Diltiazem Treatment Impairs Theophylline Elimination in Patients with Bronchospastic Airway Disease
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On the basis of reports that diltiazem may bind to the hepatic microsomal enzymes and inhibits the metabolism of some co-administered drugs, and to determine the effects of diltiazem on theophylline pharmacokinetics in patients with bronchospastic airway disease, we have investigated the effect of a 180-mg daily dose of oral diltiazem during 5 days on theophylline clearance in eight patients with that disease. Theophylline half-life increased 24%, from 5.7 +/- 1 to 7.5 +/- 1.8 h (p < 0.05), and total body theophylline clearance showed a decrease of 22%, from 87.3 +/- 20 to 68.3 +/- 18.6 ml/min (p < 0.05) after diltiazem therapy. The apparent volume of distribution was unchanged. This reduction in theophylline clearance is likely produced by inhibition of its metabolism by diltiazem. A clinically important drug interaction may occur with theophylline when diltiazem therapy is given concurrently in patients with bronchospastic airway disease.1 The effect of inhaled salbutamol following a maximally effective dose of theophylline given by intravenous infusion was determined in 12 patients with chronic bronchitis. 2 An initial single intravenous dose study was performed to estimate each patient's theophylline kinetics and to identify those patients who would respond to theophylline. 3 Pulmonary function was assessed at hourly intervals during four to five incremental steady state theophylline infusions over the concentration range 5-25 mg/l. 4 Inhaled salbutamol (400 micrograms) was administered after the maximum effect from theophylline had been achieved or when theophylline concentrations reached 25 mg/l without maximum effect: pulmonary function was again assessed. 5 Ten patients achieved a further significant improvement in pulmonary function after salbutamol: in five, predicted values for FVC were exceeded. 6 Patients with chronic bronchitis may benefit from the combination of theophylline and salbutamol if steady state theophylline concentrations of 15-20 mg/l are achieved.
Chronic bronchitis
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Bronchodilatation
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To investigate the effects of diltiazem on theophylline pharmacokinetics, nine healthy male subjects (four smokers and five nonsmokers) received intravenous aminophylline (6 mg/kg) prior to and following 10 days of oral diltiazem therapy. Theophylline half‐life increased significantly whereas total body clearance showed a significant decrease following diltiazem. Volume of distribution was unchanged. The small group of smokers had a significantly greater increase in theophylline half‐life than the nonsmokers. Inhibition of metabolism of theophylline by diltiazem likely explains the significant changes in theophylline pharmacokinetics. A clinically important drug interaction may occur with theophylline when diltiazem therapy is given concurrently.
Aminophylline
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For over 50 years, theophylline has been used regularly for the management of chronic asthma. However, because of its perceived narrow therapeutic index and the fact that it has been considered a weak bronchodilator, the use of theophylline therapy has diminished. Furthermore, with the introduction of newer pharmacologic agents and recommendations in widely accepted guidelines, both nationally and internationally, have further contributed to its decreased use. For years, theophylline has not only been considered a bronchodilator, but for many clinicians, an agent that could be used to enhance respiratory muscle function and mucociliary clearance and act at the level of the central nervous system to enhance ventilation. These properties were felt to be potentially useful for patients with severe exacerbated asthma. Recent studies have suggested that theophylline therapy can play a beneficial role in the management of both chronic stable asthma and exacerbated disease treated in the emergency department setting. Furthermore, a growing body of evidence suggests that theophylline has certain antiinflammatory and immunomodulating properties, even at plasma concentration levels below the accepted therapeutic range. If this is true, then theophylline may act best as a controller medication in the management of asthma. Because of its low cost and its ease of administration, theophylline therapy should be revisited and discussed as not only a reliever of bronchospasm, but a controller of chronic asthma.
Therapeutic index
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Theophylline, as a bronchodilator medication, is cheap and convenient. But its clinical application is limited,because that its therapeutic ratio is small and most of the benefit occurs only when near-toxic doses are given. Recent years, research have shown that low-dose theophylline also has antiinflammatory and immune regulatory role, which provided a new theoretical evidence for theophylline in the treatment of chronic obstructive pulmonary disease.
Key words:
Theophylline; Chronic obstructive pulmonary disease
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Theophylline has been widely used as a bronchodilator in asthma for many years. More recently its role as first line
asthma medication has declined as the toxic side-effects and difficulty maintaining therapeutic serum levels have
been highlighted. At best, theophylline has been shown to be only a moderately effective bronchodilator. Of greater
interest are theophyllines' recently recognised anti-inflammatory properties that have been noted at much lower therapeutic level than previously used.
In this article the anti-inflammatory property of theophylline will be explored further.
Bronchodilator Agents
Therapeutic index
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.Theophylline is an older drug that has undergone a recent transformation in usage. Long recognized as a potent bronchodilator for relief of acute asthmatic symptoms, recent definition of the pharmacodynamic and pharmacokinetic characteristics of this drug has increased its effectiveness as an anti-asthmatic agent while decreasing the risk of toxicity. Tea leaves are the source from which theophylline is extracted.
Pharmacodynamics
Bronchodilator Agents
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Serum concentration
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A double-blind crossover comparison of a 12-hour theophylline preparation (Theo-Dur) and a 24-hour theophylline preparation (Theo-24) was conducted with 20 young adult chronic asthmatic patients requiring daily bronchodilator therapy. The study group included 11 males and nine females ranging in age from 12 to 28 years. Clinical status and serum theophylline levels were monitored during the 4-week dosing interval on each medication. On the last day of each test period subjects were monitored closely throughout a 24-hour period. The results indicated little clinical difference between the two medications although there were statistically significant differences in the pharmacokinetic behavior between the two theophylline preparations.
Crossover study
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