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European Journal of
Clinical Pharmacology
Europ. J. elm. Pharmacol. 13, 103-111 (1978)
© by Springer-Verlag 1978
Dose- Response Relationships and Plasma Concentrations
of Digitalis Glycosides in Man
G. G. Belzl, R. ErbeF, K. Schumannz, and H. J. Gilfrich3
1
3
Institut flir Kardiovaskuliire Therapie, Wiesbaden, 2 Medizinische Abtei1ung, Bundeswehrzentralkrankenhaus, Koblenz, and
Medizinische Klinik und Poliklinik der Universitiit Mainz, Federal Republic of Germany
Summary. An inter-individual, randomized, doubleblind study of digitoxin (Dt) and {3-acetyldigoxin (D)
was performed in 120 healthy male volunteers.
Groups of 10 persons each received orally D 0, 0.1,
0.2,0.3,0.4, 0.5 or 0.6 mg and Dt 0.04, 0.08, 0.12,
or 0.16 mg daily for 7 days; Loading doses were
given for the first three days. Plasma levels were
measured with an 86Rb-erythrocyte assay 24 h after
the last dose. ECG, carotid artery pulse and
phonocardiogram were recorded prior to (b) and
24 h after (a) the last dose. QTc, amplitude of Twaves in V2 to V6, electromechanical systole (QSzc)
and left ventricular ejection time (LVETc) were
measured. The differences between a and b (L1-values) reflect glycoside-induced changes in heart function. The plasma glycoside concentrations depended
on dose and ranged from 0 to 2.4 ng/ml for D and
from 0 to 42 ng/ml for Dt. QTc, QSzc, and LVETc
were significantly shortened by the glycosides and
typical parallel, sigmoid, log dose-response curves
were obtained for the L1-values.Dt was 3.8-times as
potent as D in diminishing these parameters. The
maximal effect of the two glycosides was almost identical at the highest doses: L1-QTc= -45 ms, L1-QSzc
= -25 ms, L1-LVETc = -12.5 ms. The latter two
parameters showed a plateau of maximum efficacy.
Both glycosides caused significant flattening of Twaves, Dt being 7.2-times as potent as D. Significant
relationships between plasma concentration and cardiac effects were observed (p < 0.001) - L1-QTc(D:
r=0.7; Dt: r=O.77), L1-QSzc (D: r=0.7; Dt:
r=0.75), and L1-LVETc (D: r=0.46; Dt: r=0.43);
D correlated less well than Dt with the flattening of T
(r=0.46; r=0.76, respectively). The most important
conclusions were that: Dt was about 4-times as
potent as D in influencing cardiac performance; the
effects of D and Dt on systolic time intervals reached
a plateau at "therapeutic" doses; Dt induced more
pronounced flattening of the T-wave than D; and
plasma glycoside levels within the "therapeutic"
range corresponded to observed effects on the heart.
Key words: Digitoxin, (3-acetyldigoxin,plasma levels,
cardiac performance, dose-effect relationship, 86Rb-erythrocyte assay, systolic time intervals.
Determination of digitalis plasma level is a commonly used method of monitoring glycoside therapy.
For the diagnosis of glycoside intoxication, the value
of this method appears well established [17]. However, there are few data about the relationship between therapeutic plasma levels of digitalis and glycoside effects. The first attempts to correlate glycoside concentration and therapeutic effect were
made from the reduction in heart rate during atrial
fibrillation [23]. Studies correlating plasma concentration with cardiac effects using systolic time intervals (STI) have given conflicting results [8, 16, 26].
There is a further problem about the doseresponse relationship of digitalis glycosides. In contrast to many other drugs, the dose-response relationships of digitalis glycosides in man have only
been established for single doses in a relatively narrow dose range [1, 20, 28]. Ideally, however, doseresponse curves should be based on the effects
attained under equilibrium conditions and should
cover the range of therapeutic doses [10].
In order to elucidate these problems of the clinical pharmacology of digitalis glycosides, it was the
aim of the present study (a) to correlate plasma levels
of digitoxin (Dt) and the {3-acetylderivative of digoxin (D) with their cardiac effects, and (b) to establish
the dose-response relationships of these glycosides
0031-6970/78/0013/0103/$01.80
104
G, G, Belz et al.: Dose-Response Relationships of Digitalis Glycosides
for their effects on cardiac performance following
chronic administration.
Recordings and Measurements
Met h0 dS
V.o Iun teers
The study was carried out in 120 healthy male volunteers, aged 19 to 35 years (average 26 years), weighing 55 to 102 kg (average 76 kg). Persons with a
weight exceding ± 10 per cent of BROCA's index
[15] were excluded from the study. Written,
informed consent was obtained from each volunteer.
Values of cardiac variables were determined prior
to and following a 7-day period of drug administra tion, the measurements always being made at the
same time of day.
D rug Ad"mlnlS trat'zon Peno. d
Every participant received D or Dt daily for 7 days.
The treatments were performed as an inter-individual, controlled randomized double-blind study.
Ea~h volunteer took part in only one treatment
penod.
Groups of 10 volunteers each received the following daily maintenance doses of D: placebo, 0.1,
0.2,0.3,0.4,0.5 or 0.6 mg; and the daily doses of Dt
were: placebo, 0.04, 0.08, 0.12 or 0.16 mg.
