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 No. of Patient % Incidence
Receiving the Drug Complaining of ADR
Inhaled Anticholinergics
• Tiotropium
• Ipratropium
Inhaled Steroids
• Beclomethasone
• Fluticasone
Adrenergic Agonists

Total number of patients: 120

Profile of adverse drug reactions (ADRs) with inhaled steroids, and anticholinergics:
ADR Number of %
Profile Patients Incidence
with ADRs
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 Patients not having Total

ADRs ADRs
Anticholinergics
Steroids
Total 120

Type of the drug Patients having Patients not having Total

ADRs ADRs
Tiotropium
Ipratropium
Total

Type of the drug Patients having Patients not having Total

ADRs ADRs
Beclomethasone
Fluticasone
Total

Risk factor Patients having Patients not having Total

ADRs ADRs
Smoking
Non smoking
 Total 120

Gender Patients having Patients not having Total

ADRs ADRs
Male
Female
Total 120

Frequencies statistics, and chart options:

Type of Patients Percentage Type of drug make State of Gender
% this adverse effect
Adverse effect having smoking (male=0,
(anticholinergic from
this (smoking=1, female=1)
1to5 group"1",
adverse steroid from 6to12 non=2)
effect group "2")

• 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 Number of Percentage% Total

Adverse
 Effects patients
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).