Central Annals of Public Health and Research

Research Article *Corresponding author

Annia M. Avalos-Mejía, Epidemiologic and Health

Prevalence and Risk Factors Service Research Unit, Aging Area, Mexican Institute of
Social Security, National Medical Center Century XXI,
Mexico City, Mexico, USA, Email:

of Potential Drug-Drug Submitted: 31 May 2017

Interactions in Older Adults

Accepted: 26 June 2017
Published: 28 June 2017
Copyright

Treated in Primary Health Care © 2017 Avalos-Mejía et al.

OPEN ACCESS
Cristina J. Ramírez-Espejel, Teresa Juárez-Cedillo, and Annia M.
Avalos-Mejía* Keywords
• Drug-Drug interactions; Primary health care;
Epidemiologic and Health Service Research Unit, National Medical Center, USA Polypharmacy

Abstract
Geriatric patients are the population that consumes a greater number of drugs compared to other populations, so the problems derived from their use
are also more frequent. This investigation intended to estimate the prevalence and major risk factors for potential DDI among older outpatients who are
treated in primary health care. The study population consisted of 384 patients over 60 years of age, who attended at least one medical consultation to the
Family Medicine Unit (FMU) No. 28 of the Mexican Social Security Institute (IMSS) from November 2014 to May 2015. Potential drug – drug interactions were
identified using the MicromedexDrugInterac software. The number of drugs administered simultaneously ranged from 2 to 22, with an average of 8.3 ± 3.5.
97.1% of the population presented polypharmacy. Of the polypharmacy patients, 81% had at least one potential DDI. 1,563 potential pharmacological
interactions were detected, with a mean of 4.1 potential DDI per patient (95% CI 3.6-4.5). Prevalence of potential DDI in a population of older adults was
78.9%, indicating that a high proportion of outpatients treated in primary health care are exposed to at least one potential DDI. Factors found to be associated
with the risk of having a potential DDI were: the number of drugs consumed the number of doctors being treated, as well as some categories of drugs. The
high prevalence of potential pharmacological interactions in the elderly ambulatory patients seen at the in primary health care, might be a significant health
problem but can be prevented by paying more attention to polypharmacy, the type of drugs prescribed and improving the communication between prescribers.

INTRODUCTION
Geriatric patients are the population that consumes a greater
number of drugs compared to other populations, so the problems
derived from their use are also more frequent. 61% of individuals
over the age of 65 have at least one drug, most taking an average
of three to five medications [1]. In Mexico in 2015 the percentage
of the population of older adults was 10.4% of the total population
[2].
Observational studies in this group of patients show a
high proportion of treatments with potentially serious drug
interactions, inadequate medication (especially psychotropic
drugs), lack of essential dosage, treatment aspects or effective
treatments and a high volume of related problems with
medications and adverse reactions. In another area, the
percentages of self-medication in these patients that increase the
possibilities of interactions are also alarming [3-5].
Drug-drug interactions (IFF) occur when a drug interferes
pharmacodynamically or pharmacokinetically with another
drug [6]. A potential pharmacological interaction (PIF) can
be predicted from the known pharmacological properties of
the drugs involved, although not necessarily in all patients [7],
Generally, the result of a pharmacological interaction can be
detrimental if the interaction causes an increase in the toxicity
of a drug or if it favors the appearance of adverse reactions. In
the same way, the interactions become beneficial, when they
produce an increase of the therapeutic effect and a reduction of
the toxicity. Or, they are clinically insignificant. Their effects will
depend on the dose of the interacting drugs, the length of time
they have been ingested, the route of administration used, the
half-life of the drugs involved, among others [3,8,9].
Physiological changes related to age and consequent changes
in pharmacokinetics and pharmacodynamics put the elderly
patients at high risk of presenting an adverse event due to a
potential DDI. It is established that the probability of potential
DDI increases with age, the number of drugs prescribed, with the
presence of chronic diseases [3,10]. The number of physicians
involved in care for a patient is the most important risk factor for
using an inappropriate drug combination [11].
The prevalence of drug interactions specifically in older
adults is not known. The estimates that have been made vary
from 46 to 80.4% [11,12-18].
The most commonly implicated in potentially serious
interactions drugs are those that are used continuously or
permanently in the clinical management of elderly people
with chronic diseases. Digoxin, diuretics, calcium antagonists,
hypoglycaemic oral agents, tricyclic antidepressants,
antiarrhythmics, warfarin, NSAIDs (including aspirin),
phenytoin, central acting analgesics, antacids, theophylline and