The following loading scheme was used:
Day 1 2 3 4 .....
7
D
Dt
36-
under standardized conditions [18]. Daily ingestion
of the tablets was supervised.
26-
13-
11-
1- multiple of
1- maintenance dose
Thus. for D , there was
. a 2-day, and for Dt a 3-day
loadmg penod. Dunng days 1 to 3 the doses were
divided into equal parts and were given at 8 a. m. and
6 p. m. From days 4 to 6 the doses were administered
at 8 a. m., and the last dose on day 7 was given
exactly 24 h before the various records were made.
The digoxin preparation used was a ,B-acetyl
derivative (0.1 mg tablets - Novodigal mite®). It is
completely desacetylated after absorption [24] and
shows a high absolute biovailability of ~ 80 per cent
compared to an intravenous standard [11]: Tablets of
Dt 0.12 mg (for the loading period) and 0.04 mg
were used. D, Dt and placebo tablets were kindly
provided by Dr. N. Heinz, Beiersdorf AG, Hamburg,
Western-Germany. The various tablets had identical
galenical composition and showed the same rapid
dissolution rate - > 90% solution within 1 min
All measurements were done blind. Recordings of
STI (QS2 and LVET) and ECG (RR, PQ and QT.
Is) were made un d er stea dy state cond'ltlons
.
mterva
(24 C; between 6:30 and 8:30 a. m.; in the fasting
state).
Following the method of Blumberger [6], STI was
obtained from simultaneous high speed recordings
(100 mm/s) of ECG lead A [22], a carotid pulse trace
[7] and a phonocardiogram (> 140Hz). Twenty consecutive heart cycles were averaged to obtain STI.
Variables measured were: QS2 (electromechanical
systole), LVET (left ventricular ejection time), RRI
(R-R interval) from which the heart rate (HR) was
calculated, PQ-duration and QT. The amplitude of
the T-wave was measured in 5 consecutive beats in
leads V2 to V6of the standard ECG and averaged as
follows:
0
TV2- V6=
"'""'
L
N = 5
TV2+
"'""'
L
n
TV3...
"'""'
+L
= 5
n
T v61 25
= 5
QTc was calculated according to Bazett [3]. Correction of STI was done according to Weissler et al. [29].
The difference between predicted and calculated STI
was defined as QS2Cand LVETc. The effects of treatment were defined as ~-values, i. e. the difference
between the value before and after treatment.
Immediately following the second measurement
(a) of STI and ECG, plasma concentrations of glycoside were measured using a modified 86Rb-erythrocyte assay [4, 5, 19].
CaIcu Iat'zons an d St at'lSt'lcaI A na IYSlS
'
As a first step the groups of volunteers were tested
for homogeneity using the absolute values of QTc
and TV2-6'Prior to treatment, the groups were found
to be equal at the 5% level, but after treatment they
were inhomogeneous.
As a prerequisite for analysis of variance, the variance within the different groups was shown to be
equal by means of Bartlett's test [27] performed on
all absolute and ~-values.
The analysis of variance was performed both on
absolute and ~-values. Differences were considered
to be significant when p < 5%. Several tests, espedally when ~-values were used, exhibited a significance of less then 0.1%. After performance of the
analysis of variance, the means of the groups (with
G. G. Belz et al.: Dose-Response Relationships of Digitalis Glycosides
exception of HR and PQ) were compared with each
other using Duncan's test [27] at a 5% level of significance. When various data were correlated with
plasma concentrations, the slope of the regression
line was shown to differ significantly from zero. For
descriptive purposes the mean and standard error of
the mean (SEM) have been used. Logarithmic doseresponse curves of the mean effects were analysed for
half-maximal effect using graphic logit regression.
R esuIts
The measurements of STI, ECG and plasma glycoside concentrations are shown in Table 1.
'd PIasma Concen t rat'iOns
GlYCOSIe
With D 0.1 mg the average plasma level was 0.37 ng/
ml, and with D 0.6 mg it was 1.25 ng/ml. The
administration of Dt 0.04 mg daily led to a mean
lasma level of 9.3 ng/ml, and 0.16 mg to one of
~3 5 ng/ml
..
Correlation between Plasma Glycoside Concentration
and Cardiac Effects
Correlation coefficients and equations are shown in
Table 2 and the interdependence of plasma levels
and ~ QTc and ~ QS2C are illustrated in Figs. 1 and
2. There was significant shortening of the parameters
with increasing plasma concentration of each glycoside. In Figure 3 the correlation between plasma
level and ~ T is shown. In principle there seemed to
be no difference between the two glycosides, as T
flattened with increasing plasma concentration.
However, whereas for Dt the degree of correlation
was the same as for STI and QTc, the correlation for
D was much poorer than those for changes in cardiac
performance. The absolute slopes of the correlations
of the two glycosides could not be compared since the
plasma concentrations had different ranges, although
a relative comparison was possible. For this purpose
~ QS2Cwas assumed to be the most suitable variable
to represent the glycoside effect on cardiac performance. For D and Dt, respectively, the slopes of the
rrelat' ons between plasma levels and ~ QS c were
co
I
set to 1.0
as the reference slopes. The relative2·slopes
for the other parameters were calculated by dividing
their absolute slopes by the absolute slope of ~ QS2C.
