Influence of Nisoldipine on Haemodynamic Effects and Plasma Levels of Digoxin

Br. J. clin. Pharmac. (1986), 22, 155-159

Influence of nisoldipine on haemodynamic effects and plasma levels of digoxin

W. KIRCH, J. STENZEL, P. DYLEWICZ, H. J. HUTF, S. R. SANTOS & E. E. OHNHAUS I Medical Department, Christian-Albrechts Universitat, Kiel, FRG

1 In a placebo controlled double-blind study including 10 patients with heart failure the nisoldipine/digoxin interaction was studied. 2 Nisoldipine was shown to elevate digoxin plasma concentrations significantly by about 15% (trough levels). 3 During chronic combination therapy with nisoldipine trough levels and plasma concentrations 4 h after the morning dose of digoxin were 1.35 ± 0.14 and 1.92 ± 0.16 ng ml-' respectively, whereas they averaged to 1.16 ± 0.14 and 1.52 + 0.16 ng ml-1 with digoxin and placebo (P < 0.05; mean + s.e. mean). 4 Systolic time intervals were significantly altered by nisoldipine co-administration compared with digoxin plus placebo. 5 In certain patients the elevation of digoxin plasma levels due to nisoldipine co- administration could be of clinical relevance. Keywords nisoldipine digoxin interaction pharmacokinetics systolic time intervals

Introduction Several reports about elevated bioavailability 1980; Meredith etal., 1985; Pasanisi etal., 1985). and an altered haemodynamic effect of digoxin Therefore this calcium antagonist appears to during simultaneous ingestion of calcium channel be specifically indicated for patients with coronary blockers like nifedipine, verapamil and gallo- disease, heart failure and/or arterial hypertension pamil have been published (Belz et al., 1983; and it might be frequently given concurrently Kirch et al., 1984, 1986a; Pedersen et al., 1983). with digitalis glycosides. In the case of nifedipine the results in the litera- The aim of the present study was to clear up a ture are controversial (Kuhlmann, 1985; Schwartz possible pharmacokinetic and haemodynamic et al., 1984). Digitoxin plasma levels do not interaction between nisoldipine and digoxin. appear to be influenced by concurrent administration of a calcium antagonist like for example nitrendipine (Kirch et al., 1984). This might be Methods due to the predominant hepatic excretion route of this digitalis glycoside (Kirch et al., 1986b). The study was started with 10 patients (seven Nisoldipine is a new dihydropyridine substance, female, three male) aged from 21 to 74 years which does not exert an electro-physiological (61.3 -+- 5.1; mean + s.e. mean) with cardiac effect on sinus and AV-node but has a marked insufficiency, NYHA stage II-III. The data of peripheral vasodilating activity (Debbas et al., nine patients were included in the statistical 1984; Hess & Krayenbuhl, 1984; Kazda et al., analysis of the study, as one patient failed to Correspondence: Priv.-Doz. Dr W. Kirch, Med. Klinik, Christian-Albrechts Universitat, Schittenhelmstrasse 12, D-2300 Kiel, FRG 155 156 W. Kirch et al. complete the investigation (Table 1). He did not come to the control dates from the placebo phase onwards. The patients, who were all on previous digoxin therapy for at least 3 months, had given their written informed consent to as) participate in the study. The protocol of the E0 ._~~~~0.0r study was approved by a local hospital ethics EC.)Cu0 I 0 0 committee. Estimation of their digitalis glycoside la O plasma concentrations on three different days ._D 0 ° IA X before the study confirmed that their plasma P levels were in the steady state range.

