Original Papers

orIginal papers

Adv Clin Exp Med 2013, 22, 4, 555–563 © Copyright by Wroclaw Medical University ISSN 1899–5276

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 Section of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Thracian University, Stara Zagora, Bulgaria 2 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 niepożą- danych 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. 556 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 cardiovascular drugs were prevalently involved in to be an important risk factor in the development these interactions [11]. of adverse drug reactions (ADRs) [1, 2]. The aging The aim of the present study was to evaluate of the population, polymorbidity and polypharma- the frequency, nature and determinants of poten- cy, and the introduction of new drugs are all as- tial DDIs in hospitalized dermatology patients and sociated with a high probability of development of assess their contribution for the development of DDIs. The clinical outcome of DDIs may be either ADRs. 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 po- Material and Methods tential DDIs. A study of ADRs from the UK estimated that 16.6% of ADRs leading to hospital admis- Patient Population sion were associated with DDIs [3]. Although other studies have reported even higher proportions of The investigation is a part of a prospective DDIs underlying the development of ADRs, some pharmacovigilance study carried out among pa- authors question the clinical relevance of poten- tients admitted to the Clinic of Dermatology and tial DDIs [4, 5]. Data suggests that certain popula- Venereology at the University Hospital in Stara Za- tion groups like the elderly, patients from intensive gora. All consecutive adult and pediatric inpatients care units and oncology patients are at high risk of admitted to the Clinic for the period March 2009 drug-related morbidity due to DDIs [6, 7]. – August 2011 were screened for potential DDIs. The recognition and management of potential Information on systemic medication was collect- DDIs is a matter of good prescribing practice and ed on the day of admission and the medical charts clinical care for which the use of drug informa- were followed for further changes during the pe- tion services is essential. Potential DDIs are usu- riod of hospitalization. For each patient, additionally detected with various computerized screen- ally the following data was recorded: demograph- ing programs displaying different sensitivity and ic characteristics, primary diagnosis, concomitant specificity compared to the gold standard Stock- diseases, history of previous ADRs, failure of ex- ley’s Drug Interactions, as a study from Switzer- cretory organs. The International Classification of land showed [8]. Thus the results from various Diseases, version 10 (ICD-10) and the Anatomical studies on DDIs are difficult to be compared and Therapeutic Chemical (ATC) classification system interpreted. It is possible that many DDIs remain were used to codify data [12, 13]. under-recognized [9]. All ADRs including those resulting from DDIs Drug groups of particular significance for der- were recorded in a structured form containing matologists considering their potential for DDIs are further information on drug history covering the “general antiinfectives” and “antihistamines” [10]. last three months preceding hospitalization, clin- A preliminary study of adverse DDIs in derma- ical description of the adverse event, laboratory tology patients showed that 25.5% of the inves- tests and reviews of consultants. The study was ap- tigated cohort had a potential adverse DDI and proved by the local ethics committee. Clinical Relevance of Drug-Drug Interactions 557

