A Prospective Observational Study on Adverse Drug Reactions in General Medicine Department of a Tertiary Care Teaching Hospital

 

Rayees N M1, Sampath Kumar2, Bharath Raj K C1*, Rajesh K S1, Juno J Joel1, Prasanna Shama K3, Gururaja M P3, Nandakumar U P1

1Department of Pharmacy Practice, NITTE (Deemed to be University), Mangaluru- 575018 Karnataka, India.

2Department of General Medicine, NITTE (Deemed to be University), Mangaluru- 575018 Karnataka, India.

3Department of Pharmacology, NITTE (Deemed to be University), Mangaluru- 575018 Karnataka, India.

*Corresponding Author E-mail: bharathraj@nitte.edu.in

 

ABSTRACT:

Present study was carried out to estimate the incidence of ADRs reported in general medicine department, to evaluate the causality, severity and preventability of ADRs caused by any drugs. A prospective observational study was carried out for a period of 8 months. Patients admitted during the study period were included as per the study criteria and monitored for ADRs. The clinical system, spectrum of ADRs noted and assessment of ADRs was done by causality, preventability and severity. The different scales are applied for assessment of causality, severity and preventability. Data was analysed by using descriptive statistics. A total number of 270 patients were included. 55 ADRs were observed in 52 patients. Higher incidence of suspected ADRs were exhibited with the age group of 61-70 years. The hospital stay extended for more than nine days in 32 (61.5%) patients who experienced ADR. The causality assessment by WHO Probability Scale, showed that out of 55 ADRs, majority were probable 38 (69.09%), whereas 11 (22%) reactions were possible and 6 (10.91%) reactions were certain. Based on Naranjo’s scale, 29 (52.73%) reactions were probable and 26 (47.27%) reactions were possible. Majority of 29 (53%) reactions were moderate in severity. Proper monitoring of adverse reactions is useful to minimize the incidence of ADRs and prevent further occurrence of the same. The regular monitoring of ADRs can reduce the morbidity and can improve the patients compliance which in turn can produce better therapeutic outcome.

 

KEYWORDS: Adverse Drug Reaction, Causality, Severity, Preventability, Naranjo’s scale.

 

 


INTRODUCTION:

A drug is “a pharmaceutical product, used in or on the human body for the prevention, diagnosis or treatment of disease, or for the modification of physiological function”. Medicine associated problem list include - mis usage, drug abuse, poisoning, errors of medication, therapeutic failure etc.1 Adverse drug reaction (ADR) is defined as an undesirable effect which is beyond the expected therapeutic benefits of drugs during its clinical use.

 

 

 

 

According to World Health Organisation (WHO) an ADR is defined as “Any response to drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function”.2 Totally we can explain that, ADR is an injury developing from medical intervention associated to a drug. An adverse event is any untoward medical occurrence that may occur on treatment with a drug but which does not necessarily have causal relationship with the drug.3 The word adverse effects is proposal to other word such as side effects or toxic effects. A toxic effect that take place as excess of therapeutic effect, which are occurred at normal doses and always related to dose. A side effect happens by different mechanism and sometimes related to dose. Mainly ADRs are categorized into two: type A – Augmented reaction (dose dependent) and type B – Bizzarre reactions (dose independent).4 Around 80% of ADRs in the patients who were admitted to a hospital are type A. These reactions are possibly avoidable and much expected. The most common group of drugs that are responsible for ADRs are antibiotics, corticosteroids, anticoagulants, antineoplastic agents, cardiovascular agents, immunosuppressive and non-steroidal antiinflammatory agents.5 World Health Organisation (WHO) forward to each 154 countries to start pharmacovigilance programs. In Europe, pharmacovigilance was established after a huge annual death caused due to ADRs, 5% experienced ADRs during hospital stay and 5% of admission to hospitals were due to ADRs. The chief root of information on the matter of ADRs has been immediate write-up by authorities of healthcare. The survey found that reactions or outcomes were more common to each ager, also high degree of suspected ADRs were reported in children.6 In India, related data of ADRs are fixed for the occurrence, risk part, development, other clinical properties and the overall occurrence of reactions was 12.97%. Significant risk factors for suspected ADR incorporated female sex, ageing and polypharmacy.7 The events of ADRs and other drug related complications may be due to dose, polypharmacy, diseases, genetics, age, diet, people habits, pharmaceutical grades that effects in manufacturing of drugs, and distribution of drugs.8 The main application of these risk factors is that they can be used to create ADR risk prediction models, which in fact helps in identifying high risk patients for ADRs. The four marked levels behind the creation of perfect risk prediction models are development and validation assessment in first instance followed by impact and implementation assessment.9 Therefore regular monitoring of drugs are useful for detecting suspected reactions and to improve the effect of drugs. The reporting of ADR helps to secure the patients by getting safe and effective products.4 The continuing reporting system of ADRs can control the disaster caused by new medicines. Pharmacovigilance play a significant role in the healthcare system including monitoring, assessment and understanding the safety of drugs and their effects in humans. Monitoring of ADRs are important for each medicine during development of drugs both premarketing surveillance and post-marketing surveillance.1 According to the WHO “Pharmacovigilance is the sciences and activity relating to detection, assessment, understanding and prevention of ADR or any other medicine related risks, particularly long term and short term adverse effect of medicine”.10 The relationship between drugs exposure and occurrence of ADR were evaluated by using causality assessment. After reporting the ADR, it is essential to distinguish whether the reaction will be definite, probable or possible. This process is called Causality Assessment. The assessment of can be ADR done by using two scale: WHO causality scale11 and Naranjo probability scale.12 The WHO causality scale being categorizes the ADR into certain, probable, possible, unclassifiable, unlikely, conditional/unclassified11 whereas Naranjo scale categorizes ADR into definite, probable, possible, unlikely. Both scales shows the relationship between the drug and suspected clinical event.12 The severity assessment of ADR is done by using Hartwig severity scale 13 that is used to monitor the severity of ADRs. This scale classified the ADRs into mild, moderate, severe and fatal. The preventability of ADRs is determined by using Modified Shumock and Thornton’s scale.13

