· .. theophylline, ... Theophylline is a widely used bronchodilator

which has a narrow therapeutic range (10-20 ,ug/ ml) . Associated adverse effects include nausea, vomiting , diarrhoea, CNS stimulat ion and , above 40 ,ug/mL, such serious effects as cardiac arrhythmias and seizures . Therefore , administration of any drug which interferes with the metabolism of theophylline may have potentially serious consequences .

The cytochrome PA50 system has a major role in theophylline metabolism, and both cimetidine and ranitidine have inhibitory actions on this system , thus , having the potential to reduce elimination of theophylline and cause theophylline toxici ty . An interaction between cimetidine and theophylline , which is dose-related for cimetidine in the range 300-1200 mg/day, has been well established through trials involving mostly healthy (mainly young , but some elderly) volunteers taking a single dose of theophylline, where significant reductions in theophylline clearance (range 12-39%), increases in half-life (23-45%), and increases in the area under the curve (29-45%) have been observed . These findings have been paralleled by results from trials with multiple doses of theophylline , which in addition show an increase in serum theophylline levels (range 34-41 "Ie) . However, these increased levels remained within the therapeut ic range and did not result in toxicity . Only a limited number of studies of the effect of ranitidine on theophylline metabolism have been conducted , and those employing a single dose of theophylline In young , healthy subjects showed no significant effect of ran itidine 300-2200 mg/day on theophylline pharmacokinetics .

Studies In patients with obstructive lung disease show similar results to those conducted on healthy subjects, and symptoms of theophylline toxicity have been observed with cimetidine and in a few cases serum theophylline has risen to > 20 ,ug/ mL with both H2-antagonlsts. There are several case reports of clmetidine , and a few of rantidine , interacting with theophylline to produce serious , and in some cases , life-threatening conditions such as seizures and cardiac arrhythmias .

Studies on volunteers taking cimetidine with theophylline have shown that the onset of changes in theophylline pharmacokinetics occurs within 24 hours and peaks within 3-5 days of initiation of cimetidine medication. Theophylline metabolism returns to normal within 2-5 days of discontinuation of cimetidine. Age itself appears not to affect the risk of clinically significant drug interactions, although changes in pharmacokinetics

are significantly more pronounced in the elderly . Cigarette smoking st imulates the cytochrome PA50 system , as well as arylhydroxylase, an enzyme which is inhibited by cimetidine and is probably involved in theophylline metabolism. The inhibition of theophylline metabolism by cimetidine is therefore likely to be more variable in smokers , and this is supported by a limited number of studies . However, further study is required before the effect of smoking on cimetidine-theophylline interaction can be properly understood .

In conclusion , both cimetidine and ranitidine have the potential to initiate clinically significant adverse effects when given with theophylline . The effect of cimetidine on theophyll ine metabolism is well defined and predictable and this allows the clinician to anticipate an effect and adjust the theophylline dosage accordingly . The interaction between ranitidine and theophylline is less predictable , and in many cases of a smaller magnitude than with cimetidine, but it may lead to clinically significant effects and substitution of ranitidine for cimetidine should only be made with caution . Awareness of possible signs and symptoms of theophylline toxicity or failure should be heightened within 2-5 days of cimet idine or ranitidine initiation or withdrawal.

Mollnoff PB In teractions of theophytllne wl:h clmetldlne and ranltldlne a wtlcat analYSIS of the literature. Advances In Therapy 5 168·190 Sep

1988 142 references I "96