Wroclaw Medical University - Advances in Clinical and Experimental

Wroclaw Medical University - Advances in Clinical and Experimental

orIginal papers
Adv Clin Exp Med 2013, 22, 4, 555–563
ISSN 1899–5276
© Copyright by Wroclaw Medical University
Maria Ganeva1, A–F, Tanya Gancheva2, B–F, Jeni Troeva2, B, C,
Nataliya Kiriyak2, B, C, Evgenya Hristakieva2, C, E
Clinical Relevance of Drug-Drug Interactions
in Hospitalized Dermatology Patients*
Kliniczne znaczenie interakcji lekowych
u hospitalizowanych pacjentów leczonych dermatologicznie
1
2
Section of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Thracian University, Stara Zagora, Bulgaria
Clinic of Dermatology and Venereology, University Hospital, Stara Zagora, Bulgaria
A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation;
D – writing the article; E – critical revision of the article; F – final approval of article; G – other
Abstract
Background. Potential drug-drug interactions (DDIs) are known to be a risk factor for the development of adverse
drug reactions (ADRs). Data on the occurrence of ADRs related to DDIs is scarce and comes from different groups
of patients.
Objectives. The aim of the study was to evaluate the frequency, nature and determinants of potential DDIs in
hospitalized dermatology patients and assess their contribution for the development of ADRs.
Material and Methods. A prospective observational study comprising all consecutive inpatients admitted to the
Clinic of Dermatology and Venereology, University Hospital, Stara Zagora for the period March 2009 – August
2011 was carried out. Systemic medication was screened for potential DDIs using an electronic drug interactions
checker. DDIs were then verified with Stockley’s Drug Interactions and divided into “clinically important” and
“clinically unimportant”. ADRs were classified by clinical manifestation, type and severity. Causality was scored
according to Naranjo et al. (1981).
Results. The study included 674 patients, 513 (76.1%) of them with established comorbidities. Totally, 504 potential DDIs were identified (441 “clinically important” and 63 “clinically unimportant”) in 236 patients. Hypotension
was the most common expected clinical presentation of the potential DDIs. The strongest predictor for the development of DDIs was the number of systemic drugs (OR 2.25, 95% CI 1.97–2.58). Overall 43 ADRs were recorded,
53.5% “type B” and 46.5% “type A” reactions, most commonly with cutaneous and cardiovascular manifestations.
The development of ADRs was attributed to 13 DDIs (2.6% of all detected potential DDIs) in 10 of these cases
(23.25%).
Conclusions. Potential DDIs were frequent in hospitalized dermatology patients. The drug groups most commonly involved were cardiovascular drugs. The proportion of DDIs associated with the occurrence of ADRs was
relatively low, but close monitoring of patients on multiple drug regimens is essential because these reactions may
be severe (Adv Clin Exp Med 2013, 22, 4, 555–563).
Key words: drug-drug interaction, adverse drug reaction, hospital, dermatology.
Streszczenie
Wprowadzenie. Potencjalne interakcje lekowe (DDIs) są znanym czynnikiem ryzyka rozwoju działań niepożądanych leku (ADR). Dane na temat występowania działań niepożądanych związanych z DDIs są ograniczone,
a pochodzą z różnych grup pacjentów.
Cel pracy. Ocena częstości występowania, rodzaju i wyznaczników potencjalnych DDIs u hospitalizowanych
pacjentów leczonych dermatologicznie oraz ocena ich wkładu do rozwoju działań niepożądanych leku.
* Grant No. 22/2011 Family of Medicine, Thracian University, Stara Zagora, Bulgaria.
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M. Ganeva et al.
Materiał i metody. Przeprowadzono prospektywne badanie obserwacyjne obejmujące wszystkich kolejnych
pacjentów przyjętych do Kliniki Dermatologii i Wenerologii, Szpitala Uniwersyteckiego w Starej Zagorze w okresie
marzec 2009 – listopad 2011. Podawanie leków układowych monitorowano pod kątem potencjalnych DDIs za
pomocą elektronicznego urządzenia do sprawdzania interakcji. DDIs były następnie weryfikowane na podstawie
„Stockley’s Drug Interactions” i podzielone na „klinicznie istotne” i „klinicznie nieistotne”. Działania niepożądane
zostały sklasyfikowane według objawów klinicznych, rodzaju i stopnia nasilenia. Przyczynowość oceniano według
Naranjo et al. (1981).
