receptor in control of renin secretion. Am J Physiol 1971; 22: 1593-97 1 Thra KW, Dahlheim H, Grnner A, Mason J, Granger e Activation of renin in the single jxtaglomerlar apparats by sodim chloride in the tblar flid at the macla densa. Circ Res 1972; 31(sppl 2): 183-86 11 Morgan 1: Gillies A. Factors controlling the release of renin: a micropnctre stdy in the cat. Pflegers Arch 1977; 368:13-21 12 Gillies A, Morgan T. Renin content ofindividal jxtaglomerlar apparatses and the effect ofdiet, changes in nephron flid rate and in vitro acidification on the renin content. Pflegers Arch 1978; 375:15-1 Pharmacokinetics and Pharmacodynamics of Clonidine in Varying states of Renal Fnction David T. Lowenthal, M.D.; MeJlon B. A!frim, Pharm. D.; Alan Meyer., M.D.; Kwan E. Kim, M.D.; Bonita Falkner, M.D.; and Krash Sharif, M.D. Previos stdies have reported a therapetic window of.8 to 2. nglml within which clonidine exerts its antihypertensive effect. This stdy was designed to investigate whether there was any loss of blood pressre control when plasma clonidine concentrations exceeded th~s window owing to its accmlationin renalinsfficiency. TheresltsiDdicate that clonidine concentrations of p to 3 nglml in patients with end-stage renal disease (ESRD) can be associated with a maintenance of blood pressre control. It remains to be learned whether this phenomenon of high concentrations and control ofblood pressre in or ESRD patient poplation may be related to altered (decreased) peripheral *From the Likoff Cardiovasclar Institte and Department of Medicine and Pediatrics, Hahnemann University and Alexian Brothers Hospital, Philadelphia, and Elizabeth, NJ. Reprint reqests: Dr. Lowenthal, 23 North Broad Street, Philadelphia 1912 a-receptor sensitivity and inability to develop vasoconstriction. There is precedence for atonomic imbalance and altered tisse sensitivity in ESRD. The pharmacokinetics and biotransformation ofclonidine have been stdied by several investigators, 1-7 and reviews have been writt~n addressing the relationships among absorption, distribtion, metabolism, elimination, and pharmacologic correlations with plasma clonidine concentration. 8 9 It has been sggested that a plasma concentration of clonidlne greater than 2 ng/ml is associated with decreased antihypertensive effect de to peripheral a-adrenoceptor stimlation. 1.4.S. 7 Based on recent stdies by Arndts et al,1.u approximately 62 percent of clonidine is eliminated nchanged by the normal kidney. Ths, patients with abnormal renal fnction wold be likely to accmlate the drg, casing elevated concentrations to levels greater than 2 nglml. It has been or observation and that ofothers who care for patients with endstage renal disease (ESRD) that with regimens ofclonidine as high as.8 mglday there is no loss ofblood pressre control. This stdy was ndertaken to assess the pharmacokinetics of clonidine in patients with ESRD on an interdialysis and intradialysis days and to correlate these plasma concentrations with antihypertensive effect. METHODS The pharmacokinetics and dialyzability of clonidine hydrochloride were stdied in six patients with ESRD. For women, 39 to 57 years ofage, weighing 48 to 86 kg, and two men, 55 and 57 years old, weighing 67 and 74 kg, received clonidine,.2 mg orally for times a day. All patients were on this regimen for at least one month prior to stdy. All the patients were taking ferros slfate, mltivitamins, alminm hydroxide gel orcapsles, and folic acid, and two ofthe patients required concomitant hydralazine administration to maintain blood pressre control. On a dialysis day, the patients took their sal morning clonidine dose two hors prior to dialysis. Arterial and venos plasma samples 1.21.8 r1ean :!: SD.6.Lt Lf 6 lui: (HOURS) 8 1121 1:2 FIGURE 1. Clonidine concentration (ng/ml) v time in six normal volnteers receiving.2 mg daily x 1 week. 388. Central AIpha-Adrenoceptr8
1121 MEAN ± SE 7 6 m 2 3 ~ S 6 7 8 TIME (HOURS) were drawn prior to and at horly intervals dring dialysis. Simltaneos blood pressre and heart rates were monitored during the procedre. On the interdialysis day, blood was drawn for clonidine concentration assay prior to dosing and at appropriate times for 12 hors. Following drg administration, blood pressre and heart rate were monitored simltaneosly. Plasma clonidine concentration was determined according to a radioimmnoassay (RIA) techniqe described by Arndts et al in 1981. 