012) conta ins 53 medicines or drug
classes (34 of which are single drug -specific criteria) that are considered inappropriate for
people over 65 years of age receiving outpatient treatment or are institutionalized.
Potentially inappropriate medications( (PIM), defi ned as ineffective medications or
with high risk / benefit balance, are an important aspect of finding preventable prescription
problems. The prevalence of PIMs detected according to the Beers criteria varied between
18 and 42% of the studies conducted in different countries [28]. It is difficult to determine
whether the differences are due to the availability problems of drugs listed in the Beers
medicines in the local markets, or to the familiarity of prescriptive physicians with Beers
criteria or other design aspects of the study. Many international researchers have noted
difficulties in applying the Beers criteria in their countries. Several experts also disagreed
with some criteria in the Beers list [29]. Therefore, several country specific MIP criteri a
have been developed to improve the quality of prescriptions for the elderly in different
regions [30].

Laroche Criteria
The Laroche criteria were published in 2007 in France. The list contains 36 drug criteria
and was designed to detect prescriptions of potentially inappropriate medications for 75 –
year-olds in the community as well as in nursing homes. Among the 36 criteria, 29 refer
to drugs with an increased risk for use in the elderly and 5 drug criteria that should be
avoided under certain particular conditions [29].

PRISCUS criteria
The PRISCUS criteria was developed in Germany in 2010 at the request of the German
Ministry of Health. The list includes a set of 83 drug drugs or classes of drugs considered
potentially inappropriate for the elderly ≥ 65 years of age regardless of their disease or
clinical condition[31]. This list has 34 criteria, eight of which are drug -specific, including
six criteria for single medicines. The criteria are applicable to the entire population aged
65 and over, in the c ommunity or in nursing homes. [30]

START/STOPP criteria
In 2003, a group of Irish scientists developed the screening tool to alert to right treatment
(STOPP). [33] The first form of the START / STOPP criteria was published in 2008 and
includes 87 system -based criteria, and in 2015 the criteria were updated and 114 criteria
were reached, of which 80 STOPP criteria and 34 START criteria. If most of the design
criteria were drug -centered, the START / STOPP criteria link drug usage to the patient's
clinical co ndition.[33] STOPP / START version 2 shows a 31% increase in the total
number of criteria included in version 1. Gallangher et al., In a recent study reported that

the use of the STOPP / START criteria to examine elderly, along with the feedback
provided to the participating hospitals team, led to significant and sustained improvements
in prescribing adequacy. [34]
The potential of these tools has been confirmed in various clinical trials. Studies in
which the two types of criteria were applied noted that the use of the drugs included in the
Beers 2012 and STOPP criteria was associated with a hospital admission level of 30.3%
of residents of health care institutions. Matanović et al. found using the Beers criteria that
54% of hospitalizations for 454 patie nts were associated with the use of non -COX
selective nonsteroidal anti -inflammatory drugs, short and intermediate -acting
benzodiazepines and amiodarone [37]. The use of the STOPP / START criteria by
Frachentall et al has been used as a tool to reduce pres cribing errors, therefore, there has
been a reduction in the number of prescription drugs, the costs associated with therapy
and the average number of falls [38].
Moreover, some of these instruments have also been used as quality measures in several
insura nce programs, confirming their applicability to large population groups [33].
However, various studies have shown that identifying PIM with these tools depends on
the local availability of the drugs included and the local models of geriatric practice [17].
Consequently, the simultaneous use of several such instruments has been suggested as a
more effective method for detecting PIM in elderly populations different from those used
as a validation group for the original criteria. The local population follows t he trend of
aging identified at international level, while the rate of hospitalization among the elderly
people has an annual increase of 17.82% [17.25].
Medications recommended for the treatment of cardiovascular disease were most
frequently encountered, but for which the highest potential risk of inappropriate use was
observed. A potentially high risk has also been identified with anti -inflammatory drugs
prescribed for the elderly by doctors specialists or used in utomedication.Potential
concerns in this regard refer to the need for increased monitoring of treatment of the
elderly patient using cardiovascular, benzodiazepine or NSAIDs.To increase the safety of
prescribed therapies, criteria such as the STOPP criteria are a real help in this respect and
should also be used in our country.
Further research is needed to identify better solutions to evaluate the use of medicines in
the elderly

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