For D the following slopes were obtained: ~ LVETc
= 0.7, ~ QTc = 1.7,
~ TV2-6= 6.0 X 10-3;and for
..
_
Dt the correspondmg values were. ~ LVETc - 0.6,
QT
=
13
-T
=
113
10-3
Th
. 0f
Ll
c
., Ll V2-6
. X
.
e ratIOs
the relative slope D/Dt were: ~ QS2C ~ 1.0,
~ LVETc = 1.2, ~ QTc = 1.3, and ~ TY2-6= 0.5.
A
A
105
Dose Effect-Relationships
Systolic Time Intervals. The shortening of QS2C by
the two glycosides was parallel (Fig. 4). The highest
doses of the glycosides shortened this parameter by
an average of ~ 25 ms. From the digitoxin curve it
could be inferred that maximum efficacy had almost
been reached. The values for half maximum effect
(100% = maximum Dt-effect) were 0.2 mg daily for
D and 0.052 mg daily for Dt. Thus, Dt was 3.8-times
as potent as. D in shortening QS2C.
Shortemng of LVETc revealed a plateau of maximum efficacy (-12.5 ms) for both glycosides. The
half maximum effect occurred at 0.22 mg daily for D
and 0.06 mg daily for Dt, i. e. Dt was 3.8-times as
potent as D in shortening LVETc.
Electrocardiographic Parameters
.
Compared to the placebo, both glycosldes showed
only.minor and insignificant effects on heart rate and
PQ-mterval (d. Table 1). The dose dependent shortening of QTc is shown in Figure 5. Parallelism of the
curves for D and Dt is apparent. The highest doses of
the two glycosides induced almost identical shortening of QTc. A shortening of 24 ms (i. e. 50 per cent of
m~ximum effect of D) was produced by D 0.3 m.g
dally and by Dt 0.077 mg dally. ~rom these values It
~as calcul~ted ~at Dt was 3.9-tImes as potent as D
m shortemng Q c'
..
Dt .caused a ~tatistIcally significant. d~se-related
flattemng of T (F~g.5). The curve wa.ssimIlar to that
of QTc. The ~axlmum effect at the highest dose of D
was only 65 Yo of the great~st Dt effect. The dose
necessary. to cause flattemng of t~e T-wave by
0.17 mV (I. e. 50 pe.r cent of the maxlmum.effect of
?t) was 0.51 m~ dally of D and O.O~ mg daIl~ of Dt,
I.~. Dt was 7.2-tImes as potent as D m flattemng T at
thiS degree of effect.
Discussion
..
The present stu.dy mv?lved co~panson of plasm~levels of glycosldes ~Ith ~ertam pharmacodynamic
par~meters. For nomnvaslve measurement of glycoslde effect STI were used. They reflected drug
.
mduce d. chang~ m
car d'laCper f orma?ce. C'ertam e Iectroc~rdlOgraphlc parameters (ampht~de. of T-wave,
~Q-mterval and ~Tc) ~ere added ~omdlcate change
m the electrophyslOloglcal properties of the heart.
C
I t'
b t
PI
Gl
"d
orre a iOns e ween asma YCOSIe
C
t t"
de
d' E'ff
oncen ra iOn an
ar laC JJects
In the present inter-individual study on D and Dt,
relatively high correlations were found between
Table 1. Measurements before (b) and after (a) treatment with digitalis. Each group shows data from 10 volunteers; the entire series
contains 120 males. On the left the various doses of the glycosides are shown. HR = heart rate; PQ = PQ-interval; TV2-6 = mean
amplitude of the T-waves in the standard ECG leads V2 to V6; QTc = QT - interval corrected for heart rate (according to Bazett (3));
QS2 = electromechanical systole; LVET = left ventricular ejection time; plasma glycoside concentrations were measured using an 86Rb_
erythrocyte assay
No.
HR
PQ
(min-1) (ms)
1b
a
2b
a
3b
a
4b
0
a
.0
Q)
••
'"
5b
a
M
P-
...•"
><
0
""
'.-j
6b
a
7b
a
Q
I
...,
,.,
8b
M
«"
I
c<l
a
9b
a
10b
a
1b
a
2b
a
bO
E
N
0
...•"
><
0
bD
....
