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_'�#�#|_'_'&?��/ W ��?5.5.5._'��/ ��/ (�5&	5._'?5.5.�0�^1/ ������u[�AI,�0�5@05@�0,�DU-v�D1�D
1�_'_'5._'_'_'_'_'&?&?�-j_'_'_'5@_'_'_'_'���������������������������������������������������������������������D_'_'_'_'_'_'_'_'_'~	�:	Prevalence and types of potential drug-drug interactions in different wards of public and private tertiary healthcare facilities in Pakistan. A threat to patient safety.
* Dr Madeeha Malik (Corresponding Author)
Assistant Professor, Hamdard Institute of Pharmaceutical Sciences, Hamdard University, F-8 Markaz, Johar Road  Islamabad, Pakistan. madeehamalik15@gmail.com
Prof Dr Azhar Hussain
Professor/HOD, Hamdard Institute of Pharmaceutical Sciences Hamdard University, F-8 Markaz, Johar Road  Islamabad, Pakistan
Dr Mohamed Shafiq
Associate Professor, Hamdard Institute of Pharmaceutical Sciences Hamdard University, F-8 Markaz, Johar Road  Islamabad, Pakistan.
Dr Mohammed Kamran Naqi
Professor/HOD, Hamdard Institute of Management Sciences Hamdard University, F-8 Markaz, Johar Road  Islamabad, Pakistan
Safia Nadir                                                                                                                                                    Pharm D, Hamdard Institute of Pharmaceutical Sciences Hamdard University, F-8 Markaz, Johar Road  Islamabad, Pakistan.
Azhar Anees
Pharm D, Hamdard Institute of Pharmaceutical Sciences Hamdard University, F-8 Markaz, Johar Road  Islamabad, Pakistan.





Introduction
Drug-drug interaction is the consequence of the medication error, which may be defined as incorrect drug selection for the patient, varying from mild to serious consequences  ADDIN EN.CITE <EndNote><Cite><Author>Agyemang</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Agyemang, Rebecca Esi Owusu</author><author>While, Alison</author></authors></contributors><titles><title>Medication errors: types, causes and impact on nursing practice</title><secondary-title>British Journal of Nursing</secondary-title></titles><periodical><full-title>British Journal of Nursing</full-title></periodical><pages>380-385</pages><volume>19</volume><number>6</number><dates><year>2010</year></dates><isbn>0966-0461</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_1" \o "Agyemang, 2010 #1" 1]. Approximately, 44,000 to 98,000 deaths are reported due to medication errors globally each year  ADDIN EN.CITE <EndNote><Cite><Author>Kohn</Author><Year>2000</Year><RecNum>2</RecNum><DisplayText>[2]</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">2</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Kohn, Linda T</author><author>Corrigan, Janet M</author><author>Donaldson, Molla S</author></authors></contributors><titles><title>To err is human: building a safer health system</title></titles><volume>627</volume><dates><year>2000</year></dates><publisher>National Academies Press</publisher><isbn>0309068371</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_2" \o "Kohn, 2000 #2" 2]. Out of these deaths, 7,000 are due to inappropriate prescribing of wrong drug combinations. The rate of potential drug-drug interactions ranging from 1 to 66 have been reported in various developed countries. However, the true incidence is unknown due to under reporting and no authenticated statistical data base exists on prevalence of drug-drug interaction  ADDIN EN.CITE <EndNote><Cite><Author>Triplitt</Author><Year>2006</Year><RecNum>3</RecNum><DisplayText>[3]</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Triplitt, Curtis</author></authors></contributors><titles><title>Drug interactions of medications commonly used in diabetes</title><secondary-title>Diabetes spectrum</secondary-title></titles><periodical><full-title>Diabetes spectrum</full-title></periodical><pages>202-211</pages><volume>19</volume><number>4</number><dates><year>2006</year></dates><isbn>1040-9165</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_3" \o "Triplitt, 2006 #3" 3]. Administration of medication is a multidisciplinary process, which starts with prescriber, reviewing by a pharmacist, and ends with administration by a nurse. In this process error can occur at any step  ADDIN EN.CITE <EndNote><Cite><Author>Cohen</Author><Year>1999</Year><RecNum>4</RecNum><DisplayText>[4]</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">4</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Cohen, Michael Richard</author></authors></contributors><titles><title>Medication errors: causes, prevention, and risk management</title></titles><dates><year>1999</year></dates><publisher>Jones &amp; Bartlett Learning</publisher><isbn>076371271X</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_4" \o "Cohen, 1999 #4" 4]. Pharmacotherapy sometimes can be complex and requires close monitoring to minimize drug related problems. Appropriate prescribing of the medications increases the quality of medical care and decrease the waste of resources. Frequency and incidence of drug interactions