Plasma free captopril concentrations during short and

Transcription

1 Br Hert J 1985; 54: Plsm free cptopril concentrtions during short nd long term tretment with orl cptopril for hert filure T R D SHAW,* F M DUNCAN,jt B C WILLIAMS,t E CRICHTON,t S A THOMSON,* J R E DAVIS,t M RADEMAKER,* C R W EDWARDSt From the Deprtments of *Crdiology nd tmedicine, Western Generl Hospitl, Edinburgh SUMMARY Plsm free cptopril concentrtions nd hemodynmic response to cptopril were studied in 2 ptients with severe chronic hert filure. A 25 mg orl dose of cptopril produced 36% reduction in systemic vsculr resistnce, with individul responses vrying from 13% to 64%. Men systemic pressure fell by 2% nd crdic output rose 28%. The bsorption of cptopril ws rpid. Pek plsm free cptopril concentrtion occurred t 45 minutes fter the dose nd ws followed by smller second pek. Pek plsm free cptopril concentrtions vried more thn 2-fold but did not correlte with the mximl reduction in systemic vsculr resistnce. Elimintion hlf life ws seven hours. Fourteen ptients were restudied fter 1-2 months of cptopril tretment nd 12 showed symptomtic benefit. There ws sustined improvement in hemodynmic stte nd in non-invsive indices of myocrdil function. During long term tretment the predose plsm free cptopril concentrtion correlted well with dosge, but stedy stte cptopril concentrtions did not show significnt reltion with hemodynmic response. On dosge regimen of 25-5 mg three times dily the morning predose plsm free cptopril concentrtion nd plsm renin ctivity were reltively low nd suggested tht mximl inhibition of the renin-ngiotensin system ws not mintined throughout the dosge intervl. Cptopril, vsodiltor which cts by inhibiting conversion of ngiotensin I to ngiotensin II, hs been shown to benefit ptients with chronic severe hert filure.1 The response to cptopril vries pprecibly between subjects, but the resons for this re not fully understood. Mesurement of plsm concentrtions of cptopril hs been difficult becuse of the highly rective thiol group in the cptopril molecule. A rdioimmunossy for cptopril hs been developed,2 using ntibodies to cptopril-n-ethylmleimide complex, nd we hve used this ssy to study the reltion between plsm free cptopril concentrtions, hemodynmic responses, nd plsm renin ctivity. Ptients nd methods STUDY POPULATION Twenty ptients (men ge 62-4 (rnge 47-71) yers) were studied, ll of whom hd severe left ventriculr Requests for reprints to Dr T R D Shw, Deprtment of Crdiology, Western Generl Hospitl, Edinburgh EH4 2XU. Accepted for publiction 19 Mrch 1985 myocrdil impirment due to ischemic hert disese in 13 nd crdiomyopthy in seven. Nine hd n ssocited vlve bnormlity nd three mild hypertension. Ech ptient hd continued to hve crdic symptoms t rest or with mild ctivity despite tretment with digoxin nd frusemide (men dose 188 (rnge 8-5) mg/dy). All ptients were tking diet without dded slt. Potssium supplements (seven ptients) nd potssium retining gents (13 ptients) were withdrwn when cptopril tretment begn. SHORT TERM RESPONSE Ech ptient ws given n initil dose of 25 mg cptopril dissolved in 15 ml wter. Hemodynmic mesurements were mde t 3, 15, nd minutes before this dose nd for four hours (1 ptients) or 1Y2 hours (1 ptients) therefter. Ptients remined supine throughout the study period nd for t lest one hour before control recordings. They hd fsted overnight nd hd not tken other medictions on the dy of study. A blloon flow directed ctheter ws used to record right tril nd pulmonry rtery pres- 16 Br Hert J: first published s /hrt on 1 August Downloded from on 26 July 218 by guest. Protected by copyright.