Q
I
...,
3b
a
4b
a
5b
a
6b
a
,.,
7b
«"
8b
M
I
c<l
a
a
9b
a
10b
a
1b
a
2b
a
3b
a
4b
a
5b
E
""
..or
a
6b
0 a
...• 7b
0>< a
...•bO 8b
Q
"
I
a
...,
a
c<l
a
~ 9b
"
i'10b
TV2_6
QTc
QS2
LVET
(mV)
(ms)
(ms)
308.2
294.3
291.6
305.0
279.5
247.0
297.0
300.8
316.0
319.6
349.9
360.7
298.5
293.0
301.6
287.5
310.1
314.6
319.6
330.5
59.5
67.5
62.7
53.2
82.5
102.3
60.4
64.5
53.8
61.2
48.8
46.2
58.0
63.0
67.,
71.0
60.2
58.0
58.7
45.9
150.5
155.7
196.1
171.5
150.6
144.8
163.1
156.4
171.4
164.2
148.3
150.6
152.3
145.0
165.7
152.6
156.7
157.2
143.5
160.6
0.354
0.256
1.132
1.091
0.806
0.727
0.862
0.736
0.817
0.629
0.647
0.714
1.184
1.147
0.286
0.373
0.478
0.493
0.929
1.052
401.2
410.1
385.5
359.7
417.7
419.6
402.9
397.1
406.6
418.8
443.5
428.2
393.4
426.8
429.5
422.2
382.7
376.1
425.2
415.6
408.5
402.3
404.2
419.0
363.7
318.7
416.3
408.1
446.7
447.8
478.2
497.4
409.0
405.2
398.3
386.5
431.9
436.5
420.2
446.2
73.5
67.6
68.4
62.3
54.7
61.9
61.6
69.4
68·5
67.5
71.1
69.2
78.6
69.0
63.5
65.3
64.8
63.6
55.6
52.9
125.4
126.7
136.9
140.2
192.2
196.3
189.5
198.7
179.6
191.6
150.2
150.1
435.3
423.2
422.2
427.6
422.2
416.4
405.7
422.7
393.2
384.5
431.9
407.4
386.1
386.7
407.0
406.6
442.4
413.7
453.2
424.1
400.1
395.3
430.4
422.1
178.7
194.2
144.2
145.3
151.9
153.8
161.6
155.8
0.770
0.521
0.902
0.745
0.629
0.500
0.478
0.381
1.285
0.983
0.467
0.285
0.616
0.367
0.767
0.666
0.730
0.570
0.518
0.477
65.3
59.2
63.1
50.1
60.4
45.9
68.4
55.7
58.3
53.0
53.7
54.7
52.4
54.9
87.8
87.4
70.0
68.0
86.3
72.8
94.0
94.2
160.7
164.7
172.8
177.1
164.9
177.0
173.2
199·7
128.7
131.1
105.2
111 .7
162.4
149.6
180.0
187.2
203.0
199.8
0.761
0.598
0.692
0.604
0.555
0.308
0.672
0.537
0.753
0.682
0.880
0.556
0.854
0.688
0.488
0.330
0.398
0.296
0.638
0.619
No.
Plasma
Glycoside
(ms) (ng/ml)
1b
a
2b
a
a
3b
a
a
4b
a
a
E
""
~
o
0.18
a
...•"
0><
...•""
a
5b
a
6b
a
7b
a
Q
I
a
....,.,
8b
M
«"
I
c<l
a
9b
a
10b
0.25
a
1b
430.6
406.9
402.0
378.7
430.0
408.2
375.7
370.4
285.6
294.5 0.43
288.2
306.9 0.57
332.7
318.7 0.24
310.3
300.8 0·58
295.9
291.6 0.75
308.8
308.0 0.75
410.6 296.6
411.4 305.3 0.50
426.9 313.3
406.3 301.9 0.40
447.5 318.2
445.8 321.6 0.37
428.3 323.7
428.6 318.3 0.44
407.7
374.3
427.3
377.5
428.5
368.4
415.9
387.9
422.5
406.8
419.4
399.4
374.7
348.0
414.6
387.4
395.6
369.2
428.9
394.0
397.3
390.2
436.4
438.8
436.0
431.3
402.7
413.2
429.2
430.1
435.9
416.9
424.9
405.6
373.4
355.7
413.1
398.7
399.8
416.4
297.6
296.6
330.4
328.9
306.4
311.2
298.8
306.8
304.3
315.3
336.9
326.1
323.0
309.7
266.4
255.9
291.2
282.5
298.1
297.4
a
2b
a
E
""
3b
a
'".;
4b
...•"
><
5b
Q
6b
0
...•""
I
a
a
a
M
to
«"
Q)
I
c<l
7b
a
8b
a
9b
a
10b
a
1b
0.95
a
2b
0.72
a
3b
1.04
a
4b
1.19
0.80
1.10
1.13
0.94
1.09
0.55
PQ
(min-1) (ms)
a
a
HR
a
E
""
U;
5b
a
0 6b
a
...•"
7b
><
0 a
...•bD
Q
8b
I
..,.,..