Wyniki. Do badania włączono 674 pacjentów, 513 (76,1%) z nich cierpiało na choroby współistniejące. W sumie
zidentyfikowano 504 potencjalne DDIs (441 „klinicznie istotnych” i 63 „klinicznie nieistotne”) u 236 pacjentów.
Niedociśnienie tętnicze było najczęściej oczekiwanym klinicznym objawem potencjalnych DDIs. Najsilniejszym
predyktorem rozwoju DDIs była liczba leków układowych (OR 2,25, 95% CI 1.97–2.58). Ogólnie odnotowano
43 działania niepożądane leku; 53,5% reakcji „typu B” i 46,5% reakcji „typu A”, najczęściej były to objawy skórne
i pochodzące z układu krążenia. Rozwój działań niepożądanych leku był związany z 13 DDIs (2,6% wszystkich
wykrytych potencjalnych DDIs) w 10 przypadkach (23,25%).
Wnioski. Potencjalne DDIs występowały często u hospitalizowanych pacjentów leczonych dermatologicznie. Grupa
leków, które najczęściej je wywoływały to leki sercowo-naczyniowe. Odsetek DDIs związanych z występowaniem
działań niepożądanych był stosunkowo mały, ale ścisłe monitorowanie pacjentów poddanych wielolekowej terapii
jest niezbędne, ponieważ reakcje te mogą być ciężkie (Adv Clin Exp Med 2013, 22, 4, 555–563).
Słowa kluczowe: interakcje między lekami, działanie niepożądane, szpital, dermatologia.
Drug-drug interactions (DDIs) are considered
to be an important risk factor in the development
of adverse drug reactions (ADRs) [1, 2]. The aging
of the population, polymorbidity and polypharmacy, and the introduction of new drugs are all associated with a high probability of development of
DDIs. The clinical outcome of DDIs may be either
increased risk of adverse effects/toxicity or loss of
efficacy. Since the clinical manifestation of DDIs is
not always present they are often referred to as potential DDIs. A study of ADRs from the UK estimated that 16.6% of ADRs leading to hospital admission were associated with DDIs [3]. Although other
studies have reported even higher proportions of
DDIs underlying the development of ADRs, some
authors question the clinical relevance of potential DDIs [4, 5]. Data suggests that certain population groups like the elderly, patients from intensive
care units and oncology patients are at high risk of
drug-related morbidity due to DDIs [6, 7].
The recognition and management of potential
DDIs is a matter of good prescribing practice and
clinical care for which the use of drug information services is essential. Potential DDIs are usually detected with various computerized screening programs displaying different sensitivity and
specificity compared to the gold standard Stockley’s Drug Interactions, as a study from Switzerland showed [8]. Thus the results from various
studies on DDIs are difficult to be compared and
interpreted. It is possible that many DDIs remain
under-recognized [9].
Drug groups of particular significance for dermatologists considering their potential for DDIs are
“general antiinfectives” and “antihistamines” [10].
A preliminary study of adverse DDIs in dermatology patients showed that 25.5% of the investigated cohort had a potential adverse DDI and
cardiovascular drugs were prevalently involved in
these interactions [11].
The aim of the present study was to evaluate
the frequency, nature and determinants of potential DDIs in hospitalized dermatology patients and
assess their contribution for the development of
ADRs.
Material and Methods
Patient Population
The investigation is a part of a prospective
pharmacovigilance study carried out among patients admitted to the Clinic of Dermatology and
Venereology at the University Hospital in Stara Zagora. All consecutive adult and pediatric inpatients
admitted to the Clinic for the period March 2009
– August 2011 were screened for potential DDIs.
Information on systemic medication was collected on the day of admission and the medical charts
were followed for further changes during the period of hospitalization. For each patient, additionally the following data was recorded: demographic characteristics, primary diagnosis, concomitant
diseases, history of previous ADRs, failure of excretory organs. The International Classification of
Diseases, version 10 (ICD-10) and the Anatomical
Therapeutic Chemical (ATC) classification system
were used to codify data [12, 13].
All ADRs including those resulting from DDIs
were recorded in a structured form containing
further information on drug history covering the
last three months preceding hospitalization, clinical description of the adverse event, laboratory
tests and reviews of consultants. The study was approved by the local ethics committee.