Definition of Drug-Drug sex, maximum number of systemic drugs used by Interactions the patients and the length of hospital stay. Ad- justment for possible confounders was made using DDIs were defined according to Ritter et al., multiple logistic regression. A value of p < 0.05 was as the modification of the action of one drug by considered statistically significant. Analyses were another as a result of one or more of three differ- performed using SPSS for Windows version 9.0. ent kinds of mechanisms: pharmaceutical, pharmacodynamic and pharmacokinetic [1]. Using the ePocrates® drug interactions checker, DDIs were Results classified into the following categories: “therapeutic advantage”, “caution advised”, “monitor/mod- Patient Characteristics ify therapy”, “avoid/use alternative” according to clinical management [14]. For each interaction, A total of 674 patients, 355 female and the DDI checker lists the expected or possible ef- 319 male, with an age range 1–90 years (medi- fects of the drug combination, and the proposed an 54, interquartile range: 39–67) were included in mechanism of the interaction. DDIs were then ver- the study. The demographic characteristics and the ified using the hard copy of Stockley’s Drug Inter- clinico-pharmacological risk factors are shown in actions and classified into two groups: “clinical- Table 1. ly important” and “clinically unimportant”, when The main causes for hospitalization by prima- that was explicitly stated [15]. Drug preparations ry diagnosis, coded by the ICD version 10, were and DDIs not found in ePocrates® were added. infectious dermatoses “L00–L08” in 217 patients DDIs not found in Stockley’s Drug Interactions (32.2%) and eczema/dermatitis “L20–L30” in were excluded. 200 patients (29.7%). Concomitant disease states were detected in 513 cases – 76.1% of the total study population (Table 1). Cardiovascular dis- Definition of Adverse Drug eases were diagnosed in 356 patients (52.8%) and Reactions were the most frequent type of concomitant diseases. Cardiovascular drugs (ATC code C) and an- ADRs were defined according to the WHO [16]. tihistamines (ATC code R) were the groups most Patients with non-skin ADRs recognized dur- commonly used in the study population (Table 2). ing hospitalization in the department were con- Hospital stay in the examined cohort of pa- sulted by the respective specialists. The ADRs tients was median 8 days (interquartile range: were classified by clinical manifestation using 7–10 days). WHO-ART Adverse Reaction Terminology and by type as “type A” if related to the pharmacological properties of the suspected drug, and “type B” Drug-Drug Interactions if otherwise [17, 18]. According to their severity, Initial online screening for DDIs with the ADRs were assessed as “severe” (life-threatening ePocrates® drug interactions checker revealed 496 or serious condition with progressive organ dys- DDIs in 226 patients (Table 3). The prevalent type function), “moderate” (fair condition, transitory were DDIs which required careful monitoring organ dysfunction) and “mild” (good condition and modifications in drug regimens – 304 DDIs with minor/no organ dysfunction). The relation- (61.3%) in 152 patients. DDIs from the category ship between the drug and the reaction was scored “avoid/use alternative” numbered 59 (11.9%) and as “definite”, “probable”, “possible” and “doubtful” from the category “caution advised”, 112 (22.6%). following the method of Naranjo et al. [19]. More than one DDI was detected in 119 patients, the maximum number per patient being 9. Subsequent verification of these DDIs in Statistical Analysis Stockley’s Drug Interactions yielded 379 clinical- Continuous variables were tested for normally important DDIs and 63 clinically unimportant ity using the Kolmogorov-Smirnov test. Because DDIs (Table 3). Additionally, 62 clinically impor- the study values were not normally distributed, the tant new DDIs were found resulting from drugs results were presented as median and interquartile not present in the drug list of the ePocrates® drug range (25th–75th percentile). The non-parametric interactions checker. Totally, 504 DDIs were iden- Mann-Whitney U test was applied to determine be- tified (441 clinically important and 63 clinical- tween-group differences. Logistic regression analy- ly unimportant) in 236 patients – 118 male and sis was used to evaluate the relationship between 118 female, with an age range 15–89 years (medi- the occurrence of DDIs and the factors age, female an 63, interquartile range: 53–72). More than one 558 M. Ganeva et al.

Таble 1. Characteristics of the patient population Tabela 1. Charakterystyka pacjentów

Characteristic Number of pts (Cecha) (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 356 (52.8) endocrine, nutritional and metabolic diseases 152 (22.5) diseases of the digestive system 91 (13.5) diseases of the genitourinary system 83 (12.3) mental and behavioural disorders 80 (11.9) diseases of the respiratory system 48 (7.1) diseases of the musculoskeletal system and connective tissue 43 (6.4) diseases of the nervous system 42 (6.2) diseases of the blood and blood-forming organs 27 (4) diseases of the ear and mastoid process 14 (2.1) diseases of the eye and adnexa 11 (1.6) certain infectious and parasitic diseases 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 Main drug group (Główna grupa leków) N of pts (Liczba pacjentów) (Kod ATC) 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. Clinical Relevance of Drug-Drug Interactions 559

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 caution monitor/ avoid/use total clinically impor- clinically total (%) advantage advised modify alternative tant unimportant 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 pre- effects, and only 73 DDIs (14.5%) of all 504 were dictive value of the ePocrates® drug interactions associated with a possible decrease in drug effica- checker was estimated as 0.89. cy due to the antagonistic effects of the interacting Pharmacological groups like diuretics (187 drugs or pharmacokinetic mechanisms. Therapeu- DDIs), angiotensin-converting enzyme (ACE)- tic advantage resulting from enhanced bactericid- inhibitors (90 DDIs) and antidiabetic agents al activity in the combinations of penicillins and (80 DDIs) were commonly involved in DDIs aminoglycosides was the only beneficial DDI with (Table 4). no potential of adverse effects found in this study The prevalent clinical outcome of the detect- (14 DDIs or 2.8%). Risk of hypotension due to ed DDIs was increased toxicity or risk of adverse 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, potassium- 16 digitalis toxicity depleting 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 II. Dermatologic DDIs (Dermatologiczne DDIs) 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