a
M
9b
c<l
a
a
" 10b
i'
;;;
·v2-6
:t'I'c
(mV)
(ms)
LVET
Plasma
(ms)
(ms)
Glycoside
(ng/ml)
QS2
53.9
52.5
60.2
63.3
55.6
52.5
63.9
58.1
81.3
67.6
60.5
58.3
48.0
46.8
71.6
57.1
67.0
69.8
59.4
49.2
181.0
171.8
160.0
168.8
179.0
186.5
175.7
191.2
152.8
153.2
132.5
131.6
159.5
166.0
156.9
155.9
147.5
150.8
189.0
196.9
0.646
0·562
0.458
0.455
0.675
0.607
0.540
0.644
0.356
0.270
0.812
0.642
0.811
0.721
0.560
0.685
0.558
0.478
0.620
0.490
368.6
369.0
392.1
390.8
400.1
411.5
400.5
389.5
344.4
359.6
435.9
412.5
373.6
352.2
409.6
393.4
417.2
433.1
411.7
390.9
423.2
431.4
436.8
426.2
431.1
436.3
384.7
417.3
398.2
408.6
445.9
435.8
442.4
435.3
415.0
450.4
369.2
371.0
423.2
443.7
315.5
319.9
295.6
298.0
319.7
329.9
293.0
311.0
285.2
312.1
318.6
323.3
334.7
316.3
300.5
314.0
283.0
287.8
303.2
317.5
56.0
52.2
59.1
60.0
55.9
59.6
54.0
63.4
68.4
59.5
64.1
62.8
63.1
60.4
60.1
55.2
80.6
66.8
66.3
56.9
132.8
137.3
167.0
159.2
191.1
183.4
189.8
218.7
122.9
120.3
172.8
144.7
144.5
181.8
113.1
116.9
149.7
155.0
164.8
184.3
0.973
0.989
0.658
0.586
0.566
0.388
0.653
0.459
0.642
0.422
0.543
0.399
0.686
0.525
0.564
0.425
0.459
0.375
0.698
418.6
406.1
397.4
393.9
420.5
405.0
412.8
412.1
420.9
380.7
423.8
396.1
417.2
391.0
397.4
356.6
424.9
391.9
:'03.2
357.3
428.7
426.9
454.0
438.3
467.3
432.9
437.8
427.0
401.6
386.0
425.5
410.9
421.8
411.4
422.7
414.9
376.8
393.6
425.5
432.5
304.6
301.6
329.7
324.3
334.3
299.8
316.4
319.8
297.4
291.0
301.1
282.8
299.4
293.8
309.8
301.7
285.3
296.8
319.6
322.4
78.3
53.3
57.9
52.0
56.1
57.4
68.0
63.3
54.0
65.0
52.5
51.7
68.9
55.0
58.0
59.9
62.4
57.0
62.8
64.7
180.9
190.7
183.4
187.2
11>4.5
155.4
192.0
215.7
148.3
150.0
149.4
152.4
149.4
162.0
155.9
181.8
153.1
154.0
153.4
153.1
0.455
0.334
0.916
0.533
0.791
0.436
0.689
0.555
0.923
0.650
0.663
0.601
0.258
0.240
0.412
0.523
0.842
0.637
0.746
0.486
425.4
356.0
380.5
364.2
407.2
356.5
404.7
378.1
387.3
364.5
365.3
347.2
421.9
369.5
412.6
376.6
423.9
379.4
402.5
394.4
386.3
412.7
421.6
420.7
442.7
436.8
4c5.5
397.1
418.1
402.1
431.9
406.0
412.9
420.2
437.9
399.1
424.5
411.4
431.8
411.7
279.8
309.1
308.0
313.2
331.9
333.9
289.3
278.0
315.2
304.1
304.8
299.9
307.0
302.0
319.4
289.4
318.9
313.4
315.8
304.7
0.322
0.3
0.1
0.49
0.22
0.50
0.85
0.38
0.31
0.27
0.26
0.56
0.97
1.14
1.15
1.07
0.92
1.10
0.92
0.71
0.67
1.60
0.82
1.41
1.08
0.82
1.00
0.9~
1.56
1.43
1.14
G, G, Belz et al.: Dose-Response Relationships of Digitalis Glycosides
No.
HR
PQ
(min-1) (ms)
1b
a
2b
a
3b
a
4b
bD
a
E
~ 5b
0 a
"0 6ba
><
bD
7b
'M
'M
'"
a
I
8b
ri
I»
a
u
9b
..'"
-+>
a
I
"l
10b
a
1b
B
bD
E
...
2b
a
': 3b
0 a
.~ 4b
0>< a
-+>
'~ 5b
'M
'"
a
6b
a
7b
a
8b
a
9b
a
10b
a
1b
a
2b
a
3b
a
4b
a
bD
E
~
N
5b
a
0 6b
"
a
'M
0 7b
a
-+>
><
'M
,~ 8b
'" a
9b
a
10b
a
72.3
64.2
66.2
55.8
69.5
66.8
62.0
58.6
70.4
63.5
71.6
69.1
62.9
74.0
55.9
51.1
51.6
48.2
57.3
42.1
TV2_6
(mV)
QTc
(ms)
192.0 0.711 422.2
207.3 0.451 381.7
140.2 0.467 419.7
141.5 0.335 369.8
140.6 0.593 394.7
151.8 0.320 359.7
1.92.5 0.829 407.4
167.2 0.662 389.8
161.1 0.377 428.0
176.0 0.188 373.3
151.2 0.583 417.9
162.8 0.404 358.8
214.2 0.921 399.3
210.5 0.515 364.8
166.6 0.473 421.3
173.4.0.459
393.2
165.7 0.821 430.3
181.6 0.402 371.8
132.2 0.862 416.1
134.8 0.646 346.9
QS2
LVET
Plasma
Glycoside
(ng/ml)
(ms)
(ms)
414.1
413.9
418.0
402.6
387.6
385.3
422.3
421.4
420.3
408.4
402.2
384.0
417.4
388.4
444.3
433.1
451.4
425.4
450.0
451.8
308.7
306.7 0.86
291.2
291.6 1.54
291.2
292.8 0.93
314.4
314.4 0.76
314.4
305.3 0.96
301.6
292.9 1.41
313.3
286.5 1 .14
325.2