Cite this article: Ramírez-Espejel CJ, Juárez-Cedillo T, Avalos-Mejía AM (2017) Prevalence and Risk Factors of Potential Drug-Drug Interactions in Older
Adults Treated in Primary Health Care. Ann Public Health Res 4(4): 1067.
 Avalos-Mejía et al. (2017)
Email:

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antipsychotics often appear on the lists as common drugs in
potential DDI [7].
The aim of the present investigation was to estimate the
prevalence and major risk factors for potential DDI among older
outpatients who are treated in primary health care.
MATERIAL AND METHODS
The study population consisted of 384 patients over 60 years
of age, who attended at least one medical consultation to the
Family Medicine Unit (FMU) No. 28 of the Mexican Social Security
Institute (IMSS) from November 2014 to May 2015. From the
file of each patient was registered pharmacotherapy (name,
age, sex, weight and height), present diagnoses at the time of
the study, number of physicians who attended, pharmacological
treatment prescribed during the consultation (were included
the medications that the patient consumes in a chronic way by
indication of other doctors).
Potential drug - drug interactions between the prescribed
drugs and those that the patient was taking without a prescription
were not studied. When a drug presentation contained two
or more pharmacologically active ingredients each drug was
counted individually in the analysis (e.g. salmeterol/fluticasone).
However, if one patient was taking the same active ingredient in
more than one presentation, the drug was counted only once.
patients, 81% had at least one potential DDI (Figure 1). 1,563
potential pharmacological interactions were detected, with a
mean of 4.1 potential DDI per patient (95% CI 3.6-4.5).
Based on the ATC classification, the most frequently
administered drugs belong to the “A” food group and metabolism
(metformin 5.2%, omeprazole 3.1%), “C” cardiovascular system
(losartan 4.1%, pravastatin 3.2%) and “N” nervous system
(paracetamol 3.1%, clonazepam 2.3%).
Of the minor potential DDI, 23.6% consisted of the interaction
between acetylsalicylic acid + ranitidine; Of those corresponding
to moderate interactions, the most frequent was 3.4% of the
time, ranitidine + metformin; And finally between the serious
interactions 12.3% occurred after the concomitant use of
bezafibrate + pravastatin. Four contraindications were detected,
three of which were due to the concomitant use of metoclopramide
+ selective serotonin reuptake inhibitors (SSRIs).
According to their level of information, 47% of the potential
DDI detected are supported by documentation that fully suggests
that there is interaction, but there is a lack of well-controlled
studies. For 9% of interactions, controlled studies have clearly
established their existence.
Factors found to be associated with the risk of having a
potential DDI were: the number of drugs consumed the number

Potential drug – drug interactions were identified using the

MicromedexDrugInterac software [19]. From the data provided
by this program, each potential pharmacological interaction was
identified according to its clinical relevance, degree of scientific
evidence; and number of potential DDI per patient.

