1. Kavita Gulati, N Tyagi, G Vishnoi, VK Vijayan, A Ray
A study to monitor adverse drug reaction profile of theophylline in patients of obstructive airway disease
Kavita Gulati, N Tyagi, G Vishnoi, VK Vijayan, A Ray
Department of Pharmacology & Clinical Research Centre, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi
Pharmacovigilance and Drug Safety Conference (SOPI-2006), Bangalore, November 2006

2. Introduction
Respiratory diseases : a major cause of hospital admissions
Obstructive airway disease (Bronchial Asthma and COPD) affect 5-7% population in industrialized countries
Several factors (allergy and smoking) contribute to their genesis
Optimization and rationalization of drug therapy : key to effective management

3. Bronchodilators and corticosteroids are the mainstay in the treatment of these conditions
Theophylline : Emerging as an important adjuvant in the treatment of bronchial asthma and COPD
Combination with other drugs has synergistic effects in many situations

4. Theophylline : A drug of herbal origin (Camellia sinensis – tea plant)
Widely used earlier as bronchodilator
Pharmacoeconomically viable
Narrow therapeutic index and has high propensity to induce toxicity, resulting in the restricted use

5. Recently : A resurgence in the interest in theophylline
Low doses (lower than those needed to induce bronchodilation) exert beneficial effects
Anti-inflammatory and immunomodulatory effects reported
Judicious use could be of benefit in obstructive airway disease in developing countries

6. Adverse Drug Reactions : Noxious/untoward effects to drugs or chemicals given for therapeutic, preventive or diagnostic purposes
Common with drugs with narrow safety margin
Mostly preventable
Knowledge of PK-PD of the drug crucial
ADR monitoring and TDM important exercises

7. Objectives
To monitor adverse drug reactions (ADRs) with theophylline in patients of bronchial asthma and COPD attending the OPD of Vallabhbhai Patel Chest Institute, Delhi
Predict strategies to rationalize drug therapy with theophylline in such patients with obsturctive airway disease

8. Methods Subjects : OPD patients of bronchial asthma and COPD
Prospective study
Ethical clearance obtained
ADR profile recorded as per proforma for the National Pharmacovigilance Programme
Causality assessment : Naranjo`s scale (1981)

11. Methods… Age : 18 – 60 years Standard inclusion/exclusion criteria
Clinical + Lab. (PFT) diagnosis confirmed
Stable, Ambulatory patients
Exclusion : Pulm. TB, Pregnancy/Lact.
IHD/overt LVF, Liver/Kidney disease

12. Prescription monitoring in obstructive airway disease (theophylline)
Prescriptions
Total No.
With theophylline %
All patients
120 63
52.6
Br. Asthma 60 20
33.3
COPD 43
71.6

13. Prescription audit in obstructive airway disease (theophylline)

14. ADR incidence with theophylline
Patients
Received Theophylline
Showed ADRs %
Br. Asthma 20 14 70
COPD 43
46.5
Total 63 34
53.9

15. ADVERSE EFFECT PROFILE IN PATIENTS WITH ORAL THEOPHYLLINE
ADR No. of Patients %
Dyspepsia
Anxiety
Spasm of Muscles
Insomnia
Paresthesia
Others

16. Incidence of ADRs after theophylline

17. Conclusions
A study was conducted to assess the ADR profile of theophylline in bronchial asthma and COPD patients (total 120)
An appreciable proportion (54%) of patients complained of ADRs
Most patients reported anxiety and GI related problems
Others : muscle cramps, paresthesia, etc.

18. Conclusions…contd.
Causality assessment by Naranjo`s scale showed that most ADRs fell in Probable category
Dechallenge confirmed the incidence in some cases
These results indicate that theophylline admn. should be carefully monitored and such ADRs could be prevented by rational therapy

19. Aminophylline (Amino) - induced anxiety and its mechanisms
Treatment Elevated Plus Maze (%)
(mg/kg) OA entry OA time
Vehicle ± ± 3.6
Amino (10) ± 4.2* ± 2.8*
Amino (50) ± 1.3* ± 1.1*
AA(100)+Amino(50) ± ± 5.0
Mel(50)+ Amino(50) ± 6.5a ± 4.6a
* p< 0.05 (compared to vehicle)
p<0.05(compared to Amino-50)
AA: ascorbic acid ; Mel: melatonin

20. Aminophylline (Amino)-induced gastric ulcers and its mechsnisms
Treatment Gastric Ulcer parameters
(mg/kg) Incidence (%) Severity (mm)
Vehicle ± 5.6
Amino (10) ± 9.6
Amino (50) ± 8.0 *
AA(100)+Amino(50) a ± 6.1a
Mel(50)+ Amino(50) a ± 6.9a
* p< 0.05 (compared to vehicle)
p<0.05(compared to Amino-50)
AA: ascorbic acid ; Mel: melatonin

21. Conclusions
The role of oxidant/anti-oxidant balance in obstructive airway disease has been proposed
A connection between theophylline and oxidative stress pathways are reported
These experimental studies show that theophylline-induced anxiety may be due to oxidative stress, and antioxidants may have protective role