318.7 0.95
325.9
315.1 1.51
325.8
336.9 2.43
59.7
60.9
148.4
153.6
182.3
187.8
148.1
154.0
180.4
198.8
144.9
146.3
149.1
147.6
145.9
178.8
193.1
205.5
132.1
131.9
177.1
187.7
0.588
0.499
0.546
0.606
0.758
0.556
0.757
0.740
0.761
0·520
0.860
0.787
1.508
1.387
0.782
0.701
0.709
0.752
0.952
0.757
403.0 446.6
396.7 432.6
413.1 406.4
400.5 428.4
436.2 422.5
408.8 417.2
394.4 393.7
376.2 418.2
403.8 412.3
399.6 397.0
379.5 406.7
360.5 414.2
416.0 435.9
395.0 431.7
387.7 418.4
412.7 388.8
442.4 398.3
424.7 409.3
395.5 415.3
372.9 402.5
292.5
305.6 8.20
309.3
307.3 2.80
299.9
294.9 10.90
300.9
309.7 7.00
301.6
289.4 11.50
58.8
53.2
57.7
50.1
61.2
46.7
68·5
67.7
79.3
72 .3
58.0
57.9
60.1
66.0
67.7
80.2
64.9
65.7
49.6
55.0
129.2
137.7
161.6
178.0
97.4
117.0
153.4
153.4
161.5
184.5
157.1
169.~
205.4
214·5
182.9
176.8
145.4
160.7
145.1
155.3
0.825
0.743
0.937
0.576
0.578
0.416
0.817
0.606
0.536
0.454
0.762
0.591
0.607
0.458
0.686
0.198
0.833
0.504
1.200
0.788
409.2
381.0
405.7
366.2
406.0
363.8
425.3
389.3
401.0
370.1
389.3
355.3
393.1
372 .8
406.3
386.8
388.9
380.1
411.0
397.3
305.4
305.2 15.70
302.5
306.4 27.30
300.6
300.0 27.80
304.0
290.1 27.60
283.7
268.3 23.10
312.5
303.7 26.90
305.7
289.1 23.70
307.8
268.6 18.90
310.0
304.8 14.80
327.7
312.420.60
56.4
55.9
63.6
54.2
74.1
59.6
57.5
50.6
63.2
64.4
66.8
57.3
56.1
55.2
57.6
70.1
71.2
65.1
409.8
421.8
417.0
405.9
411.1
406.0
441.6
412.4
392.9
364.1
424.9
403.3
438.7
399.5
408.1
359.1
408.3
394.2
433.4
406.4
No.
HR
PQ
(min-1) (ms)
1b
a
2b
a
3b
a
0
.c
4b
"" a
ri
'"
'" 5ba
"
0>< 6b
-+>
a
bD
7b
'" a
8b
a
9b
a
10b
a
'M
'M
'M
1b
338.9
334.5 8.80
306.1
316.1 10.80
303.1
301.2 10.20
304.7
318.3 7.70
295.4
291.9 15.00
a
~ 2b
co a
0':3b
a
'~
" 4b
0 a
-+>
'.:,
5b
....• a
'" 6b
a
7b
a
8b
a
9b
a
10b
a
1b
a
2b
a
3b
a
bD
E
'"'"";
0
"
><
'M
0
-+>
4b
a
5b
a
6b
a
7b
a
'M
bD
'M
'"
8b
a
9b
a
10b
a
62.7 174.0
57.9 176.3
82.3 130.0
71.3 129.1
64.6 157.4
64.3 152.2
53.7 159.4
54.1 150.9
54.8 154.6
46.3 159.4
73.5 188.0
74.9 185.8
60.0 130.3
67.1 126.6
59.2 151.8
67.3 155.8
63.8 175.1
65.4 180.5
57.4 158.4
59.1 161.7
TV2_6
QTc
(mV)
(ms)
QS2
(ms)
1.000
429.0 414.1
1.090 413.7 433.5
0.670 433.9 414.5
0.715 436.7 424.2
0.681 399.8 407.6
0.696 402.5 412.4
0.609 409.8 428.2
0.610 409.0 430.2
1.062 388.6 406.9
1.052 379.1 423.6
0.337 392.4 401.2
0.262 392.3 399.7
0.617 385.0 412.7
0.641 399.5 407.9
0.642 409.7 426.4
0.632 406.6 407.8
0.451 369.0 402.9
0.579 362.8 413.0
0.496 408.2 416.4
0.461 398.5 419.7
LVET
Plasma
(ms)
Glycoside
(ng/ml)
310.0
314.9
286.7
289.5
295.0
305.0
312.6
315.7
299.2
308.5
264.4
262.7
292.9
303.7
318.1
294.3
306.5
303.2
307.0
300.9
0
0
0
0
3.50
0
0
0
0
0
51.1
44.7
58.4
56.8
65.4
64.0
67.6
64.5
74.5
66.9
64.2
69.6
60.3
53.7
50.2
44.2
62.4
48.2
58.0
57.4
150.3
151.2
127.1
141.5
159.0
159.8
129.7
134.0
178.9
197.7
142.7
153.1
180.9
172 .6
120.5
120,4
165.8
182.8
163.8
171.5
1.012
0.758
0.676
0.441
0.266
0.240
0.785
0.559
0.673
0·522
0.528
0.219
1.050
0.869
0.801
0.594
0.634
0.543
0.889
0.664
426.5
383.4
389.2
360.5
423.1
404.4
388.1
354.6
397.4
393.0
416.3
391,6
410.4
382.8
404.6
387.9
387.6
341.6
420.3
404.3
456.8
453.3
428.3
413.3
408.1
403.2
431.0
405.2
369.3
369.8
419.1
406.3
429.1
426.4
444.5
457.7
401.5
415.8
439.0
423.0
335.8
337.8
313.9
308.9
297.5
294.8
301.4
284.9
294.0
288.6
298.1
293.5
311.2
325.2
339.2
348.5
298.4
309.5
312.9
301.0
71.6
60.2
91.8
88.0
51.1
46.0
63.0
52.7
62.0
53.4
44.9
46.2
70.4
71.8
79.7
58.1
58.6
~4.3
66.9
60.0
134.9
224.3
139.3
133.2
193.9
218.2
196.1
