An Empirical Study to assess the Pattern and Predictors of Adverse Drug Reactions associated with Polypharmacy in the Department of General Medicine

 

S Lincy¹, M Greeshma¹, E Maheswari²*, S Tharanath³, Subeesh Viswam²

¹Department of Pharmacy Practice, M.S. Ramaiah College of Pharmacy, Bangalore-560054, Karnataka, India.

²Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bangalore-560054, Karnataka, India.

³Department of General Medicine, M.S. Ramaiah Hospital, Bangalore-560054, Karnataka, India.

 

ABSTRACT:

Objective:Adverse Drug Reactions (ADRs) are the leading cause of morbidity and mortality. Clinical pharmacists in organized health care systems have to develop comprehensive, in progress programs for monitoring and reporting of ADRs. The current study aimed to assess the pattern of ADRs associated with polypharmacy in the Department of General Medicine of a tertiary care teaching hospital. Material and methods: A prospective-observational study was conducted in theDepartment of General Medicine by clinical pharmacists for a period of six months to assess the causality, level of severity, preventability and predictability of identified ADRs. All the relevant information was collected from patient’s record file in a standard case record form. Results: During the study period 150 patients were screened for ADRs, a total of 96 ADRs were observed in 61 patients of which 31(50.8%) were females and 30(49.2%) were males. Endocrine system 38(39.58%) was found to be the most affected organ system. Hyponatremia was found to be the most frequently occurring ADR.Of the reported ADRs, type A 56 (58.3%) ADRs was the most common, compared to type B in 6(6.3%). Causality assessment of ADRs by WHO, Naranjo’s and Karch and Lasagna’s Scale which revealed that probable constituted increasingly(57.3%, 56.2%, 50% respectively). The results showed that 87(90.6%) of the ADRs were definitely preventable and 63(65.6%) ADRs were predictable.Severity assessment of ADRs disclosed that 36(37.5%) ADRs were of level 3. Conclusion:ADRs are one of the significant Drug Related Problem (DRP)in the hospital setting. Our study has revealed that prevention of ADRs are important as they cause morbidity in patients.This study highlights the importance of reinforcement strategies to appoint well-trained clinical pharmacist to identify ADR, toimprove rational prescribing and therapeutic drug monitoring.

 

 

 

INTRODUCTION:

Pharmacovigilance is defined by the World Health Organization (WHO) as ’the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems.^[1]

 

Effective and potent medication have provided some of the most significant advances in human health.^[2] However they can accompany incredible dangers when they are not managed and administered properly.^[3]

 

The WHO defines an Adverse Drug Reaction(ADR) as any response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function.^[4] ADRs in hospitalized patients are divided into two categories: those that lead to hospitalization or pre-admission ADRs (ADRAd) and that developed during hospitalization or post-admission ADRs (ADRIn).^[5] Studies have demonstrated that 3 to 14% of all hospital admissions are identified with ADRs. Moreover, 5 to 20% of all hospitalized patients develop ADRs in the course of hospitalization.^[6]

 

Poly-pharmacy may develop ADRs due to the drug antagonism, synergism, duplication, drug interactions and discontinuation of treatment.^[7] All medications can cause ADRs, yet not all patients develop similar level and types of ADRs. The larger part of ADRs happen because of the increased desirable pharmacological impacts of a medication, regularly because of the generous fluctuation in the pharmacokinetics and pharmacodynamics seen among patients. Variables that incline to ADRs are age, polypharmacy, gender, immune system and pharmacogenetics have demonstrated greater risk to cause morbidity and mortality.^[8]

 

So as to maintain more secure utilization of medications, there is a requirement for an active pharmacovigilance framework at all the levels of health care. Subsequently, the requirement of better system of reporting ADRs has been approved as a best need activity to avert ADRs in health care system.^[9,10]

 

Pharmacists in organized health care systems have to develop comprehensive, in progress programs for monitoring and reporting ADRs.^[11] Clinical pharmacist can play a major role in ADR reporting and pharmacovigilance activities since they approach the data important to report ADRs. Pharmacists will probably identify ADRs than other healthcare professionals, either in the physician’s facility or community setting.^[12] In India, epidemiological information of ADRs are restricted for the frequency, risk factors, outcome and other clinical  characteristics. A systematic review is required to evaluate the incidence of ADRs based on Indian studies.^[5] The current study aimed to assess the pattern of ADRs associated with polypharmacy in the department of general medicine.

