Incidence of Drug-Drug Interactions among Patients Admitted to the Department of General Medicine in a Tertiary Care Hospital

Bajracharya, Swaroop, Rajalekshmi, Viswam, and Maheswari: Incidence of Drug-Drug Interactions among Patients Admitted to the Department of General Medicine in a Tertiary Care Hospital

Authors

INTRODUCTION

Drugs are intended to alleviate disease and improve the quality of life in patients. However, many drugs are reported to cause unwanted reactions ranging from mild rashes to severe adverse reactions with fatal outcomes. Due to the complexity of disease and its comorbidities, multi-drug therapy is the current practice which is found to be alarming as it may result in drug related problems.1 Drug-drug interactions represent an important and widely under- recognized source of medication errors and is responsible for 23% of hospital admissions.2 Rational drug utilization may facilitate global reduction in drug induced morbidity and mortality.1 Prescriptions with polypharmacy need a thorough evaluation in order to avoid any chance of Drug Related Problems (DRPs) which might result in adverse drug reactions, therapeutic insufficiency and increase the healthcare expenses. The involvement of pharmacist in a health care system may prevent such DRPs.3

Administration of two or more drugs may lead to interactions resulting in alteration of therapeutic response or unwanted effects which are not observed with either of the drugs when consumed alone. DDIs may be severe enough to warrant hospital admissions for patients who got it manifested.4-5 Ahmad et al., 2015 has reported 66% of DDIs in the Department of General Medicine at a tertiary care hospital in Karnataka.6 Studies have confirmed polypharmacy as one of the major risk factor for the incidence of DDIs.7 DDIs contribute 20-30% incidence of ADRs which may increase the chance of hospital admission or lengthen the hospital stay.8 Bhagavathula et al, reported the occurrence of 40% DDIs in prescriptions with 5 drugs and 80% with 7 medications or more.9

Healthcare organizations must focus on patient safety monitoring for improvised health delivery. The scarcity of national studies on drug interactions and indiscriminate use of drugs, highlight the need for more studies that may contribute for planning and formulation of public health policies in this field.10 Therefore, the current study was taken up to improvise the patient safety by monitoring, identifying and preventing DDIs.

MATERIALS AND METHODS

It is a prospective study conducted to identify the DDIs in patients admitted to the Department of General Medicine at a tertiary care hospital, Bangalore and this study was conducted between January and June 2016. This study was approved Institutional Ethics Committee (IEC) of M.S. Ramaiah Medical College, Bangalore.

Data collection

The data were retrieved from case sheets, medication charts, laboratory reports and by conducting medication history interviews. The patient profile form was developed which included patient’s demographics, history of medications and allergy, diagnosis and clinical laboratory values. DDI form included the details of DDIs with its classifications based on severity, documentation and mechanism.

Data analysis

DDIs were analysed using Stockley’s textbook of drug interactions, Micromedex online database system, Medscape drug interaction checker and Drugs.com. Further, DDIs were classified based on the type and severity of interaction as contraindicated, major, moderate and minor along with mechanism of interactions.

Statistical analysis

Association between factors such as length of hospital stay, number of drugs per prescription, number of comorbidities and DDIs were analysed by chi-square test using SPSS V20.

RESULTS

In this study, a total of 411patients were enrolled, out of which 243 (59.1%) were males and 168 (40.9%) were females (Figure 1). The prescriptions of the enrolled patients were analysed and the maximum number of drugs per prescription of the study population was 22 and minimum number was 2. Among 411 prescriptions, 39 (9.5%) prescriptions were below 4 medications and 372 (90.5%) were above or equal to 4 medications. The result shows that many prescriptions followed polypharmacy.

Figure 1

Gender distribution.

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Among 411 prescriptions, 165 (40.1%) were observed with pDDIs and 23 (5.6%) showed actual DDIs respectively (Figure 2). A total of 657 DDIs were identified in 188 prescriptions. Out of 188 prescriptions with DDIs 123 (65.4%) prescriptions were in the range of 1-3 DDIs followed by 37 (19.7%) in the range of 4-6 and 28 (14.9%) above 6 DDIs (Table 1). 105(25.5%) DDIs were identified in male whereas 83(20.2%) were identified in female (Table 2). DDIs were found to be highest among patients aged above 50 years, 106 (25.7%) followed by patients aged between 25-50 years, 62 (15.1%). The difference in proportion of incidence of DDIs with different age groups was statistically significant (p<0.05) (Table 3). Majority of the study population had co-morbidities along with their primary diagnosis (Figure 3).