220.3
192.5
180.9
122.3
132.8
152.6
162.7
121.6
139.2
'188.9
182.9
157.0
172.5
1.004
0.416
0.315
0.142
0.672
0.332
1.128
0.802
0.963
0.459
0.855
0.613
0.583
0.301
0.559
0.374
1.048
0.552
0.701
0.396
411.5
370.5
443.7
398.3
386.9
341.1
420.3
370.1
395.3
356.4
373.0
340.8
427.0
387.0
436.3
369.0
395.0
364.4
397.1
365.8
377.6
388.7
367·5
346.8
415.5
399.9
439.3
435.8
409.0
398.7
462.9
448.1
423.4
400.9
398.5
402.7
427.2
405.5
415.5
405.5
270.2
293.0 33.20
273.8
259.0 28.10
310.8
299.1 32.50
316.0
321.3 31.60
283.4
281.5 36.30
326.1
322.1 26.10
312.9
302.3 32.80
293.6
306.3 34.20
299.8
301.5 38.50
291.2
300.9 41.90
23.50
23.20
17.70
24.70
20.30
21.90
14.20
16.90
26.30
24.10
G. G. Belz et al.: Dose-Response Relationships of Digitalis Glycosides
•.•••••
w
I.V
Plasma Digoxin (ng/ml;
,,-v
I•••••
L ...J
·'Rb- Ery-Assay )
Fig. 1. Correlation between individual plasma digoxin level and
changes in QTc and QSzc. Abscissa: plasma glycoside concentration 24 h after the last dose. Ordinate: differences of QTc and
QSzc before and after treatment (Ll-values).
The slopes were significantly (p < 0.001) different from zero
--
Plasma Digitoxin (ng I ml )
Fig. 3. Correlations between individual plasma glycoside level and
changes in the amplitude of the T-waves for digoxin (upper part)
and digitoxin (lower part).
Plot as in Figures 1 and 2.
Ordinate: change in the amplitude of T-waves in leads V2 to V6
(LlT VZ-6)' The slopes of the two regression lines differ significantly
from zero (p < 0.001)
Table 2. Correlation coefficients (r) and correlation equations between plasma glycoside concentration (x) and changes in ECGparameters and STI (y).
tl Heart
rate
tl PQ
..,
..,
-.,
- -
-,.
Fig. 2. Correlation between individual plasma digitoxin level and
changes in QTc and QSzc. Plot as in Figure 1.
The slopes differ significantly from zero (p < 0.0001)
plasma level of glycoside and Ll QTc and Ll QS2C.Dt
showed a distinctly higher correlation with flattening
of T than did D (Table 2) ..
It may be concluded from the results of the correlation analysis that there is a statistically close rela-
tl T V'-6
tl QTc
tl QS,c
tl LVETc
Digoxin
Digitoxin
r
r
equation
0.29 y=0.28
0.46
0.70
0.70
0.50
y=
Y=
y=
y=
y=
4.41X
+
0.15
+ 6.18x + 0.06
- 0.11 X + 0.05
-30.98X + 1.24
-18.38X + 1.98
-1O.83X + 1.01
0.30
equation
y= -0.17x
- 0.19
0.31 y=+0.39X
+ 1.82
0.76 Y= -0.01 X + 0.01
0.77 y= -1.13x - 2.39
0.75 Y= -0.89 X + 1.82
0.43 Y= -0.37 X - 0.79
tion between plasma glycoside level and the influence
of glycosides on contraction of the heart. The results
support the value of plasma glycoside measurement
in control of digitalis therapy and not only for the
diagnosis of digitalis intoxication.
Daily Digitalis Dose ( mg, log scale)
Fig. 4. Digitalis dose versus change in systolic time intervals. Daily
oral maintenance doses of the glycosides are given on the abscissa
(fJ-acetyl digoxin = D; digitoxin = Dt). Each point of the log
dose-response curves represents the mean of the 10 different individuals (Total no's. for D = 70; for Dt = 50). The differences (~values) of measurements before and after 7 days of treatment (the
latter 24 h after the last dose) are shown. LVETc = left ventricular ejection time corrected for heart rate, QS2C = total electromechanical systole corrected for heart rate. The mean values of
the following treatment groups (mg daily maintenance doses) differed significantly at the 5% level in analysis of variance and multiple t-test (27) (0 = placebo).