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Clinical Relevance of Drug-Drug Interactions
Definition of Drug-Drug
Interactions
DDIs were defined according to Ritter et al.,
as the modification of the action of one drug by
another as a result of one or more of three different kinds of mechanisms: pharmaceutical, pharmacodynamic and pharmacokinetic [1]. Using the
ePocrates® drug interactions checker, DDIs were
classified into the following categories: “therapeutic advantage”, “caution advised”, “monitor/modify therapy”, “avoid/use alternative” according to
clinical management [14]. For each interaction,
the DDI checker lists the expected or possible effects of the drug combination, and the proposed
mechanism of the interaction. DDIs were then verified using the hard copy of Stockley’s Drug Interactions and classified into two groups: “clinically important” and “clinically unimportant”, when
that was explicitly stated [15]. Drug preparations
and DDIs not found in ePocrates® were added.
DDIs not found in Stockley’s Drug Interactions
were excluded.
Definition of Adverse Drug
Reactions
ADRs were defined according to the WHO [16].
Patients with non-skin ADRs recognized during hospitalization in the department were consulted by the respective specialists. The ADRs
were classified by clinical manifestation using
WHO-ART Adverse Reaction Terminology and
by type as “type A” if related to the pharmacological properties of the suspected drug, and “type B”
if otherwise [17, 18]. According to their severity,
ADRs were assessed as “severe” (life-threatening
or serious condition with progressive organ dysfunction), “moderate” (fair condition, transitory
organ dysfunction) and “mild” (good condition
with minor/no organ dysfunction). The relationship between the drug and the reaction was scored
as “definite”, “probable”, “possible” and “doubtful”
following the method of Naranjo et al. [19].
Statistical Analysis
Continuous variables were tested for normality using the Kolmogorov-Smirnov test. Because
the study values were not normally distributed, the
results were presented as median and interquartile
range (25th–75th percentile). The non-parametric
Mann-Whitney U test was applied to determine between-group differences. Logistic regression analysis was used to evaluate the relationship between
the occurrence of DDIs and the factors age, female
sex, maximum number of systemic drugs used by
the patients and the length of hospital stay. Adjustment for possible confounders was made using
multiple logistic regression. A value of p < 0.05 was
considered statistically significant. Analyses were
performed using SPSS for Windows version 9.0.
Results
Patient Characteristics
A total of 674 patients, 355 female and
319 male, with an age range 1–90 years (median 54, interquartile range: 39–67) were included in
the study. The demographic characteristics and the
clinico-pharmacological risk factors are shown in
Table 1.
The main causes for hospitalization by primary diagnosis, coded by the ICD version 10, were
infectious dermatoses “L00–L08” in 217 patients
(32.2%) and eczema/dermatitis “L20–L30” in
200 patients (29.7%). Concomitant disease states
were detected in 513 cases – 76.1% of the total
study population (Table 1). Cardiovascular diseases were diagnosed in 356 patients (52.8%) and
were the most frequent type of concomitant diseases. Cardiovascular drugs (ATC code C) and antihistamines (ATC code R) were the groups most
commonly used in the study population (Table 2).
Hospital stay in the examined cohort of patients was median 8 days (interquartile range:
7–10 days).
Drug-Drug Interactions
Initial online screening for DDIs with the
ePocrates® drug interactions checker revealed 496
DDIs in 226 patients (Table 3). The prevalent type
were DDIs which required careful monitoring
and modifications in drug regimens – 304 DDIs
(61.3%) in 152 patients. DDIs from the category
“avoid/use alternative” numbered 59 (11.9%) and
from the category “caution advised”, 112 (22.6%).
More than one DDI was detected in 119 patients,
the maximum number per patient being 9.
