theophylline
TRANSCRIPT
CLINICAL TOXICOLOGY 14(2), pp. 157-160 (1979)
USE OF PLASMA CONCENTRATION DETERMINATIONS
Theophylline*
ROBERT WEIBERT,t Pharm.D.
University of California, School of Pharmacy
San Francisco, California 94143 (San Diego Program)
Theophylline produces bronchodilation by inhibition of phospho- diesterase and is widely used to t reat diseases of reversible airway obstruction. Theophylline is used both intravenously for acute asth- matic attacks and orally to prevent exacerbation of bronchoconstric- tive diseases.
Serum theophylline levels are among the most useful of all of the currently available drug levels. Theophylline serum levels correlate with both therapeutic and toxic effects and, if interpreted correctly, can be used quantatively to select an appropriate theophylline dosing regimen for each patient. There are several reasons why virtually any patient receiving theophylline should have a serum level measured (Table 1).
Excellent correlations between theophylline concentration and im- provement in pulmonary function have been demonstrated. Theophyl- line concentrations of 8-20 pg/ml are needed to produce maximal bronchodilation. A minimum therapeutic response is 15% improve- ment in FEVl (forced expiratory volume at 1 sec) and concentrations below 10 pg/ml are often ineffective.
*Proceedings of the 42nd Quarterly Meeting of the California Asso-
tMailing address: University Hospital (H- 765), University of Cali- ciation of Toxicologists, San Diego, California, October 29, 1977.
fornia Medical Center, San Diego, California 92 103.
157 Copyright @ 1979 hy Mdrcel Dekker. Inc Neither this work nor any part may he reproduced or transmitted in dny form or by any means, electronic or mechanical. including photocopying. miLrofilming. and recording. or by any information storage and retrieval system, without permission in writing from the publisher
All Rights Reserved
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158 WEIBERT
TABLE 1. Rationale for Measuring Serum Theophylline
1. Theophylline levels correlate with therapeutic response. 2. Theophylline levels correlate with toxicity. 3. Theophylline has a narrow therapeutic index. 4. There is a wide interindividual variability in the rate of theophylline
metabolism. 5. Theophylline levels can be used to predict the serum levels which
will be attained at different dosing regimens.
Unfortunately, theophylline toxicity can be life-threatening and can occur at drug concentrations which are relatively close to the normal range of therapeutic concentrations. Gastrointestinal reactions are the most common problem, consisting of anorexia, nausea, and vomit- ing. These are infrequent a t theophylline levels less than 13 ,ug/ml and are quite common when the concentration exceeds 20 pg/ml. Life- threatening theophylline toxicity includes cardiac arrhythmias and seizures. Seizures can occur with theophylline levels as low as 25 ,ug/ml but usually are associated with theophylline concentrations of 40-50 g / rn l . Up to 50% of patients with theophylline-induced seizures may die, so i t is of critical importance to prevent this complication. GaBtrointestinal reactions (nausea, vomiting) do not always precede seizures, and the old technique of increasing the dose of theophylline until the patient becomes nauseated is dangerous. Dosing should be adjusted according to theophylline levels to prevent major complica- tions.
the relatively narrow margin of safety between therapeutic and toxic concentrations, there is a wide variation among patients in their ability to metabolize this drug. The usual average doses of theophyl- line (4-6 mg/kg every 6 h r ) will produce an 8-fold range of concentra- tion. Thus, some patients will be below the target concentration range of 10-20 pg/ml with ineffective bronchodilation, and others will exceed the therapeutic range and r isk major toxicity.
The average half-life ( t l / z ) for theophylline is approximately 5 hr , but this varies widely. Young children and younger adults who smoke metabolize theophylline more rapidly. However, elderly patients and those with congestive heart failure metabolize the0 hylline slowly, and
Patients with liver disease metabolize theophylline very slowly, and doses should be reduced by 50%. This marked interpatient variability in theophylline metabolism is the major reason that theophylline levels are needed to plan a dosing schedule which will produce therapeutic, nontoxic theophylline concentrations.
Theophylline therapy is further complicated since, in addition to
the initial theophylline dose must be reduced 25-30 ! o to avoid toxicity.