~LVETc - D: 0 versus 0.3 to 0.6; 0.1 versus 0.3 to 0.6
-Dt: 0 versus 0.12 to 0.16
~QS2C - D: 0 versus 0.2 to 0.6; 0.1 versus 0.2 to 0.6
-Dt: 0 versus 0.04 to 0.16; 0.04 versus 0.12 to 0.16;
0.08 versus 0.16
Dose- Effect Relationship
In this study in man sigmoid-shaped, log doseresponse curves for glycoside-induced changes in STI
and ECG-parameters
were demonstrated during
maintenance therapy. The doses employed resulted
in a plateau of effect (maximum efficacy) for ~
LVETc and ~ QS2C, whereas for the electrocardiographic parameters (~ QTc, ~-amplitude of T-wave)
the highest doses still appeared too low to induce
maximum efficacy. Higher daily maintenance doses
(> 0.6 mg of D, > 0.16 mg of Dt), which would be
required to reach this goal, did not appear feasible
for ethical reasons.
Generally, it is difficult to state the lowest effective dose and the minimum dose producing maximum
efficacy, i. e. to determine the range of dose effect
Daily Digitalis Dose (mg. log scale)
Fig. 5. Digitalis dose versus change in electrocardiographic parameters. Plot as in Figure 4.
QTc = duration of electrical systole corrected for heart rate;
TV2-6 = mean amplitude of the T-waves from leads V2 to V6.
The following groups differed statistically significant:
~QTc - D: 0 versus 0.2 to 0.6; 0.1 versus 0.2 to 0.6
- Dt: 0 versus 0.04 to 0.16; 0.04 versus 0.12 to 0.16
~TV2-6 - D: 0 versus 0.2, 0.4 to 0.6
- Dt: 0 versus 0.08 to 0.16; 0.04 versus 0.12 to 0.16; 0.08 versus
0.12 to 0.16; 0.12 versus 0.16
curves. A factor of 3-6 between the lowest effective
and the minimal dose producing maximum efficacy
was estimated for both glycosides from the curves of
~ LVETc and ~ QS2C, and this range was in good
agreement with the results of Greeff and Schlieper
[14]. In a study of dose-effect curves of k-strophanthin on human, guinea pig, and rabbit atrial strips
they observed that from onset of action to maximum
contractile force the concentration had to be
increased by a similar factor (4-fold).
In considering the dose-effect curves of the two
glycosides, it should be remembered that the biological half lifes of D and Dt are different [9, 28] and that
our measurements were made in a state of equilibrium 24 h after the last dose, when relatively more
D would have been eliminated.
110
G. G. Belz et al.: Dose-Response Relationships of Digitalis Glycosides
Pharmacodynamic Differences between Digoxin and
Digitoxin?
.
II
d h
h
h
I t is
genera y accepte t at t ere are no p armacodynamic differences between the various cardiac glycosides, although they do differ in respect of
their pharmacokinetic properties [12, 13,21]. In the
present study of the mechanical, electromechanical,
and electrical phases of ventricular systole, completely analogous behavior of 0 and Ot was
observed. The only striking difference in their influence on ventricular function lay in the relative
potency of the two glycosides, which was mainly due
to pharmacokinetic differences. However, both from
the dose-effect curves and from the degree and the
..
relative slope of plasma level-effect correl~tions, Ot
was seen to cause more pronounced flattemng of the
T-wave than did O. This observation confirms older
findings of Aravanis and Luisada [2]. They observed
.
dI
...
f
th at th e S-T - depressi~n
an owenng or mverSlOn0
T was much more eVident after Ot than after 0 or
other cardiac glycosides.
Assumption of a relatively greater vagomimetic
potency of 0 than of Ot [25] could account for this
....
?bservation, whi~h ha~ now .bee~ confumed i~ two
mdependent studies usmg qmte different techmques.
However, this hypothesis requires further experimental work.
Conclusions
..
,
Smce the studies were done m normal man, translation of the results to clinical conditions should be
only done with a certain reserve. An almost identical
influence of cardiac glycosides on STI in normal sub.....
Jects and m patients suffenng from heart fallure was
shown, however, by Weissler and Schoenfeld [30].
Three points should be stressed:
1. Changes in cardiac performance induced by
....
digitahs .reach a plateau o~ maXimum e~fect, and a
further mcrease m dose Will not result m a further
increase in effect.
2. Plasma glycoside levels within the range 0 to 2 ng/
ml for 0 and 0 to 40 ng/ml for Ot agreed well with
.
the glyCOSideeffects on the heart.
3. At an identical level of effect on cardiac systole, Ot
had a more pronounced effect on the T-wave than
might be expected for O. This may indicate that vari·
I
'd d
d'ff
.
ous car dlaC g YCOSies 0 exert i erent actions on
the electrophysiological properties of the heart.
Acknowledgements
...
ThiS studies were only made pOSSibleby the support
of many persons. For skillful technical assistance the
authors thank Mrs. G. Belz and Ors. M. Kolb and H.
Fallen. The statistical design and analysis were done
by Prof. Dr. O. v. Willert, Oarmstadt.
References
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..
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Received: May 27, ]977, in revised form: November 7, ]977
accepted: November ]9, ]977
Prof. Dr. G. G. Belz
Institut fur kardiovaskuliire Therapie
WilhelmstraSe 16
D-6200 Wiesbaden
Federal Republic of Germany