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Update on the Pharmacodynamics Pharmacokinetics of Theophylline* Leslie Hendeles, Pharm.D.;t Miles Weinberger, M.D. Marc Massanari, Pharm.D.; theophylline’s unlmown. concentrations where obtaining maximal have the potential tions mechanism 10 to 20 Often, of action is used pg/ml there benefit the is the 15 formulations use. Often these T heophylline has agent controlling for asthma during States. This pharmacokinetics greatest is of serum of likelihood Slow-release safely. products sold under 29 brand with more rapid slow absorption names in this country. In patients tion, few products have sufficiently twice-daily in asthma as the range to provide more stable serum concentradosing intervals. However, clinically imin rate and sometimes extent of absorp- longer portant differences tion exist between with and § Theophylline has emerged as a major prophylactic agent for controlling the symptoms of chronic asthma, but it provides little if any relief of pulmonary symptoms caused by irreversible chrome airways obstruction. Although in vitro it inhibits phosphodiesterase and antagonizes adenosine receptors, and formulations emerged must as a major the eliminato allow be adminis- every eight hours to prevent breakthrough in asthsymptoms despite promotional claims to the confrar In patients with slower elimination, differences among products are unlikely to be clinically important with 12-hour dosing intervals. Current products approved for “once-aday” dosing are clinically inadequate because of erratic absorption or excessive serum concentration fluctuations. Moreover, food induces dose dumping of potentially toxic amounts of theophylline from Theo-24, greatly increases the extent of absorption of theophylline from Uniphyl, decreases extent of absorption from Theo-dur-Sprinkle capsules, but has no clinically important effect on Theo-Dur tablets, Theobid, Sb-Bid, or Somophyllin-CRT. The effects of food or other factors that alter gastrointestinal physiology on theophylline absorption are unknown for most other products. tered matic prophylactic symptoms of PHARMACOLOGY chronic the past 10 to 15 years in the United has been a result of definition of its and pharmacodynamics, the availa- The mechanism of theophylline’s chial smooth muscle relaxant remains tion of phosphodiesterase mechanism, but this bility of rapid specific methods of measuring serum concentrations, and the development of reliably absorbed slow-release formulations. that used Furthermore, Since there have been a great many of articles, book chapters, and proceedings from symposia published on theophylline, this review will focus on only the most chodilators. recent advances we recognize in knowledge about this that many adult patients degrees of airway hyperreactivity varying with an irreversible well-controlled benefit from symptoms Therefbre, refers chronic component studies have theophylline of airways caused by irreversible to avoid confusion, to reversible irreversible airways airways no obstruction, little or no pulmonary obstruction. airway “asthma” in this obstruction and article COPD to Pediatrics, University Pharmacokinetics, §Professor of Pediatrics and Chairman, nary Division, University of Iowa. Reprint requests: Dr Hendeles, Box Florida, Gainesville 32610 Pediatric of Florida. College of Phar- Allergy J-4. JHMHC. and PulmoUniveristy and Thus, longer be of be toxic in vivo.6 inhibitors such papaverine are phosphodiesterase accepted as the that but not bron- inhibition can of mechanism theophylline effects the- may act as a on intracellular calcium8 and increased binding of cyclic AMP (cAMP) to cAMP-binding protein9 also have been described. Recently, theophylline has been shown to antagonize adenosine induced by by receptors adenosine in vitro, Enprofylline and to block bronchial adenosine enprofylline, potency 8Fmm the Division of Clinical Pharmacokinetics, College of Pharmacy and Department of Pediatrics, University of Florida, Gainesville, and the Pediatric Allergy and Pulmonary Division, The University of Iowa, Iowa City. f Professor of Pharmacy and Fellow, Division of Clinical macy, University of Florida. dipyridamole ever, obstruction. has been a popular proposed is based on in vitro studies concentrations that would other phosphodiesterase ophylline’s action. It has been suggested pmstaglandin antagonist,7 drug. While may have combined demonstrated in relieving as theory action as a bronelusive. Inhibi- receptors a xanthine as bronchoconstriction provocation.’0 derivative that a bronchodilator than does gastric not How- are not antagonized stimulate has greater theophylline.” acid secretion or diuresis and has less CNS and cardiac toxicity than theophylline, suggesting that adenosine antagonism may be responsible for some of the side effects of methylxanthines’2 As with other but not their methylxanthines theophylline produce transiently can increase CHEST cerebral plasma / 88 / 2 / AUGUST, Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21484/ on 04/06/2017 bronchodilator such effects. caffeine, vasoconstriction, glucose, 1985 as and I Supplement inhibit 1O3S uterine contractions.#{176} actions on centrations It also exerts the cardiopulmonary >10 p.g/ml increase a complex set of system. Serum concontractility and re- companies whose products recommendations within the and/or cannot 10 to 20 ig/ml Similarly, dosing maintain range arguments around for interval concentrations using the clock. “low-dose” the- duce experimentally induced fatigue of diaphragmatic muscles,’4 decrease the work of breathing,4 increase biventricular performance,’5 stimulate hypoxic yen- ophylline in combination been based on single-dose tilatory sion,’7 hypertenHowever, ditive bronchodilator effects. There are no comparing the relative efficacy and safety studies of the are combination of drive,’6 reduce pulmonary artery and enhance mucociliary clearance.’8 it is unclear clinical from if these importance pharmacologic or result effects in the relief of any PHARMACODYNAMICS range various studies published of theophylline of serum have on led the efficacy to a carefully concentrations, and defined between 10 and 20 p.g/ml, where there is an optimal likelthood of maximal safe effect.’ It is this optimal range for maximal safe effect that has been commonly termed the “therapeutic range.” The connotations of this term have sometimes effect der been from 10 p.g/ml misinterpreted to suggest theophylline and at serum no further argue that theophylline tions,#{176} and tainly would However, ward this is the studies extension serum over literature, so. A that of the been effect un- 20 g/ml. however, Even a would measurable have therapeutic limited or some is no for antiasthmatic effect is apparent at lower serum higher serum concentrations provide more effect for some generally have bronchodilator lower not there concentrations potential effect at serum concentrations cursory examination of the that argued for a down- range to 5 pg/ml to demonstration decrease in symptoms concentrations of concentraalmost cerpatients. and have not strated that the measurable effects imal or, alternatively, associated were with indeed a lower of a at demonmaxfre- quency of side effects than serum concentrations within the 10 to 20 pg/ml range. Moreover, no studies examining the efficacy of serum concentrations less than 10 pg/ml have demonstrated degree of efficacy of theophylline the remarkably in preventing toms that interfere with sleep,’92’ reduction for emergency medications19 n3#{176}including steroids,2 and blocking of exercise-induced chospasm3#{176} documented pg/ml. As to the argument attained ftr some patients concentrations safe clinical effect The most is well in need corticobron- at concentrations above 10 that more effects might be at serum concentrations over 20 pg/ml, it is acknowledged not with adequate safety. serum high symp- that this may 10 to 20 g/ml likely supported to obtain by multiple be so, but range for maximal clinical 104S decreases with exercise-induced these drugs on an annual basis, expensive and less theophylline doses, even doses the symptoms. This since the intensity 13 agonists,3#{176} and not inhibited when ments titrated suppressing of asthmatic important, have ad- the- frequency and would be and duration parof continued use bronchospasm are given orally. of oral is Last, #{176} the combination therapy is more convenient than a slow-release product when the used cost alone in individualized of serum level measure- is included. Thus, the target issue then 10 to 20 g/ml safe maximal is no longer range effect is when products, and the whether optimal desired, but maintain, and sustain these given the interpatient variability, realities or not to likelihood how to of attain, serum concentrations the range of available of patients’ lifestyles. COPD Although serum a definite relationship concentration asthma, serum pulmonary and over, several ies’5 have exists effect concentrations function in in patients double-blind, with patients exercise be tients with investigated most the noticeable COPD effect 4 in of theophylline walking, a large in since increase El Placebo 0 Theophyllune riririririri Cough stud- rest (standing) and any potential benefit during experience Wheezing with COPD.#{176}4 More- and theophylline at (Fig 1). Jenne et al,4 with emphysema during (walking). Theoretically, would with poorly placebo-controlled little or no difference demonstrated for example, between patients correlate symptom control between placebo serum concentrations >10 pg/ml Dyspnea studies’5 and by considerable clinical experience by many clinicians over the past ten years. It appears that to some extent efforts to promote a wider therapeutic range, ie, 5 to 20 pg/ml, have been motivated by drug carefully in bronchodilatation Asthma The alone severity ticularly COPD. toxicity with ophylline of symptoms with an oral agonist studies demonstrating Sputum Walkung pain the Feeling FIGURE 1. Mean symptom scores from patients with COPD who received placebo and individualized oral doses of theophylline, each for one month, in a double-blind, cross-over manner. (Reproduced with permission of Journal of American Medical Association.’) Recent Advances in Management Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21484/ on 04/06/2017 of Obstructive AirWayS Disease work of breathing, found a modest lung work, particularly increase and theophylline slight during in FEy,, subjective at a mean exercise. a small They decrease improvement concentration improvement work. Patients ferred in this theophylline study of COPD did not alter theophylline there where in the that overall effects management diaphragmatic correpre- 20 treating or with COPD, respiratory are no preventing but there support this conjecture. Since theophylline particularly in COPD disease. work some of stimulabenefit in failure controlled associated studies toxic drug,3#{176} may be more effects3’ and concentrations result of impaired the small potential from cor pulmonale, be weighed against must at risk of as a the potential greater caution risk of toxicity. If it is used in COPD, must be exercised to prevent accumu- lation serum of toxic concentrations. In such it might be prudent to maintain at the lower end of the therapeutic FIGURE 2. average coated child tablets is rapidly, from oral the patients, and and plain, com- doses, release rapid-release fluctuations particularly products mulated in disintegration formulations in serum in have various ways and dissolution can result to in between absorbed products, absorption may ences in serum result in concentration However, dosing if the 8 9 is either relatively interval on Absorption: and pathology release erratic, The influence on the Food absorption markedly (a bead-filled capsule with pH-independent given to children 8 to 12 years old, but important Theo-bid, data). effect absorbed bioavailability the the from on Somophyllin-CRT, In contrast, food amounts that, on Theo-Dur excessive serum or results concentrations is appropriate for coating rapidly at 7.4 to 8.0, after a meal.4’ Food the of absorption Uniphyl, appears from 71 a clinical dissolves of toxicity, taken with much 24-hour incompletely effect product that, absorbed dissoluis pH- at pH on 6.8 but rate from like Theo-24, when taken fasting.41 CHEST I 88 / 2 I AUGUST, Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21484/ on 04/06/2017 1985 / Supplement a with a dose was 3). Apparently, Theo-24 beads slowly no In the pH range of the small intestine also appears to increase the extent without another to be only and (Fig the of Sb-Bid in dump- of theophylline average, is most severe symptoms after a single dose taken fasting coating on the tab- was taken with food but had the dose was taken fasting.39 