increases with the number of concurrent medications  ADDIN EN.CITE <EndNote><Cite><Author>Kohn</Author><Year>2000</Year><RecNum>2</RecNum><DisplayText>[2]</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">2</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Kohn, Linda T</author><author>Corrigan, Janet M</author><author>Donaldson, Molla S</author></authors></contributors><titles><title>To err is human: building a safer health system</title></titles><volume>627</volume><dates><year>2000</year></dates><publisher>National Academies Press</publisher><isbn>0309068371</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_2" \o "Kohn, 2000 #2" 2]. High prevalence of potential interactions due to polypharmacy has been reported in various countries  ADDIN EN.CITE <EndNote><Cite><Author>Juurlink</Author><Year>2003</Year><RecNum>5</RecNum><DisplayText>[5]</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Juurlink, David N</author><author>Mamdani, Muhammad</author><author>Kopp, Alexander</author><author>Laupacis, Andreas</author><author>Redelmeier, Donald A</author></authors></contributors><titles><title>Drug-drug interactions among elderly patients hospitalized for drug toxicity</title><secondary-title>JAMA: the journal of the American Medical Association</secondary-title></titles><periodical><full-title>JAMA: the journal of the American Medical Association</full-title></periodical><pages>1652-1658</pages><volume>289</volume><number>13</number><dates><year>2003</year></dates><isbn>0098-7484</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_5" \o "Juurlink, 2003 #5" 5]. 
An effective pharmacovigilance program can minimize drug related problems and potential drug interactions  ADDIN EN.CITE <EndNote><Cite><Author>Bates</Author><Year>1995</Year><RecNum>6</RecNum><DisplayText>[6]</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bates, David W</author><author>Boyle, Deborah L</author><author>Vander Vliet, Martha B</author><author>Leape, Lucian</author></authors></contributors><titles><title>Relationship between medication errors and adverse drug events</title><secondary-title>Journal of General Internal Medicine</secondary-title></titles><periodical><full-title>Journal of General Internal Medicine</full-title></periodical><pages>199-205</pages><volume>10</volume><number>4</number><dates><year>1995</year></dates><isbn>0884-8734</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_6" \o "Bates, 1995 #6" 6]. Various educational interventions and monitoring by a clinical pharmacist can effectively reduce medication errors  ADDIN EN.CITE <EndNote><Cite><Author>Berwick</Author><Year>1999</Year><RecNum>7</RecNum><DisplayText>[7]</DisplayText><record><rec-number>7</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">7</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Berwick, Donald M</author><author>Leape, Lucian L</author></authors></contributors><titles><title>Reducing errors in medicine: it�s time to take this more seriously</title><secondary-title>BMJ: British Medical Journal</secondary-title></titles><periodical><full-title>BMJ: British Medical Journal</full-title></periodical><pages>136</pages><volume>319</volume><number>7203</number><dates><year>1999</year></dates><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_7" \o "Berwick, 1999 #7" 7].  Automated drug alert systems have been reported as useful tools for clinicians in identifying drug interactions and improving practice  ADDIN EN.CITE <EndNote><Cite><Author>Bailey</Author><Year>1998</Year><RecNum>8</RecNum><DisplayText>[8, 9]</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bailey, David G</author><author>Malcolm, J</author><author>Arnold, O</author><author>David Spence, J</author></authors></contributors><titles><title>Grapefruit juice�drug interactions</title><secondary-title>British journal of clinical pharmacology</secondary-title></titles><periodical><full-title>British journal of clinical pharmacology</full-title></periodical><pages>101-110</pages><volume>46</volume><number>2</number><dates><year>1998</year></dates><isbn>1365-2125</isbn><urls></urls></record></Cite><Cite><Author>Goodman</Author><Year>1990</Year><RecNum>9</RecNum><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">9</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Goodman, Louis Sanford</author></authors></contributors><titles><title>Goodman and Gilman&apos;s the pharmacological basis of therapeutics</title></titles><volume>1157</volume><dates><year>1990</year></dates><publisher>Pergamon Press New York</publisher><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_8" \o "Bailey, 1998 #8" 8,  HYPERLINK \l "_ENREF_9" \o "Goodman, 1990 #9" 9]. On the other hand, training of health professionals regarding drug interactions can also be useful in provision of appropriate patient care and achievement of desirable therapeutic outcomes  ADDIN EN.CITE <EndNote><Cite><Author>Rothschild</Author><Year>2002</Year><RecNum>10</RecNum><DisplayText>[10]</DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rothschild, Jeffrey