ACE – angiotensin-converting enzyme; ARBs – angiotensin2-receptor-blockers. ACE – inhibitory konwertazy angiotensyny, ARB – leki blokujące receptor angiotensyny 2. 560 M. Ganeva et al. receptor-blockers (ARBs) plus diuretics was the The development of ADRs was attributed to most frequently encountered potential effect of underlying DDIs in 10 of these cases (23.25%). The DDIs in the study population. majority of them presented as hypotension (7 cas- Pharmacodynamic mechanisms were involved es), the rest being single cases of melena, hypokale- in 410 of the detected DDIs (81.35 %), pharmaco- mia and somnolence and dizziness (Table 5). kinetic in 49 DDIs (9.72%) and the rest were not In two patients, more than 1 DDI per patient well understood (e.g. increased effects of anticoag- that could contribute to the development of ADRs ulants when combined with certain antibacterials, was detected. Overall 13 DDIs were found in 10 pa- hypoglycemia following the combination of qui- tients who experienced an ADR. nolones and antidiabetics). Elderly patients (above 65 years) took a higher number of drugs (median 5, interquartile range: Discussion 4.0–7.0) than younger patients (median 3, interquartile range: 2.0 – 5.0), p = 0.0001. Patients with Potential DDIs were found in a significant part DDIs received significantly (p = 0.0001) more of the hospitalized dermatology patients – 35.5% drugs (median 6, interquartile range: 5.0–8.0) than (236 patients) of the study population (674 pa- patients without DDIs (median 2, interquartile tients). This frequency is similar to the results of range: 1.0–4.0). Zwart-van Rijkom et al., who report 27.8% of hos- The logistic regression analysis showed that pitalized patients to have experienced at least one the development of DDIs was significantly associ- DDI, although many studies have identified high- ated with a higher number of drugs (adjusted OR er proportions of hospitalized patients with DDIs 2.23, 95% CI 1.96–2.55) and old age (adjusted OR – 49.7% in the study of Cruciol-Souza and Thom- 1.02, 95% CI 1.01–1.04). Female sex (adjusted OR son, 66% in the study of Blix et al. [20–22]. These 0.8, 95% CI 0.51–1.25) and the length of hospital differences can be attributed to variations in the stay (adjusted OR 0.99, 95% CI 0.89–1.09) were not morbidity and drug use in the examined patient found to be predictive of the occurrence of DDIs. cohorts, and also to the methods used for the de- tection of DDIs. It is also possible that the time of observation in this study was too short (medi- Adverse Drug Reactions an 8 days) for the clinical or laboratory manifesta- For the study period, 43 ADRs were recorded tion of expected ADRs resulting from DDIs, and at in 42 patients. The distribution of ADRs accord- least some of these events might have been evident ing to ADR type revealed 23 (53.5%) “type B” reac- after hospital discharge. tions and 20 (46.5%) “type A” reactions. Severe re- Consistent with findings from studies of po- actions numbered 3, moderate 33, and mild 7. The tential DDIs in various patient populations, the causal relationship between the drug and the reac- number of prescribed drugs was significantly asso- tion were scored as „possible” in 24 ADRs and as ciated with DDIs [23, 24]. In this study it was the „probable” in 19 ADRs. strongest predictor for the development of DDIs. Cutaneous ADRs (24 ADRs) presented with The drug groups most commonly involved in a variety of clinical manifestations, the prevalent DDIs were cardiovascular drugs (diuretics, ACE- clinical patterns being exanthematous and urti- -inhibitors, ARBs, beta-blockers, etc.). High con- carial. Cardiovascular ADRs (7ADRs) were in all sumption of cardiovascular drugs due to the pres- cases hypotonia. Resistance mechanism disorders ence of cardiovascular diseases in 52.8% of the (3ADRs) were detected in patients with microbi- patients included in the study provides the basis ological evidence for mucocutaneous or intestinal for such interactions. candidiasis after treatment with antibiotics or glu- Cardiovascular drugs have often been found to cocorticosteroids. There were few cases of urinary be among the most frequent drug groups involved in system disorders, metabolic and nutritional disor- potential DDIs in studies from hospitals and ambu- ders, vision disorders, etc. latory patients [4, 20, 25, 26]. Cardiovascular drugs The most common etiologic agents were anti- are often combined for additive beneficial effects in infectious drugs (15 ADRs). Other drug groups as- the treatment of a common disease like hyperten- sociated with the development of ADRs were anal- sion or for handling a coexistent cardiovascular dis- gesics and non-steroidal antiinflammatory agents ease state. Careful monitoring and dosage adjust- (5 ADRs), glucocorticosteroids (3 ADRs), thiazide ment may be required due to the risk of adverse diuretics (3 ADRs). In 10 cases, it was impossible effects. DDIs involving different groups of cardio- to detect a single ADR-inducing drug due to the vascular drugs led to the development of hypoten- concomitant use of drugs capable of inducing the sion and hypokalemia, and these ADRs constituted adverse event. 80% of all ADRs caused by DDIs in this study. Clinical Relevance of Drug-Drug Interactions 561

Table 5. Adverse drug reactions related to drug-drug interactions Tabela 5. Działania niepożądane związane z interakcjami lek–lek