 

MATERIAL AND METHODS:

A prospective observational study of 8 months duration was conducted in the inpatients of General medicine wards of a multispecialty teaching hospital, in Dakshina Kannada district of South India. Central research ethics committee approval was obtained before starting the study. The study includes all the in- patients treated with any classes of drugs and Patients with any comorbid conditions with either gender of age more than 18 years. Patients being treated as outpatients, Accidental and intentional poisoning patients were excluded from the study. Patient data collection form was designed as per the need of study. Approval was taken from Institutional Ethics Committee and an informed consent was taken from the patients before initiating the study. The patients who were admitted due to an ADR and those who developed an ADR during hospital stay were enrolled in the study. The ADR was confirmed with treating physicians and collected the informations including patient demographics, past medication history, laboratory test, diagnosis, drugs used by patient and the suspected ADRs were documented in an ADR reporting form. All the drugs were classified with Anatomical Therapeutic Chemical Classification (ATC code – level 1, WHO, 2016). All ADRs were classified according to the International Statistics Classification of Diseases and related health problems. Management of ADRs (dose altered, drug withdrawn, no change) were documented in the ADR reporting form. The causality assessment of the suspected ADRs were done by using Naranjo’s scale (Definite, probable, possible, unlikely) and the WHO probability scale (Certain, probable, possible, unclassifiable, unlikely, conditional). The Hart-wigs severity scale (Mild, moderate, severe) was used to analyze the severity level of ADRs and the preventability determined by using Modified Schumock and Thornton scale.

 

Frequencies with percentage was used to summarize gender, age, number of drugs prescribed, frequency of ADRs, drugs involved in the ADRs and severity of ADRs. Mean with standard deviation were used to deriveage and length of stay. All analysis were conducted by using SPSS (Statistical Package for the Social Sciences) software.

RESULTS:

In the study period, a total number of 270 patients were included and assessed for ADRs. Out of 270 patients, 52 patients developed a total of 55 ADRs. The overall percentage of ADRs was 19.3%

 

Demographic details of the patients:

Age wise distribution of patients:

In the age wise distribution, patients were classified based on age group from 18 to 86 years of age. Higher incidence of suspected ADRs were reported in patients with the age group of 61-70 years followed by age group greater than 70 years. The mean age of the patients with ADRs was 58.31±17.60 years and without ADRs was 52.63±15.24 years. Table 1 summarizes the age wise distribution of patients and occurrence of ADRs.

 

