Theophylline A “State of the Art” Review

Abstract

Theophylline is a bronchodilator and respiratory stimulant that is effective in the treatment of acute and chronic asthma, Cheyne-Stokes respirations, and apnea/bradycardia episodes in newborns. It is also used as an adjunct in the treatment of congestive heart failure and acute pulmonary edema, but it has no established efficacy in patients with chronic irreversible airways obstruction. Benefits and risks from theophylline relate directly to serum concentration, which is a function of both dose and elimination characteristics of the drug in an individual patient. When used to treat acute symptoms, an initial loading dose based on a mean volume of distribution is required to rapidly obtain maximum bronchodilator effect. Because of large interpatient differences in elimination, constant intravenous infusion rates for continued therapy must be guided by monitoring serum theophylline concentration at intervals until a steady-state serum concentration is reached within the 10-20 micrograms/ml therapeutic range. Intravenous, oral or rectal solutions and plain uncoated tablets are appropriate for acute therapy, while reliably absorbed slow-release formulations offer therapeutic advantages for the management of chronic asthma, particularly in patients with rapid elimination. Dosage for long-term therapy is determined by starting with low doses that allow virtually complete acceptance of the medication followed by gradual increases, if tolerated, at three day intervals until mean age-specific doses are reached. Subsequent adjustment in dosage regimens are then based upon serum concentration measurements. Most clinical laboratories now measure theophylline, and newer systems have been developed to provide emergency results within minutes at a reasonable cost. In cases of theophylline poisoning, the drug must be rapidly removed to prevent life-threatening toxicity. When serum concentrations are in excess of 60 micrograms/ml charcoal hemoperfusion dialysis may be indicated, even in the absence of obvious signs of toxicity.

Enoxacin decreases the clearance of theophylline in man.

“…All patients were on maintenance treatment with a slow release theophylline administered twice daily. Drugs known to influence theophylline clearance were avoided prior to the study and during administration of enoxacin (Hendeles & Weinberger, 1983;Jonkman & Upton, 1984). Infections caused by Pseudomonas aeruginosa were treated with oral enoxacin, 600 mg twice daily, whereas other infections were treated with 400 mg enoxacin, twice daily.…”

“…Many factors are known to influence theophylline clearance (Hendeles & Weinberger, 1983). Simultaneous treatment with drugs such as allopurinol (Manfredi & Vesell, 1981), cimetidine (Jackson et al, 1981;Reitberg et al, 1981), erythromycin (Prince et al, 1981), troleandomycin (Weinberger et al, 1977), can cause decreased theophylline clearance, whereas coadministration of phenobarbitone (Landay et al, 1978), phenytoin (Marquis et al, 1982) and isoprenaline (Hemstreet et al, 1982) In a previous study with enoxacin in respiratory tract infections by Davies et al (1984), the drug had to be discontinued in 9 of 15 patients because of side effects mainly related to the digestive system; seven of these patients used concomitant theophylline medication.…”

Theophylline affects three different potassium currents in dissociated rat cortical neurones.

“…Theophylline is a methylxanthine widely used in treating bronchial asthma, pulmonary oedema and apnoea in premature infants (Hendeles & Weinberger, 1983). Theophylline has potent stimulating effects on the central nervous system MS 1816 (CNS), resulting in nervousness, anxiety and severe convulsions when administered in an overdose (Samuel, 1987).…”

Annual Review of Chronopharmacology. Volume 7. Biological Rhythms and Medications. Proceedings of the Conference of Chronopharmacology Held in Nice, France on 12-15 March 1990

“…Moreover, high theophylline concentrations can be maintained for a prolonged period of time by taking advantage of the chronokinetics of some preparations which exhibit a slower absorption during the night without loss of bioavailability ) (Busse et al 1985). Although theophylline has been a very important agent in the therapy of asthma for many years, its role in the treatment of bronchial hyperresponsiveness is controversial, and therapeutic strategies for its use are based predominantly on its bronchodilating properties (Hendeles et al 1983) (Mitenko eta!. 1973) (Fairshter et al 1986).…”