Theophylline A reassessment of its role in reactive airways disease

Theophylline has been used in the treatment of asthma since 1936 and is still regarded by many as the drug of choice for acute episodes of this condition. However, it does have a limited therapeutic range so treatment is sometimes inadequate or excessive. Recent research (during the last decade or so) has attempted to unravel its pharmacokinetics and thus help to establish more appropriate dosage regimes .

Hepatic metabolism can be affected by various factors Biotransformation via the microsomal mixed-function oxidases occurs in the liver. Hydroxylation and N­

demethylation convert theophylline into various metabolites. Elimination of theophylline is dose-dependent. Deviation from first-order kinetics can thus occur at high plasma concentrations. Small changes in dosage can then produce large changes in plasma concentrations which may not always be predictable.

The microsomal oxidase system is susceptible to alteration by many physiological, psychological and pharmacological factors. Drugs metabolised by this system can thus be affected by any of these factors. Theophylline metabolism is no exception . It has been shown to be related to age, smoking, diseases of the heart and liver, infection and other conditions such as acidosis and cystic fibrosis. Interactions with other drugs can also affect the metabolism of theophylline.

Changes in elimination half-life reflect changes in clearance. Since the volume of distribution of theophylline remains fairly constant in both adults and children,

variations in the elimination half-life of the drug can indicate changes in its clearance. Clearance is less rapid In Infants and elderly people than in adolescents and adults. Clearance occurs more rapidly in smokers than in non-smokers. Induction of hepatic enzymes by cigarette tars is the likely cause of this. Dosage regimes established in the early years of theophylline usage did not distinguish between smokers and non-smokers and thus may have created a false impression of the variability of its required dosage.

The presence of liver disease inevitably depresses most liver functions. Microsomal enzyme activity is depressed and thus clearance of theophylline tS reduced. Heart dis8ase can also reduce theophylline clearance. It is important to realise this since theophylline is often prescribed for asthmatics who have concomitant heart disease. The mechanism of the reduced rate of clearance is uncertain but it may be related to congestion of the liver.

The presence of infections such as influenza have in the past been thought to reduce theophylline clearance. More recent research has suggested that this is not necessarily true in general although it may be true for a small subpopulation of patients. The relationship between acidosis and theophylline clearance is also unclear. Some workers have reported that clearance is increased by acidosis. Others have not found any relationship between blood pH and theophylline clearance. Cystic fibrosis has, however, (in a small scale study) been shown to increase both clearance and volume of distribution.

Interactions with other drugs can produce significant changes in clearance Since theophylline is so widely used , it is often used at the same time as other drugs. Many of these can

affect the microsomal oxidation system and thus alter the rate of theophylline clearance. This is reduced by some antibiotics, oral contraceptives, cimetidine, allopurinol and the presence of other xanthines. It may be increased by phenobarbitone and phenytoin. The interaction between theophylline and erythromycin (and other marcrolides) has been extensively studied. However, it is difficult to say whether the decrease in theophylline clearance which has been observed in most of these studies is clinically significant (i.e. potentially toxic). However, it could be so in patients suffering from chronic pulmonary disease. Antibiotics which do not affect theophylline clearance include ampicillin, tetracycline, rifampicin and cephalexin.

Cimetidine, an H2 blocking agent, is widely used for various gastric disorders and thus may often be given to patients receiving theophylline treatment. It produces a rapid fall in the rate of theophylline clearance, often within 24 hours of its first dose. It probably competes with theophylline for microsomal enzyme sites. Ranitidine, another H2 blocking agent, is structurally dissimilar to cimetidine. It does not affect theophylline clearance and thus should be given in preference to cimeditine to patients already receiving theophylline therapy .

Oral contraceptives are widely used. Few studies have been carried out to determine potential interactions between these and theophylline. However, 2 sma" scale trials have shown that these contraceptives reduce theophylline clearance in both smokers and non-smokers. The effect of allopurinol on theophylline clearance is not clear-cut but at least 1 study reported a reduction in theophylline clearance following high doses of allopurinol. Other xanthines may compete with theophylline for metabolising sites. Methylxanthines are found in the cups of tea and coffee drunk by many individuals. If patients established on theophylline at home need to go into hospital their intake of tea/coffee - and hence of their additional xanthines - is likely to be reduced. Thus, their clearance rate of theophylline is likely to be increased. Induction of cytochrome enzymes is probably a factor in the increased rate of theophylline seen when phenobarbitone or phenytoin are given concomitantly. It has been recommended that theophylline doses be increased when phenytoin is to be given also (although it is possible that this can have adverse effects on seizure control since theophylline may reduce phenytoin absorption).

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Adverse effects of theophylline are not usually life-threatening Such effects are usually termed 'minor' since they typically consist of such conditions as heartburn,

diarrhoea, insomnia and other symptoms of CNS irritability. These can occur at subtherapeutic doses and may lead to termination of therapy. More serious adverse effects occur with increasing serum concentrations. These include seizures (which have a mortality rate of about 50%) and, possibly, cardiac arrhythmias.

Theophylline's place in bronchodilator therapy Theophylline is of value in the treatment of acute asthma but is usually used only after other drugs in the

treatment of chronic asthma. Recent improvements in formulation may help to improve patient compliance by maintaining steady serum concentrations with longer acting sustained release preparations. Recognition of the role played by factors which affect clearance rates of theophylline should also improve therapy with this agent.

Respiratory muscle fatigue may be treated successfully with theophylline. This may be of considerable value in the treatment of patients suffering from dyspnoea and respiratory failure. The effects of theophylline on the CNS may be utilised to augment the ventilatory response to hypoxia (just as it has been used for years to restore normal ventilatory patterns to patients with Cheyne-Stoke respiration). Bukowsky} M. et at· Annals of Internal Medicine 101.' 67·73 (Jul 1984) [102 references]

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