In a placebo controlled double-blind cross- Cu) over study the patients were treated in a random- rA ~~~~~~~~~~C E S E ized order for 7 days, first with digoxin (Lanicorg, % Boehringer Mannheim, FRG) 0.25 mg twice 0 'It daily plus a tablet of placebo twice daily or digoxin 0.25 mg twice daily combined with nisoldipine 10 mg twice daily. Thereafter the cross- := ..g: . . . over to the corresponding therapy period lasting again 7 days was performed. Patients were treated 00 00 00 020 for at least 14 days prior to the study with digoxin ._. . _ ._. _ _. 0.25 mg twice daily. Plasma samples for determination of digoxin were collected during each treatment week on day 5, 6 and 7 before and 4 h after the morning dose. The plasma levels of digoxin were estimated by a commercially available radio-immunoassay e (RIA; Diagnostic Products Corporation). Sys- (A 0- tolic time intervals (STI) were determined on Ij e" tC.) m day 7 of each treatment week before the morning E 'n 44 LLO LL, 0 -t :z z C.) dose, 3 and 8 h afterwards, whereby detailed IS w u 6 u restrictions concerning food, fluid and physical lm 0 0 .) < z 0D activities were strictly adhered. STJ were deter- UU LLl 33 uuu 0 mined after an overnight fast (pre-dose and 3-h U values). Thereafter a standardized breakfast i l-e' 0%8 r^e QO cuM with caffeine-free beverages was given. Drink- 0 -"P, C.) ing of alcoholic beverages and smoking were not allowed on day 7 of each treatment period. Also e~ strenuous physical exercises were forbidden 12 h Ncq sQ "IC,t4 % s s G1000u e 0 before the pre-dose values and on the entire day C.)0 7. Preceding the 8 h value besides the breakfast .0 no other meal was taken by the patients. Systolic Uco time intervals were calculated from simultaneous recordings of ECG, phonocardiogram 0.) and carotid pulse tracing in supine position after Cu° a 15 min resting period, using 3-channel Cardirex Cu 3T recorder (Siemens). Measurements were cu en N C., -4 !.. ef) Ng S made from five consecutive heart beats & r- .o W) eq r- r- r- (Erbel t ~0 co Belz, 1977) at a paper speed of 100 mm s-, they C.) were repeated three times, and then the results 0. C_ .4' were averaged. Total electromechanical systole Po 024.) 0 (QS2) was measured from the beginning of the Cu. QRS complex in ECG to the beginning of the &I, 4.)C C.) high frequency vibrations of the second heart ,-- N en 't W) 110 r- 00 a, 2 +I sound in phonocardiogram. Left ventricular ejection time (LVET) was measured from the beginning ofthe upstroke to the dicrotic notch in the carotid pulse tracing. Pre-ejection period Nisoldipine-digoxin interaction 157

(PEP) was calculated from difference between 0.15 nq ml[' on day 7 on placebo to 1.33 ± 0.21 QS2 and LVET (PEP = QS2 - LVET). Ratio ng ml[ on day 7 under simultaneous nisoldipine PEP/LVET is also given. Heart rate was calcu- ingestion (P < 0.05). Comparing mean values of lated from 20 RR-intervals in ECG at 10 mm s-1. digoxin plasma levels from day 5, 6 and 7 under Heart rate corrections for QS2, LVETC, and placebo with those from day 5, 6 and 7 when PEPC were done using equations from Weissler nisoldipine was given concomitantly there was et al. (1968). Statistical analysis was performed also a significant difference (1.16 ± 0.14 ng ml-' with the Wilcoxon test for paired differences. on placebo vs 1.35 ± 0.14 ng ml-1 in combined treatment; P < 0.02). Also the digoxin plasma concentrations 4 h after the morning dose were Results significantly elevated by nisoldipine co-administration. Mean values ofday 5, 6 and 7 were 1.52 In Table 2 mean plasma concentrations of digoxin + 0.16 ng ml[' for digoxin plus placebo and 1.92 (mean + s.e. mean) of nine patients are shown + 0.16 ng ml[, when nisoldipine was given during placebo plus this digitalis glycoside and concurrently. under combined treatment with nisoldipine. In Table 3 mean data of systolic time intervals are Systolic time intervals presented for the treatment periods. The systolic time intervals with digoxin and Plasma concentrations ofdigoxin placebo were not significantly different from the values with combined treatment with nisoldipine Digoxin trough levels were distinctly increased 3 h after administration. However, 8 h following by nisoldipine co-administration from 0.98 + simultaneous ingestion of nisoldipine with digoxin

Table 2 Mean plasma concentrations of digoxin (ng ml-') during the placebo phase and on co-administration with nisoldipine on day 5, 6 and 7 of each treatment week (mean + s.e. mean) Plasma concentrations (ng mt') Mean value of * * Treatment Day S Day 6 Day 7 Days 5, 6, 7 Trough levels 1.24 ± 0.22 1.10 ± 0.26 0.98 ± 0.15 1.16 ± 0.14 Digoxin + placebo 4 h post-dosing 1.60 ± 0.31 1.46 ± 0.27 1.53 ± 0.30 1.52 ± 0.16 concentrations Trough levels 1.39 ± 0.20 1.24 ± 0.27 1.33 ± 0.21* 1.35 ± 0.14** Digoxin + nisoldipine 4 h post-dosing 2.04 ± 0.27* 2.07 ± 0.27* 1.64 ± 0.27 1.92 ± 0.16** concentrations *P < 0.05, *P < 0.02 compared with monotherapy, ***average of all individual data taken together for days 5, 6, and 7