RESULTS
The demographic and clinical variables of the patients
were analyzed using descriptive statistical tests. Continuous Figure 1 Distribution of patients according to the type of
variables were expressed as mean and standard deviation and pharmacological therapy, polypharmacy and presence of potential
for categorical variables, percentages were calculated, and the pharmacological interactions.
corresponding 95% confidence intervals (Figure 1).
The normal distribution of the variables was verified, the Table 1: General characteristics of exposed patients who participated
comparison of numerical variables between patients presenting in the study.
with a potential DDI or more and controls was done with the Variable Exposed to a Unexposed to a
Mann Whitney U test and data are presented as mean and potential DDI potential DDI
standard deviation. Categorical variables were analyzed using
n=303 (%) n=81 (%)
Chi-square or Fisher’s exact test as required. To identify factors
associated with the presence of a potential DDI, univariate and Age (years) 73.9±8.0 75.0±8.8
multivariate binary logistic regression models were constructed Gender
to identify risk factors. Data analysis was performed with SPSS 23 Female 196 (64.7) 48 (59.3)
for Windows and STATA / SE 11.1.
Male 107 (35.3) 33 (40.7)
The sample analyzed consisted of 384 older adults, of whom No. of 5.3±2.4 4.9±2.3
244 (63.5%) were women, with a mean age of 74.1 ± 8.2 years. diagnostics
The most frequent diagnosis was systemic arterial hypertension
HAS 225 (58.6)* 50 (13)*
71.6% followed by type 2 diabetes mellitus with 54.9% and
chronic obstructive pulmonary disease with 24.2% (Table 1). Diabetes Mellitus 182(47.4)* 29(7.6)*
tipo II
A total of 3,164 drugs, involving 188 active ingredients, were
analyzed. The number of drugs administered simultaneously EPOC 67 (17.4) 26 (6.8)
ranged from 2 to 22, with an average of 8.3 ± 3.5 drugs. 97.1% *p≤0.05. Mann Whitney U test and Chi-square were used as appropriate,
of the population presented polypharmacy. Of the polypharmacy data are presented as mean and standard deviation. p values ≤ 0.05
were considered statistically significant.

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of doctors being treated, as well as some categories of drugs Table 2: Patient and pharmacotherapy characteristics associated with
(Table 2). potential DDI.
Univariate analysis Multivariate analysis
Medications of the cardiovascular system and musculoskeletal Variable
OR (IC95%) OR (IC95%)
system (codes C and M respectively) were found to be associated
with a potential DDI. There was no association between the Age
presence of a potential DDI and the use of the pharmacological 60-64
therapy to the ATC D, G, H, J, L, N, P, R, S codes. Among these are 65-69 1.9 (0.8-4.6) 1.3 (0.5-3.7)
ketoconazole, miconazole, clioquinol (ATC D); fenzopyridine, 70-74 1.8 (0.8-4.3) 1.0 (0.4-2.8)
sildenafil, tolterodine (ATC G); levothyroxine, pregabalin, > 75 1.2 (0.6-2.3) 0.6 (0.3-1.4)
prednisone. Gender
Female 1.3 (0.8-2.1)
Consuming five or more drugs increases the likelihood of
Diagnostics
a potential DDI by eight times. Figure (2) shows the risk of
01-may
presenting a potential DDI in patients exposed to polypharmacy
06-oct 1.2 (0.7-2.0)
in relation to the number of drugs administered simultaneously.
11-15 3.3 (0.4-25.8)