Figure 2

Presence of DDIs.

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Figure 3

Presence of comorbidities.

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Table 1

Number of DDIs per prescription.

Number of DDIsNumber of patientsPercentage (%)
1-312365.4%
4-63719.7%
>62814.9%
Total188100%
Table 2

Gender wise distribution of DDIs per prescription.

RangeMaleFemaleTotal
Number of patientsPercentageNumber of patientsPercentage
1-36735.6%5629.8%123
4-62111.2%168.5%37
>6179.1%115.9%28
Total10555.9%8344.1%188

The chi square statistic is 0.3758. The p-value is 0.828694. The result is not significant at p<0.05.

Table 3

Age wise categorization of DDIs per prescription.

Age group (years)1-34-6>6Total
Number of patientsPercentNumber of patientsPercentNumber of patientsPercent
<251910.1%10.5%00%20
25-504825.5%105.3%31.6%61
>505629.8%2613.8%2513.3%107
Total12365.4%3719.6%2814.9%188

The chi square statistic is 23.01. The p-value is 0.000126. The result is significant (p<0.05).

In this study, the identified DDIs were classified based on the severity, documentation and mechanism (Table 5, 6 and Figure 4). Among the 657 DDIs per prescription, 6 interactions (0.9%) came under the classification of contraindication, 240 (36.5%) fall under major severity, 374 (56.9%) were of moderate severity and 37 (5.6%) were of minor severity. 657 DDIs were analysed for their type or mechanism of interaction. Out of which, 310 were pharmacodynamic DDIs, 243 were pharmacokinetic DDIs. Out of 657 DDIs, 68 (10.4%) were excellent, 249 (37.9%) were good and 340 (51.8%) were fair based on documentation criteria. Mechanism of actual DDIs and most frequently identified pDDIs along with their manifested and anticipated effects are described in Table 7 and 8 respectively. Factors such as length of hospital stay, number of co-morbidities and number of drugs per prescription were analysed and a statistically significant association between occurrence of DDIs and their factors were noted (Table 4).

Figure 4

Mechanism of DDIs.

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Table 4

Predictors associated with the occurrence of DDI.

DDIsLength of Hospital Stay in DaysNumber of Co-morbiditiesNumber of drugs per prescription
1-34-6>6Total01-34-6>6Total2-45-78-10>10Total
013483622393112013137304212286
1-313151644341622189074126579
4-61122245729132628961684220131
>6113442871113244881311964115
Total1691548841115751100103411391829991411
PredictorsChi-square statisticP value
Length of hospital stay126.75<0.001
Number of medicines116.69<0.001
Concurrent illness186.65<0.001
Table 5

Severity of DDIs.

SeverityNumber of DDIsPercentage (%)
pDDIsActual DDIs
Contraindicated600.9%
Major2192136.5%
Moderate366856.9%
Minor3615.6%
Total62730100%
Table 6

Documentation of DDIs.

DocumentationNumber of DDIs% of DDIs
pDDIsActual DDIs
Excellent68010.4%
Good243637.9%
Fair3262451.8%
Total62730100%
Table 7

Mechanism of identified actual DDIs and the effect produced.