Table 3 Mean parameters of the systolic time intervals (mean + s.e. mean) on day 7 before, 3 and 8 h after the last dose of placebo and digoxin as well as of digoxin and nisoldipine Time of measurement after last QS2c LVETC PEPC PEP Heart rate Treatment dose (h) (ms) (ms) (ms) LVET (beats min-') Digoxin + before 516 ± 11 382 ± 8 134 ± 14 0.362 ± 0.046 66.8 ± 5.2 placebo 3 508 ± 10 378 ± 8 131 ± 14 0.352 ± 0.045 65.8 5.0 8 497±9 358±7 139±11 0.395±0.037 68.9±4.8 Digoxin + before 505 ± 11 369 ± 7 135 ± 12 0.359 ± 0.036 70.3 ± 4.9 nisoldipine 3 502 ± 9 373 ± 7 130 ± 12 0.352 ± 0.041 69.4 ± 5.1 8 499 ± 10 369 ± 6 129 ± 11* 0.356 ± 0.036* 72.8 ± 4.7 *P < 0.05 compared with digoxin monotherapy 158 W. Kirch et al. a significant shortening of pre-ejection period Such a spectrum of the behaviour of systolic from 139 + 11 ms with placebo to 129 + 11 ms time intervals is indicative for an afterload re- with nisoldipine co-administration was found (P duction, accompanied by some increase in con- < 0.05). Also the ratio PEP/LVETC was signifi- tractility (Belz et al., 1982; Stern et al., 1984). cantly decreased from 0.395 ± 0.037 to 0.356 ± Therefore these changes seem to be mainly due 0.036 ms (P < 0.05; Table 3). to the calcium antagonist itself, accompanied by some effect of the increasing plasma digoxin Adverse effects concentration. Similar effects of nisoldipine on systolic time intervals have been described by One patient complained about slight headache Debbas et al. (1984). Other afterload-reducing and one patient about weakness, when nisoldi- factors like various diseases or concomitant pine was co-administered. With digoxin plus therapy do not appear to be responsible for the placebo another patient reported headache and alterations in systolic time intervals seen in the one patient described reddening of the face on present investigation (see Table 1). Remarkable the seventh treatment day. appears to be the fact that in our investigation 3 h after concurrent administration of the calcium antagonist and digoxin the influence of nisoldipine Discussion on systolic time intervals could not be detected, whereas it was seen 8 h afterwards. This observa- Comparable to results found for other calcium tion has to be clarified by further investigations channel blockers like verapamil, gallopamil, about the effect of nisoldipine combined with nifedipine and nitrendipine, in the present study digoxin on systolic time intervals. the new calcium antagonist nisoldipine also in- In conclusion data found in our study indicate creased significantly plasma levels of digoxin a significant interaction between nisoldipine and (Belz et al., 1983; Kirch et al., 1984, 1986a; digoxin on a pharmacokinetic basis. The changes Pedersen et al., 1983). The rise of the digoxin in systolic time intervals observed in the present plasma concentrations with concomitant therapy investigation are not necessarily related to the with calcium channel blockers has been specu- altered plasma digoxin levels, but may be simply lated to be due to a reduction of renal excretion a consequence of the addition of the calcium of digoxin caused by these drugs (Belz et al., antagonist to the therapy. No adverse effects of 1983; Pedersen et al., 1981). According to data the higher digoxin levels were seen in the present described by Belz et al. (1983) for nifedipine, study, but in some patients this effect of nisoldi- verapamil and gallopamil with digoxin treat- pine on digoxin plasma concentrations might be ment, the systolic time intervals in the present of clinical relevance. study were altered by nisoldipine co-administration, too. Eight hours following the last concurrent This work was supported by a grant from the Bayer ingestion of digoxin and nisoldipine, pre-ejec- Pharmaceutical Company, Wuppertal and the Sandoz tion period (PEP) and the ratio of PEP/LVET Stiftung fuir Therapeutische Forschung, Nurmberg, were significantly shortened compared with the FRG. digoxin/placebo values.

