Theophylline chronic obstructive pulmonary disease

Inhibitors of phosphodiesterase increase the intracellular level of cyclic AMP, which is associated with increased myocardial contractility. One of the first POE-inhibitors so studied is theophylline (21), an important drug in the treatment of asthma. Its actions have been extensively reviewed.81 Several recent studies have indicated that it might stimulate contractility also by adenosine receptor antagonism.82 In patients with chronic obstructive pulmonary disease, theophylline (14 mg/kg, p.o.) improved cardiac performance.83,94 severe adverse side effects were observed.85,96 Many derivatives of theophylline and other purine analogs were prepared and tested as PDE-inhibitors and cardiac stimulants, some of them being several times more active than... 

Jubran A, Gross N, Ramsdell J, et al. Comparative cost-effectiveness analysis of theophylline and ipratropium bromide in chronic obstructive pulmonary disease. A three-center study. Chest 1993 103 678-84. 

Theophylline reduces contractile activity of smooth musculature, widens bronchi and blood vessels, reduces pulmonary vascular resistance, stimulates the respiratory center, and increases the frequency and power of cardiac contractions. It is used for bronchial asthma, preventing attacks, and systematic treatment. Theophylline is also used for symptomatic treatment of bronchospastic syndrome of a different etiology (chronic obstructive pulmonary disease, chronic bronchitis, and pulmonary emphysema). A large number of combined drags are based on theophylline. Synonyms of theophylline are adophyllin, asthmophyllin, theocin, and many others. 

Cazzola M, Donner CF, Matera MG. Long acting beta2-agonists and theophylline in stable chronic obstructive pulmonary disease. Thorax 1999 54 730-6. 

The principal use of theophylline is in the management of asthma. It is also used to treat the reversible component of airway obstruction associated with chronic obstructive pulmonary disease and to relieve dyspnea associated with pulmonary edema that develops from congestive heart failure. 

Barnes PJ. Theophylline in chronic obstructive pulmonary disease new horizons. Proc Am Thorac Soc. 2005 2 334-341. 

Culpitt SV, de Matos C, Russell RE, et al. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002 165 1371-1376. 

Hansel TT, Tennant RC, Tan AJ, et al. Theophylline mechanism of action and use in asthma and chronic obstructive pulmonary disease. Drugs Today. 2004 40 55-69. 

Ram FS, Jardin JR, Atallah A, et al. Efficacy of theophylline in people with stable chronic obstructive pulmonary disease a systematic review and meta-analysis. RespirMed. 2005 99 135-144. 

The mode of action of theophylline is different from that of Beta2-adrenergic agonists and anticholinergic agents, so it is still used in the treatment of selected patients with asthma or chronic obstructive pulmonary disease. 

Theophylline (Uniphyllin) treatment and prophylaxis of bronchospasm associated with asthma, chronic obstructive pulmonary disease and chronic bronchitis. Also indicated for the treatment of left ventricular and congestive cardiac failure. 

The efficacy of long-acting beta2-adrenoceptor agonists in patients with chronic obstructive pulmonary disease remains unclear, but their role in treatment regimens, particularly in comparison with oral theophylline, has been reviewed (1). 

In a randomized, double-blind study, 943 patients with chronic obstructive pulmonary disease were treated over 12 weeks with either inhaled salmeterol 42 micrograms bd via a metered-dose inhaler or oral modified-release theophylline bd, titrated to serum concentrations of... 

Tsukino M, Nishimura K, Ikeda A, et al. Effects of theophylline and ipratropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease. Thorax 1998 53 269-273. 

Vaz Fragoso CA, Miller MA. Review of the clinical efficacy of theophylline in the treatment of chronic obstructive pulmonary disease. Am Rev Respir Dis 1993 147 S40-47. 

More importantly, the effects of theophylline are not limited to bronchodila-tion, bnt also include immunomodulatory, anti-inflammatory, and bronchoprotec-tive activity that substantially contribute to its usefulness as a prophylactic drug in asthma and other respiratory diseases. Additional effects include an increase in mucociliary clearance, a decrease of microvascular leakage into the airways, and an improvement of respiratory mnscle fatigue, especially that of the diaphragm. Theophylline fnrthermore acts centrally, blocking the decrease in ventilation that occurs with sustained hypoxia. While some of these effects are the rationale for its use in asthma, others form the basis for its effectiveness in chronic obstructive pulmonary disease (COPD) or in the treatment of apnea in premature newborns. 

Hendeles, L. et al, Unpredictability of theophylline saliva measurements in chronic obstructive pulmonary disease, J. Allergy Clin. Immunol., 60(6) 335-338, 1977. 

The concurrent use of xanthines such as theophylline and beta-agonist bronchodilators is a useful option in the management of asthma and chronic obstructive pulmonary disease, but potentiation of some adverse reactions can occur, the most serious being hypokalaemia and tachycardia, particularly with high-dose theophylline. Some patients may have a significant fall in serum theophylline levels if given oral or intravenous salbutamol (albuterol) or intravenous isoprenaline (isoproterenol). 

The risk of severe, possibly even fatal bronchospasm when beta blockers are taken by asthmatics would seem to be far more important than any pharmacokinetic interaction with theophylline. See the warning in Anti-asthma drugs + Beta blockers , p.ll60. Therefore the non-cardioselective beta blockers, such as propranolol, are contraindicated in patients with asthma or chronic obstructive pulmonary disease (COPD). Bronchospasm can occur with beta blockers given by any route of administration, even topically as eye drops. Cardioselective beta blockers have less effect on the airways, but can still cause bronchoconstriction. See Table 22.1 , (p.833), for details of the selectivity of beta blockers. 