M</author><author>Federico, Frank A</author><author>Gandhi, Tejal K</author><author>Kaushal, Rainu</author><author>Williams, Deborah H</author><author>Bates, David W</author></authors></contributors><titles><title>Analysis of medication-related malpractice claims: causes, preventability, and costs</title><secondary-title>Archives of Internal Medicine</secondary-title></titles><periodical><full-title>Archives of Internal Medicine</full-title></periodical><pages>2414</pages><volume>162</volume><number>21</number><dates><year>2002</year></dates><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_10" \o "Rothschild, 2002 #10" 10]. Although, pharmacovigillance is the most highly prioritized area of research globally but unfortunately it is almost absent in Pakistan  ADDIN EN.CITE <EndNote><Cite><Author>Najmi</Author><Year>1998</Year><RecNum>11</RecNum><DisplayText>[11]</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Najmi, Muzammil Hasan</author><author>Hafiz, Rehan A</author><author>Khan, Inayat</author><author>Fazli, FRY</author></authors></contributors><titles><title>Prescribing practices: an overview of three teaching hospitals in Pakistan</title><secondary-title>JOURNAL-PAKISTAN MEDICAL ASSOCIATION</secondary-title></titles><periodical><full-title>JOURNAL-PAKISTAN MEDICAL ASSOCIATION</full-title></periodical><pages>73-76</pages><volume>48</volume><dates><year>1998</year></dates><isbn>0030-9982</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_11" \o "Najmi, 1998 #11" 11]. High prevalence of potential drug-drug interactions was recorded in pulmonology ward of Ayub teaching Hospital, Abbottabad  ADDIN EN.CITE <EndNote><Cite><Author>Ismail</Author><Year>2011</Year><RecNum>13</RecNum><DisplayText>[12]</DisplayText><record><rec-number>13</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">13</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ismail, Mohammad</author><author>Iqbal, Zafar</author><author>Khattak, Muhammad Bilal</author><author>Javaid, Arshad</author><author>Khan, Tahir Mehmood</author></authors></contributors><titles><title>Prevalence, types and predictors of potential drug-drug interactions in pulmonology ward of a tertiary care hospital</title><secondary-title>African Journal of Pharmacy and Pharmacology</secondary-title></titles><periodical><full-title>African Journal of Pharmacy and Pharmacology</full-title></periodical><pages>1303-1309</pages><volume>5</volume><number>10</number><dates><year>2011</year></dates><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_12" \o "Ismail, 2011 #13" 12]. Co-dispensing of number of interacting drugs of major, moderate and minor severity was reported by a study conducted in Karachi  ADDIN EN.CITE <EndNote><Cite><Author>Shah</Author><Year>2011</Year><RecNum>14</RecNum><DisplayText>[13]</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shah, Shajahan</author><author>Naqvi, Baquar Shyum</author><author>Ale-Zehra, Ale-Zehra</author><author>Ali, Danish</author><author>Saeed, Rehana</author><author>Naqvi, Ghazala Raza</author></authors></contributors><titles><title>Quantitative Analysis of Drug-Drug Interactions of OTC Drugs with other Prescribed Drugs Collected from Different Hospitals and Clinics of Karachi, Pakistan</title><secondary-title>Jordan Journal of Pharmaceutical Sciences</secondary-title></titles><periodical><full-title>Jordan Journal of Pharmaceutical Sciences</full-title></periodical><volume>4</volume><number>2</number><dates><year>2011</year></dates><isbn>1995-7157</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_13" \o "Shah, 2011 #14" 13]. More than half of prescriptions were manifested with medication errors, of which 9 % were due to drug-drug interaction, in DI khan  ADDIN EN.CITE <EndNote><Cite><Author>Amin</Author><RecNum>15</RecNum><DisplayText>[14]</DisplayText><record><rec-number>15</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">15</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Amin, Adnan</author><author>Shah, Sayed Mohsin Ali</author><author>Hussain, Abid</author></authors></contributors><titles><title>Prescribing and Dispensing Practices in a Public sector Pedriatric Ward in DI Khan, Pakistan</title></titles><dates></dates><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_14" \o "Amin,  #15" 14]. Underreporting of medication errors has been the most important challenge faced by the healthcare system of Pakistan and thus no authenticated national epidemiological data base is currently present in the country. Limited data has been reported on the incidence of occurrence of drug-drug interactions in public and private healthcare facilities in Pakistan. Thus, the present study was designed to assess the potential drug-drug interactions in various wards i.e. (gynecology, cardiac & medicine)of public and private tertiary health care facilities in two cities of Pakistan; Islamabad (national capital) and Rawalpindi (twin city).
