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It is not possible to establish a single dosage regimen for theophylline or its derivatives (for example, aminophylline) that will suit all patients because the metabolism of theophylline varies greatly from person to person. This variation is reflected in its elimination half life, which varies from four hours in healthy adult smokers to about 25 hours in patients with hepatic cirrhosis.

Several of the factors responsible for the variation (age, smoking habits, body weight, diet, concomitant illness, and drug interactions) can be considered when estimating the most appropriate dosage regimen. But the therapeutic:toxic ratio for theophylline is very small, and only by measuring the plasma theophylline concentration can the dosage be tailored for individual patients.

In this chapter we apply to theophylline the criteria that must be fulfilled in part or in full before the measurement of its plasma concentration can be considered worth while.

Criteria for measurement

Is there difficulty in interpreting clinical evidence of the therapeutic or toxic effects?

There is a relation between the dose of theophylline and the reduction in airways resistance achieved. The drug's chief therapeutic effect, however, is the relief of bronchoconstriction, which is only one of the three factors that cause airways obstruction in asthma, the other two being mucosal oedema and mucus plugging of the airways. Thus in asthmatic patients a change in FEV₁, which reflects all three factors, is an unreliable guide to theophylline dosing, and monitoring of plasma concentrations is essential in order to optimise treatment.

Many patients experience gastrointestinal symptoms when their plasma concentration is within the therapeutic range, but minor adverse effects do not always precede major ones. Several of the adverse effects (nervousness, tachycardia, arrhythmias, and cardiorespiratory arrest) can be features of an acute attack of asthma, and it may be impossible to distinguish between features of the underlying disease and those attributable to theophylline toxicity without measuring the plasma theophylline concentration.

Is there a good relation between the plasma concentration and its therapeutic or toxic effects?

In experimental studies there is a linear relation between changes in forced expiratory volume in the first second (FEV₁) and the logarithm of the plasma theophylline concentration over the range 17-110 µmol/l. Improvement in FEV₁ is often only slight with concentrations less than 55 µmol/l, and clinical evidence suggests that 55 µmol/l may be considered as the lower limit of the therapeutic range. The upper limit is generally accepted as 110 µmoll, which is the concentration at which agitation and tachycardia usually become apparent.

Minor adverse effects, such as nausea, insomnia, nervousness, and headache, are common if the plasma theophylline concentration is rapidly increased above 55 µmol/l. Most patients will tolerate the drug better if the dose is gradually increased to attain maintenance plasma concentrations in the middle or upper part of the therapeutic range. About 5% of patients develop unacceptable nausea and diarrhoea at plasma concentrations below 80 µmol/l. Serious adverse effects-persistent vomiting, gastrointestinal bleeding, seizures, cardiac arrhythmias, and cardiorespiratory arrest-often occur at concentrations above 110 µmol/l. Plasma concentrations above 190 µmol/l are invariably associated with a high risk of dangerous cardiac arrhythmias.

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