A patient with chronic obstructive pulmonary disease had a 53% reduction in his serum theophylline levels accompanied by bronchospasm when he was fed continuously through a nasogastric tube with OsmoUte. The interaction occurred with both theophylline tablets (Theo-Dur) and liquid theophylline, but not when the theophylline was given intravenously as aminophylline. It was also found that the interaction could be avoided by interrupting feeding 1 hour either side of the oral liquid theophylline dose. Conversely, hourly administration of 100 mL of OsmoUte did not affect the extent of theophylline absorption from a slow-release preparation Slo-bid Gyrocaps) in healthy subjects, although the rate of absorption was slowed. Similarly, in healthy subjects, hourly administration of 100 mL of Ensure for 10 hours did not affect the rate or extent of absorption of theophylline from Theo-24 tablets. ... 

Famotidine 40 mg twice daily for 5 days had no effect on the pharmacokinetics of theophylline (given as intravenous aminophylline) in 10 healthy subjects. In another study, 16 patients with bronchial asthma or chronic obstructive pulmonary disease (COPD) found that famotidine 20 mg twice daily for at least 3 days did not affect the clearance of theophylline. Two further studies also found no interaction between intravenous theophylline and famotidine 20 or 40 mg twice daily for 4 or 9 days in COPD... 

A study in 17 patients with chronic obstructive pulmonary disease found that nizatidine 150 mg twice daily for a month had no effect on the steady-state pharmacokinetics of theophylline. However, there were 6 reports of apparent interactions in the Spontaneous Adverse Drug Reaction Database of the FDA in the US up to the end of August 1989. Four patients taking theophylline developed elevated serum theophylline levels, with symptoms of toxicity in at least one case, when given nizatidine. The problems resolved when either both drugs, or just nizatidine were stopped. ... 

Bachmann K, Sullivan TJ, Reese JH, Jauregui L, Miller K, Scott M, Yeh KC, Stepanavage M, King JD, Schwartz J. Controlled study of the putative interaction between famotidine and theophylline in patients with chronic obstructive pulmonary disease. J Clin Pharmacol (1995) 35, 529-35. 

Dal R, POmari C, Turco P. Famotidine and theophylline pharmacdcinetics. An unex-j)ected cimetidine-like interactiem in p>atients with chronic obstructive pulmonary disease. Clin Pharmacokinet 1993) 24,255-8. 

One study in 12 healthy subjects and another in 16 patients with chronic obstructive pulmonary disease found only minor increases in steady-state theophylline levels, which were not considered clinically relevant, when they were given roxithromycin 150 mg twice daily.Another study in 5 healthy subjects similarly showed that roxithromycin 300 mg twice daily did not affect the pharmacokinetics of theophylline." However, further study reported a significant increase in serum theophylline levels in 14 patients with asthma who were given roxithromycin 150 mg twice daily, but since the rise was not quantified it is difficult to assess the clinical relevance of this finding. ... 

A retrospective study in asthmatic children aged 3 months to 6 years found that the mean half-life of theophylline did not differ between those treated with ampicillin and those not. The pharmacokinetics of theophylline 8.5 mg/kg daily were not altered in 12 adult patients with chronic obstructive pulmonary disease when they were given ampicillin 1 g plus sulbactam 500 mg every 12 hours for 7 days. ... 

The apparently stable serum theophylline levels of a 78-year-old man with steroid-dependent chronic obstructive pulmonary disease were approximately doubled after he received intravenous clinafloxacin 200 mg every 12 hours for 5 days. Two theophylline doses were withheld, and then the dosage was reduced from 300 mg every 8 hours to 200 mg every 8 hours. Within another 5 days his serum theophylline levels had returned to his previous steady-state level. 

After taking tetracycline hydrochloride 250 mg four times daily for 8 days a patient with chronic obstructive pulmonary disease (COPD) showed evidence of theophylline toxicity. After 10 days of tetracycline her serum theophylline levels had risen from about 13 mg/L to 30.8 mg/L. Both drugs were stopped, and after 24 hours her theophylline level was 12.4 mg/L. A later rechallenge in this patient confirmed that the tetracycline was responsible for the raised theophylline levels. ... 

Murciano D, Aubier M, Lecocguic Y, et al. Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. N Engl J Med 1984 311(6) ... 

A study of the effect of bronchodilators on patients with chronic obstructive pulmonary disease who had atrial and/or ventricular arrhythmias following cessations of therapy for 16-24 hours compared isoproterenol (Iso) aerosol with 250 mg theophylline orally or intravenously (6 ) and stressed that theophylline compounds often worsened arrhythmias and should be used with caution. 

Pharmacology The methyixanthines (theophylline, its soluble salts and derivatives) directly relax the smooth muscle of the bronchi and pulmonary blood vessels, stimulate the CNS, induce diuresis, increase gastric acid secretion, reduce lower esophageal sphincter pressure, and inhibit uterine contractions. Theophylline is also a central respiratory stimulant. Aminophylline has a potent effect on diaphragmatic contractility in healthy people and may then be capable of reducing fatigability and thereby improve contractility in patients with chronic obstructive airways disease. Pharmacokinetics ... 

---