2 Plsm free cptopril concentrtions in hert filure sures nd the crdic output. Crdic output ws mesured by indictor dye dilution (eight ptients) or thermodilution (12 ptients). Systemic pressure ws recorded with sphygmomnometer nd rm cuff. Chnges for ll hemodynmic vribles were mesured t the time of ech individul's mximl chnge in systemic vsculr resistnce. LONG TERM RESPONSE Ptients were restudied t 1-2 months fter beginning cptopril tretment. Dosge hd been djusted until symptomtic hypotension occurred or until mximum dosge of 45 mg/dy (12 ptients) or 15 mg/ dy (eight ptients) ws reched. Hemodynmic mesurements, plsm free cptopril concentrtions, nd plsm renin ctivity were recorded t three intervls over 3 minutes s in the control period described bove. The lst cptopril dose ws given 4-6 hours before the repet study. Left ventriculr function ws ssessed by nucler ventriculogrphy nd echocrdiogrphy before cptopril tretment nd t repet study 1-2 months lter. Ptients underwent exercise testing on tredmill using the Bruce protocol modified to include n initil lower stge of 15 kph t n 8 incline: prctice run hd been given. ASSAY OF PLASMA FREE CAPTOPRIL CONCENTRATION For the rdioimmunossy of cptopril 1 mg N-ethylmleimide ws dded to 5 ml plsm seprted in refrigerted centrifuge immeditely fter withdrwl of the blood smple. The rdioimmunossy technique hs been described elsewhere.2 The sensitivity of the ssy is 2 ng/ml nd the interssy coefficient of vrince is 7.5%. PLASMA RENIN ACTIVITY Plsm renin ctivity ws mesured using the technique of Drury nd Edwrds.3 The rnge for norml supine subjects is -3-1*5 ng/ml/h. The coefficients of vrince were 1% (intr-ssy) nd 18% (interssy). Results 161 SHORT TERM RESPONSE Hemodynmic response-tbje 1 shows hemodynmic chnges found fter the first 25 mg dose of cptopril. Systemic vsculr resistnce fell by 36% to rech men level just bove the upper limit of the norml rnge. The percentge reduction in systemic vsculr resistnce for individul subjects rnged from 13% to 64%. Plsm free cptopnil-cptopril ws bsorbed rpidly with the pek concentrtion t 45 minutes fter the dose. The rise in plsm free cptopril coincided with the fll in systemic vsculr resistnce nd ws followed closely by n increse in plsm renin ctivity. Figure 1 shows the time profiles of chnges in systemic vsculr resistnce, plsm free cptopril concentrtion, nd plsm renin ctivity in 1 ptients. The res under the four hour free cptopril bsorption curves vried from 44 to 689 mg/mi/h (men (SD) 352(237)). Pek plsm free cptopril concentrtions vried pprecibly, but there ws no significnt correltion (Fig. 2) between the mximl percentge reduction in systemic vsculr resistnce nd the pek plsm free cptopril concentrtion (r=-28) or its log concentrtion (r=.4). A smll second pek of plsm free cptopril concentrtion ws seen in 16 of the 18 ptients who hd plsm free cptopril concentrtions mesured up to four or 24 hours fter the dose. The men secondry rise ws 38*1 mg/ml from men preceding concentrtion of 56-3 mg/ml. Of the eight subjects in whom plsm free cptopril ws mesured for 24 hours, two hd slow bsorption with pek cptopril concentrtions t 9 nd 24 minutes fter the dose. The other six ptients showed rpid bsorption of cptopril (pek concentrtion <6 minutes fter the dose); smll second pek ws pprent t two hours in these subjects (Fig. 3). The elimintion rte of free cptopril, mesured from five to 24 hours fter the dose in these six subjects, ws seven hours. Tble 1 Short tmn hendyn i response to 25 mg orl cptopril m 2 pens. Vhls re men (SD) unless stted odteise Before cptpl After il 25 mg % Chnge p vle (pired p orl dose t test) Systemic vsculr resistnce (dyn s cm-5) 235 (788) 153 (693) -36. <-1 Men systemic pressure (mm Hg) 91-3 (14-2) 73-3 (14-7) <-1 Crdic output (/min) 2-8 (-58) 3-57 (-81) <1 Pulmonry end distolic pressure (mm Hg) 3-5 (7-3) 25-1 (6 8) <-1 Men right tril pressure (mm Hg) 13.2 (4-4) 11-4 (4-2) <.1 Hert rte (bets/min) 75-7 (1-4) 75-5 (12-5) --3 NS Plsm renin ctivity (ng/ml/h) 5-7 (6-23) (33-21) <-1 Br Hert J: first published s /hrt on 1 August Downloded from on 26 July 218 by guest. Protected by copyright.

