IMPAIRED THEOPHYLLINE CLEARANCE IN PATIENTS WITH COR PULMONALE

Transcription

1 Br. J. cli. Pharmac. (1979), 7, IMPAIRED THEOPHYLLINE CLEARANCE IN PATIENTS WITH COR PULMONALE N. VICUNA,1 J.L. McNAY,l T.M. LUDDEN2 & H. SCHWERTNER3 'Divisio of Cliical Pharmacology, Departmets of Medicie ad Pharmacology 2College of Pharmacy, Uiversity of Texas-Austi, Austi, Texas, ad 3Departmet of Pathology, UTHSCSA, ad Audie Murphy Veteras Admiistratio Hospital, Sa Atoio, Texas. I The relatioship betwee serum theophyllie cocetratio ad daily dose was studied i 45 patiets receivig amiophyllie orally ad i 36 patiets receivig it by costat itraveous ifusio. 2 Patiets were categorized as ucomplicated chroic obstructive pulmoary disease (COPD) or COPD with cor pulmoale (CP). 3 Serum theophyllie cocetratio relative to daily theophyllie dose was sigificatly higher i patiets with COPD plus CP tha i patiets with COPD aloe. 4 Total body clearace of theophyllie estimated from data obtaied durig costat itraveous ifusio was sigificatly lower i COPD plus CP tha i patiets with COPD aloe. 5 We coclude that reduced maiteace doses of theophyllie are idicated i patiets with COPD whe complicated with CP. Itroductio There is kow to be a wide itersubject variatio i the relatioship of serum cocetratio of theophyllie to dosage (Jacobs, Seior & Kessler, 1976; Jee, Wyze, Rood & MacDoald, 1972; Lougha, Sitar Ogilvie, Eise, Fox & Neims, 1976; Miteko & Ogilvie, 1973). This is partially attributable to differeces i rate of metabolism. Factors which have bee show to affect theophyllie metabolism iclude age (Lougha et al., 1976), smokig habits (Hut, Jusko & Yurchak, 1976), ad liver disease (Piafsky, Sitar, Rago & Ogilvie, 1977b). Left vetricular heart failure sufficiet to produce pulmoary edema also decreases the rate of metabolism of theophyllie (Piafsky, Sitar, Rago & Ogilvie, 1977a). I oe study, a high proportio of patiets with a diagosis of COPD i combiatio with cor pulmoale ad/or cogestive heart failure was foud to have a icreased serum theophyllie cocetratio relative to daily dose (Zwillich, Sutto, Neff, Coh, Matthay & Weiberger, 1975). However, o systematic study has bee performed which permits quatitative estimatio of the extet to which cor pulmoale i combiatio with COPD affects theophyllie metabolism. The preset study was udertake to determie the ifluece of cor pulmoale, i combiatio with COPD, o the relatioship of serum theophyllie to dosage. Theophyllie admiistered by either the oral or itraveous route to patiets with COPD ucomplicated by CP provided a referece group with which compariso was made. I the subgroup of patiets who received the drug by costat itraveous ifusio, the apparet serum clearaces of theophyllie i patiets with ad without CP were compared. We established that the serum cocetratio of theophyllie relative to the dose is icreased i patiets with COPD plus CP whe compared to patiets with COPD aloe. The icrease i cocetratio relative to the dose was show to be associated with a reductio i apparet serum clearace i patiets with COPD plus CP, whe compared to the clearace of patiets with ucomplicated COPD. Methods Subjects of this study were ipatiets at the Bexar Couty ad Audie Murphy Veteras Admiistratio Hospitals with the cliical diagosis of chroic obstructive pulmoary disease (COPD) or COPD ad cor pulmoale (CP). The diagoses were accepted by the authors o the basis of iclusio i the problem list of patiets' records ad therefore represeted the cliical assessmet of the attedig physicia or house-officers of The Uiversity of Texas Health Scieces Ceter at Sa Atoio. Oral route ofadmiistratio Forty-five patiets received oral theophyllie as amiophyllie tablets i equally divided doses every