 

MATERIAL AND METHODS:

A prospective observational study was conducted among the inpatients and outpatients of the Department of General Medicine of Ramaiah Hospital, Karnataka for a duration of 6 months from November 2016 to April 2017. The study protocol was approved by Human Ethics Committee of Ramaiah Medical College. The informed consent was obtained from all the patients included in the study. All patients of both gender aged 18 years and above and visited the Department of General Medicine and who met the study criteria were included.  Patients admitted to intensive care units or other units were excluded. The inpatients were regularly monitored for ADRs during the hospital stay and outpatients were monitored for ADRs during their subsequent visits within the study period.

 

Data collection procedure:

The ADR assessment form was prepared with the details of suspected ADRs and brief description, nature of reaction, date of onset of reaction, treatment and outcome of reaction and complete dosing regimen of the suspected drugs. It also, included the causality categories, severity ratings, predictability, and preventability from different standard scales to be adopted in the assessment of ADR.

 

Data analysis:

ADRs were identified using WHO’s definition and the causality assessment was done using WHO causality scale, Naranjo’s algorithm and Karch and Lasagna’s scales. ADRs were categorized into definitely preventable, probably preventable and not preventable using the Schumock and Thornton criteria. Predictability of ADRs was also assessed.ADRs were classified into mild, moderate and severe reactions using the Modified Hartwig criteria for severity assessment.Individual reactions were classified depending on the type of reactions as type A (Augmented) and type B (Bizarre) reactions based on the classification by Rawlins and Thompson.

 

Statistical Analysis:

To find out the incidence of ADRs between gender, age group, comorbidities and number of drugs prescribed, chi- square was applied.The predictors of ADRs were analysed by using the statistical package for social sciences (SPSS) V21.0 software.

 

RESULTS:

Over six months, there were a total of 150 patients assessed for ADRs. Demographic characteristics of study population is described in table 1.

 

Table 1: Demographic characteristics of the study patients.

Variables	Characteristics	Number (%)
Gender	Male	75 (50)
	Female	75 (50
Age	18-40 years	33 (22)
	41-60 years	54 (36)
	>60 years	63 (42)
Comorbidities	None	32 (21.3)
	1	42 (28)
	2	38 (25.3)
	3	22 (14.7)
	>4	16 (10.7)
Number of drugs prescribed	2-5	14 (9.3)
	6-10	63 (42)
	>10	73 (48.7)

 

During the study period, 150 patients were screened for ADRs, a total of 96 ADRs were observed from 61 patients. Chi square test was used to analyse the association between age, gender, comorbid condition, number of drugs prescribed and the occurrence of ADRs. The ADRs experienced by bothfemale 31(50.8%) and male patients 30(49.2%) showed no statistical significance (p=0.8696). Age distribution of total population revealed that geriatrics were more prone to develop ADRs with a p value of 0.0002, accounting to 62.2%. Majority of ADRs occurred in patients with 2 comorbidities which was statistically significant with p value of 0.005. It was observed that patients who were prescribed with more than 10 drugs 43(74%) developed more ADRs (p=0.000). Correlation between the gender, age, comorbidities, number of drugs prescribed and ADRs is shown in table 2.

 

Table 2: Association of ADRs with demographic characteristics.

Variables	Number of patients without ADRs (%)	Number of patients with ADRs (%)	Total number of patients	P value
Gender
Male	45 (50.6)	30 (49.2)	75 (50)	P= 0.8696*
Female	44 (49.4)	31 (50.8)	75 (50)
Age group
18-40 years	24 (27)	9 (14.8)	33 (22)	P=0.0002
41-60 years	40 (45)	14 (23)	54 (36)
>60 years	25 (28)	38 (62.2)	63 (42)
Comorbidities
None	27 (30.3)	5 (8.2)	32 (21.3)	P= 0.0005
1	29 (32.6)	13 (21.3)	42 (28)
2	19 (21.3)	19 (31.1)	38 (25.3)
3	7 (7.9)	15 (24.6)	22 (14.7)
>4	7 (7.9)	9 (14.8)	16 (10.7)
Number of drugs prescribed
2-5	14 (15.7)	0(0)	14 (9.3)	P= 0.0000
6-10	45 (50.6)	18(26)	63(42)
>10	30 (33.7)	43(74)	73(48.7)

*Not significant at P<0.05

 

The classes of drugs that showed ADRs among the study population are shown in table 3. It was observed that the incidence of ADRs were more in patients who received antihypertensives (28.1%).

 

Table 3: Classes of drugs associated with ADRs.