subject with the peak concentration dependent; has Theo-Dur when taken fasting.3#{176}39 During study, four of eight volunteers when Theo-24 effects when the of bio- formulations evaluated. Sprinkle dissolution) clinically be serum levels patients.3#{176}’4’ theophylline adequately of can incomplete, constant in most previously tion of rates 12 range around the from the so-called decrease the rate of of the drug. However, in 11 rate generally was 31.4 compared the same 1,500-mg differences 10 elimination the therapeutic of theophylline of slow been and bacon and eggs breakfast peak of 12.5 g/ml when clinically important differfluctuations3#{176}37 (Fig 2). interval 7 metabolizers,3#{176}37 slowpopular. They are for- extent and, particularly, rate of absorption differ among the 29 brands of the 15 slow-release formulations available in this country. Even among completely 6 product of Food physiology, developed rectal supabsorbed.3#{176} 5 concentrations ing of potentially toxic Theo-24,3#{176} a product uncoated concentrations rapid become qt2t, 9128 theophylline toxicity adverse Because 10mg/kg 10.9mg/kg impairs tions are positories but of the serum formulations not percent recent nearly completely absorbed, are erratically and incompletely 4 3 or too rapid to achieve over a 24-hour dosing tablets, while enteric coating (eg, Choledyl) delays dissolution, which can result in incomplete absorption and/or unpredictable absorption rates.’5 Rectal solu- large rate patient, once-daily no consistently, 2 maintained within clock. #{176}Absorption has serum concentrations range. liquids Oyrocaps. 9121, 9128 12.3mg/kg Predicted steady-state serum concentrations for an (ti/I = 3.7 hours; V = 422 mI/kg) receiving plain, Unand four slow-release products at 12-hour dosing intervals. The more rapid the rate of absorption, the greater the fluctuation and the longer the amount of time the serum concentration remains in the subtherapeutic range (less than 10 g/ml). (Reproduced by permission of Pharmacotherapy.5t) lets,aL (unpublished absorbed 1 availability Absorption Theophylline StoghylIk, 0128 128mg/kg Time (hours) Influence age, GI PHARMACOKINETICS pletely o 0 absorption to sensitive to its arrythmogenic accumulating excessive serum metabolism benefit PhYSOCOntIn. of are clinically and is a potentially patients, who S #{163} debut effects patients, of this performance,” might offer - 8.2mg/kg 200&300, airways contractility,’4 breathing,4 biventricular tion of hypoxic drive’6 Thso-Dur #{149} PWafl Tiblit., altered the In another Thus, in COPD these O double-blind reversible exercise performance.5 can be demonstrated on 25 carefully excluded, theophylline to a small and significant degree is no evidence important Effects placebo that theophylline was not excluded. patients, obstruction was creased dyspnea but over the possibility of dyspnea 30 but of 12 .ig/ml, - Serum Theophyiiine (pg/mi) during neither spirometric nor subjective lated with the decrease in lung study, but perception in 105S Subject VA 30 Nausea. Vomiting Headache 25 Fasting After Serum Theophyihne Concentration rates which Breakfast 20 8 16 24 32 Time 40 48 serum concentrations in an individual subject after a single 1,500mg dose ofTheo-24 taken fasting and after breakfast. Shaded area indicates the period during which patient experienced nausea, repeated vomiting, or severe, throbbing headache. The pattern of drug release during the food regimen is consistent with “dose-dumping.” (Reproduced with permission of Chest. Food decreases the from Theolair-SR, rate, but a product tion dissolution, in significantly increase from children Theolair-SR or Slo-Phyllin from products not extent, with pH and adults.47 the rate of theophylline but not from also absorp- Theo-Dur tablets Gyrocaps.49 Theoretically, absorption with pH-dependent dissolution may be the effect of food and pH characteristics of slow-release may alter products unaffected should by Ibod be considered and other factors for routine as use. theophylline enters the systemic on average 40 percent becomes protein and the remaining free throughout ing reported elevated due theophylline both children a single by the volume after to the to plasma distributes lower temperature binding increased apparwhich averages 0.5 IJkg among Since the peak concentration distributes, and adults. loading dose of distribution, concentration, and during in vitro testing.3#{176}The distribution, the space into on volume of distribution and hepatic cirrhosis, protein circulation, bound drug body water. The 60 percent protein bindin previous studies was artifactually pH that occurred ent volume of serum the is equal to the dose divided 1 mg/kg will increase the average, 2 g/ml. The during uncorrected is slightly larger, acisince is reduced in these is eliminated from by Elimination Theophylline at variable individuals occurs as a result body. Interpatient ing concurrent reports have been normal-weight diac thyroid published in to differences that change function, on smokConflict- the subjects or between influence and men and require a major However, the or stable COPD reduced. the fever cause event, warrant cine ance, is the or the the magnitude a temporary viral of the dosage during febrile it is unclear if infection. effect can reduction. In either be sufficient Influenza was also thought to reduce theophylline but several subsequent well-controlled Cigarette ance on achieve the demonstrate any therapeutic serum among than have rapid clearlarger doses to hepatic of theophylline, metabolism in part Changes protein alter persistent eater clearance, alterations Recent Advances even but the magnitude of to require changes in except when radical in diet occur, eg, a heavy a high-carbohydrate vegetarian. in Management Airways Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21484/ on 04/06/2017 in in theophylline clearof dietary carbohydrate and is unlikely for individuals becoming increased but there is a correlation clearance, suggesting in thyroid function con- to the variability in the amount can from thyrotoxicosis, euthyroid asthmatic patients, between T4 and theophylline that interpatient differences non- is more rapid than in adolescents increases the presumably during than clearance More average clearance has also been found with cystic fibrosis.3#{176} Hyperthyroidism clearance important concentrations the elderly, in nonsmokers. to vac- clearstudies