A drug is “a pharmaceutical product, used in or on the human body for the prevention, diagnosis or treatment of disease, or for the modification of physiological function”. Medicine associated problem list include - mis usage, drug abuse, poisoning, errors of medication, therapeutic failure etc.1 Adverse drug reaction (ADR) is defined as an undesirable effect which is beyond the expected therapeutic benefits of drugs during its clinical use. According to World Health Organisation (WHO) an ADR is defined as “Any response to drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function”.2 Totally we can explain that, ADR is an injury developing from medical intervention associated to a drug. An adverse event is any untoward medical occurrence that may occur on treatment with a drug but which does not necessarily have causal relationship with the drug.3 The word adverse effects is proposal to other word such as side effects or toxic effects. A toxic effect that take place as excess of therapeutic effect, which are occurred at normal doses and always related to dose. A side effect happens by different mechanism and sometimes related to dose. Mainly ADRs are categorized into two: type A – Augmented reaction (dose dependent) and type B – Bizzarre reactions (dose independent).4 Around 80% of ADRs in the patients who were admitted to a hospital are type A. These reactions are possibly avoidable and much expected. The most common group of drugs that are responsible for ADRs are antibiotics, corticosteroids, anticoagulants, antineoplastic agents, cardiovascular agents, immunosuppressive and non-steroidal antiinflammatory agents.5 World Health Organisation (WHO) forward to each 154 countries to start pharmacovigilance programs. In Europe, pharmacovigilance was established after a huge annual death caused due to ADRs, 5% experienced ADRs during hospital stay and 5% of admission to hospitals were due to ADRs. The chief root of information on the matter of ADRs has been immediate write-up by authorities of healthcare. The survey found that reactions or outcomes were more common to each ager, also high degree of suspected ADRs were reported in children.6 In India, related data of ADRs are fixed for the occurrence, risk part, development, other clinical properties and the overall occurrence of reactions was 12.97%. Significant risk factors for suspected ADR incorporated female sex, ageing and polypharmacy.7 The events of ADRs and other drug related complications may be due to dose, polypharmacy, diseases, genetics, age, diet, people habits, pharmaceutical grades that effects in manufacturing of drugs, and distribution of drugs.8 The main application of these risk factors is that they can be used to create ADR risk prediction models, which in fact helps in identifying high risk patients for ADRs. The four marked levels behind the creation of perfect risk prediction models are development and validation assessment in first instance followed by impact and implementation assessment.9 Therefore regular monitoring of drugs are useful for detecting suspected reactions and to improve the effect of drugs. The reporting of ADR helps to secure the patients by getting safe and effective products.4 The continuing reporting system of ADRs can control the disaster caused by new medicines. Pharmacovigilance play a significant role in the healthcare system including monitoring, assessment and understanding the safety of drugs and their effects in humans. Monitoring of ADRs are important for each medicine during development of drugs both premarketing surveillance and post-marketing surveillance.1According to the WHO “Pharmacovigilance is the sciences and activity relating to detection, assessment, understanding and prevention of ADR or any other medicine related risks, particularly long term and short term adverse effect of medicine”.10 The relationship between drugs exposure and occurrence of ADR were evaluated by using causality assessment. After reporting the ADR, it is essential to distinguish whether the reaction will be definite, probable or possible. This process is called Causality Assessment. The assessment of can be ADR done by using two scale: WHO causality scale11 and Naranjo probability scale.12 The WHO causality scale being categorizes the ADR into certain, probable, possible, unclassifiable, unlikely, conditional/unclassified11 whereas Naranjo scale categorizes ADR into definite, probable, possible, unlikely. Both scales shows the relationship between the drug and suspected clinical event.12 The severity assessment of ADR is done by using Hartwig severity scale13 that is used to monitor the severity of ADRs. This scale classified the ADRs into mild, moderate, severe and fatal. The preventability of ADRs is determined by using Modified Shumock and Thornton’s scale.13

 

 

 

MATERIAL AND METHODS:

A prospective observational study of 8 months duration was conducted in the inpatients of General medicine wards of a multispecialty teaching hospital, in Dakshina Kannada district of South India. Central research ethics committee approval was obtained before starting the study. The study includes all the in- patients treated with any classes of drugs and Patients with any comorbid conditions with either gender of age more than 18 years. Patients being treated as outpatients, Accidental and intentional poisoning patients were excluded from the study. Patient data collection form was designed as per the need of study. Approval was taken from Institutional Ethics Committee and an informed consent was taken from the patients before initiating the study. The patients who were admitted due to an ADR and those who developed an ADR during hospital stay were enrolled in the study. The ADR was confirmed with treating physicians and collected the informations including patient demographics, past medication history, laboratory test, diagnosis, drugs used by patient and the suspected ADRs were documented in an ADR reporting form. All the drugs were classified with Anatomical Therapeutic Chemical Classification (ATC code – level 1, WHO, 2016). All ADRs were classified according to the International Statistics Classification of Diseases and related health problems. Management of ADRs (dose altered, drug withdrawn, no change) were documented in the ADR reporting form. The causality assessment of the suspected ADRs were done by using Naranjo’s scale (Definite, probable, possible, unlikely) and the WHO probability scale (Certain, probable, possible, unclassifiable, unlikely, conditional). The Hart-wigs severity scale (Mild, moderate, severe) was used to analyze the severity level of ADRs and the preventability determined by using Modified Schumock and Thornton scale.

 

Frequencies with percentage was used to summarize gender, age, number of drugs prescribed, frequency of ADRs, drugs involved in the ADRs and severity of ADRs. Mean with standard deviation were used to deriveage and length of stay. All analysis were conducted by using SPSS (Statistical Package for the Social Sciences) software.

 

RESULTS:

In the study period, a total number of 270 patients were included and assessed for ADRs. Out of 270 patients, 52 patients developed a total of 55 ADRs. The overall percentage of ADRs was 19.3%

 

Demographic details of the patients:

Age wise distribution of patients:

In the age wise distribution, patients were classified based on age group from 18 to 86 years of age. Higher incidence of suspected ADRs were reported in patients with the age group of 61-70 years followed by age group greater than 70 years. The mean age of the patients with ADRs was 58.31±17.60 years and without ADRs was 52.63±15.24 years. Table 1 summarizes the age wise distribution of patients and occurrence of ADRs.

