Monitoring Adverse Drug Reactions in Patients of Chronic Obstructive

Pulmonary Disease.

Introduction:

No drug is absolutely safe and an adverse drug reaction (ADR) can occur when it is

administered alone or in combination (Tyagi et al, 2008). According to WHO, an ADR is

defined as "A response to a drug which is noxious and unintended and which occurs at

doses normally used in man for the prophylaxis, diagnosis or therapy for a disease and

for the modification of function excluding failure to accomplish the intended purpose" (Esch AF, 1972).

Chronic obstructive pulmonary disease (COPD) is "an obstructive airways disease

characterised by airflow limitation that is not fully reversible. The airflow limitation is

usually progressive and associated with an abnormal inflammatory response of the

lungs to noxious particles or gases" (Petty TL, 2003). It includes emphysema, chronic

bronchitis or a combination of the two [4].

Tobacco use is a key factor, also asthma, exposure to air pollutants in the home and

workplace, genetic factors, and respiratory infections play a role in the development and

progression of COPD [5]. COPD is usually treated with inhaled adrenergic agonists,

inhaled corticosteroids, anticholinergics, oral theophylline, oral steroids, antibiotics, and

polypharmacy is common [6].

Depending on the dose, the adverse reactions of anticholinergics causes: Dry mouth,

thirst, blurred vision, "sandy eyes", urinary difficultly, and constipation [7].

And corticosteroids adverse effects range from minor to severe and life threatening. The

nature and severity of it depends on the route, dose, frequency of administration, and the

specific agent used. The most frequent side effects are locally, they include: Oral

candidiasis, dysphonia, glossitis, hyperpigmentation of face, hoarseness of voice, sore

throat and throat irritation, and coughing [8].

The classical Cushing-like syndrome "redistribution of body fat, moon face, increased

body hair growth, acne, insomnia and increased appetite" are observed when excess

corticosteroids are present [7].

Therapy does not cure the disease or even significantly slow its progress [7], So

treatment of COPD requires a careful and thorough evaluation by a physician [5], and

ADR monitoring is absolutely essential for drugs, and thus careful therapeutic drug

monitoring is required [6].

General objectives:

To monitor adverse drug reactions in patients with chronic obstructive pulmonary

disease.

Specific objectives:

1-General profile of drug treatment and adverse drug reactions for chronic obstructive

pulmonary disease.

2-Making profile with incidence of adverse drug reactions with inhaled steroids and

anticholinergics in combination of each with adrenergic agonists.

3-Rationalize drug therapy according to the adverse effects by making comparisons

between different types of drugs used.

4-Measure the effect of smoking in the incidence of adverse effects.

5-Differntiation between males and females in the incidence of adverse effects.

6-To increase patients awareness of the disease and the adverse reactions to make sure

they can recognize it and are aware of the severity of associated problems.

Problem Statement and Justification:

ADR are one of the major causes of morbidity and account for nearly 5% of all hospital

admissions all over the world. Over two million ADRs occur yearly that result in 5%

fatality annually, ADR is the fourth leading cause of death ahead of pulmonary disease,

diabetes mellitus, AIDS, pneumonia and automobile deaths [9].

According to WHO estimates, 80 million people have moderate to severe COPD, more

than 3 million people died of COPD in 2005, which corresponds to 5% of all deaths

globally. It is known that almost 90% of COPD deaths occur in low- and middle-income

countries [10]. COPD kills on average one person every 10 seconds [11].

COPD is not one single disease but an umbrella term used to describe chronic lung

diseases that cause limitations in lung airflow. It is not a simple smoker's cough, but an

under-diagnosed, life threatening lung disease. The most common symptoms of COPD

are breathlessness, or a "need for air"', excessive sputum production, and a chronic

cough [11].

The major risk factors for COPD are smoking, indoor and outdoor air pollution, and the

place of work, (dusts and chemicals) [10].

COPD is preventable, but not curable. Treatment can help slow disease progression, but

it generally worsens slowly over time. So it is diagnosed frequently in people aged 40

years or older [10]. And ADRs may happen for reasons such as alteration in

pharmacokinetic, pharmacodynamic, and homeostatic mechanisms related to age which

make them more sensitive to drugs [12],and the type and the frequency of drugs used

because multiple drugs used in the treatment of COPD may result in a variety of ADRs

during therapy, so this could contribute significantly to morbidity and mortality and it is

important to monitor ADRs, with an aim to rationalize drug therapy in these patients [1].

Methodology:

Design:

Study design:

The study is a prospective-analytical design.

It will measure the incidence of adverse drug reactions during therapy in patients of

chronic obstructive pulmonary disease.

Setting of the study and Study population:

The study population are patients from both gender (male and female) with chronic

obstructive pulmonary disease who attends to hospitals – Gaza Strip -Palestine.

Sampling size:

According to the relationship between Smoking and COPD as major risk factor, and

with aid of Epi Info program to calculate the sample size of this study, I found that one-

quarter of smokers get COPD in Gaza Strip [13]. So sample size will be 120 participants

by using Epi info program, (95% Confidence Interval, Study population 1000).

Selection (diagnostic) criteria:

1)Age: 40 years, or older.

2)Sex: both gender.