clinically and marijuana smokers average3#{176} and require smokers. Even rapid in smokers meat be quite to prevent in patients with cor pulmonale3’ clearance is reduced tract infections,3#{176} but and women.3’ can decrease clearance without of clearis no and clearance hepatitis, car- cor pulmonale dosage Theophylline viral respiratory tribute ance, and the decrease in theophylline with hepatic cirrhosis, acute decompensation, large of variability ing, aberrations in diet, and other drugs.5’ Effects of Disease and Altered Physiology: and the body P-450 dosage illness, age, un- the cytochrome Variability of with change is not large dose requirements patients.5’ by liver. kidneys to rela- appears to be due biotransformation have failed to interaction.3#{176} Distribution Once metabolites in the the is metabolized clearance is large and in the rate of hepatic is not the dif- such clinical by remainder some of Approx- rates of elimination. Total body clearance, of volume of distribution and elimination most accurately reflects theophylline toxic reaction. cholestasis52 ferently, since product formulation design and rates of absorption vary. Studies are needed to define these effects on most slow-release products. Clearly, only products is eliminated the from In contrast, associated more rapid in patients with less acid gastric contents, such as the elderly, or during concurrent administration of H2-receptor antagonists. Thus, absorption parallel pathways, capacity-limited. obesity, old age, and gender on theophylline ance. Available evidence suggests that there clinically important difference between obese of absorpdependent Antacids or among removal 56 (houra) 3. Theophylline FIGURE 106$ while the variable the product rate constant, 0 mean demia 10 percent requirements 5 pH imately changed, tively inactive enzyme system (pg/mi) tion through multiple are saturable of Obstructive Disease patients, the before total serum guide final tration range, dose level should not exceed measurements dosage, and the should be at the eg, 10 g/ml. 400 are final target lower end phylline. mg/day obtained serum of the to 14 J Eur Murciano D, theophylline concen- with therapeutic Respir on chronic OF THEOPHYLLINE Matthay obstructive RA, chronic CONCENTRATION As a result of physician methodology, ophylline communities in serum are now in the United pensive are office rapid, facilities methods specific, serum or blood have immunoassay by Ames on a plastic strip measured in Another method thein most inex- of measuring theophylline that require small very recently utilizes a colormetric by amounts indicator photometer Syntex HJ, MR. structive line: of that pulmonary ML, Efficacy tion. Ann 3 Eaton disease with Effects BA, Intern Med 1980; patients orally administered JAMA TR, McGowan chronic 19 20 a JW, Siever effect and 22 5 Mahler JR. DA, obstruction. 6 Bergstrand H. Respir 7 Horrobin BA, 23 DE. MS. CR, coupling of action muscle. Sharp JT work standing Lunell CK, J. Loke Sus- of MJ, Respir Dis 1985; DJ, and Effects Med 1978; in 65:903- of aminophylline Am Rev 5, West Respir RO. on Dis 1978; Hemodynamic obstructive of theophylline et al, eds. MM, pulmonary on mucociliary Sustained release Amsterdam: Bronsky in asthmatic Pollock J, serum theophylline Hambleton dis- transport. theophylline Excerpta Evaluation J F, Cooper in Medica, G, 1984: and theophylline 1977; J Med Pedi- Cavanaugh M, of cromoglycate symptoms M, Thompson 1981; of chronic R, Huntley in W. The steroid-dependent value asthma. 304:71-75 L, Green M, of orally in the J, Taylor of exercise- cromolyn. Comparison in controlling theophylline Dusdieker of 1:381-85 Weinberger maintenance Relationship inhibition with M, S. et al. bronchodilaror 84:421-27 M. to comparison Weinberger Lancet 1974; D, Weinberger and Godfrey of oral Pediatr concentration E, NassifEC, EA. children. Kiechel 26 theophylline. 27 P Methylxanthine as mesenteric prostaglandin artery Smith GD, Ekwo administered control Pros- preparation. WJ. The insulin stimulus-secre- release. 3’5’-cycic JG, cAMP Smith VII. EE, Weinberger metaproterenol of chronic J Clin 29 Pharmacol Effect protein 1979; AE, on tracheal 30 J asthma. M. and Pediatr Am N, Andersson a xanthine with mediator J Allergy KE, FER, for treatment Rev 31 Adenosine-induced Respir Dis 1984; theo- 1982; 101: M, KE, lacking chronic adenosine obstructive in asthma Clin Persson CC. its CGA. receptor lung MJ. and Immunol Persson Adenosine antagonism Effects Tabachnik E, Scott Sustained L, Bighley L, Frequent toxicity AL. disease. Eur J Clin by methylxan- effects of theo- Rev effect 34 Pediatr Dis JL, 1979; theo- 1982; C, et in the 100:489-92 CD, infusions Intell 11:1218 Clin of Rozea P, oral salbutamol Dis Pharm 1977; drug tolerance to Carin beta, 73:949-57 1976; Bandler T. Multifocal Lancet Ludden L, Theobald C, in exercise-induced 114:493-500 Guarnieri of theophylline. clearance 5, Lewth advance JP, JR, McNay A, MacLeod a significant and Respir Michael Isles J and Richardson RH, Hepler from IV aminophylline 1978; Seale Inhaled Am N, J Am 17:585-92 development Chest SD, DA. Vicuna TM, in patients with atrial 1985; 1:12-13 Schwertner H. tachycarImpaired cor pulmonale. J Clin Br 7:33-37 Weinberger M, formulation to absorption 1978; as a bronchocon- 1984; 74:302-06 Extrapulmonary 33 Drug The agents. Anderson J, asthma. ill patients. a toxic theo- children. of ephedrine 1975; theophylline: of childhood JH, Clin Sustained-release Interaction P, Correia Hendeles michael Plummer asthma of erythromycin. KJ. J. P. Guidicelli in bronchial in preschool Ther release J. influence Simons E. treatment Pharmacol antagonism, GH, Pharmacol theophylline of flow of asthma Bronsky Clin Levine C, Duroux ventilatory 136:790-93 Weinberger dia: 129: Luciuk 1982; asthma. ST H, Thuillez and airflow obstruction: Ther 1982; 31:579-86 phylline Lindsay smooth 28:3687-88 Holgate in asthma. of theophylline from M, Bah kinetics critically A proposed monophosphate. TB. to soluble ‘Ikttersfield Svedmyr C, Mathieu Simons al. antag28 F, Malaisse Richer phylline. Hamet behave 1982; 22:395-402 ST, Mann JS, Cushley strictor 110$ J JV. Effect man. DiGiorgi of CRAO. Weinberger Child 131:22-25 32 E, Pharmacol Holgate Andersson treatment adrenergic Niedzwicki Biochem in patients 13 25 in non-reversible 51:232-41 enprofylline, thine. BL. 35:365-72 effect JGH, and chronic Pharmacol and 380-84 12 The Theophylline 109):37-44 Franks