11 This assay acconts for clonidine alone. There is no interference with any metabolite. Blood was sampled from 16 hypertensive adolescents and 21 adlts at varios ages and on varios steady-state clonidine dosage regimens to compare concentrations ofclonidine with renal fnction. RESULTS There was no demonstrable impairment to the gastric riouu: 3. Repre.entatfve elimination crve and olontdine extraction drinl dialy.i.. Not. blood pr r. and olontdme concentration. --. i... ca c: c.i c: o Ii j,,,!, I ; Figre 2. Elimination crve of mean 9 1121 1 1 12 clonidine concentration,,8 mg daily, in for ~ents with ESRD. absorption ofclonidine. According to the specific RIA, only clonidine was qantified, and, therefore, no metabolite interference cold explain the elevated clonidine concentrations. However, pharmacodynamiceffects cold be attribtable to a retained, somewhat active metabolite(s}. Figre 1 presents the mean plasma clonidine concentrations in six normal volnteers receiving.2 mg clonidine daily for one week. The mean clonidine concentrations in for ESRD patients on the interdialysis day is depicted in Figre 2. At no time did the plasma concentrations in any of the patients fall below 6 ng/ml. Peak concentration was achieved by one hor and reached a platea by two hors. There appeared to be a slight increase at for to six hors, followed by a gradal decline in concentration. Using the slope of the p-phaseof the elimination crve, the half-life is Arterial oveno8 C. T. --. Interdlalysls.s, i i ~ I in I: @! N i : : '"atig c.i t. 8 t. I t4 31 Ita It.2 U 2/H/. i ~ i i 3 4., I' I"~ 1 tao I I to tl.' t.' Tim. (houri) Tim. (hra) Dring DI.1y111 OHIIT I I I I IItbrIry.,. I IppIImInt 117
ARTERIAL (X) A:m VENOUS () PLASM ClONlDINE CONCENTRATION DURI!4G DiAlYSIS 2S O C. T. ~ 2m -!5 ~- IS IIZI 2S J.S. M- 21Z1 w~ s~ ~- IS IIZI -EXTRACTION RATIO PRE 2 3 TUF CHnlHa) FICURE 4. Meanarterialandvenos plasmaconcentrations of clonidine dring dialysis and extraction ratios in for patients. PlASM CLO!UDINE CONCENTRATION IN 2 ESRD PATIENTS <INTERDIALYSIS DAY) VS. TU 32 X-C. T. QaJ.S. PRE 3 s: 6 7 8 TItI: (HOURS> 9 liz! II 12 FIGURE 5. Interdialysis plasma clonidine time in two patients with very high clonidine concentrations. 388
Lf PEM ARTERI Al <X) AND VENOUS () PlA91A ClMIDI~ C(lI(ENTRATI~ 1ft,. ESRD PATIENTS <DURING DIALYSIS) AND EXTRACT! on RATJ VS. TH1E.3.2. I a s FIGURE 6. Dialysance of clonidine in the two patients with very high concentration. PRE 2 3 lu (HOURS) calclated tobe somewhere arond 4 hors. Blood pressre control was maintained in all patients throghot the corse of the stdy day. Figre 3 is a representative depiction of the relationship between the '11igh" plasma clonidine concentrations and blood pressre control. Note that at each pointofthe plasmatime crve, the concentration ofclonidine is tenfold that of the 2 nglml "danger zone" and that blood pressre, determined simltaneosly with each sampling ofblood, is within therapetically normal range. The observations in this patient are apparent on the interdialysis and intradialysis days and are tre for the 6ve other ESRD patients. The mean arterial and venos plasma clonidine concentrations in for ofthe six patients stdied during dialysis as well as diagramatic depiction of concuitent extraction ratio prodced by the hollow 6ber dialyzer are seen in Figre 4. Dialysis decreases the clonidine concentration from abot 8 to 5 ng/ml. The extraction ratio is between.2 and.3 throghot dialysis. 1\vo of the six patients had greatly elevated plasma clonidine concentrations. The interdialysis day plasma clonidine vs time crves are depicted in Figre 5. There was no detectable elimination pattern in either of the patients reslts. Of significant interest was an apparent frther increase in concentration with time, sggesting recirclation ofdrg either throgh an enterohepatic rote or from tisse sorces. Venos plasma concentrations for these two individals predialysis were 2 and 23 ng/ml, respectively, and only fell to 15 ng/ml by the end ofthe dialysis procedre in both cases. Theextractionratios indicatethatdialysanceis negligible in these patients as well (Fig 6). Blood pressre control was adeqately maintained in these two patients. There was no indication ofintolerance to the antihypertensive effects of clonidine even at these high plasma concentrations. Becase the adolescentand geriabichypertensive poplations represent twogrops who may have compromised renal fnction leading to clonidine accmlation, steady-state plasma clonidine concentrations were determined in these grops following dose titration to the maximm antihypertensive effect. The reslts are as follows: in children from 11 to 18 years of age, reqiring.2 mglday, steady-state plasma concentrations were.38±.17 ng/ml. In these adolescents CHEST I 83 I 2 I Febrary, 1983 I Spplement 381