Organ/system Symptom/laboratory abnormality DDIs* (N) (Układ) (Objaw/zaburzenie laboratoryjne) Central nervous system disorders somnolence and dizziness antihistamine + neuroleptic (1) (Zaburzenia układu nerwowego) Metabolic and nutritional disorders hypokalemia loop diuretic + thiazide (1) (Zaburzenia metabolizmu i odżywiania) Cardiovascular disorders hypotension ACE-inhibitor + thiazide (3) (Zaburzenia sercowo-naczyniowe) ACE-inhibitor + loop diuretic (2) thiazide + loop diuretic (1) ARB + thiazide (2) ARB + nitrate (1) Gastro-intestinal system disorders melena clopidogrel + aspirin (1) (Zaburzenia żołądkowo-jelitowe) 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, anticoagu- all patients with potential DDIs were admitted be- lants were also found to be frequently implicated cause of an ADR caused by a DDI [28]. in DDIs [20, 23, 24]. Since strict clinical and labo- A higher incidence of DDI-related ADRs has ratory monitoring of hospitalized dermatology pa- been found in elderly hospitalized and outpatients on coumarins has been performed, no actual tients [4, 7, 29]. Sixteen studies performed from DDIs with these high risk drugs were detected dur- 2000 to 2010 reported an elevated risk for hospi- ing the study period. talization in older adults associated with adverse Typical for this cohort of patients were DDIs drug interactions [30]. Alterations in physiologi- including central nervous system (CNS) depres- cal functions, polymorbidity and polypharmacy in sants like antihistamines, benzodiazepines and elderly patients account for higher frequencies of antipsychotics with potential additive CNS de- DDIs in this age group. Age was not a strong pre- pressant effects (Table 4). Although second-gen- dictor of DDIs in this study compared to the factor eration antihistamines (loratadine, desloratadine, “number of drugs used”. Polymorbidity and relat- cetirizine, levocetirizine, etc.) are designated as ed consumption of multiple drugs but not age it- “non-sedating”, some studies show that they can self seem to be more important predisposing fac- also induce sedation, especially if used in higher tors for the occurrence of DDIs. doses [27]. Sleepiness and impaired psychomotor Although limited to dermatology patients from function are the expected clinical outcomes result- one hospital, this study provides evidence that the ing from DDIs between first- and second-gener- DDI risk profile of this patient group does not dif- ation antihistamines as well as between antihis- fer substantially from the profile of patients from tamines and benzodiazepines or antipsychotics. other medicinal wards. It is well established that Sedation may not always be an unwanted effect in the number of medications and old age are predic- hospitalized dermatology patients with intensely tors for DDIs, although other factors like female pruritic dermatoses, but in outpatients it is always sex, length of hospital stay and suffering from car- problematic. diovascular disease have also been mentioned in Although a substantial part of the potential literature [21, 24, 25]. Variations in the report- DDIs in this study (87.5%) were considered clini- ed prevalence rates of DDIs coming from diverse cally significant, only 2.6% (13 DDIs) were impli- study populations are due not only to differences cated in the development of ADRs. These results in patient characteristics and drug consumption, are very similar to the results from a study evalu- but also to the methods used to detect DDIs. The ating admissions to medical hospital departments authors applied a two-step method using a quick because of potential DDIs showing that 2.4% of on-line drug interactions checker followed by 562 M. Ganeva et al. verification in Stockley’s Drug Interactions. This is Potential DDIs were detected in one-third a time-consuming procedure but it was necessary of hospitalized dermatology patients. The drug to accurately identify DDIs despite the differenc- groups most commonly involved in DDIs were es in drug nomenclature in these two information cardiovascular drugs. The present findings con- resources. ePocrates® demonstrated a satisfactory firm results from studies showing that the propor- sensitivity to detect positive cases for DDIs. tion of DDIs associated with potentially relevant The proportion of patients with DDI-related clinical consequences appears to be relatively low. ADR amounted to 23.25% of all patients present- No matter how rare these cases are, patients at risk ing with ADRs for the study period. It is general- for potential DDIs should be closely monitored in ly estimated that between 6 and 30% of all ADRs order to prevent the development of ADRs which are due to DDIs [6]. The authors report one case of may be severe and require specific treatment. Spe- gastrointestinal bleeding due to DDIs between an- cial attention should be paid to elderly patients and tiplatelet agents and glucocorticosteroids. Others patients with chronic diseases on long term medi- investigating ADRs caused by DDIs have detected cation, especially cardiovascular, and to those us- gastro-intestinal bleeding as a very common clin- ing high-risk drugs like anticoagulants and anti- ical manifestation of such ADRs, along with elec- platelet agents. trolyte disturbances, hyper- or hypotension and cardiac rhythm disorders [5, 29].

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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