References Belz, G. G., Aust, P. E., Doering, W., Heinz, M. & Erbel, R. & Belz, G. G. (1977). Untersuchungen zur Schneider, B. (1982). Pharmacodynamics of a single Messmethode der systolischen Zeitintervalle. Z. dose ofquinidine duringchronic digoxin treatment- Kardiol., 66, 433-435. A randomized double blind placebo and sparteine Hess, 0. M. & Krayenbuhl, H. P. (1984). Die anti- controlled crossover study. Eur. J. clin. Pharmac., anginose Wirkung von Calcium-Antagonisten, 22, 117-122. dargestellt am Beispiel des Nisoldipin. Schweiz. Belz, G. G., Doering, E., Munkes, R. & Matthews, J. med. Wschr., 114, 1126-1131. (1983). Interaction between digoxin and calcium Kazda, S., Garthoff, B., Meyer, H., SchloSmann, K., antagonists and antiarrhythmic drugs. Clin. Stoepel, K., Torwart, R., Vater, W. & Wehinger, Pharmac. Ther., 33, 410-417. W. (1980). Pharmacology of a new calcium Debbas, N. M. G., Jackson, S. H. D. & Turner, P. antagonistic compound, isobutyl-methyl 1,4- (1984). A comparison ofthe haemodynamic effects dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyri- of nifedipine, nisoldipine and nitrendipine in man. dinedicarboxylate (Nisoldipine, Bay 5552). Arz- Br. J. clin. Pharmac., 18, 295P-296P. neim. Forsch.lDrug. Res., 30, 2144. Nisoldipine-digoxin interaction 159 Kirch, W., Hutt, H. J., Heidemann, H., Ramsch, K., Pedersen, K. E., Dorph-Pedersen, A., Hvidt, A., Janisch, H. D. & Ohnhaus, E. E. (1984). Drug Klitgaard, N. A., Kjaer, K. & Nielson-Kudski, F. interactions with nitrendipine. J. cardiovasc. (1981). Effect of nifedipine on digoxin kinetics in Pharmac., 6, S982-S985. healthy subjects. Clin. Pharmac. Ther., 32, 562- Kirch, W., Hutt, H. J., Dylewicz, P., Graf, K. J. & 565. Ohnhaus, E. E. (1986a). Dose dependence of the Pedersen, K. E., Tayssem, P., Klitgaard, N. A., nifedipine/digoxin interaction. Clin. Pharmac. Christiansen, B. D. & Nielsen-Kudski, F. (1983). Ther., 39, 35-39. Influence of verapamil on the inotropism and Kirch, W., Ohnhaus, E. E., Dylewicz, P., Pabst, J. & pharmacokinetics of digoxin. Eur. J. clin. Pharmac., Storstein, Liv (1986b). Bioavailability and elimina- 25, 199-206. tion of digitoxin in patients with hepatorenal in- Schwartz, J. B., Raizner, A. & Akers, S. (1984). The sufficiency. Am. Heart J., 111, 325-329. effect ofnifedipine on serum digoxin concentration Kuhlmann, J. (1985). Effects ofnifedipine and diltiazem in patients. Am. Heart J., 107, 669-673. on plasma levels and renal excretion ofbeta-acetyl- Stem, M. C., Matthews, J. M. & Belz, G. G. (1984). digoxin. Clin. Pharmac. Ther., 37, 150-156. Influence of dihydralazine induced afterload re- Meredith, P. A., Pasanisi, F., Elliott, H. L. & Reid, duced on systolic time intervals and echocardio- J. L. (1985). The effect of nisoldipine on apparent graphy in healthy subjects. Br. Heart J., 52, 435- liver blood flow and effective renal plasma flow. 539. Br. J. clin. Pharmac., 20, 235-237. Weissler, A. M., Harris, W. S. & Schoenfeld, C. D. Pasanisi, F., Meredith, P. A., Reid, J. L. (1985). The (1968). Systolic time intervals in heart failure in pharmacodynamics and pharmacokinetics of a new man. Circulation, 37, 149-159. calcium antagonist nisoldipine in normotensive and hypertensive subjects. Eur. J. clin. Pharmac., (Received 16 January 1986, 29, 21-24. accepted 22 March 1986)