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Pharmacokinetics and pharmacodynamics of intravenous digoxin and digitoxin

Pharmakodynamische und pharmakokinetische Untersuchungen nach i.v. Gabe von Digoxin und Digitoxin

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Summary

Healthy volunteers received single 1.0-mg doses of intravenous digoxin (n=10) or digitoxin (n=12). Glycoside pharmacokinetics were determined from multiple plasma samples drawn over the 48 hours (for digoxin) or 14 days (for digitoxin) after the dose. Electrocardiogram, echocardiogram, and blood pressure were recorded at multiple time points 24 h after the dose. To control for nonspecific cardiovascular changes, pharmacodynamic measurements were repeated on a second occasion for 8 hours after an intravenous injection of saline. Mean (±S.E.) kinetic variables for digoxin were: volume of distribution (Vd), 8.3 (±0.6) l/kg; elimination half-life (t1/2), 49 (±5) h; clearance 2.1 (±0.2) ml/min/kg. Changes in blood pressure, ventricular rate, and corrected QT-interval attributable to digoxin were small. However, echocardiographically-determined mean rate of circumferential fibre shortening (mVcf) and ejection fraction (EF) increased significantly following digoxin when compared to saline infusion. Changes were maximal at 4–6 h after dosage, and were highly correlated with plasma digoxin concentration. mVcf and EF returned to baseline by 24 h post-dosage. Mean kinetic variables for digitoxin were: Vd, 0.63 (±0.03) l/kg; t1/2, 7.3 (±0.4) days; clearance, 0.043 (±0.003) ml/min/kg. Like digoxin, digitoxin infusion produced minimal change in blood pressure, ventricular rate, or QT-interval. However, mVcf and EF increased significantly when compared to saline control. Changes were maximal at 4–8 h after infusion, and were correlated with plasma digitoxin concentration; at 24 h post-dosage, mVcf and EF were still increased over baseline. Thus, digoxin and digitoxin significantly increase myocardial contractility in healthy humans, but without important change in heart rate and blood pressure. Changes in contractility are of slow onset, probably due to slow distribution of glycoside to sites of pharmacologic activity.

Zusammenfassung

Gesunde Versuchspersonen erhielten eine einmalige Gabe von 1,0 mg Digoxin (n=10) oder Digitoxin (n=12). Die Kinetik der Glykoside wurde anhand der Plasma-Konzentrationszeitkurve über 48 h (Digoxin) oder 14 Tage (Digitoxin) analysiert. Während der ersten 24 h nach der Glykosidapplikation erfolgten in häufigen Zeitabständen die Registrierung von EKG, Echokardiogramm und Blutdruck. Um unspezifische kardiovaskuläre Änderungen auszuschließen, wurden die pharmakodynamischen Parameter nach Kochsalzinjektion erneut bestimmt. Die kinetischen Variablen (±SE) für Digoxin lauteten: Verteilungsvolumen (Vd) 8,3±0,6 l/kg Körpergewicht, Eliminationshalbwertzeit (Elt 1/2) 49±5 h, Clearance 2,1±0,2 ml/min/kg Körpergewicht. Die Digoxingabe führte nur zu geringen Änderungen von Blutdruck, Herzfrequenz und korrigiertem QT-Intervall. Dagegen nahm die echokardiographisch bestimmte zirkumferentielle Faserverkürzungsgeschwindigkeit und Ejektionsfraktion nach Digoxin im Vergleich zu Placebo signifikant zu. Das Maximum der Inotropie-Änderung wurde 4–6 h nach Digoxin-Applikation registriert. Die Änderungen von mVcf und EF korrelierten signifikant mit den Plasma-Digoxinkonzentrationen. 24 h nach Digoxin-Injektion waren die Ausgangswerte von mVcf und EF wieder erreicht. Die kinetischen Variablen für Digitoxin lauteten: Vd 0,63±0,03 l/kg; Elt 1/2 7,3±0,4 Tage; Clearance 0,043±0,003 ml/min/kg. Wie die Gabe von Digoxin führte die Digitoxininfusion nur zu geringfügigen Änderungen von Blutdruck, Herzfrequenz und QT-Intervall. Dagegen nahmen mVcf und EF im Vergleich zur Kochsalzinfusion signifikant zu. Die maximalen Änderungen wurden 4–8 h nach der Digitoxin-Infusion gemessen und korrelierten mit den Plasma-Digitoxinkonzentrationen. Somit steigern Digoxin und Digitoxin die myokardiale Kontraktilität gesunder Versuchspersonen im Vergleich zu einer Placebo-Gabe, jedoch ohne Herzfrequenz und Blutdruck zu beeinflussen. Das Maximum der Kontraktilitätsänderung ist erst nach ca. 4 h erreicht und hängt wahrscheinlich mit der langsamen Verteilung der Glykoside zusammen.

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Supported in part by Grant Oc 10/4 from Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, FRG; and by Grant MH-12279 from the United States Public Health Service

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Ochs, H.R., Grube, E., Greenblatt, D.J. et al. Pharmacokinetics and pharmacodynamics of intravenous digoxin and digitoxin. Klin Wochenschr 59, 889–897 (1981). https://doi.org/10.1007/BF01721922

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