Asthma - since early days has been described as an episodic shortness of breath or dyspnea, which may or may not be associated by a whistling sound. According to the committee on Diagnostic Standards of American Thoracic Society ëAsthma is an airways obstruction disorder characterised by an increased responsiveness of the trachea and bronchi to a variety of stimuli and henceforth is manifested by widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapyí[1]. Thus the asthmatics experiences the tightness of chest during breathing and exhibits hypersensitivity of the airways either to physical, chemical and pharmacological stimuli which may be regarded as a hallmark of an asthmatic attack [2]. This disease is regarded as one of the most typical of severe, persistent ailments among the population specially the children. In a statistics conducted in USA it is found that on an average 1 out of every 10 children in school suffers from asthma symptoms and 10,500,000 days of school absentees per year. Unfortunately the symptoms displayed by asthmatic patients is increasing and the figure changed from 20.3 billions to 24.6 billions spanning a period of 8 years starting from 2001 to 2009. The yearly cost associated with asthma and health care are estimated to be more than US$ 20,000,000,000 worldwide [3]. The graph underneath gives the feature of the statistics.
In Bangladesh management of asthma alone or in association with other diseases requires taka 20,000 millions [4]. Thus asthma has become a social, health and socioeconomic problem in the world and in Bangladesh as well. Therefore the problem ought to be solved. Unfortunately it is reported that till today a complete recovery from asthma has not been successfully achieved; rather management therapy prevailed. In practice in the field of asthma therapy several anti- asthma drugs proved to be successful and theophylline is one of them. This drug has been using over the last 50 years or so [5]. The major advantages of theophylline are :
But the major disadvantages of this drug are that it has a narrow therapeutic index (5-20 mg/ml of blood) and flexible pharmacokinetic (pK ) parameters (i.e. time dependent changes occurring in the drug in -vivo ). It is reported that pK parameters of this drug are much sensitive to environmental conditions (like humidity, cold), food and drinking habit (like drinking tea, coffee or alcohol), smoking cigarettes even states of emotion. Such changes in pK parameters demands a change in the course of theophylline therapy. Because bioavailability of the drug also changes. The major markers of drug bioavailability are biological half life (t1/2 bio), total clearance (CLT) and fraction unbound in blood plasma (%fu) in terms of blood. Fraction excreted unchanged (%fe), and fraction excreted changed as metabolites (%fm) in urine could be other important markers for bioavailability data in terms of urine. As a rule of thumb an increase in tΩ bio, signifies a decrease in metabolism. The decrease in metabolism causes a simultaneous increase in %fe and a decease in %fm. When drug metabolism is decreased then residence time of drug in blood prolongs and this at certain stages needs dose adjustment. If not subsequent therapy using the same drug may result dose dumping and drug toxicity. Asthma in many cases is found co-existent with other diseases like diabetes, hypertension where multiple therapy with other drugs is done.
A recent study reported that in Bangladesh the total diabetic patients are 5 millions and patients likely to be affected with diabetes is 1 crore and 2 millions [10] and diabetes complicates asthma with a frequency of 10% in pregnant mothers [11l]. Not only that 1 in every 3 women above 35 and 1 in every 5 men are affected with high blood pressure [4]. In such cases treatment involving simultaneous uses of other drugs along with theophylline may result a change in theophylline pK values. Here the other drugs establishes a competitive inhibition of enzymatic functions needed for theophylline metabolism. So, tΩ bio of theophylline prolongs. If this happens dose interval regimen ought to be longer so that there occurs no accumulation of theophylline in blood and no drug toxicity results. This holds true with cases like pregnant asthmatics being treated with theophylline.
It is reported that in pregnancy theophylline metabolism is reduced and experimental evidences conducted on pregnant rats supports the fact. In the experiment results showed that tΩ bio of theophylline elevated in pregnancy. Value changed from 4 hours to 6 hours at terms. Not only that in pregnant rat urine level of %fm was found much less than that of non pregnant rats. And %fe excreted in urine was much higher in pregnant rats than that in non pregnant rats (table 1 and 2).
However in many cases opposite phenomenon may prevail. Some chemicals may initiate theophylline metabolism and may decrease (t1/2) bio. In that case dose adjustment is also needed where frequency of dose ought to be shorter in order to have effective drug concentration and hence effective therapy. Regarding pregnancy case is little bit different. It is found that theophylline avidly binds with albumin fraction of blood. While in pregnancy the level of circulating endogenous hormones becomes higher and these compounds also binds with albumin fraction of blood. Therefore there occurs a competition between the two for the binding sites and this consequently elevates the level of unbound fraction of theophylline (i.e.fu). It is reported that the unbound fraction of drug is pharmacologically active. So a rise in the level in fu causes drug toxicity. The experiment as stated earlier proved the fact (table 1). It is important to state that for pregnant mothers drug toxicity is harmful not to her, also to her unborn child. Because theophylline can cross the placental barrier easily and can be found in appreciable amount in amniotic fluid. So drug would be found in foetus also. So life of the foetus may be put under a threat because of drug toxicity if dose regimen is not adjusted. In this context it is important to mention that asthma is one of the rare patho-physiological conditions which exhibits circadian rhythm [12]. Therefore as a conclusive remark it may be stated that therapy in asthma needs extreme care and attention, especially when therapy is carried out with theophyllin.
The writer is Professor of Department of Pharmacy,
Jahangirnagar University, Savar, Dhaka
References : 1. ìCommittee on Diagnostic Standards. Definition and classification of chronic bronchitis, asthma, and pulmonary emphysema. Am. Rev.Respir.Dis. 1962. 85 : 762
2. McFadden ER. Pathogenesis of asthma. J Ahllergy Clin Immunol 1984. 73 (4) : 413 - 424
3. http://www.copewithasthma.com/asthma-statistics/8.11.2013
4. `Bangladesh Janomity o Shashtha Japip. BDHS : 2011
5. Australian Drug Evaluation Committee. 1989
6. Cote A. Blanchard PW. Beehan B. Metabolic and cardiovascular effects of doxapran and theophylline in sleeping newborn piglets. J Appld Physiol 1992: 72(2): 410-415
7. Fairshter RD and Busse WW. Theophylline - how much is enough? J Allergy Clin Immunol 1986. 77 (4): 646-648
8. Hendeles S., Weinberger M., Szefler S and Ellis s. Safety and efficacy of theophylline in children with asthma. J Pediatr. 1992. 120 (2): 177 - 183
9. Arkinstall WW. The role of theophylline in a preventive approach for subjects with both mild and severe asthma. Postgard Med J. 1991. 67 (Suppl 4): s25-s29
10. Special correspondence. ìDiabetes rog barchheî. Prothom Alo. Published on 31.01.2013
11. S. Sultana, Md Kamruzzaman Bhuiyan, Md Akter Sayeed and Kishor Mazumder. ìAwareness on good prescription practices among the physicians about INN drugs in 3rd world country : Bangladeshî. Journal of Bangladesh Society for Pharmaceutical Professionals. 2012; 2(1) : 16-23.
12. Sakina Sultana. ìDrug-Drug Interaction : key factor to considerî. Medipharm. 1st Issue. 2012 : 29
2016 © The Pharma World. All Rights Reserved.