adenosine bronchoconstriction 11 24 in 13:33-40 fur binding Cushley Wells dyspnea Rev of glucose-induced 1972; while inhibition Malaisse-Lagae site RP, rat SM, on lung disease PE, 61(suppl a perfused tion Miech Am inhibitors 1977; JV, Cohen reduces 1980; Manku DF, in Invest 10 SW. phylline 1982; 130:600-05 Phosphodiesterase phosphodiesterase the 1984; performance Am in chronic 1967; Comparison tolerance Chest therapy Snyder disease. Dis taglandins Solano pulmonary Dis 1984; theophylline airway 8 Brisson WS, theophylline Matthay obstructive onists Druz obstructive Rev Respir tained-release 9 Clarke of obstruc- exercise PB, Circulation asthma. T, Nieuuehner Niewoehner Ashekian (cromolyn) 244:2286-90 airflow JO, of aminophylline Cinchansky ob- theophyl- 1980; TR, airflow of maintenance severe chronic walking. Am J Med 281-87 4 Jenne Eur J A, Zaret ventricular disease. SA, Weil induced bronchospasm atrics 1977; 60:840-44 82:538-42 The left in normal effects N EngI Church on breathlessness with of 22-25 re- of chronic 5, Sahn Parker the 92:758-61 FM, of theophylline Treatment in “irreversible” MacDonald Effects in patients N Engl Gottschalk and pulmonary responses therapy Diagnostics study, Church of theophylline ML, JE. controlled Green DE. 18 21 Kasik obstructive In: Jonkman is can be performed on only from a finger stick. WL, a double-blind, 2 Eaton in Dull B. fatigue disease, J, Loke right upon Lakshminarayan ease. REFERENCES 1 Alexander and 117:33-38 17 (Seralyzer). Medical and blood strength pulmonary Berger ventilatory become available. An a dry reagent contained reflectance quires no instrument 12 j.il-dmp of whole for readily States. 16 and measuring with a demand available In addition, and 109):17-28 Y, Pariente 10 increased improved 61(suppl 311:349-53 15 MEASURING 1980; Lecocguic M, diaphragmatic of aminophylline METHODS Dis Aubier Hendeles L, Bighley of oral L. The relation theophylline. of product N Engl J Med 299:852-57 Hendeles L, lafrate macokinetic basis theophylline products. Recent P. Weinberger for Advances the Clin selection Pharmacokinet In Management Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21484/ on 04/06/2017 M. and A clinical use of 1984; of Obstructive and slow pharrelease 9:95-135 Airways Disease reports as drugs ophylline; but interactions that potentially well-controlled have not studies been of a with on these reported in the Table 2-Predicted During a 12-Hour the- alleged literature. theophylline Fluctuationt product, dose, .. and tV= Manufacturer Plain or maintenance prophylactic therapy for chronic asthma, the absorption characteristics of the formulation, and the rate of elimination of the drug in the individual patient. For the treatment toms in the patient with intermittent inhaled 13 agonist such as terbutaline provides greater bronchodilation fects than theophylline.3#{176} However, is required, the most an intravenous rapid and ensured between formulations, and interchangeably.3#{176} To benefit achieve from the various rapid generally these products the greatest theophylline concentrations should be 20 jig/ml therapeutic width of the therapeutic range concentration cent (% Fluctuation oral within the must be less than 10 to the peak function elimination of the rate 100 per- within this Fluctuations rate of the product, from the patient, absorption of theophylline range, even in concentration vals (Table clinically important fluctuations 2). However, elimination, such differences when among as most if are by the differdo not in serum interrapid children, the a the and given at 12-hour patients with average ciga- rette or marijuana smoker, and about 25 percent of nonsmoking adults, most products are absorbed too rapidly to be given routinely twice daily without excessive serum concentration All but two of these products hours to avoid tional claims Recently, excessive fluctuations, to the contrary.3#{176} the FDA approved Theo-24, Theo-Dur tablets for once-a-day ever, none of these products 108S fluctuations must be given (Table 2). every eight despite Uniphyl, promo- 465 125 230 73 130 47 Theobid 140 54 Theovent-LA 167 60 43 18 155 57 S-R Gyrocaps Somophyllin-CRT SR Elixophyllin Rorer Sb-bid Slow-release Gyrocaps tablets Cord Laboratories Constant-T Key Pharmaceuticals Theo-Dur Mead Theo-Dur Quibron Johnson 200, 300 100 T/SR 39 17 88 35 128 48 Mundipharma Phyllocontin 165 58 Norwich-Eaton LaBID 252 77 Parke-Davis Choledyl 154 57 Biker Theolair 1221: 471: theophylline, see *For a comprehensive SA SR tPercent fluctuation serum concentration and the average indicate the values The has for the average child. that peak and 1:Prediction taken with when p.g/ml methodology dosing, with of the even bid., derivation of the once-a-day tuations mean averaged half-life of then 12-hour of these previously.’37 food, rate Fluctuations of this product of absorption concentrations range around unless and if peak are or may be smaller is pH dependent, the within the the clock labeling, serum in Management Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21484/ on 04/06/2017 of than ten the FDA 196 percent about seven Advances 10 to 20 in most from Theo-24394’ by food. Absorption half-life if is slowed. from Theo-Dur, a 100 percent or without food,45 is too rapid administration. Howis capable of reliably than maintaining intervals for are of 100 be more range, validation adult in excess with 8-hour claims patient variable, is greater multiple-dose study on which Recent ex- respectively. will therapeutic attained; and described hr), compatible and absorption is markedly affected theophylline product with somewhat smoking concentrations the are (7.7 Fluctuations not for dose taken fasting. food, since dissolution taken #{247} trough may cigarette of advertising maintaining serum jag/ml therapeutic patients, Uniphyl4’ serum therefore within as 20 been adult average regardless intervals. concentration fluctuations nonsmoking concentrations advisable, serum actual for the trough as high a-day slow-release because of circadian variation in absorption. Half (t#{189}) are the medians for the average child (3.7 to those serum and x 100; fluctuations percent levels of peak-trough = predictions of elimination twice review 34. similar jig/ml. hr Theophyl-SR Aerolate Laboratories Predicted as 20 Theophyl, Bronkodyl K-V Laboratories hr) 100) the length of the dosing interval selected physician.37 In patients with slow