Univariate analysis determined that risk factors include Diagnostics > 3 1.2 (0.7-2.1)
the alimentary tract and metabolism (A code) and blood and Diagnostic de HTA 1.1 (0.7-2.0)
hematopoietic organs (B code) in pharmacotherapy, but the Diagnostic Diabetes 1.4 (0.9-2.4)
multivariate analysis did not confirm this association (Table 2). Diagnostic EPOC 0.5 (0.3-0.8)*
Drugs > 5 9.3 (5.4-16.1) Ɨ 8.5 (4.3-16.6) Ɨ
DISCUSSION
Physician > 2 2.2 (1.1-4.7)* 2.0 (0.8-4.9)
The prevalence of pharmacological interactions specifically ATC A 2.4 (1.3-4.5)* 1.3 (0.6-2.7)
in older adults is not well established, from the results of other ATC B 2.6 (1.5-4.8)* 1.7 (0.8-3.3)
studies it has been estimated that the prevalence ranges from ATC C 4.2 (2.2-8.2) Ɨ 3.6 (1.6-8.3)*
46% to 80.4% [11,12-18]. It was determined that the prevalence ATC D 1.8 (0.7-4.4)
of potential DDI in a population of older adults is 78.9%, indicating ATC G 1.2 (0.6-2.6)
that a high proportion of outpatients treated in primary health ATC H 3.2(0.8-14.1)
care are exposed to at least one potential DDI. This is similar to ATC J 1.3(0.5-3.3)
what was reported in Mexico and Germany [12,19]. However, ATC L 0.7 (0.1-3.5)
this result is above that reported in Brazil (47.4%), however,
ATC M 4.1 (2.2-7.5) Ɨ 3.1 (1.5-6.1)*
the great variability in design makes it very difficult the data
ATC N 1.4 (0.9-2.3)
comparison.
ATC R 0.9 (0.6-1.6)
High prevalence means that the frequency with which older ATC S 1.5 (0.8-2.9)
adults may present adverse effects caused by a pharmacological ATC V 0.6 (0.3-1.0)* 0.4 (0.2-0.9)*
interaction is greater, a preventable problem in taking into *p ≤ 0.05, Ɨ p < 0.001. Adjusted for age and gender. p values ≤ 0.05
account some practices such as assessing the risk benefit of adding were considered statistically significant. Multivariate analysis
one drug over another, Monitor the patient in order to determine adjusted for age and sex.
whether or not the adverse effect is present and to manage it
in the best way, either by changing one of the medications, the shortest possible period, and periodically reassess the need for
route and / or the schedule of administration. It is necessary to continued use. Special care should be taken with narrow-margin
limit prescribed drugs to essential drugs, administer them for the drugs [20].
The clinical relevance of potential DDI is not only determined
by what is reported in the literature, but will depend on the
characteristics of each patient, as increased interindividual
variability, fragility and reduced homeostasis increase the
complexity of management of the potential DDI in the elderly
[20].
In the analysis of potential DDI, it is necessary to include the
characteristics of the patient that can make the clinical relevance
of an interaction increase. For example, diuretics and digoxin
dependent on potassium levels, as the risk of digitalis toxicity
increases in the presence of hypokalemia such as that caused by
loop diuretics and thiazides; the association of oral anticoagulants
and NSAIDs in patients with a history of peptic ulcer significantly
increases the risk of gastrointestinal bleeding compared to the
Figure 2 Percentage of patients exposed to a potential DDI according population with no history [21]. It is equally important to know
to the number of drugs administered simultaneously.
those interactions that could be beneficial.