 

Table 1: Age wise distribution of patients

Age group

(years)

With ADRs

N=52

Without ADRs

N=218

18-30

6 (11.5%)

23 (10.6%)

31-40

3 (5.8%)

18 (8.3%)

41-50

7 (13.5%)

44 (20.2%)

51-60

8 (15.4%)

62 (28.4%)

61-70

16 (30.8%)

48 (22.0%)

>70

12 (23.1%)

23 (10.6%)

 

Gender wise distribution of patients:

Out of total 270 cases, 155 were males and 115 were females. Out of 55 adverse drug reactions reported in 52 cases, 29 were females (55.8%) and 23 were males (44.2%). The detailed gender wise distribution are shown in the Table 2.

 

Table 2: Gender wise distribution of patients

Gender

With ADRs N=52

Without ADRs N=218

Male

23 (44.2%)

132 (60.6%)

Female

29 (55.8%)

86 (39.4%)

 

Distribution of patients based on social habit:

It was observed that 76 patients were found with social habits, out of that 39 patients were alcoholic, 24 patients were smoker and 13 patients were both alcoholic and smoker. Remaining 194 patients were found without social habits. The summarized results given in Table 3.

 

Table 3: distribution of patients based on social habits

Habits

With ADRS

N= 52

Without ADRS N=218

Smoking

 

Yes

7 (13.5%)

17 (7.8%)

No

45 (86.5%)

201 (92.2%)

Alcohol

Yes

5 (9.6%)

34 (15.6%)

No

47 (90.4%)

184 (84.4%)

Smoking

+ Alcohol

Yes

4 (7.7%)

9 (4.1%)

No

48 (92.3%)

209 (95.9%)

 

Disease pattern among patients:

During the study, 361 diseases were diagnosed from 270 cases. The most common diseases among the patients were found to be diabetes mellitus (20.77%) followed by hypertension (17.73%), pulmonary tuberculosis (8.31%), UTI (4.98%), COPD (4.15%). The details of distribution of diseases among patients with or without ADRs are given Table 4.

 

Number of drugs prescribed per patient:

The median number of drugs prescribed for patients with ADR was found to be 14. Higher incidence of adverse events occurred in patients who were prescribed with more number of drugs, 32.7% of the prescription contain drugs between 6 -10 and 9 patients were prescribed with less than 6 drugs. The details were given in Table 5.

 

Table 4: Disease pattern among patients

Diseases

With ADRs

N= 79

Without ADRs

N= 282

Diabetes mellitus

21 (26.58%)

54 (19.14%)

Thyroid Disorder

2 (2.53%)

10 (3.54%)

Hypertension

15 (18.98%)

49 (17.37%)

Ischemic heart disease

4 (5.06%)

13 (4.6%)

Asthma

-

6 (2.12%)

COPD

5 (6.32%)

13 (4.6%)

LRTI

2 (2.53%)

6 (2.12%)

Pulmonary Tuberculosis

10 (12.65%)

20 (7.09%)

Chronic kidney disease

3 (3.79%)

12 (4.25%)

Acute kidney disease

-

10 (3.54%)

Chronic liver disease

-

7 (2.4%)

Alcoholic liver disease

1 (12.6%)

8 (2.83%)

Cirrhosis

-

2 (0.70%)

Migraine

1 (1.26%)

-

Cerebrovascular accident

-

4 (1.41%)

Arthritis

4 (5.06%)

3 (1.06%)

Dyslipidemia

3 (3.79%)

1 (0.35%)

Epilepsy

3 (3.79%)

3 (1.06%)

Anxiety

1 (1.26%)

-

Urinary tract infection

1 (1.26%)

17 (6.02%)

Deep vein thrombosis

1 (1.26%)

2 (0.70%)

Dermatomyositis

1 (1.26%)

1 (0.35%)

Anemia

-

11 (3.90%)

Dengue fever

-

10 (3.54%)

Malaria

-

3 (1.06%)

Gastroenteritis

-

6 (2.13%)

Hepatitis

-

3 (1.06%)

Acute fever

-

5 (1.77%)

Acid peptic disease

-

1 (0.35%)

Cholelithiasis

-

1 (0.35%)

Pancreatic gastritis

-

1 (0.35%)

Ulcerative colitis

-

1 (0.35%)

*LRTI – Lower respiratory tract infection *COPD – Chronic obstructive pulmonary disease

 

Table 5: Number of drugs prescribed

Number of medications

With ADRs N=52

Without ADRs N=218

< 6

9 (17.3%)

64 (29.4%)

6 - 10

17 (32.7%)

119 (54.6%)

>10

26 (50.0%)

35 (16.1%)

 

Drugs responsible for ADRs:

The most common class of drug was found to be antidiabetic (29.09%) followed by antitubercular (20%), antihypertensive drugs, corticosteroids, anticonvulsant. The details about drugs responsible for ADRs are shown in Table 6.