3 162 Shw, Duncn, Willims, Crichton, Thomson, Dvis, Rdemker, Edwrds Minutes fter dose Fig. 1 Men plsm free cptopil concenttion (), systemic vsculr resistnce (A), nd plsm renin cntivy () msured before ndforfow howms fter 25 mig orl dose of cptopril (n = 1). LONG TERM RESPONSE Four ptients, ll of whom hd control plsm renin ctivity >1 ng/ml/h, did not tolerte cptopril tret- 7,,, 6-2! 5-4 E m 3- - c 2..o c v t ll 2 4- C > 3- C *- 2- ~ Q X 1. 'I 3 Ct c 2._2 c I- C u u ~ - * * -3. 1i Pek plsm free cptopril concentrtion (ng/ml) Fig. 2 Reltion between percentge reduction in ystmnic vsulr resistnce nd pek plsm free cptopil concentrtion in 2 ptiets uith severe chronic hertfilure.. r 3 ment, three becuse of lighthededness or syncope nd one becuse of tste disturbnce. One ptient with three vessel coronry rtery disese died suddenly fter 17 dys of cptopril tretment. A further ptient, who hd mitrl stenosis nd myocrdil impirment, showed progressive deteriortion: he died nine dys fter cptopril tretment ended. Fourteen ptients were therefore vilble for repet study. Twelve of these ptient showed symptomtic improvement with cptopril tretment (Fig. 4). Hemodynmic response-tble 2 summrises the hemodynmic nd non-invsive vribles before nd fter 1-2 months of cptopril tretment. Plsm firee cptopril-the dosge of cptopril t repet study rnged from 75 mg/dy to 45 mg/dy. The men plsm concentrtions for dily dosges of 75 (n=4), 15 (n= 7), nd 3-45 mg (n=3) were 46, 73, nd 233 ng/ml respectively. There ws significnt correltion between dosge nd free cptopril concentrtion (r= 77, p<c1). As with the short term response, no correltion existed between percentge reduction in systemic vsculr resistnce nd plsm free cptopril concentrtion (r=-9). Plsm free cptopril concentrtion nd plsm In A ta E p2 c In t XE 1 D L.o I Br Hert J: first published s /hrt on 1 August Downloded from on 26 July 218 by guest. Protected by copyright.