Class of drug	No. of ADRs reported (n=96)	Percentage of ADRs
Antihypertensives	27	28.1
Antidiabetics	12	13
Diuretics	11	11.3
Antibiotics	10	10.4
Bronchodilators	8	8.3
Anticonvulsants	8	8.3
Corticosteroids	5	5.2
Antifungals	4	4.2
NSAIDs	3	3.1
Antirheumatic agents	3	3.1
Lipid lowering agents	1	1
Calcium supplements	1	1
Thyroid hormone supplements	1	1
Hepatoprotectants	1	1
Neuropathic pain agents	1	1
Total	96	100

 

The organ system affected due to ADRs were classified and coded according to System and organ(WHO- ART code).The endocrine system 38 (39.58%) was found to be the most affected organ system followed by vascular system 12 (12.5%) which is mentioned in table 4.

 

 

 

 

Table 4: Analysis of organ system associated with ADRs.

SOC (WHO-ART Code)	Number of ADRs (%) n=96	Suspected ADRs (Number of affected patients)
Endocrine disorder (0900)	38 (39.58)	Hyperkalemia (3), hyponatremia (18), hypokalemia (9), hypoglycaemia (3), hyperglycemia (4), hypothalamic-pituitary-adrenal axissuppression (1)
Cardiovascular disorder (1010)	7 (7.29 )	Hypotension (8)
Vascular disorder (1040)	12 (12.5)	Pedal edema (12)
Heart rate and rhythm disorders (1030)	6 (6.25)	Tachycardia (4), QT interval prolongation (1), bradycardia (1)
Gastrointestinal system disorders (0600)	9 (9.4)	Vomiting (2), diarrhoea (4), constipation (2), gastric ulcers (1)
Skin and appendages disorders (0100)	7 (7.3)	Rashes (5), redness at injection site (1), alopecia (1)
Central and peripheral nervous system (0410)	6 (6.2)	Nystagmus (2), numbness (1), ataxia (1), headache (2)
Respiratory system disorders (1100)	4 (4.2)	Dry cough (3), bronchospasm (1)
Liver and biliary system disorders (0700)	3 (3.1)	Increased liver enzyme (3)
Urinary system disorders (1300)	1 (1)	Nephrotoxicity (1)
Hearing and vestibular disorders (0432)	1 (1)	Tinnitus (1)
Psychiatric disorders (0500)	1 (1)	Insomnia (1)
Red blood cell disorders (1210)	1 (1)	Pancytopenia (1)

 

WHO- ART: World Health Organisation- Adverse Reaction Terminologies, SOC: System Organ Class, ADRs: Adverse Drug Reactions

Of the total 96 ADRs, hyponatremia was found to be most frequently occurring ADR followed by pedal edema, hypokalemia and hypotension which is depicted in figure 1.

 

 

 

Figure 1: Frequency of ADRs.

 

 

Figure 2: Types of ADRs.

 

Of the reported ADRs, type A 56 (58.3%) ADRs was the most common, compared to type B in 6 (6.3%), type C in 23 (24%), type D in 11 (11.4%) which is represented in the figure 2.

 

Table 5 demonstrates causality assessment of ADRs by WHO scale, Naranjo’s Scale and Karch and Lasagna’s Scale which revealed that probable constituted increasingly (57.3%, 56.2%, 50% respectively).

 

Table 5: Causality assessment of ADRs.

Causality Assessment	Number of Patients with ADR
	Male	Female	Total%
WHO Scale
Certain	3	1	4 (4.2)
Probable	30	25	55 (57.3)
Possible	13	8	21 (21.9)
Conditional	6	10	16 (16.6)
Naranjo’s Scale
Probable	30	24	54 (56.2)
Possible	18	17	35 (36.5)
Conditional	2	5	7 (7.3)
Karch and Lasagna’s Scale
Definite	3	2	5 (5.2)
Probable	23	25	48 (50)
Possible	23	13	36 (37.5)
Conditional	2	5	7 (7.3)

 

Preventability of reported ADRs was assessed using Schumock and Thornton method. Using this scale, results showed that 87 (90.6%) of the ADRs were definitely preventable, while 9 (9.4%) were probably preventable (Figure 3).

 

 

Figure 3: Preventability of ADRs

 

Predictability analysis indicated that 63 (65.6%) ADRs were predictable (Figure 4).

 

 

Figure 4: Predictability of ADRs

 

Severity assessment of ADRs by Hartwig’s and Siegel Severity Scale (Table 6) disclosed that 36 (37.5%) ADRs were of level 3 followed by 23 (24%) of level 1 and 22 (22.9%) of level 2.