 

Table 6: Drugs responsible for ADRs

Drug Class

Drug Name

ATC Code

Frequency

(N=55)

Percentage

(%)

Anti-Diabetic

 

 

 

Insulin

A10AB01

9

16.4

Glibenclamide

A10BB01

2

3.6

Glipizide

A10BB07

1

1.8

Insulin/

Metformin

A10AB01

A10BA02

1

1.8

Glibenclamide+

Metformin

A10BB01

A10BA02

1

1.8

Glimepiride+

Metformin

A10BB12

A10BA02

2

3.6

Anti-Tubercular

Isoniazid

J04AC01

1

1.8

Pyrazinamide/

Ethambutol

J04AK01

J04AKO2

1

1.8

HRZ

J04AM05

1

1.8

HRZE

J04AMO6

8

14.5

Diuretics

Furosemide

C03CA01

1

1.8

Anti-Convulsant

Phenytoin

N03AB02

2

3.6

Sodium Valproate

N03AG01

1

1.8

Antihypertensive Agents

 

Amlodipine

C08CA01

3

5.5

Ramipril

C09AA05

1

1.8

Olmesartan

C09CA08

1

1.8

Losartan+

Hydrochlorothiazide

C09AD01

2

3.6

Telmisartan+ Hydrochlorothiazide

C09AD07

1

1.8

Telmisartan+

Chlorthalidone/

Prazosin/Metoprolol

C09DA07

CO2CA01

C07AB02

 

1

 

1.8

Anti-Coagulant

Warfarin

B01AA03

1

1.8

 

Corticosteroids

Prednisolone

A07EA01

2

3.6

Hydrocortisone

A01AC03

2

3.6

 

Analgesic

Naproxen

G02CC02

1

1.8

Aceclofenac

M01AB16

1

1.8

Tramadol+

Acetaminophen

N02AJ13

1

1.8

 

Anti-Depressant

Amitriptyline

N06AA09

1

1.8

Mirtazapine

N06AX11

1

1.8

Antibiotic

Cefixime+

Clavulanic Acid

J01DD08

1

1.8

Anti-Hyperlipidemic

Atorvastatin

C10AA05

1

1.8

 

Antianginal

Aspirin

A01AD05

1

1.8

IsosorbideMononitrate

C01DA14

1

1.8

 

Antibiotic+ Antihypertensive

 

Telmisartan/

Piperacillin+

Tazobactam/

Sulfamethoxazole+

Trimethoprim

CO9CA07

 

J01CR05

 

J01EE01

 

 

1

 

 

1.8

*H - Isoniazid, R - Rifampicin, Z - Pyrazinamide, E - Ethambutol, ATC – Anatomical Therapeutic Chemical Classification

 

Clinical patterns of ADRs:

The most commonly observed reaction in the study was hypoglycemia (27.27%) followed by rashes (5.45%), hypokalemia (5.45%), hyponatremia (5.45%) and other reactions were vomiting, hyperglycemia, pedel edema. Different types of reactions are given in Table 7.

 

Suspected drugs with ADRs:

The most common causative drugs responsible for ADRs were insulin (16.36%) and Isoniazid/Rifampicin/ Pyrazinamide/Ethambutol (14.55%). The suspected drugs with ADRs are shown below in Table 8.

 

 

 

Organ systems affected by ADRs:

The major organ system affected by ADRs include endocrine metabolic (30.91%) followed by multiple organ system (16.36%), gastrointestinal (12.73%) and nervous system (10.91%). The organ systems affected by ADRs are given below Table 9.

 

Seriousness of the reactions:

Out of 55 ADRs, 36 (65%) reactions had prolonged of hospitalization, 16 (29%) reactions required intervention to prevent further damage and 3 (6%) reactions were disability. The seriousness of the reaction are illustrated in Figure 1.

 

 

Figure 1: Seriousness of the reactions

 

Length of hospital stay on ADRs:

Out of 52 patients presented with ADRs, the hospital stay was extended for more than nine days in 32 (61.5%) patients followed by less than nine days in 16 (30.7%) and for patients who stayed for nine days 4 (7.69%). The occurrence of the suspected ADRs had prolonged the hospitalization in majority of the patients. The brief description of hospitalization of patients due to ADRs are given in Table 10.