4 Plsm free cptopnrl concentrtions in hert filure cc io u Hours fter dose Fig. 3 Men (SEM) plsm free cptopril concetions diing 24 hows fter 25 mg orl dose of cptopril in six ptents who showed rpid bsorption (pek plsm free cptopril 6 mintes). renin ctivity were mesured throughout n eight hour dose intervl during long term tretment in six ptients. Two were receiving 25 mg three times dily nd four 5 mg three times dily Figure 5 shows the results. The predose (9 h) plsm free cptopril concentrtion ws low, nd there ws pronounced rise in drug concentrtion fter bsorption of the dose, with smll second pek t six hours. Plsm renin ctivity showed further increse fter the dose. Discussion In individul crdic ptients the hemodynmic nd symptomtic response to cptopril cn vry from miniml to very substntil. Our results, like other studies,' 4 5 show n overll moderte degree of improvement in symptoms, resting hemodynmic indices, nd non-invsive indices of crdic function, nd they confirm the wide rnge of individul responses. Since this ws n open study nd plcebo period ws not included the chnges in symptom sttus hve to be interpreted with cution. Similr benefits from cptopril in hert filure hve, however, been found in double blind controlled studies.68 Wide differences in pek plsm free cptopril concentrtion were found but did not correlte with.ft ft.,....ft.. ftft " - ft ftft.r I -1 j, mximl percentge chnge in systemic vsculr resistnce. Plsm lso contins cptopril linked to the plsm proteins, cysteine nd glutthione, nd cptopril molecules linked together s disulphide bond dimers,9 IO but these compounds re not thought to be biologiclly ctive. The lck of reltion between mximl response nd pek plsm free cptopril concentrtion fter 25 mg orl dose my be explined by the flt dose-response reltion found in incrementl dose studies when cptopril dose exceeded 6-25 mg. There ws lso no correltion between cptopril concentrtion nd long term response, nd our results do not show ny evidence tht mesurement of plsm free cptopril concentrtion would be useful in monitoring response. The erly pek concentrtions of plsm free cptopril indicte tht bsorption of cptopril occurred rpidly in the fsting ptients in this study. This coincided with rpid onset of ction. The pronounced vrition in the pek plsm free cptopril concentrtions nd in the re under the four hour curves could rise from severl fctors including impirment of the extent of bsorption due to the presence of crdic filure, degrdtion or binding of cptopril within the gstrointestinl trct, differentil metbolism, or differences in the volume of drug distribution. McKins- eo Br Hert J: first published s /hrt on 1 August Downloded from on 26 July 218 by guest. Protected by copyright.

5 164 NYHA clss IS JIM III IV Before Shw, Duncn, Willims, Crichton, Thomson, Dvis, Rdemker, Edwrds After Fig. 4 Synptom stts (NYHA clss) in the 14 ptents before nd fter lmg tmn tretm with cptopil. try et l gve orl doses of isotopiclly lbelled cptopril to norml subjects nd estimted totl bsorption to be 68% (SD 9/%), but in the first few hours fter the dose less thn hlf of the totl plsm rdioctivity ws ssocited with free cptopril nd there ws extensive conversion to the inctive forms."i Cody et l lso found tht the concentrtion of bound cptopril ws higher thn the concentrtion of free cptopril during -8 hours fter n orl dose.'2 They suggested tht the bound forms might constitute reservoir for the ctive drug. A smll second pek in the bsorption curve ws Tble 2-4 u -3 J: 2 _ 43 3_ 1 7 % Hours fter dose Fig. 5 Men plsm free cptopil conctrtions () nd plsm renin ctiviy () in six ptients sudied during dosge intervl while receiving long temn tretm with cpoptill. found in most of our ptients. This my be due to enteroheptic recircultion. This second pek ws not lrge nd ws ssocited with only smll nd sttisticlly insignificnt secondry decrese in systemic vsculr resistnce t 18 minutes fter the dose (Fig. 1). Levine et l lso observed smll secondry pek in response.13 The true elimintion rte of drug is often difficult to estblish s the bsorption nd distribution phses cn continue until the plsm drug concentrtion is too low for the sensitivity of the ssy. This second pek complictes the estimtion of the elimintion rte of plsm free cptopril, but when tken between 5 nd 24 hours fter the dose we found the log concentrtion time plot to be liner nd the elimintion hlf life to be seven hours. We found tht throughout n eight hour dose intervl during long term tretment (25-5 mg three times dily) the plsm free cptopril concentrtion ws mintined t levels which hd provided some Long tm response to cptopil tretnent in 14 pents. Vlues re men (SD) unless sttd otwise Before cptopril. After 1-2 monhs' % Chnge p vhwe (pired p trebnet t test) Systemic vsculr resistnce (dyn s cm-5) 2397 (768) 1926 (635) <-1 Men systemic pressure (mm Hg) 92-7 (14-8) 88-7 (1-8) -4 3 NS Crdic output (1/min) 2-88 (-61) 3-49 (-8) <C1 Pulmonry end distolic pressure (mm Hg) 3-1 (6-3) 24-4 (5 5) <-2 Men right tril pressure (mm Hg) 11-8 (3-3) 9-6 (3 5) NS Hert rte (bets/min) 76-6 (9-3) 72-3 (9 5) -5-6 NS Plsm renin ctivity (ng/ml/h) 2-6 (2-9) 8-3 (4 3) +219 (n=ll) <-1 Exercise durtion (min) 2-64 (3-3) 4.48 (3-26) +7 <-2 Echocrdiogrphic frctionl shortening (%) 18 (3-6) 14- (3-8) +3 <-1 Nucler ejection frction (%) 24-1 (7.) 34 (11-3) +41 (n= 1) <-5 Br Hert J: first published s /hrt on 1 August Downloded from on 26 July 218 by guest. Protected by copyright.