Methodology
A comparative, cross-sectional study was designed to evaluate the case records of patients including (daily registers, medical records, prescriptions, or patient-held record cards) treated in different wards i.e. (gynecology, cardiac & medicine) in public and private tertiary healthcare facilities in the twin cities, namely Islamabad (federal capital) and Rawalpindi. There is no ethical committee in Pakistan for research. However, permission was taken from the director of Hamdard Institute of Pharmaceutical Sciences, Hamdard University, medical superintendent of respective public tertiary hospital and record controllers at each individual ward. The study population included all the public and private tertiary health care facilities in Islamabad and Rawalpindi. A list of all the public and private tertiary healthcare facilities was obtained from respective District Health Offices. All the 20 public and private tertiary healthcare facilities were selected for the study and the sample size was Islamabad (n = 10, 5 each public and private healthcare facilities) and Rawalpindi (n = 10, 5 each public and private healthcare facilities). A total of 600 patient encounters i.e. 300 from each sector (public and private) healthcare facilities situated in both cities were collected from daily registers, medical records, prescriptions, or patient-held record cards  ADDIN EN.CITE <EndNote><Cite><Author>World Health Organization</Author><Year>2002</Year><RecNum>53</RecNum><DisplayText>[15]</DisplayText><record><rec-number>53</rec-number><foreign-keys><key app="EN" db-id="pvtzwtzr3t29emetremx5wfarvz0epfz5rtz">53</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>World Health Organization,</author></authors></contributors><titles><title>How to investigate drug use in health facilities:Selected drug use indicators</title></titles><volume>2012</volume><number>1 May</number><section>92</section><dates><year>2002</year><pub-dates><date>20th April</date></pub-dates></dates><publisher>International Network for Rational Use of Drugs</publisher><urls><related-urls><url>http://apps.who.int/medicinedocs/pdf/s2289e/s2289e.pdf</url></related-urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_15" \o "World Health Organization, 2002 #53" 15]. Thirty prescriptions from each facility were collected. Quota sampling technique was used and sample size for each ward of each facility i.e. (gynecology n = 10, cardiac n = 10 & medicine n = 10) was fixed  ADDIN EN.CITE <EndNote><Cite><Author>World Health Organization</Author><Year>2002</Year><RecNum>53</RecNum><DisplayText>[15]</DisplayText><record><rec-number>53</rec-number><foreign-keys><key app="EN" db-id="pvtzwtzr3t29emetremx5wfarvz0epfz5rtz">53</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>World Health Organization,</author></authors></contributors><titles><title>How to investigate drug use in health facilities:Selected drug use indicators</title></titles><volume>2012</volume><number>1 May</number><section>92</section><dates><year>2002</year><pub-dates><date>20th April</date></pub-dates></dates><publisher>International Network for Rational Use of Drugs</publisher><urls><related-urls><url>http://apps.who.int/medicinedocs/pdf/s2289e/s2289e.pdf</url></related-urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_15" \o "World Health Organization, 2002 #53" 15]. 
A drug-drug interaction assessment structured form was designed which included two sections. Section one included demographics of the patients such as (patient name, age, gender and diagnosis) while the second section included questions regarding drugs prescribed, drug contraindicated to condition of patient, type of DDI, signs and symptoms of toxicity and signs appeared. The assessment form was filled after assessing the collected prescriptions whether if they indicate any potential drug-drug interaction or not. The drug interactions were reported as major, moderate and minor. Data was collected by the principal investigator along with two teams comprised of five trained data collectors in each team trained by the group of experts including principal investigator  ADDIN EN.CITE <EndNote><Cite><Author>Rational Pharmaceutical Management Plus Program</Author><Year>2004</Year><RecNum>110</RecNum><DisplayText>[16]</DisplayText><record><rec-number>110</rec-number><foreign-keys><key app="EN" db-id="waasww0vq0avx3epftpp2029dtvfae5v5ftx">110</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>Rational Pharmaceutical Management Plus Program,</author></authors><secondary-authors><author>USAD</author></secondary-authors><tertiary-authors><author>USAID</author></tertiary-authors></contributors><titles><title>Pharmaceutical Management for Malaria</title></titles><dates><year>2004</year></dates><pub-location>USA</pub-location><publisher>U.S. Agency for International Development</publisher><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_16" \o "Rational Pharmaceutical Management Plus Program, 2004 #110" 16]. The data collectors were students of the final year Doctor of Pharmacy program. After the data collection, data was coded and analyzed using statistical software SPSS version 16 for potential occurrence of drug-drug interactions.