elimination, ences in rates of absorption between products result Graham ceed lives concentrations is as high Laboratories reference Trough to maintain 7.7 Resbid = Peak_Trough hr Theolair (IV) fordelivery around the clock. Since the range is only 10 jig/ml, serum fluctuations Slo-Phyllin, Slo-Phyllin can be used tY2= 3.7 Name capsules Cord of maximum asthma, serum maintained & Riker Bead-filled side efaddition release likelihood for chronic Johnson Johnson, of acute sympasthma, an or albuterol with fewer when the Brand tablets Rorer, of medication, but plain, uncoated or chewable tablets, liquids or liquid-filled capsules, and rectal solutions (but not suppositories) may also be satisfactory. There are no clinically important differences in rates of absorption in Serum Concentrations with Selected Slow-release Products* SELECTION dosing interval must be based on the specific clinical indication, ie, treatment of acute asthmatic symptoms of theophylline mulation provides Fluctuations Dose interval Theophylline % PRODUCT Selection interact and of absorbed for once- elimination, hours. based concentration in volunteers hours, but of Obstructive a In the approval flucwith a only 46 Airways Disease Adults and children over 1 year INITIAL DOSE old: The leser after FIRST Adults and Children of 400 or 16 mg/kglday 3 days INCREMENTAL children 45 kg: mglday INCREASE 5 45 kg: The lesser 600mg/day of 600 mg/day 20 mg/kg/day for ages 16mg/kg/day for ages9 after or-- ff0 9 3 days + Adults Children SECOND INCREMENTAL and children 545 kg: < 45 kg: The lesser INCREASE 800mg of 800 mg/day 24 mg/kg/day 1 to 9 for ages 9fo 12 for ages 12 to 16 20 mg/kg/day 18 mg/kg/day Check serum concentration have been or-- for ages about 4 hourS missed or added after a dose for 3 days when none 4. Scheme for establishing optheophylline dosage in ambulatory patients to prevent transient caffeine-like side effects. This is a conservative application of the recommendations incorporated into the FDA-approved package insert. Ideal body weight should be used for obese patients. In patients with cardiac decompensation, cor pulmonale, or liver dysfunction or in those taking drugs such as cimetidine that markedly impair metabolism, the initial dose before a serum concentration measurement is obtained should not exceed 400 mg/day. (Reproduced by permission of the New England Journal of FIGURE timal SERUM CONCENTRATION DIRECTIONS 10 to 20 xg/ml Maintain dose CONCENTRATION 20 to 25 y.g/ml 25 to 30 1Lg/mI Over 30 g/ml Decrease Skip next Skip next RECHECK FURTHER 7.5 to 10 p.g/ml Below 7.5 g/ml Increase dose about 25% it tolerated. Increase dose about 25%nd RECHECK FOR GUIDANCE IN FURTHER DOSE ‘Finer adfustmenls in dosage may be needed mandate earlier reexamination it tolerated. RECHECK SERUM THEOPHYLLINE AT 6 TO 12 MONTH INTERVALS. dose at least 10% dose and decrease subsequent doses at least 25%. 2 doses, decrease subsequent doses 50%, and SERUM THEOPHYLLINE FOR GUIDANCE IN DOSE ADJUSTMENT. for some patients: drug inferactions SERUM THEOPHYLLINE ADJUSTMENT. or physiologic abnormalities may oral Medicine.tm) percent when the same doses.w In contrast, the United States), when taken dose was divided fasting,3#{176}’’4’ will result fluctuations with once-daily dosing nonsmoking adult, but higher doses because of incomplete absorption’39 percent of the dose) and, if taken ophylline In one when were toxicity may study, Uniphyl taken fasting, absorbed when appears from hour products to slow but the these with absorption into Theo-24 (Pulmo-’flmelets an ultraslowly absorbed in result from dose dumping.396#{176} was only 55 percent absorbed substantially larger dose was taken with and other ultra-slow sufficiently tion with will current absence frequency relatively be available technical of constant amounts food.4’ It Variations quently, for once daily limitations of the dosing. products data documenting that of dosing from twice-a-day absorpWith and the the decreasing the to once-a-day guide Unless a clearance of theophylline among must be low to circumvent transient caffeine-like sideeffects (eg, 400 mg fur otherwise healthy adults) and slowly titrated over a period of nine days to average to minimize fluctuations in the individuals result in large differences in dosage requirements to maintain serum concentrations within the 10 to 20 p.g/ml therapeutic range. Initial dosage requirements concurrent complete dosing appears to be than an advance in DOSAGE data on experimental 24absorption that attempts and once-a-day gimmick acceptable in the average will be needed (on average, 71 with food, the- during 24-hour dosing generally result in incomplete absorption proportional to the degree of slowing. Thus, innovative technology will be needed before product improves compliance, more of a marketing formulation technology. 12-hr outside product according physiologic serum to age and abnormalities concentrations should the final dosage adjustments this slow titration process frequency In patients the presence of (Fig 4). Subsebe obtained to (bottom of Fig 4). is followed, the of adverse effects will be unacceptably with cardiac failure, liver dysfunction high. or cor pulmonale, where theophylline clearance may fluctuate, alternative therapy with other safer drugs, eg, inhaled 13 agonists, should be selected for maintenance therapy. If theophylline use cannot be avoided in such CHEST / 88 / 2 / AUGUST, Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21484/ on 04/06/2017 1985 I Supplement 109S patients, the before total serum guide final tration range, dose level should not exceed measurements dosage, and the should be at the eg, 10 g/ml. 400 are final target lower end phylline. mg/day obtained serum of the to 14 J Eur Murciano D, theophylline concen- with therapeutic Respir on chronic OF THEOPHYLLINE Matthay obstructive RA, chronic CONCENTRATION As a result of physician methodology, ophylline communities in serum are now in the United pensive are office rapid, facilities methods specific, serum or blood have immunoassay by Ames on a plastic strip measured in Another method thein most inex- of measuring theophylline that require small very recently utilizes a colormetric by amounts indicator photometer Syntex HJ, MR. structive line: of that pulmonary ML, Efficacy tion. Ann 3 Eaton disease with Effects BA, Intern Med 1980; patients orally administered JAMA TR, McGowan chronic 19 20 a JW, Siever effect and 22 5 Mahler JR. DA, obstruction. 