Table I-PltmtJ Clonidine ConcenIrGlionl and DtJilrI DottJga in ftjtimti tditla ESBD Dose (mg/day) so.2.2-.8.9 DBP 12 mm Hg; ESRD tdbp 116 mm Hg; creatinine 2. mgldl All others have ESRD and DPB <9 mm Hg Clonidine Cone (nglml).5 2.1 3.* 3.1 2.8t 4. 6.1 7.2 7.5 9. who reqired.4 mglday, the plasma concentration was 1.22 nglml. Those adolescents with poor blood pressre control were also fond to be noncompliant to drg therapy with plasma clonidine concentrations less than.1 nglml. In yong normotensive adlts serving as controls receiving.2 mglday for 12 days, a mean plasma clonidine concentration of.57 nglml was achieved. In adlts over 4 years ofage with normal renal fnction, steady-state plasma concentration ranged from.1 to 3.4 nglml (.2 to.8 mgclonidine per day) with satisfactory blood pressre control. These data contrast with the higher plasma concentrations seen in the dialysis patients, regardless of age. Eight patients with ESRD whose clonidine dosage rangedfrom.2 to.9mglday had plasma clonidine concentrations ranging from.5 to 9.nglml. These patients maintained a diastolic pressre less than 9 mm Hg. However, two patients, one with a serm creatinine of 2 mgldl, had a clonidine concentration of 2.8 nglml and a diastolic pressre of 116 mm Hg (1able 1), and another patient with ESRD had a clonidine vale of 3. nglml, with a diastolic pressre of 12 mm Hg. These patients reqired the addition ex hydralazine for normalization ofpressre. DISCUSSIONS AND CONCLUSIONS We can conclde from this stdy that clonidine is not appreciably dialyzable. Owing to accmlation in ESRD dosage alteration may be necessary, especla1j.y if blood pressre control is lost (increases) or prodces hypotension. Drowsiness and dry moth were no more apparent in those patients with very high plasmaclonidine concentrations than those with lower clonidine concentratiodl. Howeveli based on these data, blood pressre control cold still be maintained at concentrations p to 3 nwml ofclonidine. It remains to be learnedwhetherthis phenomenonofhigh concentrations and controlled blood pressre in or ESRD patient poplation may be related to altered (decree) peripheral (I-receptor sensitivity and the inability to develop voconstr1ction. There is precedent fbr atonomic imbalance and altered tisse sensitivity in ESRD.II-W 11Ua may inclde a decree in relponle at Cll and CIt looi. According to recent data,15 dose-dependent kinetics associated with an increase in plasma clearance and a fall in bioavailability cold explain the pharmacodynamic changes with clonidine known to be associated with increased doses. However, althogh we did not se IV administration of the drg and did not calclate plasma clearance, the high plasma concentrations and adeqate pharmacodynamic effect mitigate against any decrease in bioavailability or adverse effects from dose-dependent kinetics. Finally, according to the improved specific RIA method, we have rled ot the possibility that an inactive (or active) metabolite of clonidine contribted to the elevated plasma concentrations in the ESRD grop bt have not eliminated the remote likelihood of the pharmacodynamic effect of a retained metabolite. REFERENCES 1 Davies DS, Wmg LMH, Reid JL, Neill E, TIppett ~ Dollery CI: Pharmacokinetics and concentration-eft"eet relationships ex intravenos and oral elonidine. Clin Pharmacol Ther 1977; 21:593 2 DolleryCI: Davies DS, Draffim GR, Dargie HI, Dean CR, Reid JL, et ale Clinical pharmacology and pharmacokinetics of elonidine. Clin Pharmacol Ther 1976; 19:11 3 Rehbinder D, Deckers W. Investigations into the pharmacokinetics and the metabolism of ST 155. Arzneimittelforsch 1969; 19:169 4 Frisk-Holmberg M, Edlnd PO, Paalzow L. Pharmacokinetics of clonidine and its relation to the hypotensive effect in patients. Br J Clin Pharmacol 1978; 6:227 5 Wing LMH, Reid JL, Davies DS, Neill EAM, TIppett ~ Dollery cr Pharmacokinetic and concentration-effect relationships of elonidine in essential hypertension. Er J Coo Pharmacoll977; 12:463 6 Kerinen A, Nykinen S, 18skfnen J. Pharmacokinetics and side effects of clonidine Er J Clin Pharmacol 1978; 13:97 7 Frisk-Holmberg ~l, Paalzow L. Relationship between clonidine kinetics and its blood pressre effects. Acta Med Scand 1979; 25(sppl625):68 8 Lowenthal D1: Pharmacokinetics of clonidine. J Cardiovasc Pharm 198; 2(s'ppll):29 9 Schmitt H. The pharmacologyofclonidine and related prodcts. In: Handbook ex experimental pharmacology, vol 39. Heffte)\ Hebner New Series. Berlin, Heidelberg, New York: Springe)\ Verlag, 1977, ch 7 1 Amdts D, Doevendans J, ICirsten R, Heintz B. New aspects of the pharmacokinetics and pharmacodynamics of clonidine in man (in pre) 11 Amdts D, Stlhle H, F6nter HJ. 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