Subsequent verification of these DDIs in
Stockley’s Drug Interactions yielded 379 clinically important DDIs and 63 clinically unimportant
DDIs (Table 3). Additionally, 62 clinically important new DDIs were found resulting from drugs
not present in the drug list of the ePocrates® drug
interactions checker. Totally, 504 DDIs were identified (441 clinically important and 63 clinically unimportant) in 236 patients – 118 male and
118 female, with an age range 15–89 years (median 63, interquartile range: 53–72). More than one
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Таble 1. Characteristics of the patient population
Tabela 1. Charakterystyka pacjentów
Characteristic
(Cecha)
Number of pts
(Liczba pacjentów)
N (%)
Age above 65 years (Wiek powyżej 65 lat)
203 (30.1)
Children (Dzieci)
41 (6.08)
Female (Kobiety)
355 (52.7)
Previous ADR (Uprzednie niepożądane działania leku)
73 (10.8)
Excretory organ failure (Niewydolność układu moczowego)
9 (1.3)
Concomitant diseases (grouped according to ICD-10)
(Choroby współistniejące pogrupowane według klasyfikacji ICD-10)
   diseases of the circulatory system
   endocrine, nutritional and metabolic diseases
   diseases of the digestive system
   diseases of the genitourinary system
   mental and behavioural disorders
   diseases of the respiratory system
   diseases of the musculoskeletal system and connective tissue
   diseases of the nervous system
   diseases of the blood and blood-forming organs
   diseases of the ear and mastoid process    diseases of the eye and adnexa    certain infectious and parasitic diseases 356 (52.8)
152 (22.5)
91 (13.5)
83 (12.3)
80 (11.9)
48 (7.1)
43 (6.4)
42 (6.2)
27 (4)
14 (2.1)
11 (1.6)
1 (0.1)
pts – patients; % – percent of total; ADR – adverse drug reaction; ICD-10 – International Classification of Diseases, version 10.
pts – pacjent; % – procent wszystkich; ADR – niepożądane działanie leku, ICD-10 – Międzynarodowa Klasyfikacja Chorób,
wersja 10.
Table 2. Systemic therapy according to the Anatomical Therapeutic Chemical (ATC) classification
Tabela 2. Leczenie układowe według klasyfikacji „Anatomiczno-terapeutycznej związków chemicznych” (ATC)
ATC code
(Kod ATC)
Main drug group (Główna grupa leków)
N of pts (Liczba pacjentów)
A
alimentary tract and metabolism
150
B
blood and blood forming organs
242
C
cardiovascular system
324
G
genitourinary system and sex hormones
5
H
systemic hormonal preparations, excl. sex hormones and insulins
80
J
anti-infectives for systemic use
311
L
antineoplastic and immunomodulating agents
1
M
musculo-skeletal system
24
N
nervous system
178
R
respiratory system
321
S
sensory organs
1
pts – patients.
pts – pacjenci.
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Clinical Relevance of Drug-Drug Interactions
Table 3. Distribution of drug-drug interactions by type (ePocrates® and Stockley’s Drug Interactions)
Tabela 3. Rozkład interakcji lekowych według rodzaju (ePocrates® i Stockley’s Drug Interactions)
ePocrates®
Stockley
N
(%)
therapeutic
advantage
caution
advised
monitor/
modify
avoid/use
alternative
total
clinically important
clinically
unimportant
total
Pts
21 (9.3%)
93 (41.2%)
152 (67.3%)
50 (22.1%)
226*
225 (95.3%)
54 (22.8%)
236**
DDIs
21 (4.2%)
112 (22.6%)
304 (61.3%)
59 (11.9%)
496
379+62 (87.5%)
63 (12.5%)
504
pts – patients; *70 pts had more than 1 type of DDI (ePocrates); **43 pts had more than 1 type of DDI (Stockley’s).
pts – pacjenci; * 70 pkt miał więcej niż 1 rodzaj DDI (ePocrates); ** 43 pkt miał więcej niż 1 rodzaj DDI (Stockley’s).
DDI was present in 125 patients. The positive predictive value of the ePocrates® drug interactions
checker was estimated as 0.89.
Pharmacological groups like diuretics (187
DDIs), angiotensin-converting enzyme (ACE)inhibitors (90 DDIs) and antidiabetic agents
(80 DDIs) were commonly involved in DDIs
(Table 4).