2 34 N. VICUNA, J.L. McNAY, T.M. LUDDEN & H. SCHWERTNER 6 h. Of this group, thirty-ie patiets (four females) had COPD aloe. The mea age was 56.1 years. Six patiets (three females), mea age of 63.8 years, had COPD ad CP. For the etire group the mea daily dose was 15.4 mg/kg (rage mg/kg). Serum samples for assay of theophyllie cocetratio were obtaied.5 h predose after at least 48 h of cotiuous therapy. Itraveous admiistratio Thirty-six patiets received a loadig dose of amiophyllie via itraveous ifusio over 2 to 3 mi ad were subsequetly placed o a ifusio of amiophyllie at a costat rate. Twety-eight of these patiets (three females), mea age of 62.5 years, had COPD. The remaiig eight patiets (two females) had both COPD ad CP. The mea age of these patiets was 64.5 years. Serum theophyllie cocetratios were determied after at least 36 h of costat ifusio. The mea rates of itraveous theophyllie ifusio for patiet groups with COPD aloe ad COPD with CP were.756 mg kg-' h-') (rage: mg kg-' h-') ad.665 mg kg-' h-' (rage: mg kg-' h-'), respectively. Xathie cotaiig beverages were ot restricted sice a specific gas-liquid chromatographic method was used for the assay of serum theophyilie (Schwerter, Ludde & Wallace, 1976). Caffeie, theobromie or metabolites of caffeie, theobromie, ad theophyllie do ot iterfere with the determiatio of theophyllie by this techique. Although theophyllie itself is a metabolite of caffeie, igestio of the usual amouts of caffeie produces serum theophyllie cocetratios less tha 3 &g/ml (Jacobs etal., 1976). Apparet theophyllie plasma clearace was calculated for patiets receivig a costat itraveous ifusio of amiophyllie by dividig the ifusio rate (expressed i terms of theophyllie) by the apparet steady state serum theophyllie cocetratio. It is ecessary to refer to these calculated clearaces as apparet values sice multiple samplig was ot performed to cofirm that the observed serum theophyllie cocetratios were truly steady state. Compariso of group meas was carried out usig the upaired t-test. Regressio aalysis was performed usig the techique of least squares. Results Oral route ofadmiistratio The dose of theophyllie was lower ad the predose serum cocetratio of theophyllie higher i patiets with CP plus COPD tha i patiets with COPD aloe. However, i either istace was the differece sigificat. Mea values for each cliical group are preseted i Table 1. Whe, however, serum cocetratio was related to total daily dose ad expressed as (jag/ml) / (mg kg-' 24 h-'), ratio was sigificatly (P <.2) greater i patiets with COPD plus CP tha i patiets with COPD aloe. The mea values for each group are preseted i Table 2. Table 1 Daily theophyllie doses ad predose serum cocetratios (Cp ) i patiets with chroic obstructive pulmoary disease (COPD) with ad without cor pulmoale (CP); oral route. Cliical group 39 6 Dose Cp Dose* Cp (mg kg-' 24 h)4ig/ml)(mg kg-1 24 h-1) 4Ltg/ml) Mea s.e. mea *Dose expressed as theophyllie sigifies umber of patiets per group Table 2 Serum theophyllie cdcetratios relative to 24 h doses i patiets with chroic obstructive pulmoary disease (COPD) with ad without cor pulmoale (CP). Cliical class Mea plasma cocetratio: dose ratio* s.e. mea COPD Oral Route of admiistratio Itraveous COPD + CP * Plasma cocetratio: dose ratio expressed as (tig/ml)/(mg kg-1 24 h-1) umber of patiets per group + Sigificace of itergroup differeces; oral COPD-oral COPD+CP, P<.2, i.v. COPD-i.v. COPD+CP, P<.1

3 THEOPHYLLINE CLEARANCE IN COR PULMONALE 35 Itraveous route ofadmiistratio The rate of itraveous admiistratio of theophyllie was virtually idetical i the patiet groups with ad without cor pulmoale. I cotrast, the serum theophyllie cocetratio was sigificatly (P <.1) greater i the patiets with cor pulmoale tha i those with COPD aloe. A compariso of the two groups is preseted i Table 3. I additio, whe serum cocetratio was related to total daily dose, ad expressed as (jg/ml)/(mg kg-' 24 h-'), the ratio was sigificatly (P <.1) greater i patiets with COPD plus CP tha i patiets with COPD aloe. The mea values for each group are preseted i Table 2. It is of