 

Table 6: Severity assessment of ADRs.

Severity of ADRs	Number of ADRs
	Male	Female	Total (%)
Mild
Level 1	13	10	23 (24)
Level 2	7	15	22 (22.9)
Moderate
Level 3	18	18	36(37.5)
Level 4a	7	0	7 (7.3)
Level 4 b	6	2	8 (8.3)
Severe
Level 5	0	0	0 (0)
Level 6	0	0	0 (0)
Level 7	0	0	0 (0)
Total	51	45	96 (100)

 

From the study, it was found that 70 (73%) ADRs were recovered and it is depicted in figure 5.

 

 

Figure 5: Outcome of ADRs

 

Table 7 shows that in most of the ADRs 35 (36.5%), the suspected drug was discontinued and specific treatment was given and in 25 (26%) ADRs, the suspected drug was discontinued without providing any other treatment.

 

Table 7:Management of ADRs

Management of ADRs	Total	Percentage
Discontinue with suspected drug and specific treatment given	35	36.5
Discontinue with the suspected drug and no treatment given	25	26
Continue with the suspected drug and specific treatment given	16	16.7
Continue with the suspected drug and no specific treatment given	14	14.6
Replacement of suspected drug	4	4.2
Dose reduction	1	1
Dose increased	1	1
Total	96	100

 

Table 8 shows the results of our bivariate analysis. The result of the binary logistic regression showed that association was observed between age above 60 years (OR: 4.374, 95% CI: 2.183-8.765, p=0.000), presence of more than 2 comorbidities (OR: 2.884, 95% CI: 1.470-5.658, p=0.003) and polypharmacy (OR: 4.095, 95% CI: 1.737-9.655, p=0.001) with the occurrence of ADRs. Gender was not determined as a predictor of ADR(OR: 1.180, 95% CI: 0.615-2.266, p=0.740).

 

 

Table 8: Binary logistic regression result of predictors associated with ADRs.

Factor	Odds ratio	95% CI		P value	Adjusted Odds ratio	95 % CI		P value
		Lower limit	Upper limit			Lower limit	Upper limit
Gender  Male  Female	1.180 Reference	0.615	2.266	0.740	-	-	-	-
Age <60 years >60 years	4.374 Reference	2.183	8.765	0.000*	3.562	1.703	7.447	0.001**
Comorbidities <2 >2	2.884 Reference	1.470	5.658	0.003*	1.916	0.915	4.011	0.085
Number of drugs Prescribed  2-5 drugs >5 drugs	4.095 Reference	1.737	9.655	0.001*	3.470	1.399	8.605	0.007**

CI: Confidence Interval, *Significance at <0.05 based odds ratio, **Significance at <0.05 based on adjusted odds ratio

 

DISCUSSION:

Among 150 patients reviewed, ADRs were observed in 61 patients.The incidence of ADRs experienced by male and female patients were found to be almost equal. In general, gender related influences due to estrous cycle, pharmacokinetic and pharmacodynamic changes contribute to predominance of ADRs in female patients. But in our study, no gender related difference was observed among the patient experienced the ADRs. This finding is in agreement with the study conducted by Rydberg DM et al., on Adverse Drug Reactions in a Tertiary Care Emergency Medicine Ward - Prevalence, Preventability and Reporting.^[13] The majority of ADRs occurred in geriatric patients 38(62.2%) followed by adults 23(37.8%) is in correlation with the study conducted by Shareef et al., on a study on ADRs in hospitalized patients with diabetes mellitus in a multi-speciality teaching hospital.^[14] The elderly population has higher prevalence of chronic multiple diseases, heading to polypharmacy, which makes them more susceptible to the occurrence of ADRs. Most of the patients 73(48.7%) in our study has received more than 10 drugs during their hospital stay out of which 43(74%) patients developed ADRs. The class of drugs most commonly responsible for causing ADR was found to be antihypertensives 2(28.1%). Our results were similar to the finding observed by the Ramadaniati et al., on DRP in chronic kidney disease patients in an Indonesian hospital.^[15]Other classes of drugs that reported ADRs were found to be antidiabetics drugs 12(13%), diuretics 11(11.3%), antibiotics 10(10.4%), bronchodilators 8(8.3%), anticonvulsants 8(8.3%) and corticosteroids 5 (5.2%).