The prevalent clinical outcome of the detected DDIs was increased toxicity or risk of adverse
effects, and only 73 DDIs (14.5%) of all 504 were
associated with a possible decrease in drug efficacy due to the antagonistic effects of the interacting
drugs or pharmacokinetic mechanisms. Therapeutic advantage resulting from enhanced bactericidal activity in the combinations of penicillins and
aminoglycosides was the only beneficial DDI with
no potential of adverse effects found in this study
(14 DDIs or 2.8%). Risk of hypotension due to
a combination of ACE-inhibitors or angiotensin2-
Table 4. Most common clinically important drug-drug interactions in hospitalized dermatology patients
Tabela 4. Najczęstsze klinicznie istotne interakcje lekowych u hospitalizowanych pacjentów leczonych dermatologicznie
I. General DDIs (Ogólne DDIs)
Drug groups (Grupy leków)
DDIs (N)
Potential effects (Potencjalne działania)
ACE-inhibitors + Diuretics, thiazides/loop diuretics
65
first-dose hypotension
Antipsychotics + Benzodiazepines and related drugs
27
additive CNS depressant effects
ARBs + Diuretics, thiazides
26
symptomatic hypotension
Coumarins + Antibacterials
18
increased risk of bleeding
Beta-blockers + Digoxin and related drugs
17
potential for additive bradycardia
Digoxin and related drugs + Diuretics, potassiumdepleting
16
digitalis toxicity
Beta-blockers + Clonidine and related drugs
15
worsening the rebound hypertension following
clonidine withdrawal, bradycardia
Penicillins + Aminoglycosides
14
enhanced bactericidal activity
Antidiabetics + Diuretics, thiazides
12
impaired control of diabetes
Thiazides + Loop diuretics
12
hypokalemia, hypotension
Clonidine + Calcium-channel blockers
11
additive effects such as bradycardia and AV
block
Drug groups (Grupy leków)
DDIs (N)
Potential effects (Potencjalne działania)
Antihistamines + Benzodiazepines and related drugs
16
sedation, additive CNS depressant effects
Antihistamines + Antihistamines
15
additive CNS depressant effects
II. Dermatologic DDIs (Dermatologiczne DDIs)
ACE – angiotensin-converting enzyme; ARBs – angiotensin2-receptor-blockers.
ACE – inhibitory konwertazy angiotensyny, ARB – leki blokujące receptor angiotensyny 2.
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M. Ganeva et al.
receptor-blockers (ARBs) plus diuretics was the
most frequently encountered potential effect of
DDIs in the study population.
Pharmacodynamic mechanisms were involved
in 410 of the detected DDIs (81.35 %), pharmacokinetic in 49 DDIs (9.72%) and the rest were not
well understood (e.g. increased effects of anticoagulants when combined with certain antibacterials,
hypoglycemia following the combination of quinolones and antidiabetics).
Elderly patients (above 65 years) took a higher number of drugs (median 5, interquartile range:
4.0–7.0) than younger patients (median 3, interquartile range: 2.0 – 5.0), p = 0.0001. Patients with
DDIs received significantly (p = 0.0001) more
drugs (median 6, interquartile range: 5.0–8.0) than
patients without DDIs (median 2, interquartile
range: 1.0–4.0).
The logistic regression analysis showed that
the development of DDIs was significantly associated with a higher number of drugs (adjusted OR
2.23, 95% CI 1.96–2.55) and old age (adjusted OR
1.02, 95% CI 1.01–1.04). Female sex (adjusted OR
0.8, 95% CI 0.51–1.25) and the length of hospital
stay (adjusted OR 0.99, 95% CI 0.89–1.09) were not
found to be predictive of the occurrence of DDIs.
Adverse Drug Reactions
For the study period, 43 ADRs were recorded
in 42 patients. The distribution of ADRs according to ADR type revealed 23 (53.5%) “type B” reactions and 20 (46.5%) “type A” reactions. Severe reactions numbered 3, moderate 33, and mild 7. The
causal relationship between the drug and the reaction were scored as „possible” in 24 ADRs and as
„probable” in 19 ADRs.
Cutaneous ADRs (24 ADRs) presented with
a variety of clinical manifestations, the prevalent
clinical patterns being exanthematous and urticarial. Cardiovascular ADRs (7ADRs) were in all
cases hypotonia. Resistance mechanism disorders
(3ADRs) were detected in patients with microbiological evidence for mucocutaneous or intestinal
candidiasis after treatment with antibiotics or glucocorticosteroids. There were few cases of urinary
system disorders, metabolic and nutritional disorders, vision disorders, etc.
The most common etiologic agents were antiinfectious drugs (15 ADRs). Other drug groups associated with the development of ADRs were analgesics and non-steroidal antiinflammatory agents
(5 ADRs), glucocorticosteroids (3 ADRs), thiazide
diuretics (3 ADRs). In 10 cases, it was impossible
to detect a single ADR-inducing drug due to the
concomitant use of drugs capable of inducing the
adverse event.