iterest that the ratios of serum cocetratio to admiistered dose were of similar magitude to those obtaied durig oral admiistratio. Pooled oral ad itraveous results Serum cocetratios of theophyllie i patiets with COPD with ad without CP were related to the rate of admiistratio by least squares regressio aalysis idepedet of the route of admiistratio. There was a sigificat correlatio betwee serum cocetratio ad the admiistratio rate both for patiets with COPD (P<.1) ad with COPD plus CP (P <.5). I additio, the slopes of the two liear regressio lies differed-with the probability <.6, beig greater i patiets with COPD plus CP tha i patiets with COPD aloe. The relatioship of serum cocetratio to dose for each group of patiets is preseted i Figure 1. 6 E 5 a, 4 C -C 3 ad. -C a) s 2 E a) 1 (-I so Theophyllie dose (mg kg-' 24 h-1) Figure 1 The relatioship of serum theophyllie cocetratio to rate of admiistratio, accordig to cliical group idepedet of route of admiistratio. * Patiets with COPD aloe, patiets with chroic obstructive pulmoary disease plus cor pulmoale. Lies represet the correlatios betwee serum cocetratios ad doses, calculated by least squares regressio. A sigificat correlatio was preset for each group. A compariso of the slopes of the two liear regressio lies was suggestive of a differece, with a probability<.6. slope itercept r p COPD <.1 /I. COPD + CP < Table 3 Itraveous ifusio rates ad serum theophyllie cocetratios i patiets with chroic obstructive pulmoary disease (COPD) with ad without cor pulmoale (CP). Theophyllie ifusio rate (mg kg-1 h-1) Mea s.e. mea Serum cocetratio (gg/ml)* Mea s. e. mea Cliical class * Sigificace of differece betwee groups, P<.1 umber of patiets per group Table 4 Compariso of average apparet plasma clearaces of theophyllie, accordig to cliical class: itraveous route oly. Mea apparet plasma clearace (ml kg-1 mi-')* s.e. mea Cliical group COPD sigifies chroic obstructive pulmoary disease; CP sigifies cor pulmoale * Sigficace of itergroup differeces; COPD-COPD + CP, P <.1 umber of patiets per group

4 36 N. VICUNA, J.L. McNAY, T.M. LUDDEN & H. SCHWERTNER Apparet serum clearace oftheophyllie We compared the observed clearaces of theophyllie from sub-groups havig a diagosis of COPD with or without cor pulmoale. Oly patiets who had received the drug itraveously were icluded i this compariso, which is preseted i Table 4. The mea clearace of the goup of patiets with COPD plus CP was sigificatly (P<.1) less tha that of the patiets with COPD aloe. Discussio We have established that patiets with cor pulmoale associated with COPD costitute a additioal group of patiets predisposed to elevated plasma theophyllie cocetratio. Although our classificatio of patiets was based exclusively o cliical observatios, this is the usual situatio i practice ad should serve to alert physicias to the eed for dosage idividualizatio i this type of patiet. The icreased plasma cocetratio relative to dose i patiets with cor pulmoale was foud to be attributable quatitatively to a decrease i plasma clearace, of theophyllie. The average total body clearace of theophyllie i patiets receivig itraveous ifusio with the diagosis of COPD aloe was.798 ml kg-' mi-'. Patiets with COPD plus CP had o average total body Clearace of.481 ml kg-' mi-'. Thus, the clearace rate i the latter group of patiets was 6% of that i the former group of patiets. We foud that the most feasible approach by which to idetify the effect of cor pulmoale o theophyllie clearace was by compariso of patiet groups with COPD aloe ad COPD cocomitat with cor pulmoale. This compariso teds to elimiate other factors which may separate patiets with COPD per se from the ormal populatio. A example of such a factor would be the amout ad duratio of cigarette cosumptio, a factor which i itself ehaces theophyllie dispositio clearace (Hut, Jusko & Yurchak, 1976). However, it should be oted that the total