6 Bergstrand H. Respir 7 Horrobin BA, 23 DE. MS. CR, coupling of action muscle. Sharp JT work standing Lunell CK, J. Loke Sus- of MJ, Respir Dis 1985; DJ, and Effects Med 1978; in 65:903- of aminophylline Am Rev 5, West Respir RO. on Dis 1978; Hemodynamic obstructive of theophylline et al, eds. MM, pulmonary on mucociliary Sustained release Amsterdam: Bronsky in asthmatic Pollock J, serum theophylline Hambleton dis- transport. theophylline Excerpta Evaluation J F, Cooper in Medica, G, 1984: and theophylline 1977; J Med Pedi- Cavanaugh M, of cromoglycate symptoms M, Thompson 1981; of chronic R, Huntley in W. The steroid-dependent value asthma. 304:71-75 L, Green M, of orally in the J, Taylor of exercise- cromolyn. Comparison in controlling theophylline Dusdieker of 1:381-85 Weinberger maintenance Relationship inhibition with M, S. et al. bronchodilaror 84:421-27 M. to comparison Weinberger Lancet 1974; D, Weinberger and Godfrey of oral Pediatr concentration E, NassifEC, EA. children. Kiechel 26 theophylline. 27 P Methylxanthine as mesenteric prostaglandin artery Smith GD, Ekwo administered control Pros- preparation. WJ. The insulin stimulus-secre- release. 3’5’-cycic JG, cAMP Smith VII. EE, Weinberger metaproterenol of chronic J Clin 29 Pharmacol Effect protein 1979; AE, on tracheal 30 J asthma. M. and Pediatr Am N, Andersson a xanthine with mediator J Allergy KE, FER, for treatment Rev 31 Adenosine-induced Respir Dis 1984; theo- 1982; 101: M, KE, lacking chronic adenosine obstructive in asthma Clin Persson CC. its CGA. receptor lung MJ. and Immunol Persson Adenosine antagonism Effects Tabachnik E, Scott Sustained L, Bighley L, Frequent toxicity AL. disease. Eur J Clin by methylxan- effects of theo- Rev effect 34 Pediatr Dis JL, 1979; theo- 1982; C, et in the 100:489-92 CD, infusions Intell 11:1218 Clin of Rozea P, oral salbutamol Dis Pharm 1977; drug tolerance to Carin beta, 73:949-57 1976; Bandler T. Multifocal Lancet Ludden L, Theobald C, in exercise-induced 114:493-500 Guarnieri of theophylline. clearance 5, Lewth advance JP, JR, McNay A, MacLeod a significant and Respir Michael Isles J and Richardson RH, Hepler from IV aminophylline 1978; Seale Inhaled Am N, J Am 17:585-92 development Chest SD, DA. Vicuna TM, in patients with atrial 1985; 1:12-13 Schwertner H. tachycarImpaired cor pulmonale. J Clin Br 7:33-37 Weinberger M, formulation to absorption 1978; as a bronchocon- 1984; 74:302-06 Extrapulmonary 33 Drug The agents. Anderson J, asthma. ill patients. a toxic theo- children. of ephedrine 1975; theophylline: of childhood JH, Clin Sustained-release Interaction P, Correia Hendeles michael Plummer asthma of erythromycin. KJ. J. P. Guidicelli in bronchial in preschool Ther release J. influence Simons E. treatment Pharmacol antagonism, GH, Pharmacol theophylline of flow of asthma Bronsky Clin Levine C, Duroux ventilatory 136:790-93 Weinberger dia: 129: Luciuk 1982; asthma. ST H, Thuillez and airflow obstruction: Ther 1982; 31:579-86 phylline Lindsay smooth 28:3687-88 Holgate in asthma. of theophylline from M, Bah kinetics critically A proposed monophosphate. TB. to soluble ‘Ikttersfield Svedmyr C, Mathieu Simons al. antag28 F, Malaisse Richer phylline. Hamet behave 1982; 22:395-402 ST, Mann JS, Cushley strictor 110$ J JV. Effect man. DiGiorgi of CRAO. Weinberger Child 131:22-25 32 E, Pharmacol Holgate Andersson treatment adrenergic Niedzwicki Biochem in patients 13 25 in non-reversible 51:232-41 enprofylline, thine. BL. 35:365-72 effect JGH, and chronic Pharmacol and 380-84 12 The Theophylline 109):37-44 Franks adenosine bronchoconstriction 11 24 in 13:33-40 fur binding Cushley Wells dyspnea Rev of glucose-induced 1972; while inhibition Malaisse-Lagae site RP, rat SM, on lung disease PE, 61(suppl a perfused tion Miech Am inhibitors 1977; JV, Cohen reduces 1980; Manku DF, in Invest 10 SW. phylline 1982; 130:600-05 Phosphodiesterase phosphodiesterase the 1984; performance Am in chronic 1967; Comparison tolerance Chest therapy Snyder disease. Dis taglandins Solano pulmonary Dis 1984; theophylline airway 8 Brisson WS, theophylline Matthay obstructive onists Druz obstructive Rev Respir tained-release 9 Clarke of obstruc- exercise PB, Circulation asthma. T, Nieuuehner Niewoehner Ashekian (cromolyn) 244:2286-90 airflow JO, of aminophylline Cinchansky ob- theophyl- 1980; TR, airflow of maintenance severe chronic walking. Am J Med 281-87 4 Jenne Eur J A, Zaret ventricular disease. SA, Weil induced bronchospasm atrics 1977; 60:840-44 82:538-42 The left in normal effects N EngI Church on breathlessness with of 22-25 re- of chronic 5, Sahn Parker the 92:758-61 FM, of theophylline Treatment in “irreversible” MacDonald Effects in patients N Engl Gottschalk and pulmonary responses therapy Diagnostics study, Church of theophylline ML, JE. controlled Green DE. 18 21 Kasik obstructive In: Jonkman is can be performed on only from a finger stick. WL, a double-blind, 2 Eaton in Dull B. fatigue disease, J, Loke right upon Lakshminarayan ease. REFERENCES 1 Alexander and 117:33-38 17 (Seralyzer). Medical and blood strength pulmonary Berger ventilatory become available. An a dry reagent contained reflectance quires no instrument 12 j.il-dmp of whole for readily States. 16 and measuring with a demand available In addition, and 109):17-28 Y, Pariente 10 increased improved 61(suppl 311:349-53 15 MEASURING 1980; Lecocguic M, diaphragmatic of aminophylline METHODS Dis Aubier Hendeles L, Bighley of oral L. The relation theophylline. of product N Engl J Med 299:852-57 Hendeles L, lafrate macokinetic basis theophylline products. Recent P. Weinberger for Advances the Clin selection Pharmacokinet In Management Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21484/ on 04/06/2017 M. and A clinical use of 1984; of Obstructive and slow pharrelease 9:95-135 Airways Disease 35 Cinchansky E, Pediatr 36 Weinberger oral to clearance 1977; in Relationship children with of theophylline chronic asthma. 