The development of ADRs was attributed to
underlying DDIs in 10 of these cases (23.25%). The
majority of them presented as hypotension (7 cases), the rest being single cases of melena, hypokalemia and somnolence and dizziness (Table 5).
In two patients, more than 1 DDI per patient
that could contribute to the development of ADRs
was detected. Overall 13 DDIs were found in 10 patients who experienced an ADR.
Discussion
Potential DDIs were found in a significant part
of the hospitalized dermatology patients – 35.5%
(236 patients) of the study population (674 patients). This frequency is similar to the results of
Zwart-van Rijkom et al., who report 27.8% of hospitalized patients to have experienced at least one
DDI, although many studies have identified higher proportions of hospitalized patients with DDIs
– 49.7% in the study of Cruciol-Souza and Thomson, 66% in the study of Blix et al. [20–22]. These
differences can be attributed to variations in the
morbidity and drug use in the examined patient
cohorts, and also to the methods used for the detection of DDIs. It is also possible that the time
of observation in this study was too short (median 8 days) for the clinical or laboratory manifestation of expected ADRs resulting from DDIs, and at
least some of these events might have been evident
after hospital discharge.
Consistent with findings from studies of potential DDIs in various patient populations, the
number of prescribed drugs was significantly associated with DDIs [23, 24]. In this study it was the
strongest predictor for the development of DDIs.
The drug groups most commonly involved in
DDIs were cardiovascular drugs (diuretics, ACE-inhibitors, ARBs, beta-blockers, etc.). High consumption of cardiovascular drugs due to the presence of cardiovascular diseases in 52.8% of the
­patients included in the study provides the basis
for such interactions.
Cardiovascular drugs have often been found to
be among the most frequent drug groups involved in
potential DDIs in studies from hospitals and ambulatory patients [4, 20, 25, 26]. Cardiovascular drugs
are often combined for additive beneficial effects in
the treatment of a common disease like hypertension or for handling a coexistent cardiovascular disease state. Careful monitoring and dosage adjustment may be required due to the risk of adverse
effects. DDIs involving different groups of cardiovascular drugs led to the development of hypotension and hypokalemia, and these ADRs constituted
80% of all ADRs caused by DDIs in this study.
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Table 5. Adverse drug reactions related to drug-drug interactions
Tabela 5. Działania niepożądane związane z interakcjami lek–lek
Organ/system
(Układ)
Symptom/laboratory abnormality
(Objaw/zaburzenie laboratoryjne)
DDIs* (N)
Central nervous system disorders
(Zaburzenia układu nerwowego)
somnolence and dizziness
antihistamine + neuroleptic (1)
Metabolic and nutritional disorders
(Zaburzenia metabolizmu i odżywiania)
hypokalemia
loop diuretic + thiazide (1)
Cardiovascular disorders
(Zaburzenia sercowo-naczyniowe)
hypotension
ACE-inhibitor + thiazide (3)
ACE-inhibitor + loop diuretic (2)
thiazide + loop diuretic (1)
ARB + thiazide (2)
ARB + nitrate (1)
Gastro-intestinal system disorders
(Zaburzenia żołądkowo-jelitowe)
melena
clopidogrel + aspirin (1)
aspirin + glucocorticosteroid (1)
* Specific drugs involved in DDIs: cyproheptadine–chlorpotixene; indapamide–furosemide; enalapril–indapamide;
quinapril–indapamide; trandolapril–indapamide; enalapril–furosemide; quinapril–furosemide; chlorthalidone–furosemide;
losartan–hydrochlorothiazide; telmisartan–hydrochlorothiazide; losartan– isosorbide dinitrate; aspirin–methylprednisolone.
* Leki wywołujące DDiS: cyproheptadyna–chlorprotiksen; indapamid–furosemid; enalapryl–indapamid; chinapryl–
indapamid; trandolapryl–indapamid; enalapryl–furosemid; chinapryl–furosemid; chlortalidon–furosemid; losartan–
hydrochlorotiazyd; telmisartan–hydrochlorotiazyd; losartan–izosorbidu diazotan; aspiryna–metyloprednizolon.