body clearace of theophyllie which we observed i patiets with COPD plus CP was ot oly sigificatly less tha that observed i our ow series of patiets with COPD, but also sigificatly less tha values reported for ormal subjects i the literature (Miteko & Ogilvie, 1973). Literature published to date suggests that COPD complicated by heart disease may be associated with toxic plasma theophyllie cocetratios. I a report of patiets with theophyllie-iduced seizures, there was a clear associatio of elevated plasma cocetratio with toxic effects (Zwillich et al., 1975). Of twelve patiets with toxic maifestatios, the average serum cocetratio of theophyllie relative to average oral dose was elevated. Seve of these twelve patiets had a cliical diagosis of cogestive heart failure. This suggests that the presece of cardiac isufficiecy predisposes to reduced metabolism of theophyllie. It has bee demostrated that theophyllie clearace is reduced i pulmoary edema (Piafsky et al., 1977a). However, the effect of cor pulmoale per se to reduce theophyllie clearace has ot bee previously documeted. While it has bee suggested that passive cogestio of the liver i patiets with heart failure might alter the hepatic capacity to extract ad metabolize theophyllie (Piafsky et al., 1977b), this possibility has ot bee experimetally verified. Our observatio that cor pulmoale, as well as pulmoary edema, reduces theophyllie clearace would be compatible with this mechaism of decreased hepatic cleace, sice cardiac output per se ad possibly liver perfusio, are ormal i cor pulmoale (Parker, Kelkar & West, 1966). I coclusio, we observed that the plasma cocetratio of theophyllie i COPD plus CP was higher relative to orally or itraveously admiistered doses tha was the case i patiets with COPD aloe. A sigificatly lower total body clearace of theophyllie was also established i the patiets with COPD plus CP. The combiatio of COPD ad CP was associated with a average decrease i clearace to 38% of that observed i a selected ormal series (Miteko & Ogilvie, 1973). I light of these fidigs, it would seem prudet to appropriately adjust oral ad itraveous maiteace doses of theophyllie i the preset of these cliical diagosis, ad to idividualize dosage regimes by serum theophyllie assays. Supported i part by Faculty scholarship from Uiversidad de Los Ades, Merida, Veezuela (N.V.). Refereces HUNT, S.N., JUSKO, W.J. & YURCHAK, A.M. (1976). Effect of smokig o theophyllie dispositio. Cli. Pharmac. Ther., 19, JACOBS, N.H., SENIOR, R.M. & KESSLER, G. (1976). Cliical experiece with theophyllie relatioships betwee dosage, serum cocetratio ad toxicity. J. Am. med. Ass., 235, JENNE, J.W., WYZE, E., ROOD, F.S. & MacDONALD, F.M.

5 THEOPHYLLINE CLEARANCE IN COR PULMONALE 37 (1972). Pharmacokietics of theophyllie: Applicatio to adjustmet of the cliical dose of amiophyllie. Cli. Pharmac. Ther., 13, LOUGHNAN, P.M., SITAR, D.S., OGILVIE, R.J., EISEN, A., FOX, A. & NEIMS, A.H. (1976) Pharmacokietic aalysis of the dispositio of itraveous theophyllie i youg childre. J. Pediatr., 88, MITENKO, P.A. & OGILVIE, R.I. (1973). Pharmacokietics of itraveous theophyllie Cli. Pharmac. Ther., 14, PARKER, J.O., KELKAR, K. & WEST, R.O. (1966). Hemodyamic effects of amiophyllie i cor pulmoafe. Circulatio, 33, PIAFSKY, K.M., SITAR, D.S., RANGNO, R.E. & OGILVIE, R.I. (1977a). Theophyllie kietics i acute pulmoary edema. Cli. Pharmac. Ther., 21, PIAFSKY, K.M., SITAR, D.S., RANGNO, R.E. & OGILVIE, R.I. (1977b). Theophyllie dispositio i patiets with heapatic cirrhosis. N. Egl. J. Med., 296, SCHWERTNER, H.A., LUDDEN, T.M. & WALLACE, J.E. (1976). Determiatio of theophyllie i plasma by electro-capture gas chromatography. Aalyt. Chem., 48, ZWILLICH, C.W., SUTTON, F.D., NEFF, T.A., COHN, W.M., MATTHAY, R.A. & WEINBERGER, M.M. (1975). Theophyllie-iduced seizures i adults: Correlatio with serum cocetratios. A. iter. med., 82, (Received Jauary 4, 1978)