Results
Demographics
Out of 600 prescriptions, 50% (n = 300) of the prescriptions were collected from public sector while 50 % (n= 300) were from the private sector. Out of 600 prescriptions, 33.33 % (n = 200) of the prescriptions were collected from General Medicine ward, 33.33 % (n = 200) from Gynecology and Obstetrics and 33.33 % (n= 200) of the prescriptions were collected from Coronary Care Unit. Of the total prescriptions, 40.55% (n = ) were of the male patients while 59.44 % (n = ) were of the females patients. The mean age of the patient was (42.21 � 20.94).



Prevalence of different types of drug interactions in different wards of public and private healthcare facilities
No drug-drug Interactions were present in 56.6% (n = 170) and 50% (n =150) of the total encounters observed in public and private healthcare facilities in the twin cities respectively. Drug disease interactions were present in 8.3% (n = 25) and 14% (n = 42) of the total cases whereas toxicity was expected in 62% (n = 186) and 65% (n = 195) of the total prescriptions observed in public and private healthcare facilities in the twin cities respectively. On the other hand, occurrence of toxicity was not documented in any of the encounters observed. A detail description of different types of DDI in the three wards of public and private health care facilities in the twin cities is given (Table1).
SectorPublic n = 300Private n =300Gynea           n = 100              F (%)Medicine n = 100       F (%)CCU            n = 100 F (%)Gynea           n = 100              F (%)Medicine n = 100       F (%)CCU            n = 100          F (%)Type of Drug InteractionsNo  drug-drug interactions60 (60)50 (50)60 (60)50 (50)50 (50)50 (50)Major drug-drug interactions003 (3)03 (3)4 (4)Moderate drug-drug interactions10 (10)8 (8)3 (3)12 (12)7 (7)5 (5)Minor drug-drug interactions20 (20)10 (10)9 (9)25 (25)10 (10)20 (20)Major + moderate drug-drug interactions03 (3)003 (3)0Major + minor  drug-drug interactions03 (3)1 (1)04 (4)2 (2)Moderate +Minor drug-drug interactions10 (10)13 (13)13 (13)13 (13)12 (12)8 (8)Major + Moderate + Minor drug-drug interactions013 (13)11 (11)011 (11)11 (11)Drug disease interaction and expected toxicitiesDrug disease interaction5 (5)20 (20)030 (30)12 (12)0Toxicity expected36 (36)66 (66)84 (84)60 (60)66 (66)69 (69)Toxicity documented000000Table 1. Prevalance of different types of drug interactions in different wards of public and private healthcare facilities
  
  Potential interacting drug combinations in public and private healthcare facilities
Different drug-drug interactions were identified in the prescriptions collected from different public and private healthcare facilities in the twin cities. The most frequently identified drug-drug interactions were: Aspirin+ Clopidogrel (n = 38, 6.3%), ACEI + Aspirin (n = 37, 6.1%), Aspirin + Metoprolol (n = 20, 3.3%) and Cephalosporin + NSAIDs (n = 36, 6%). A detail description of different interacting drug combinations is given (Table 2).
Table 2. Potential interacting drug combinations in public and private healthcare facilities
Drug InteractionsPublic                            n = 300                            F (%)Private                 n = 300                 F (%)Composite            n = 600                        F (%)Enoxaparin + Clopidogrel5 (1.6)5 (1.6)10 (1.6)Selective beta blocker + Carvedilol4 (1.3)4 (1.3)8 (1.3)Omeprazole + Clopidogrel4 (1.3)4 (1.3)8 (1.3)Clarithromycin + Simvastatin4 (1.3)4 (1.3)8 (1.3)Ibufropen + aspirin5 (1.6)3 (1)8 (1.3)Aspirin+ Clopidogrel12 (4)26 (8.6)38 (6.3)ACEI + Aspirin13 (4.3)24 (8)37 (6.1)Aspirin + Metoprolol8 (2.6)12 (4)20 (3.3)Enoxaparin + Aspirin10 (3.3) 7 (2.3)17 (2.8)ACEI + Furosemide8 (2.6)4 (1.3)12 (2)Aspirin + Carvedilol3 (1)6 (2)9 (1.5)NSAIDs + Furosemide5 (1.6)3 (1)8 (1.3)Heparin + Aspirin2 (0.6)6 (2)8 (1.3)Aspirin + Losartan6 (2)2 (0.6)8 (1.3)Warfarin + PPI3 (1)4 (1.3)7 (1.1)Cephalosporin + NSAIDs15 (5)21 (7)36 (6)Metronidazole +  NSAIDs8 (2.6)4 (1.3)12 (2)Aspirin+ Insulin(R)4 (1.3)4 (1.3)8 (1.3)ACEI + Insulin(R)9 (3)5 (1.6)14 (2.3)Ceftriaxone + Furosemide2 (0.6)2 (0.6)4 (0.6)Total130 (43.3)150 (50) 280 (46.6)Comparison of prevalance of DDI among different wards of public and private healthcare facilities in the twin cities
Mann-Whitney U test (p d" 0.05) was used to compare occurrence of DDI in routine practice carried in obstetrics and gynaecology wards, medicine ward and coronary care units of different public and private healthcare facilities located in the twin cities. No significant differences (p d" 0.05) were observed in practices in different public and private healthcare facilities located in the twin cities. However, significant differences (p d" 0.05) were seen in practices carried in obstetrics and gynaecology and CCU wards of public and private healthcare facilities. The drug-drug interactions observed were comparatively less in both gynaecology and CCU wards of public healthcare facilities (Table 3).