 

Table 7: Different types of ADRs

ADRs

ICD Code

Frequency  (n= 55)

Percentage  (%)

Heart burn

R12

1

1.8

Dizziness

R42

2

3.6

Pedel edema

J81

2

3.6

Rashes

L27

3

5.5

Vomiting

R11

2

3.6

Elevated INR

R79.1

1

1.8

Oesophageal candidiasis

B37

1

1.8

Dry cough

R05

1

1.8

Hypoglycemia

E16.2

15

27.3

Subdural hematoma

I62

1

1.8

Hyperkalemia

E87.5

1

1.8

Hyperglycemia

R73.9

2

3.6

Fatigue

R53

1

1.8

Drowsiness

R40

1

1.8

Hepatitis

K71

1

1.8

Hypokalemia

E87.6

3

5.5

Hyponatremia

E87.1

3

5.5

Peripheral neuropathy

G62

1

1.8

Leucocytosis

D70.2

1

1.8

Ataxia

G11

1

1.8

Nephropathy

N07

1

1.8

Myopathy

G72

1

1.8

Hepatotoxicity

K71.11

1

1.8

Swelling

R22.7

1

1.8

Nausea

R11

1

1.8

Acute kidney injury

N17.9

1

1.8

Hyperuricemia

E79

1

1.8

Gastritis

K29

1

1.8

Hypotension

I95

1

1.8

Loss of appetite

R63

1

1.8

Arthralgia

M25.5

1

1.8

*INR- International normalized ratio *ICD - International Classification of Diseases


 

Table 8: Suspected drugs with ADRs

Drug

Clinical Pattern

Frequency (N=55)

Percentage (%)

Insulin

Hypoglycemia

8

14.55

Insulin

Hypokalemia

1

1.82

Glibenclamide

Hypoglycemia

2

3.64

Glipizide

Hypoglycemia

1

1.82

Insulin/ metformin

Hypoglycemia

1

1.82

Glibenclamide+ metformin

Hypoglycemia

1

1.82

Glimepiride+ metformin

Hypoglycemia

2

3.64

Isoniazid

Peripheral neuropathy

1

1.82

Pyrazinamide/ethambutol

Hyperuricemia

1

1.82

Isoniazid/rifampicin/pyrazinamide

Hepatotoxicity

1

1.82

Isoniazid/rifampicin/pyrazinamide/ethambutol

Vomiting

2

3.64

Isoniazid/rifampicin/pyrazinamide/ethambutol

Hepatitis

1

1.82

Isoniazid/rifampicin/pyrazinamide/ethambutol

Dizziness

1

1.82

Isoniazid/rifampicin/pyrazinamide/ethambutol

Rashes

1

1.82

Isoniazid/rifampicin/pyrazinamide/ethambutol

Gastritis

1

1.82

Isoniazid/rifampicin/pyrazinamide/ethambutol

Loss of appetite

1

1.82

Isoniazid/rifampicin/pyrazinamide/ethambutol

Arthralgia

1

1.82

Furosemide

Hypokalemia

1

1.82

Phenytoin

Rashes

1

1.82

Phenytoin

Ataxia

1

1.82

Sodium valproate

Hyponatremia

1

1.82

Amlodipine

Pedel edema

2

3.64

Amlodipine

Swelling

1

1.82

Ramipril

Dry cough

1

1.82

Olmesartan

Hyperkalemia

1

1.82

Losartan+ Hydrochlorothiazide

Hyponatremia

1

1.82

Losartan+ Hydrochlorothiazide

Hypokalemia

1

1.82

Telmisartan+ Hydrochlorothiazide

Hyponatremia

1

1.82

Telmisartan+ chlorthalidone/ Prazosin/ metoprolol

Hypotension

1

1.82

Warfarin

Elevated INR

1

1.82

Prednisolone

Oesophageal candidiasis

1

1.82

Prednisolone

Hyperglycemia

1

1.82

Hydrocortisone

Leucocytosis

1

1.82

Hydrocortisone

Hyperglycemia

1

1.82

Naproxen

Heart burn

1

1.82

Aceclofenac

Nephropathy

1

1.82

Tramadol+ Acetaminophen

Nausea

1

1.82

Amitriptyline

Fatigue

1

1.82

Mirtazapine

Drowsiness

1

1.82

Cefixime+ clavulanic acid

Rashes

1

1.82

Atorvastatin

Myopathy

1

1.82

Aspirin

Subdural Hematoma

1

1.82

Isosorbidemononitrate

Dizziness

1

1.82

Telmisartan/piperacillin+

Tazobactam/sulfamethoxazole+Trimethoprim

Acute kidney injury

1

1.82

*INR – International normal ratio

 


Table 9: Organ systems affected by ADRs

Organ system

Frequency  (n=55)

Percentage  (%)

Gastrointestinal

7

12.73

Auditory system

2

3.64

Lymphatic

2

3.64

Dermal

4

7.27

Circulatory system

3

5.45

Respiratory

1

1.82

Endocrine metabolic

17

30.91

Nervous

6

10.91

Hepatic

2

3.64

Multiple organ system

9

16.36

Renal

2

3.64

 

Table 10: length of hospital stay on ADRs

Length of hospital stay (days)

Frequency (n=52)

Percentage

(%)

Less than nine days

16

30.76

Nine days

4

7.69

More than nine days

32

61.54

 

Assessment of ADRs:

WHO causality:

The WHO causality assessment exhibited that majority of reactions were found to be probable 38 (69.09%), whereas 11 (22%) reactions were possible and 6 (10.91%) reactions were certain. The assessment of ADRs by WHO scale is illustrated in Figure 2.