In agreement with other studies, anticoagulants were also found to be frequently implicated
in DDIs [20, 23, 24]. Since strict clinical and laboratory monitoring of hospitalized dermatology patients on coumarins has been performed, no actual
DDIs with these high risk drugs were detected during the study period.
Typical for this cohort of patients were DDIs
including central nervous system (CNS) depressants like antihistamines, benzodiazepines and
antipsychotics with potential additive CNS depressant effects (Table 4). Although second-generation antihistamines (loratadine, desloratadine,
cetirizine, levocetirizine, etc.) are designated as
“non-sedating”, some studies show that they can
also induce sedation, especially if used in higher
doses [27]. Sleepiness and impaired psychomotor
function are the expected clinical outcomes resulting from DDIs between first- and second-generation antihistamines as well as between antihistamines and benzodiazepines or antipsychotics.
Sedation may not always be an unwanted effect in
hospitalized dermatology patients with intensely
pruritic dermatoses, but in outpatients it is always
problematic.
Although a substantial part of the potential
DDIs in this study (87.5%) were considered clinically significant, only 2.6% (13 DDIs) were implicated in the development of ADRs. These results
are very similar to the results from a study evaluating admissions to medical hospital departments
because of potential DDIs showing that 2.4% of
all patients with potential DDIs were admitted because of an ADR caused by a DDI [28].
A higher incidence of DDI-related ADRs has
been found in elderly hospitalized and outpatients [4, 7, 29]. Sixteen studies performed from
2000 to 2010 reported an elevated risk for hospitalization in older adults associated with adverse
drug interactions [30]. Alterations in physiological functions, polymorbidity and polypharmacy in
elderly patients account for higher frequencies of
DDIs in this age group. Age was not a strong predictor of DDIs in this study compared to the factor
“number of drugs used”. Polymorbidity and related consumption of multiple drugs but not age itself seem to be more important predisposing factors for the occurrence of DDIs.
Although limited to dermatology patients from
one hospital, this study provides evidence that the
DDI risk profile of this patient group does not differ substantially from the profile of patients from
other medicinal wards. It is well established that
the number of medications and old age are predictors for DDIs, although other factors like female
sex, length of hospital stay and suffering from cardiovascular disease have also been mentioned in
literature [21, 24, 25]. Variations in the reported prevalence rates of DDIs coming from diverse
study populations are due not only to differences
in patient characteristics and drug consumption,
but also to the methods used to detect DDIs. The
authors applied a two-step method using a quick
on-line drug interactions checker followed by
562
M. Ganeva et al.
verification in Stockley’s Drug Interactions. This is
a time-consuming procedure but it was necessary
to accurately identify DDIs despite the differences in drug nomenclature in these two information
resources. ePocrates® demonstrated a satisfactory
sensitivity to detect positive cases for DDIs.
The proportion of patients with DDI-related
ADR amounted to 23.25% of all patients presenting with ADRs for the study period. It is generally estimated that between 6 and 30% of all ADRs
are due to DDIs [6]. The authors report one case of
gastrointestinal bleeding due to DDIs between antiplatelet agents and glucocorticosteroids. Others
investigating ADRs caused by DDIs have detected
gastro-intestinal bleeding as a very common clinical manifestation of such ADRs, along with electrolyte disturbances, hyper- or hypotension and
cardiac rhythm disorders [5, 29].
Potential DDIs were detected in one-third
of hospitalized dermatology patients. The drug
groups most commonly involved in DDIs were
cardiovascular drugs. The present findings confirm results from studies showing that the proportion of DDIs associated with potentially relevant
clinical consequences appears to be relatively low.
No matter how rare these cases are, patients at risk
for potential DDIs should be closely monitored in
order to prevent the development of ADRs which
may be severe and require specific treatment. Special attention should be paid to elderly patients and
patients with chronic diseases on long term medication, especially cardiovascular, and to those using high-risk drugs like anticoagulants and antiplatelet agents.
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Address for correspondence:
Maria Ganeva
Section of Pharmacology and Clinical Pharmacology
Faculty of Medicine
Thracian University
11 Armeiska St
6000 Stara Zagora
Bulgaria
Tel.: 00359 42664/310
E-mail: [email protected]
Conflict of interest: None declared
Received: 31.08.2012
Revised: 28.01.2012
Accepted: 12.08.2013