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THEOPHYLLINE 159
Of course, the serum theophylline level provides qualitative infor- mation about the therapy. A subtherapeutic serum theophylline level may indicate that the patient is not taking the drug; that the absorp- tion of theophylline may be decreased because of patient o r drug product factors; o r simply that the dose is inadequate for that par- ticular patient who may metabolize theophylline at a more rapid rate. A therapeutic serum level verifies that the dosing regimen is adequate and, for patients with a poor clinical response, indicates that additional therapy is needed. Elevated serum levels suggest that the patient is receiving an excessive dose which, because of the patients slower theophylline metabolism, is resulting in accumulation to possibly toxic levels. Patient dosing mistakes o r acute ingestions should also be considered.
If the patient has received an infusion o r oral doses for a time period so that a steady state concentration is achieved (after 4 half- lives-approximately 24 h r for most patients), the serum theophylline level provides a quantitative estimate of the rate at which the patient metabolizes theophylline referred to as Total Body Clearance ( CLB)
Intravenous:
cLB = cpss (mg/li ter) - steady state theophylline level
Oral:
RO (mg/hr) - infusion rate
- Daily dose (mg/day)
(mg/li ter) trough level cLB cpssmin
Once the patients clearance (CLB) has been estimated it can be used to approximate the doses which will be needed to achieve the de- s i red target theophylline concentration.
lection time and the time of the last dose should be recorded on all specimens. Fo r oral therapy serum theophylline levels should be ob- tained at the valley concentration just before the administration of the next dose. If peak theophylline levels are to be measured, the samples should be taken 2 h r after o ra l theophylline/aminophylline tablets, capsules, o r liquids have been given.
When theophylline is given by intravenous infusion the potential ex- ists for patients to rapidly accumulate the drug to possibly toxic levels. Theophylline levels should be drawn as follows:
The timing of the collection of blood samples is important. The col-
1. P r io r to the infusion of a loading dose ( i f the patient has taken oral theophylline).
2. Postdistribution, 1-2 h r after start ing the infusion. 3. Steady state, at approximately 24 hr. 4. For critical patients a midpoint level drawn at 12 h r may be
needed.
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160 WEIBERT
Levels drawn at these times will help to avoid toxicity and provide information which can be used to make pharmocokinetic predictions for the adjustment of future doses.
Because the patient must be placed on dosing regimens before theo- phylline serum levels can provide individualized feedback, some initial guidelines must be followed:
Oral therapy: initial dose of the lesser of 16 mg/kg/day o r 400 mg/ day of theophylline.
Increase the dose every 2-3 days to a maximum of 13 mg/kg/day (adults and children older than 9 years) o r 24 mg/kg/day (children less than 9 years) of theophylline. Measure a theophylline level a t maximal doses o r at the dosage one step below doses which produce any signs of theophylline toxicity.
Intravenous therapy: initial dose of 5 mg/kg of theophylline, then an infusion of approximately 0.75 mg/kg/hr of theophylline. These doses should be decreased by 30% for patients with congestive heart failure and 50% for patients with l iver disease.
tage varies as follows: theophylline loo%, aminophylline 85%, and oxtriphylline 64%. The actual doses must be adjusted for the theo- phylline content of each preparation.
patients and the possibility of major toxicity emphasize the need for a cautious approach to initial doses. To avoid toxicity and to attain effective drug concentrations within a relatively narrow therapeutic range, refinement of the theophylline dosing regimen should be guided by measurement of theophylline serum levels.
Theophylline is available in several forms, and the actual percen-
In summary, the great variation in theophylline metabolism among
G E N E R A L R E F E R E N C E S
R. Wyatt, M. Weinberger, and L. Hendeles, Oral theophylline dosage for the management of chronic asthma, J. Pediat., 92, - 125 (1978). D. C. Webb-Johnson and J. A. Andrews, Bronchodilator therapy, New Engl. J. Med., 297, 476, 738 (1971). W. J. Jusko et al., Intravenous theophylline therapy, Nomogram Guidelines, Ann. Int. Med., 86, 400 (1977). L. E. Matheson, L. B igh leysnd L. Hendeles, Drug interference with the Schack and Waxler plasma theophylline assay, Am. J. Hosp. Pharm., 34, 496 (1977). M. H. Jackobs,x. M. Senior, and G. Kessler, Clinical experience in theophylline, JAMA, 235, 1983 (1976). K. M. Piafsky a n d 1 . E i l v i e , Dosage of theophylline in bron- chial asthma, New Engl. J. Med., 292, 1218 (1975). P. A. Mitenko and R. I. Ogilvie, -Tonal intravenous doses of theophylline, New Engl. J. Med., - 289, 600 (1973).
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