 

Figure 2: WHO causality assessment of ADRs

Naranjo’s causality assessment of ADRs:

According to Naranjo’s scale, majority of reactions were found to be probable 29 (52.73%) and 26 (47.27%) reactions were possible. The assessment of ADRs by Naranjo’s scale is illustrated in Figure 3.

 

Figure 3: Naranjo’s causality assessment of ADRs

 

Severity assessment of ADRs:

The severity assessment of the suspected ADRs was done by Hartwig severity scale, which showed that 29 (53%) reactions were moderate, 25 (45%) were mild and 1 (2%) reaction were severe. Summarized details of severity levels are given in Figure 4.

 

Figure 4: Severity assessment of ADRs

 

Preventability assessment of ADRs:

The Modified Schumock and Thornton Criteria was used to assess the preventability of ADRs which showed that 32 (58.2%) reactions were probably preventable, 14 (25.45%) reactions were not preventable and 9 (16.36%) reactions were definitely preventable. The details regarding preventability assessment scale is illustrated in Figure 5.

 

 

Figure 5: Preventability of ADRs

 

Predictability of ADRs:

The majority of reactions were found to be predictable 53 (96%), whereas 2 (4%) were non-predictable. The predictability of ADRs is illustrated in Figure 6.

 

Figure 6: Predictability of ADRs

 

Management of ADRs:

Out of 55 suspected ADRs, the management of ADRs was done through withdrawal of the suspected drug in 34 (61.82%) cases, There was no changes of the suspected drugs in 15 (27.27%) and in 6 (10.91%) cases dose of drugs were altered. The details regarding management of ADR is diagrammatically represented in Figure 7.

 

Figure 7: Management of ADRs

 

Treatment of ADRs:

No treatment were required in 24 (43.64%) cases whereas specific treatment was provided in 21 (38.18%) cases and in 10 (18.18%) cases the patients received symptomatic treatment. The treatment of ADRs is illustrated in Figure 8.

Figure 8: Treatment of ADRs

 

Outcome of management of ADRs:

Outcome shows that 38 (69.09%) reactions were recovered whereas 16 (29.09%) case symptoms were continued and 1 (1.82%) cases was categorized as unknown. The details regarding outcome is summarized in Figure 9.

 

Figure 9: Outcome of management of ADRs

 

Dechallenge of ADRs:

There was no dechallenge in 23 (41.82%) reactions and in 32 cases dechallenge was done, out of which definite improvement was shown in 27 (49.09%) cases, whereas no improvement in 1 (1.82%) cases and 4 (7.27%) were unknown. Figure 10 shows the details.

 

Figure 10: Dechallenge of ADRs

 

Rechallenge of ADRs:

In 51 cases there was no rechallenge. Rechallege was done in only 4 cases, recurrence of symptoms was found in 1 (1.82%) cases and no occurrence of symptoms was found in 3 (5.45%). Rechallenge shows in Figure 11.

 

 

Figure 11: Rechallenge of ADRs

Assessment for predisposing factor:

The most common predisposing factor associated were multiple drug therapy 20 (36.36%) followed by age 18 (32.73%), recurrence of disease 8 (14.55%), gender 6 (10.91%) and other factors 3 (5.45%). Predisposing factors for adverse drug reactions shows in Figure 12.

 

 

Figure 12: Assessment for predisposing factor

 

DISCUSSION:

Adverse drug reactions are the unwanted and unintended problems that occur with any type of drugs in the patients. As per the reports suggested, the majority of the ADRs are accounted from department of medicine. Details obtained from the study will be beneficial for the physician in concern about the careful choosing and restricted use of suspected drugs.14 ADR can remain undetected due to ignorance from patient’s side and at times physicians fail to distinguish them from the symptoms of common illness. Therefore, a hospital-based ADR monitoring and reporting system is required to specify and quantify the risks related with the drugs used in the hospital settings.15 In this study incidence of ADRs was found to be 19.3% and similar results was observed in the study conducted by Asawari R et al., 16 reported an incidence of 25%.

 

The majority of suspected ADRs were observed in the age group of patients with 61-70 years. This study was resembling with the reports of Sriram S et al.,17 that high number of ADRs were observed in patients who were above 60 years of age. But in study conducted by Lokesh K, 18exhibited that higher ocuurence of ADRs were in age group between 41-60 years.