3)Residency: Gaza Strip.

4)Diagnosis: physical examination, clinical and pulmonary features (history of smoking,

exertional dyspnoea, cough and expectoration, forced expiratory volume in 1 sec. is less

than 80% of the predicted value for the patients age and height).

5)Exclusion criteria: other diseases as (Pulmonary Tuberculosis, any other respiratory

disorder, Diabetes mellitus, Congestive heart failure, renal and hepatic dysfunction, and

pregnant/lactating females).

6)Inclusion criteria: only patients with chronic obstructive pulmonary disease without

any other diseases or complications selected according to diagnosis.

Sampling method:

Making stratified sampling method:

1-Prepare sample frame of all COPD patients in hospitals of Gaza strip according to

diagnosis.

2-Divide patients into groups "strata" according to which hospital the patients belong,

(group.1: Al-Shifa hospital, group.2: Al-European hospital …..).

3-Select from each strata the required number Randomly.

Dependent and Independent variables:

1. Dependent variables :

The incidence of adverse drug reactions.

2. Independent variables :

Universal variables :

1-Age

2-Sex

Variables related to the study :

1-Type of the drug.

2-Concentration of the drug, "dose".

3-Frequency of drug usage.

4-Seriousness/Severity of adverse drug reactions.

5-Seriousness of the disease condition.

6-Smoking.

7-Type and place of job.

Methods:

The patients will be enroll after a written informed consent, for each patient, current

medical history, diagnosis, Complete blood count (CBC), demographic profile, and

general physical examination will done.

Treatment:

Patients will categorized into four groups, that two groups will take combination

therapy of adrenergic agonist with inhaled anticholinergics, (one will take Tiotropium,

and the other will take Ipratropium), and the other two groups will take adrenergic

agonist with inhaled steroid, (one will take Beclomethasone, and the other will take

Fluticasone), (the categorization, and the choice of drug type will be according to

diagnosis). The patients will follow up for six months every two weeks during this study

for evaluation of adverse effects of these drugs in participated patients.

General profile of drug treatment and adverse drug reactions (ADRs) in COPD:

Drug Given No. of Patient Receiving the Drug

No. of Patient Complaining of ADR

% Incidence

Inhaled Anticholinergics

Tiotropium

Ipratropium

Inhaled Steroids Beclomethasone

FluticasoneAdrenergic Agonists

Total number of patients: 120

Profile of adverse drug reactions (ADRs) with inhaled steroids, and anticholinergics:

ADR Profile

Number of Patients

with ADRs

% Incidence

Inhaled Anticholinergics:

Dry mouth

Thirst

Blurred vision

Urinary difficulty

constipation

Others

Inhaled Steroids:

Oral candidiasis

Dysphonia

Glossitis

Hyper pigmentation of face

Hoarseness of voice

Sore throat, and throat irritation

Coughing

Others

Total number of patients receiving inhaled anticholinergics:

Total number of patients receiving inhaled steroids:

Investigations:

These laboratory tests will carried out if needed.

Allergy tests.

Skin biopsy.

Blood level.

Liver biochemistry.

Data collection:

Data will be collected from reports that written by doctors and nurses from the visits of

patients to the hospital he/she belongs to, every two weeks during this study.

Data analysis:

Analysis will be done by using the SPSS (Statistical package for social science).

Method of Data analysis:

Analysis of data will be carried out using several tests as:

Chi square test:

Type of the drug Patients having

ADRs

Patients not having

ADRs

Total

Anticholinergics

Steroids

Total 120

Type of the drug Patients having

ADRs

Patients not having

ADRs

Total

Tiotropium

Ipratropium

Total

Type of the drug Patients having

ADRs

Patients not having

ADRs

Total

Beclomethasone

Fluticasone

Total

Risk factor Patients having

ADRs

Patients not having

ADRs

Total

Smoking

Non smoking

Total 120

Gender Patients having

ADRs

Patients not having

ADRs

Total

Male

Female

Total 120

Frequencies statistics, and chart options:

Type of

Adverse effect

Patients

having

this

adverse

effect

Percentage

%

Type of drug make

this adverse effect

(anticholinergic from

1to5 group"1",

steroid from 6to12

group "2")

State of

smoking

(smoking=1,

non=2)

Gender

(male=0,

female=1)

Dry mouth(1)

Thirst(2)

Blurred vision(3)

Urinary difficulty(4)

Constipation(5)

Oral candidiasis(6)

Dysphonia(7)

Glossitis(8)

Hyper pigmentation

of face(9)

Hoarseness of voice(10)

Sore throat and throat

irritation(11)

Coughing(12)

Total 100%

Also can make t-Test between (Patients having this adverse effect as continuous

variable), and (Gender or State of smoking which are categorized variables).

Also can make Recode for the type of adverse effects to groups as:

Severity of

Adverse

Effects

Number of

patients

Percentage% Total

None (no

adverse effects)

(1)

Mild (from 1to3

adverse effects)

(2)

Moderate (from

4 to 7)(3)

Sever (more

than 7 adverse

effects)(4)

Total 120 100% 120

Can make Frequencies statistics and chart options, and ANOVA (between number of

patients as continuous and severity of the adverse effects).