InteractionsFrequencySeverityDocumentationMechanismEffect produced
Quetiapine + Carbamazepine2MajorFairPharmacokineticIncreased drowsiness and reduced Quetiapine concentration
Pyrazinamide +Rifampin1MajorGoodUnknown (additive)Hepatic injury (ALP increased)
Oxcarbazepine +Tolvaptan1MajorFairPharmacokineticReduced tolvaptan concentration and hyponatremia (123.5mEq)
Aspirin+ Calcium carbonate2ModerateFairPharmacokineticDecreased salicylate effect
Aspirin + Hydrocortisone1MinorGoodPharmacodynamicGastric ulceration
Aspirin +Clopidogrel6MajorFairPharmacodynamicGI bleeding
Cefotaxime + Warfarin1MajorGoodUnknownIncreased INR (3.5)
Metalazone + Torsemide2MajorGoodPharmacodynamicHyponatremia (122, 120.9mEq/L)
Digoxin + Aspirin1MajorGoodPharmacokineticHyperkalemia (6.1mEq/L)
Heparin + Enoxaparin3MajorFairPharmacodynamicBleeding manifestation
Furosemide + Metoprolol2ModerateFairPharmacodynamicHypotension (98/64, 86/60 mmHg)
Furosemide + Albuterol2ModerateFairPharmacodynamicHypokalemia (2.5, 2.7mEq/L)
Metformin + Insulin aspart2ModerateFairPharmacodynamicHypoglycaemia (GRBS- 65, 91 mg/dl)
Levofloxacin + Tramadol1MajorFairPharmacodynamicSeizures
Ondansetron + Levofloxacin3MajorFairPharmacodynamicProlongation of QT interval
Table 8

Mechanism of most frequently identified pDDIs and their anticipated effects.

InteractionsFrequencyAnticipated effects
ContraindicatedFluconazole+Ondansetron4Increased risk of QT prolongation
Clarithromycin+Ivabradine1Increased ivabradine exposure and risk of QT prolongation
Clarithromycin+Fluconazole1Increased Clarithromycin exposure and risk of cardiotoxicity
MajorClopidogrel+Aspirin37Increased risk of bleeding
Enoxaparin+Aspirin19Increased risk of bleeding
Azithromycin+Ondansetron15Increased risk of QT prolongation
Clopidogrel+Enoxaparin14Increased risk of bleeding
Amlodipine+Clopidogrel11Decreased antiplatelet effect and increased risk of thrombotic effect
Metronidazole+Ondansetron10Increased risk of QT interval prolongation and arrhythmia
ModerateAtorvastatin+Clopidogrel26Decreased formation of clopidogrel active metabolite
Furosemide+Aspirin23Decreased diuretic and antihypertensive efficacy
Iron+Pantoprazole22Reduced iron bioavailability
Aspirin+Insulin15Increase the risk of hypoglycemia
Atorvastatin+Azithromycin13Increased risk of rhabdomyolysis
Aspirin+Spironolactone11Decreased diuretic effectiveness hyperkalemia or nephrotoxicity
Aspirin+Ramipril10Reduced ramipril effectiveness
MinorFolic acid+Nitrofurantoin5Decreased folic acid serum level
Aspirin+Ranitidine4Decreased salicylate blood levels and antiplatelet effect of aspirin
Aspirin+Phenytoin3Decreased phenytoin concentrations

DISCUSSION

As the number of medications increase, the complexity of therapy also increases which could lead to DRP and further reduce the clinical outcome. Drug interactions are recognized as the most dangerous DRP.11

In this study, majority of the population were males which was similar to a study conducted by Ahmed et al.. (2015).6 and contrast to the study conducted by Mateti U et al..12

In this study, majority of patients fall under the age group of 25-50 years. The mean age was 45.7 ± 19 years. The maximum and minimum age of patients were 88 years and 15 years rspectively. Cruciol-Souza et al.. (2006) has reported in their study that the average age of inpatients was 52.7 ± 18.9 years ranging from 12 to 98 years.8 Our study is online with the studies conducted by Jimmy et al.. (2012), Bhagavathula et al.. (2014), Nag et al. (2011).9,13,14 In this study, there was no appreciable difference in proportion of DDIs among both the genders.

It was found that the maximum number of drugs per prescription was 22 and minimum was 2. Out of 411 prescriptions, 188 were found with the DDIs. A total of 657 DDIs were found with an average of 3.49 DDIs per patients. Our work revealed that the overall prevalence of DDIs were 46% and the prevalence rate of DDIs were reported to be 49.7%, 56.2%, 63% and 78% were reported by Cruciol-Souza et al.. (2006), Vonbach et al.. (2008), Umretiya et al.. (2015) and Bhagavathula et al.. (2014) respectively.8-9,15-16

The study showed that the incidence rate of DDIs were more in males than females, this may be because maximum of the study population were males. These findings were similar to the studies carried out by Umretiya et al.. (2015) and Nag et al.. (2011).13,16 whereas in contrast to the studies by Lubinga et al.. (2011), Jimmy et al..(2012) and Moura et al.. (2009) which reported high incidence rate of DDIs in females.7,17,14