Table 3. Comparison of potential occurrence of DDI among different wards of public and private healthcare facilities in the twin cities

VariablesOccurrence of DDI in routine practicenUMean rankp-valueCitiesIslamabad = 300
Rawalpindi = 3003743.50Islamabad = 93.91
Rawalpindi = 87.95
0.306SectorPublic = 300
Private = 300
3543.50Public = 90.21
Private = 88.76
0.306WardsPublic = 100
Private = 100
267.00Public = 36.60
Private = 24.40
0.002Public = 100
Private = 100
450.00Public = 30.50
Private = 30.50
0.959Public = 100
Private = 100
406.00Public = 29.03
Private = 31.97
0.0428*Man Whitney U Test significant at (p d" 0.05)


Discussion



DDI can be classified as major, moderate and minor on basis of their severity. They can be avoided by well-timed recognition and selection of safer alternatives  ADDIN EN.CITE <EndNote><Cite><Author>Agyemang</Author><Year>2010</Year><RecNum>1</RecNum><DisplayText>[1]</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Agyemang, Rebecca Esi Owusu</author><author>While, Alison</author></authors></contributors><titles><title>Medication errors: types, causes and impact on nursing practice</title><secondary-title>British Journal of Nursing</secondary-title></titles><periodical><full-title>British Journal of Nursing</full-title></periodical><pages>380-385</pages><volume>19</volume><number>6</number><dates><year>2010</year></dates><isbn>0966-0461</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_1" \o "Agyemang, 2010 #1" 1]. The current study revealed high prevalance of potential drug-drug interactions, drug disease interactions and the expected toxicities in both public and private healthcare facilities of Pakistan. ACEI should be avoided in pregnancy as they adversely affect fetal blood pressure control, renal function, oligohydraminos and contributes to skull defects  ADDIN EN.CITE <EndNote><Cite><Author>Goodman</Author><Year>1990</Year><RecNum>9</RecNum><DisplayText>[9]</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">9</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Goodman, Louis Sanford</author></authors></contributors><titles><title>Goodman and Gilman&apos;s the pharmacological basis of therapeutics</title></titles><volume>1157</volume><dates><year>1990</year></dates><publisher>Pergamon Press New York</publisher><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_9" \o "Goodman, 1990 #9" 9]. The results of the present study revealed highest rate of drug disease interactions in the obstetrics and gynecology ward in private healthcare facilities where patients with pregnancy induced hypertension (PIH) were prescribed captopril (capoten) 25mg S/L stat and methyldopa 250mg TDS (aldomet) to control the condition. Similar practice was reported by a study conducted in Australia which revealed skull hypoplasia along with renal dysfunction as the most consistent anomaly of neonates as outcomes in hundred of pregnancies where ACEI were prescribed  ADDIN EN.CITE <EndNote><Cite><Author>Burrows</Author><Year>1998</Year><RecNum>17</RecNum><DisplayText>[17]</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">17</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Burrows, RF</author><author>Burrows, EA</author></authors></contributors><titles><title>Assessing the Teratogenic Potential of Angiotensin Converting Enzyme Inhibitors in Pregnancy</title><secondary-title>Australian and New Zealand journal of obstetrics and gynaecology</secondary-title></titles><periodical><full-title>Australian and New Zealand journal of obstetrics and gynaecology</full-title></periodical><pages>306-311</pages><volume>38</volume><number>3</number><dates><year>1998</year></dates><isbn>1479-828X</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_17" \o "Burrows, 1998 #17" 17]. The overall trend of practice in both hospitals was indistinguishable. However, the frequency of occurrence of major, moderate, minor and multiple drug interactions in a single prescription were relatively more in private healthcare facilities than public facilities. This might be attributed to prescribing multiple medications per patient in private healthcare facilities which eventually step up DDIs. The results of the present study are in line with the study conducted in Sweden where DDIs were classified as major and moderate and association of multiple drugs prescribed per patient to increase in occurrence of DDI was reported  ADDIN EN.CITE <EndNote><Cite><Author>Haider</Author><Year>2009</Year><RecNum>18</RecNum><DisplayText>[18]</DisplayText><record><rec-number>18</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">18</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Haider, Syed Imran</author><author>Johnell, Kristina</author><author>Weitoft, Gunilla Ringb�ck</author><author>Thorslund, Mats</author><author>Fastbom, Johan</author></authors></contributors><titles><title>The Influence of Educational Level on Polypharmacy and Inappropriate Drug Use: A Register Based Study of More Than 600,000 Older People</title><secondary-title>Journal of the American Geriatrics Society</secondary-title></titles><periodical><full-title>Journal of the American Geriatrics Society</full-title></periodical><pages>62-69</pages><volume>57</volume><number>1</number><dates><year>2009</year></dates><isbn>1532-5415</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_18" \o "Haider, 2009 #18" 18].