 

High incidence of ADRs were observed in females than males. Study conducted by Prasad RV et al., Khurshid F et al., Singh H et al., 19, 20, 21 also showed similar results. There was predominance of ADRs among females due to pharmacodynamic and pharmacokinetic variations along with the difference in response to drug treatment.

 

The median number of drugs prescribed for patients with ADRs was found to be 14. In correspondence with the study conducted by Vora MB et al., Davies EC et al. 22, 23 exhibited that, incidence of ADRs were high in patients prescribed with higher number of drugs, which was similar with the present study where 50% of the prescription with higher number of drugs experienced ADRs.

 

Antidiabetic (29.09%) and antitubercular (20%) were the common classes of drugs responsible for ADRs. The study done by Shareef J et al., 24 repoted that the main class of drugs involved in the occurrence ADRs were antibiotics followed by antidiabetic agents and study of Prajapati K et al., 25 exhibited that the majority of the causal drug groups were antitubercular drug (34.4%) followed by antiretroviral drug (20.3%).

 

The most commonly observed ADR was hypoglycemia which was in accordance with the study conducted by Lokesh K.18

 

Endocrine metabolic system was the most commonly affected organ system with ADRs. The study conducted by Lokesh K, 18 exhibited the results with 28% of ADRs affecting the dermal system, 24% involved in GI system and 16% affected endocrine metabolic system.

 

Out of the 52 patients, the hospitalization had prolonged to more than nine days in 32 (61.5%) patients who experienced ADRs which was in accordance with the study conducted by Shareef J et al., 24 exhibited that adverse reactions were observed in 82.85% of patients and was admitted in hospital for more than seven days. They concluded that development of ADRs can extend the hospitalization. But the study conducted by Davies EC et al., 23 showed that the median extend of hospital stay for patient who experienced ADRs was 20 days and they concluded that the extend of hospital stay was raised by an adverse reaction.

 

WHO causality assessment exhibited that out of 55 reported ADRs, 38 (69.09%) were probable, 11 (22%) reactions were possible and 6 (10%) were certain. The related results were conducted by Lokesh K, Shrivastava M et al., 18, 14 where causality assessment by Naranjo’s scale shown that, 29 (52.73%) reactions were probable and 26 (47.27%) reactions were possible. The comparitable results were observed in the study conducted by Ramakrishnaiah H et al.26

 

Suspected ADRs were assessed for its severity and found that the majority of the events were moderate (53%), followed by mild 45% and some had severe reactions. The similar results found in study conducted by Lokesh K, Ramakrishnaiah H et al.18, 26which reported that more percentage of events were moderate followed by mild and severe reactions.

 

Preventability assessment shown that 58.2% reactions were probably preventable, 25.45% reactions were not preventable and 16.36% reactions were definitely preventable. These findings were in accordance with study conducted by Shareef J et al., Lokesh K, 24, 18 which manifested that, most cases are probably preventable followed by not preventable and definitely preventable.

 

The management of ADRs was done through withdrawal of the suspected drugs in 61.82% cases, there was no changes of suspected drugs in 27.27% and no dose adjustment in cases of 10.91%. The comparitable results were observed in the study conducted by Sriram S et al.17 out of which 37% of patients had improved their reactions by withdrawal of drugs and in 21% patients, dose adjustment was carried out.

 

Outcomes of management of ADRs revealed that 69.09% reaction were recovered whereas 29.09% cases symptoms continued and this result resembled the study of Lokesh K, 18where 67% of reactions were recovered.

 

The most common predisposing factors associated were multiple drug therapy 36.36% followed by age 32.73% and recurrence of disease 14.55%. The findings are similar in study conducted by Sriram S et al., Shareef J et al.17, 24where multiple drug therapy and age are the common predisposing factors.

 

CONCLUSION:

During the study 270 patients were enrolled. Out of which the incidence of adverse drug reactions was 55 in 52 patients. Predominance of reactions were seen in females than males. Antidiabetic and antitubercular drugs are the common classes of drugs responsible for the ADRs. The major system involved in manifesting ADR was endocrine metabolic system. The severity assessment of suspected ADRs was done by Hartwig severity scale which showed that most of them were moderate. Causality assessment were carried out by using Naranjo’s and WHO scale gives that majority of reactions were probable. In most case, suspected drug were withdrawn so treatment was not required to manage the ADRs. Proper monitoring of adverse reactions is useful to minimize the incidence of ADRs and to prevent further occurrence of the same. Continuing reporting system of ADRs that helps to improve the patient safety. This information may be effective in classifying and reducing the avoidable ADRs.

 

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of NITTE (Deemed to be University), Justice K S Hegde Hospital, NGSM Institute of Pharmaceutical sciences, Mangaluru for providing all the facilities.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 09.11.2018          Modified on 25.01.2019

Accepted on 27.03.2019        © RJPT All right reserved

Research J. Pharm. and Tech. 2019; 12(5):2289-2298.

DOI: 10.5958/0974-360X.2019.00382.2