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Table 3: Most frecuent potential DDI.
Potential Drug-Drug Interaction Possible clinical effect
Ranitidine + Metformin Increased Metformin exposure
Enalapril + Metformin Increased risk of hypoglycemia
Hypoglycemia or hyperglycemia; decreased
Metoprolol + Metformin
symptoms of hypoglycemia
Bezafibrate + Pravastatin Increases the incidence and severity of myopathy
Diclofenac + Losartan Renal dysfunction and/ or increased blood pressure Pharmacodynamic
Acetylsalicilyc acid + Glyburide Increased risk of hypoglycemia
Chlorthalidone + Enalapril Reduction of blood pressure
Abbreviations: ATC H: aciclovir, amikacin, dicloxacillin; ATC J: ariastrazol, bicalutamide, methotrexate; ATC L: quetiapine, clonazepam, carbamazepine;
ATC N: albendazole, dimethicone, metronidazole; ATC P: fluticasone, salmeterol, theophylline; ATC R: timolol, dorzolamide, hypromellose .
It was detected that major potential DDI with higher
prevalence was caused by bezafibrate and pravastatin; with
this interaction the onset of myopathy or rhabdomyolysis has
been associated. In order to give a correct management of this
interaction, it is recommended to evaluate the risk / benefit of
this therapy and to monitor the patient in search of signs and
symptoms of such pathologies (muscle pain, tenderness or
weakness), and to suspend the use if creatine kinase levels (CK)
show a marked increase [19].
The prevalence of contraindicated interactions is low (0.8%),
three of which were due to the concomitant use of metoclopramide
and selective serotonin reuptake inhibitors, which may result
in an increased risk of extrapyramidal reactions or neuroleptic
malignant syndrome. Although the risk of this contraindication
is lower, it should be taken into account that antidepressants
are the treatment of choice for depression, anxiety disorders,
generalized anxiety [22] and that the elderly are one of the groups
that are more vulnerable to presenting these diseases [23], so it is
important to present care to patients under treatment with these
drugs, so as to avoid confusing an adverse effect with behavioral
disorders typical of psychiatric problems.
The use of ASA at low doses (≤ 100 mg / day) seems to
cause fewer interactions than at higher doses, depending on
the individual susceptibility that makes the interaction be or
not I presented [24]. It is reasonable to assume that these drugs
can interact at multiple levels, with agonism and antagonism of
varying intensity, depending on their concentrations and the
variable preponderance of the various types of prostaglandins
[25].
Potential DDI are more common in older adults treated in
older adults treated in primary health care (78.9%) than those
admitted to the department of internal medicine at a second
health care hospital (62.7%), according to Rosas et al.[18], This
can be explained by the fact that the outpatients included in
this study are treated at different levels, and the primary care
doctor usually adapts to the prescription of the specialist doctor,
adding more drugs to the therapy in order to attend to others
symptoms and / or comorbidities, according to the results of
this investigation, when 5 or more drugs are co-administered,
an increase of 8.49 times the risk of having a potential DDI. With
this, it is established that polypharmacy is a risk factor for older
adults to be exposed to a potential DDI.
Ann Public Health Res 4(4): 1067 (2017)
Avalos-Mejía et al. (2017)
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Mechanism Severity n (%)
Pharmacokinetic Moderate 40 (2.6)
Unknown Moderate 39 (2.5)
Pharmacodynamic Moderate 38 (2.4)
Unknown Major 37 (2.4)
Moderate 19 (1.2)
Unknown Moderate 18 (1.2)
Pharmacodynamic Moderate 18 (1.2)
Gender and age were not found to be associated with the
presence of potential DDI, unlike other studies where they
determined as risk factors for female gender (OR 2.71, 95% CI
2.49-2.95) and also increased risk of exposure to potential DDI as
age increased (OR 0.90; 95% CI 0.82-1.03) in patients aged 60-64
years to 4.03 (95% CI 3.79 - 4.28) in those aged 75 years or older
[13].
It was determined that if a patient receives prescriptions
from two doctors or more increases the risk of being exposed to
a potential DDI, this result is similar to that reported in previous
studies [13,26]. This problem is derived from different factors
that influence the prescription of pharmacological therapy, such
as the lack of communication between doctors treating the same
patient, as was observed during the preparation of this study, the
patient is used as a means of communication between levels of
care, therefore the information that reaches each doctor is scarce
[27,28], it also influences the technique used by the physician to
prescribe, most of them only use the medicines with which they
are familiar, generating a lack of agreement among prescribers.
With regard to the influence of ATC codes, C and M codes
were associated with the occurrence of potential DDI, univariate
analysis determined the A and B codes as risk factors, however
this association was not corroborated in the multivariate analysis.
The study conducted in Brazil by Obreli P et al., reports ATC
codes B, C, S and J as risk factors [13]. This discrepancy could be
due to the difference in the list of standard medicines for each
health system, determined by the epidemiological characteristics
and the current situation of each health service, which lead to
different characteristics of the prescription.
CONCLUSIONS
The prevalence of potential pharmacological interactions was
78.9% in the elderly ambulatory patients seen at the in primary
health care, which might be a significant health problem.
Most of the potential DDI detected were moderate which
means that the interaction may lead to an exacerbation of the
patient’s condition and / or require an alteration in therapy. It is
important to emphasize that the clinical relevance of a potential
DDI depends on the susceptibility of the patient.
The use of drugs of the cardiovascular and musculoskeletal
systems was determined as a risk factor, so it is important to pay
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attention to what type of drugs are prescribed to the elderly in
primary care.
Potential DDI in patients over 60 years of age can be
prevented by paying more attention to polypharmacy. To achieve
this, communication between prescribers should be encouraged
and the possible pharmacological interactions to which patients
may be exposed should be evaluated.
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