 

The organ system most commonly affected by ADRs were found to be endocrine system 38 (39.8%) followed by vascular system 12(12.5%), this is because most of the antihypertensives and antidiabetics causes electrolyte imbalance (hypokalemia, hyponatremia, hypoglycaemia, hyperkalemia). The current study is in contrary with the study conducted by Tiwari P et al., on Adverse Drug Reaction Monitoring in a North Indian Public Teaching Hospital in which the most affected system was GIT.^[8]The most commonly reported ADR was found to be hyponatremia 18 (18.7%) followed by pedal edema 11 (11.4%), hypokalemia 9 (9.4%) and hypotension 7 (7.3%). Most of the patients have co-morbid conditions like hypertension and type 2 diabetes mellitus for which they were treated with antihypertensives such as amlodipine, furosemide and antidiabetics such as metformin. Administration of all these medications have increased the incidence of causing hyponatremia.

 

Analysis of the type of reported ADRs according to Rawlin and Thompson revealed type A predominance. This result is in line with the study conducted by Shamna et al., type A reactions are dose related thus were predictable from their known pharmacology and therefore all of them were potentially avoidable.^[4] ADRs were analysed by different scale for determining its causality, severity, preventability and predictability. Assessment of ADR was done by WHO’s,Naranjo’s and Karch and Lasagna’s causality assessment scale. In our study most of the ADRs were Probable as the patients responded positively to the withdrawal of the suspected drug and the specific treatment that has been provided to them. The study is in congruence with the study conducted by Kumar BN et al on the pharmacovigilance study in medicine department of care hospital, Chattishgarh.^[16]

 

The severity of the reported reactions was analysed using modified Hartwig and Siegel Scale and accordingly, 51(53.1%) of the ADRs were categorised as ‘Moderate’ and 45(46.9%) as ‘Mild’. None of the ADRs were found to be severe. In moderate reactions level 3 contributedto highest percentage that is 36(37.5%) ADRs which requireddiscontinuation, changed to alternative drug, antidote or other treatment. These findings were similar to the result of the study conducted by Palaniswamy et al on assessment, monitoring and reporting of ADRs in Indian hospital.^[17]

Predictability of the reactions was based on the incidence of the reaction and literature reports. The current study found majority of theADRs to be ‘Predictable’ 63 (65.6%). Preventability analysis by using Schumock and Thornton scale revealed that majority of the reactions was ‘Definitely Preventable’ 87 (90.6%) followed by ‘Probable preventable’ 9 (9.4%). This study is similar to the study which is conducted by Shamna et al.^[4]

 

The outcomes of the suspected reactions were determined to understand the patient’s conditions who were treated for different adverse reactions. In this study, outcomes of the reaction were analysed and majority of the patients experienced ADRs (73%) were recovered. Severity and outcome were correlated, most of the mild reaction showed faster recovery when compared to moderate reactions which were still under recovery during the time of discharge. This study is similar to the study conducted by Vijayakumar et al.^[18]

Management of ADRs plays an important role in promoting the safe and rational use of medicines. This can be done by withdrawing the suspected drug, reducing or increasing the dose, replacement of suspected drug or by providing specific treatment to the suspected reaction. In this study management regarding ADR is concerned, most of the drugs that were thought to cause ADR were discontinued and specific treatment was given 35 (36.5%) and the majority of these patients fully recovered before discharge from medicine wards. This observation is similar to the study conducted by Vora et al on ADRs in inpatients of internal medicine wards at a tertiary care hospital.^[3]Our results supports that the geriatric population (AOR:3.562, p=0.001) and polypharmacy (AOR:3.470, p=0.007) are the important risk factors for ADRs.This study is in congruence with the study conducted by Rydberg DM et al., which shows similar results.^[13]Awareness and identification of ADRs in patients is critical in tertiary care.This setting is perfect for improving patient wellbeing concerning drug use. Medical experts awareness of the high frequency of medication related issues and adverse drug reactions could be stimulated by continous education.

 

CONCLUSION:

The outcomes of our study gave interest to the health care professionals on the significance of observing and reporting of ADRs in a health care system. Monitoring of ADRs make the therapy safer and more effective. ADRs are one of the significant drug related issues in the hospital setting. Antihypertensives and antidiabetics add up to the large volume of the drug family and requires constant vigilance and close monitoring of patients for early detection of ADRs to avoid harmful consequences.This study has revealed that ADRs are an important cause of morbidity in patients.This highlights the importance of appointment of well-trained clinical pharmacists in hospitals for the implementation of strategies to improve rational prescribing, dispensing and therapeutic drug monitoring which in turn improve the quality of life of patients.

 

CONFLICT OF INTEREST

The authors have no conflict of interest.

 

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Accepted on 10.10.2018           © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(11): 5042-5048.