DDIs have to be ignored on basis of risk to benefit ratio as the severity of diseases increases but in most cases safer alternatives subsists. The present study illustrated number of DDIs including co-prescription of clopidogrel (Platelet aggregation inhibitor) with anti-coagulants (heparin , enoxaparin) and proton pump inhibitors (omeprazole, esomeprazole). The patient receiving clopidogrel and anti-coagulants together is at high risk of bleeding with increase prothrombin time whereas studies have shown that patients exposed to clopidogrel with PPI are at high risk of recurrent MI as PPI are inhibitors of CYP2C19, an enzyme required for conversion of clopigogrel into its active metabolite  ADDIN EN.CITE <EndNote><Cite><Author>van Boxel</Author><Year>2010</Year><RecNum>19</RecNum><DisplayText>[19]</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van Boxel, Ofke S</author><author>van Oijen, Martijn GH</author><author>Hagenaars, Matthijs P</author><author>Smout, AJPM</author><author>Siersema, Peter D</author></authors></contributors><titles><title>Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study</title><secondary-title>The American journal of gastroenterology</secondary-title></titles><periodical><full-title>The American journal of gastroenterology</full-title></periodical><pages>2430-2436</pages><volume>105</volume><number>11</number><dates><year>2010</year></dates><isbn>0002-9270</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_19" \o "van Boxel, 2010 #19" 19]. In the same line the patients receiving ibufropen with aspirin may not get benefit of anti platlet properties of latter as ibufrofen antagonizes anti- platlet effects of aspirin  ADDIN EN.CITE <EndNote><Cite><Author>Fauci</Author><Year>2008</Year><RecNum>20</RecNum><DisplayText>[20]</DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">20</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Fauci, Anthony S</author></authors></contributors><titles><title>Harrison&apos;s principles of internal medicine</title></titles><volume>2</volume><dates><year>2008</year></dates><publisher>McGraw-Hill Medical New York</publisher><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_20" \o "Fauci, 2008 #20" 20]. The study also identified frequent prescribing of Aspirin with ACEI.  Aspirin being prostaglandin inhibitor, by irreversibly inhibiting cyclooxygenase enzyme, decreases levels of PGI2 and PGE2 required for vasodilatory and anti-thrombolic effects of ACEI. On the other hand ACEI by impeding degradation of bradykinin, increase levels of prostaglandin  ADDIN EN.CITE <EndNote><Cite><Author>Spaulding</Author><Year>1998</Year><RecNum>21</RecNum><DisplayText>[21]</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Spaulding, Christian</author><author>Charbonnier, Bernard</author><author>Cohen-Solal, Alain</author><author>Juilli�re, Yves</author><author>Kromer, Eckhard Peter</author><author>Benhamda, Khaldoun</author><author>Cador, Romain</author><author>Weber, Simon</author></authors></contributors><titles><title>Acute Hemodynamic Interaction of Aspirin and Ticlopidine With Enalapril Results of a Double-Blind, Randomized Comparative Trial</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title></periodical><pages>757-765</pages><volume>98</volume><number>8</number><dates><year>1998</year></dates><isbn>0009-7322</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_21" \o "Spaulding, 1998 #21" 21]. The results of present studies are in line to another study conducted in Karachi where DDI of OTC  drugs with  other prescribed drugs  was analyzed and important interactions like NSAIDs with ACEI, aspirin with clopidogrel and ciprofloxacin with iron, zinc and calcium supplements were reported  ADDIN EN.CITE <EndNote><Cite><Author>Shah</Author><Year>2011</Year><RecNum>14</RecNum><DisplayText>[13]</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shah, Shajahan</author><author>Naqvi, Baquar Shyum</author><author>Ale-Zehra, Ale-Zehra</author><author>Ali, Danish</author><author>Saeed, Rehana</author><author>Naqvi, Ghazala Raza</author></authors></contributors><titles><title>Quantitative Analysis of Drug-Drug Interactions of OTC Drugs with other Prescribed Drugs Collected from Different Hospitals and Clinics of Karachi, Pakistan</title><secondary-title>Jordan Journal of Pharmaceutical Sciences</secondary-title></titles><periodical><full-title>Jordan Journal of Pharmaceutical Sciences</full-title></periodical><volume>4</volume><number>2</number><dates><year>2011</year></dates><isbn>1995-7157</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_13" \o "Shah, 2011 #14" 13]. The results of current study showed considerable number of women exposed to category D and category X drugs during pregnancy. The results of the study are similar with the study conducted in Ethiopia  ADDIN EN.CITE <EndNote><Cite><Author>Kebede</Author><Year>2009</Year><RecNum>22</RecNum><DisplayText>[22]</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">22</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kebede, Binyam</author><author>Gedif, Teferi</author><author>Getachew, Ashebir</author></authors></contributors><titles><title>Assessment of drug use among pregnant women in Addis Ababa, Ethiopia</title><secondary-title>Pharmacoepidemiology and drug safety</secondary-title></titles><periodical><full-title>Pharmacoepidemiology and drug safety</full-title></periodical><pages>462-468</pages><volume>18</volume><number>6</number><dates><year>2009</year></dates><isbn>1099-1557</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_22" \o "Kebede, 2009 #22" 22].
The results of the current study showed no significant difference in the overall practice of public and private tertiary healthcare facilities in the twin cities. Drug interactions were prevalent in both sectors. This might be due to lack of training of prescribers regarding potential drug-drug interactions and no involvement of hospital pharmacists in ADR monitoring in Pakistan. Various studies have reported traditional duties of hospital pharmacists such as inventory management instead of patient-orientated pharmaceutical care due to reluctance of doctors to accept their role in clinically-focused pharmacy services in Pakistan  ADDIN EN.CITE <EndNote><Cite><Author>Azhar</Author><Year>2010</Year><RecNum>23</RecNum><DisplayText>[23]</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="wtwx5d2wef2rtzess9c5fxpc0exzaaafdxa5">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Azhar, Saira</author><author>Hassali, M</author><author>Ibrahim, M</author></authors></contributors><titles><title>Doctors� perception and expectations of the role of the pharmacist in Punjab, Pakistan</title><secondary-title>Tropical Journal of Pharmaceutical Research</secondary-title></titles><periodical><full-title>Tropical Journal of Pharmaceutical Research</full-title></periodical><volume>9</volume><number>3</number><dates><year>2010</year></dates><isbn>1596-9827</isbn><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_23" \o "Azhar, 2010 #23" 23]. The results of the current study showed significant differences in the practices carried out at the gynaecology and CCU wards in the public and private healthcare facilities. The practices at gynaecology and CCU wards in public healthcare facilities were comparatively better and had less prescribed drug interactions. This might be due to better monitoring and prescribing by more experienced doctors working at the public healthcare facilities. Training of prescribers regarding most commonly occurring drug interactions must be exercised after every three months. Computer software for monitoring of DDI and ADRS must be installed in hospitals for better survivellance. Hospital pharmacist must play an active role in identification of drug interactions and should screen all the prescriptions before dispensing o drugs to the patients. Adverse drug interactions reporting box should be placed in the wards so healthcare professional can easily get feedback of practice to improve their practices.
Conclusions
This study highlighted potential incidence of drug interactions in both the public and private healthcare facilities of Pakistan. Absence of pharmacovigillance program, lack of installation of ADR reporting software�s and reluctance of doctors to accept the role of hospital pharmacists in monitoring DDI are the main reasons for the occurrence of DDI�s in the healthcare facilities in Pakistan. Patients were being treated with multiple drugs without any understanding of possible drug interactions. Strict pharmacovigillance, installation of updated computer software for identification of drug interactions and active involvement of hospital pharmacists in ADR monitoring can minimize the risk of possible drug interactions and improve the current prescribing practices in both public and private healthcare facilities in Pakistan.
















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h�HCJjh�HUmHnHuh�U�jh�U�Uh]p�jh3VUUh�Ouh�Ou5�mHnHuh�Ouh�Ou6�mHnHuh�OumHnHu0Assessment of drug use among pregnant women in Addis Ababa, Ethiopia. Pharmacoepidemiology and drug safety, 2009. 18(6): p. 462-468.
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