56 J 57 91:655-60 J, Mirtallo Dasta M. dosage JM, sustained-release Altman M. theophylline obstructive pulmonary Comparison tablets disease. in patients J Am of standard Hosp Pharm chronic 1979; 36:613- A, Spino cystic fibrosis. Vozeh of M, formulation and theophylline Pediatr 38 39 Hendeles 1981; MM. report on 24-hour lations with Administration 1984; 4: 181-98 NH, and the 3rd 61 prod- Baltimore, Oct J. sprinkle product P, Purohit and Sips J Eur MA, theophylline tions in fasted 1983; 4:63-72 Pedersen Walter of Clin Kulstad a slow Pediatrics 1984; RB, DS, from enteric Irwin coated non-fasted and J. from FA, Dijkman from JH. Theolin 26:405-07 Welling PG. Absorption sustained subjects. S, Moller-Pedersen of theophylline 22:196-200 of theophylline Pharmacol on the a sustained-release 1982; Patel and of food Effect of 5, de Wolff bioavailability Clin JB. release Pharmacol PM, not affect Osman tion J Edelbroek Retard. AA, pattern tablet. AP, release Biopharm Influence of lbrmula- Drug Dispos of food on the absorp- Somophyllin-CRT Clin Allergy (in press) 47 Pedersen 5, Moeller-Petersen tion and rate Myhre tion Allergy KI, Walstad of two different line. 49 Br Shargel J Clin Shaw J LM, serum 51 influence Pharm Fuchs Hendeles 1981; binding. rapid of antacid Effect and timed-release influencing Pharmacol M. Ther Theophylline: theophylline 1982; 32:490-96 a “state of the 1983; 3:2-44 D, Lissner B, Zilly W, Bombard Schuppan E. Pharmacokinetics with liver diseases. on drug 70:599-602 Clin Pharmacotherapy StaibAH, Yu ABC. K. Factors L, Weinberger absorp- of theophyl- 15:683-87 JE, from L, Mayock on the formulations 1983; Sci absorp- theophylline of antacid sustained-release JA, release 37:531-34 The Pharmacol Fields protein review. 52 1982; of theophylline products. of food on the Influence of a sustained BA. L, Stevens bioavailability 50 J. bioavailability preparation. 48 art” G, Richter and metabolism of theophylline in patients Int J Clin Pharmacol Ther Toxicol 1980; 18: 500-02 53 KC, 1978; Lauer BA, 55 during JHC, TD, acute Upton theophylline. Jusko Enhanced tobacco Bell Chai H. Altered respiratory viral theophylline illness. WJ, BA. Clin JJ, Schentag Pharmacokinetic Pharmacokinet Clark biotransfbrmation smokers. Clin JH, drug 1984; Gardner of theophylline Lancet Pharmacol Ther 1978; interactions 9:309-34 M, Yurchak AM. in marihuana and 24:405-10 of thyroid 1984; Ther and inhaled Rev Respir intervals L, DH, Dis Meyer 1980; ML, Wubbena of acute infused 122:365-71 AB. dosed Presented Academy Disposition at 12 and at the 36th Pharmaceutical 24 Annual Sciences, p 108 P. Weinberger of once-a-day McFadden of the and Straughn theophylline 1984 abstract JR, sympathomimetics [Abstract]. APhA Snapper comparison M. theophylline dose Food-induced [Letter]. 1984; Lancet 2: M, basis Hendeles L. Slow-release for product selection. N EngI theophylline: ration- J Med 1983; 308:760- compared the tablet fbrm of a beta agonist such as albuterol vs oral theophylline? Dr Hendeles: There has been a comparison study with TheoDur given every eight hours and Alupent tablets given every Has anybody hours. There were significant differences between the two groups fuvoring the theophylline regimen, particularly when a standardized exercise stress test was used as an endpoint. The oral beta adrenergic agonists were not efficacious in blocking exercise-induced bronchospasm, whereas the inhaled beta agonists had a potent effect even though the same degree of brochodilatation was obtained through both furmulations. In other words, if you raise the FEy1 to the same point, the inhaled adrenergic agonist will block exercise-induced asthma and the oral form will not, suggesting that the topical effect of the beta adrenergic agonist is important. Theophylline, with a therapeutic serum level, has a reasonably good effect on exercise-induced bronchospasm, but not as good as inhaled beta adrenergic agonists. Audience: There have been a number of studies comparing the cardiovascular effects of theophylline and beta adrenergic agonists. Usually beta adrenergic agonists appear to have a bit more potential for causing cardiac ectopy. In your discussion on this point, could you clarify the experimental design? Dr Hendeles: In the study which I cited, there were some patients receiving Digoxin whose levels were measured and were in the therapeutic range. Arterial blood gas abnormal!ties were not associated with arrhythmias. The most important factor was stopping or adding theophylline to the therapeutic regimen. So theophylline itself or through synergy with other agents may cause cardiac arrhythmia. In patients with normal hearts without pre-existing cardiac arrhythmia, the combination of inhaled beta adrenergic agonists with theophylline in usual clinical doses does not arrhythmia. It’s only when excessive doses are employed 1:1132-33 Jonkman with and produce Chang pharmacokinetics 54 dosing Weinberger eight by food. caused Influence Pharmacol adrenergic on of in DIsCussIoN Trials, absorption F of asthma: AL, Uniphylline. 4, 1984 Erratic disposition 127:417-21 Clin Goldstein of controlled-release May, 64 of the CA, Am of the study Clinical 1983; kinetics. Golub Montreal, 85:758-65 Conference and Dis JJ, Follath Staub therapy Meeting ale formula- Annual Biopharmaceutics E, et al. Theophylline Respir 1471 L. theophylline Fanta MA, Hendeles dumping 60 Vaughan 1985; hour Food and controlled-release at in Gal Food does 46 M, of Theo-dur Moller-Petersen theophylline 45 Hill M, of parenteral Audience: Presented bioavailability TH, Gonzalez A Pharmacotherapy Chest absorption, theophylline Leeds 59 formu- C. A pharmacokinetic schedules qd? 74:534-38 1984; 44 now to obtain C, toxicity. of Maryland, 5, release J 39:634-38 food. Pedersen and Rev theophylline aminophylline. serum asthma. theophylline a “once-a-day” A, Edwards Concepts University bid used Milavetz from A. Theophylline and of chronic Theo-24. for M, dosing Current fluctuation tid, of data of theophylline 1984; Karim effects L. Relationship with slow-release approval B, Cope tions 43 with dumping as a cause Purkiss to qid, on analyses L, Weinberger recommended 42 Theophylline dosing Drug Allergy 41 interval in children Otten Emergency kinetics emphasis Hendeles L, Vaughan 99:145-52 Weinberger uct dosing concentration Food-induced 40 L, Wong Am on Rossing 58 ER. Weinberger M, lhbachnik 36:634-40 17 37 S, function and with Isles that cardiac arrhythmia occurs. Audience: But my question was specifically addressed as to whether or not the threshold for causing cardiac arrhythmia was lowered because of other drugs they were using. Dr Hendeles: It’s entirely possible that some of them were on oral terbutaline or fenoterol and it is possible that the effects were additive. CHEST I 88 / 2 / AUGUST, Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21484/ on 04/06/2017 1985 / Supplement ills