Age distribution revealed the incidence rate of DDIs to be highest among patients aged above 50 years which could be attributed to the fact that the number of co morbidities are more in older patients which leads to poly-pharmacy in this population and it has further increased the chances of developing DDIs. The studies conducted by Bista et al.. (2009), Merlo et al.. (2001), Jimmy et al.. (2012) showed that the incidence rate of DDIs was 36% in the age range of 46-60 years and 30.95% in the age above 60 years.14,18,19 Whereas the study conducted by Ismail et al.. (2011), Lubinga et al.. (2011), Nag et al.. (2011) reported incidence rate of DDIs more in the age range of 30-40 years.7,13,20 Here, the ranges for the DDIs were categorized as: 1-3, 4-6 and >6. Among 188 prescriptions with DDIs, 1-3 DDIs were found in maximum prescriptions. There was no statistically significant difference between male and female with respect to incidence of DDIs.

In 411 prescriptions, 188 (45.7%) prescriptions had at least one interacting drug combination. Among the 657 DDIs, majority were classified as moderate which is comparable with the results of Ahmad et al.. (2015) where the major, moderate and minor pDDIs were 44 (31.65%), 75 (53.95%) and 20 (14.38%) respectively.6 Most of the DDIs were fair in documentation which is similar to the work of Jimmy et al.. (2012) who reported the documentation of DDIs to be fair 165 (50%), good 134 (40.61%) and excellent 31 (9.39%).14

657 DDIs were analyzed for their type or mechanism of interaction. Out of which, maximum were pharmacodynamic mechanism. Lubinga et al.. (2011) revealed that the majority of DDIs were postulated to occur through pharmacodynamic mechanism followed by pharmacokinetic. In our study the most commonly interacting drug combination was found to be aspirin and clopidogrel 43 (6.5%), which was expected to increase the risk of bleeding manifestations.

As the length of hospital stay increased, the number of medicines also escalated, which further increased the chance of occurrence of DDIs. In our study there was a positive association between the length of hospital stay, number of comorbidities, number of drugs per prescription and the number of DDIs (p< 0.001). Similar associations were observed by Sharma et al.. (2014) among cardiac patients in a teaching hospital in Nepal.21

Out of 188 prescriptions, 23 of them showed 30 clinical manifestations and upon reporting of those DDIs by Clinical pharmacist few drug combinations were withdrawn from the regimen and appropriate management was done. Among those manifestations, the serious reactions were QT prolongation and bradycardia due to Ondansetron and Levofloxacin combination in a 31 year old female patient admitted in MICU and manifestation of seizures due to Tramadol and Levofloxacin combination in a 19 year old female. In both the cases the interacting drug levofloxacin was withdrawn and substituted with suitable alternatives, which resulted in improvement of the above conditions.

CONCLUSION

Our study concludes that the incidence rate of DDIs is high at the study site. Majority of the patients received polypharmacy. The identified predictors responsible for DDIs were polypharmacy, age, duration of hospital stay and the number of comorbidities. Hence, it is important to develop a systemic approach to minimize the possible DDIs. Clinical relevance of certain DDIs might be because of their pharmacological actions. The clinical pharmacist is of prime importance to provide information for a better decision on therapy, improve quality of treatment and reduce risks in the patients.

This study tries to put forward the common DDIs which we came across in tertiary care hospitals and this may be a forewarning to health care team about reactions that may occur due to an interaction, as well as provide a support material for physicians to choose an alternate therapy, dose adjustments and patient monitoring. Most often the consequences of DDIs can be managed by withdrawal of potential drugs, specific symptomatic treatments, using alternative drug or dose adjustments. Awareness on the most prevalent DDIs can help the practitioners prescribe drugs with a low risk for DDIs and thereby prevent the concomitant use of dangerous medication combinations.

LIMITATION

Long-time follow up of the patients was not possible because of which delayed onset DDIs could not be assessed.

ACKNOWLEDGEMENT

We sincerely thank our Dean, Dr. V. Madhavan for giving us an opportunity and for his constant support during our project work.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ABBREVIATIONS

DDIs

Drug-Drug Interactions

DRPs

Drug related problems

IEC

Institutional Ethics Committee.

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