6 Plsm free cptopril concentrtions in hert filure hemodynmic response in the cute study. Plsm renin ctivity remined incresed but showed further increse fter the dose. This suggests tht thrice dily dosge schedule is dequte for mintining hemodynmic response but possibly not t mximl level throughout the eight hour period t this dosge. Lrger doses of cptopril re, however, ssocited with greter incidence of side effects, nd for this reson dosges of >15 mg/dy re now seldom used. References 1 Romnkiewicz JA, Brogden RN, Heel RC, Speight TM, Avery GS. Cptopril: n updte review of its phrmcologicl properties nd therpeutic efficcy in congestive hert filure. Dnigs 1983; 25: Duncn FM, Mrtin VI, Willims BC, Al-Duiili EAS, Edwrds CRW. Development nd optimistion of rdioimmnunossy for plsm cptopril. Clin Chtm Act 1983; 131: Drury PL, Edwrds CRW. Studies on the cryoctivtion of humn renin. Clin Chim Act 1981; 113: Cohn JN, Levine TB. Angiotensin-converting enzyme inhibition in congestive hert filure: the concept. Am J Crdiol 1982; 49: Drgie HJ, Bll SG, Atkinson AB, Robertson JIS. Converting enzyme inhibitors in hypertension nd hert filure. Br Hert 1983; 49: Krmer B, Mssie B, Topic N. Controlled tril of cptopril for hert filure: effects on hemodynmics, scintigrphy nd exercise tolernce [Abstrct]. Am J Crdiol 1982; 49: Cptopril Multicenter Reserch Group. A plcebo controlled tril of cptopril in refrctory chronic congestive filure. J Am Coll Crdiol 1983; 2: Clelnd JGF, Drgie HJ, Robertson JIS, Bll SG, Hodsmn GP. The use of cptopril in the mngement of crdic filure. Scott Med J 1984; 29: Wong KK, Ln SJ, Migdlof BH. In vitro biotrnsformtions of [14C]-cptopril in the blood of rts, dogs nd humns. Biochen Phcmuwol 1981; 3: Kriplni KJ, Meeker FS Jr, Den AV, McKinstry DN, Migdlof BH. Biotrnsformtion of 14C-cptopril in hypertensive ptients nd norml subjects [Abstrct]. Fed Proc 198; 39: McKinstry DN, Singhui SM, Kriplni KJ, Willrd DA, Migdlof BH. Kinetics of cptopril in helthy subjects. In: Brunner HR, Gross F, eds. Recent dvnces in hypertnsion derpy: cptzpil. Amsterdm: Excerpt Medic, 1981: Cody RJ, Covit A, Scher G, Willims G. Cptopril phrmcokinetics nd the cute hemodynmic nd hormonl response in ptients with severe chronic congestive hert filure. Am Hert J 1982; 14: Levine TB, Frncios JA, Cohn JN. Acute nd longterm response to n orl converting-enzyme inhibitor, cptopril, in congestive hert filure. Circultion 198; 62: Br Hert J: first published s /hrt on 1 August Downloded from on 26 July 218 by guest. Protected by copyright.