ANNUAL REVIEWS
Further
Quick links to online content
Copyright 1975. All rights reserved
CLINICAL PHARMACOLOGY
.7139
Annu. Rev. Med. 1975.26:159-171. Downloaded from www.annualreviews.org Access provided by San Diego State University on 01/28/15. For personal use only.
OF DIGITALIS GLYCOSIDES1 James E Doherty, MD., F.A.G.P', F.A.G.G. and James 1. Kane, MD. Division of Cardiology. Department of Medicine. Veterans Administration Hospital. and University of Arkansas School of Medicine. Little Rock. Arkansas 72206 INTRODUCTION
The clinical importance of digitalis glycosides in American medicine is illustrated by the fact that in 1971 digoxin was fourth on the list of most frequently prescribed drugs; digitoxin. sixteenth; and digitalis leaf. nineteenth (1). The first botanical with documented inotropic properties. the squill (urginea maritima or sea onion). was used by Egyptian physicians about 1500 B.C. (2). Continuing scientific interest is demonstrated by the listing of more than 600 citations for digitalis and similar products in the 1972 Index Medicus (3). The purpose of this review will be to apply appropriate clinical pharmacologic principles to these very commonly used prepara tions which possess the narrowest therapeutic:toxic ratio of almost any drug in common use today. PHARMACODYNAMICS OF DIGITALIS PREPARATIONS
The pharmacodynamic properties of digitalis glycosides inclUde the following: I. Inotropic effect-the induction of increased increments of contractile force of cardiac muscle. 2. Chronotropic effect-the "slowing" effect on heart rate. 3. Toxic and/or side effects-undesirable reactions to the drugs brought about by excessive concentration of the glycoside at the myocardial receptor site and/or extracardiac binding sites. Idiosyncracy to digitalis. although rare. may also be included here.
Inotropic Effect of Digitalis Glycosides The ability of the glycoside to cause increased myocardial fiber shortening is pre sumably related to inhibition of the sodium-potassium ATPase enzyme which sec'Supported in part by National Institutes of Health Grant 5ROI HL 06642-12 and Veterans Administration Medical Research Information System Grant 1887--01. 159
160
DOHERTY & KANE
ondarily alters the amount of calcium ion available for binding to specific myocardial proteins (4). The recent work of Okita (5) questions the role of Na-K ATPase in this area and it may be hoped that further work will resolve this contro versy.
Annu. Rev. Med. 1975.26:159-171. Downloaded from www.annualreviews.org Access provided by San Diego State University on 01/28/15. For personal use only.
Chronotropic Effect of Digitalis Glycosides
The chronotropic or "slowing" effect of digitalis glycosides is thought to have two phases: 1. a "vagal" effect which is operative very shortly after administration of the drug, and 2. a direct myocardial effect which relates to (a) improved cardiac performance in the intact subject and (b) slowing of impulse propagation from the atria to the ventricles in the atrio-ventricular nodal area (6). Toxic and/or Side Effects of Digitalis Glycosides
Digitalis intoxication as a clinical entity seems to be increasing in incidenc� in the hospitalized cardiac patient. It probably represents the most frequent adverse drug reaction (as well as the most dangerous) physicians observe. A full scale discussion of digitalis toxicity will follow the section on pharmacokinetics of the various glycosides, as duration of intoxication is dependent on kinetic properties of the various preparations. PHARMACOKINETICS OF DIGITALIS GLYCOSIDES
Much of the recent scientific data regarding the kinetic behavior of digitalis glyco sides has been generated through turnover studies with a radioactive label (14C, 3H) applied to the compound. These studies are supplemented by later studies of serum levels and excretory products by inhibitions of red cell rubidium uptake by the sample (7) or radioimmunoassay (8). Kinetic behavior is well described for the purified glycosides: digoxin, digitoxin, ouabain, deslanoside, and the similar product lanatoside C. Digitalis leaf is a mix ture of glycosides containing mostly digitoxin and is probably closest in its kinetic behavior to that glycoside. An attempt will be made to discuss in depth the kinetics of digoxin and digitoxin. Digoxin Pharmacokinetics
Digoxin ( l 2-hydroxydigitoxin) is now the most popular glycoside used in the United States by both oral and parenteral routes of administration. Tritium labeled digoxin was given by mouth to 12 human subjects who were in congestive heart failure. Digoxin was recovered from serum, urine, and stool for a 7-day period and digoxin extracted by a technique previously reported (9). Figure 1 is a composite graph of the serum turnover of these patients. Radioactivity representing digoxin appears in the serum almost immediately and rises to a peak level at 45-60 min and then falls more gradually to a plateau level at 5-6 hr after administration of the drug. DIGOXIN TURNOVER KINETICS AFfER ORAL ADMINISTRATION
DIGITALIS PHARMACOLOGY ;;-
100
161
\
�
.. .. ... , .. � O!: >:: '"
�
10
Annu. Rev. Med. 1975.26:159-171. Downloaded from www.annualreviews.org Access provided by San Diego State University on 01/28/15. For personal use only.
�
\e ., ,.. ,, ,, ,, ,, ,
O!: �
O!:
�
.. Q
B
\
O!:
I
12
0
Figure 1
24
36
48
HOURS
Composite
(12
patients) serum concentration of digoxin following oral administra
tion. Serum concentration is plotted on the vertical axis; time on the horizontal axis on a semilogarithmic scale. Although studies were continued for seven days, only the first two days are shown in order to demonstrate the important early differences in the serum turnover curves. Note that serum concentration reaches a peak 45 to 60 min after being administered. Line B is the best straight line that can be drawn back to zero time and represents the dominant T� of digoxin (31.3 hr) and is associated with metabolism and excretion of the glycoside. Line C is derived by subtracting line B from the descending limb of curve A, thus eliminating metabolism and excretion. This exponential function now represents distribution and binding of the glycoside to the tissue and has a T� of 60 min (reproduced with permission from Doherty, J. E., Perkins, W. H., Mitchell, G. D. 1961. Arch. Intern. Med. 108:351).
Two exponential functions may be derived from this disappearance curve. The first of these is attributed to the distribution and binding of the glycoside and has a half time (TIh) of 60 min, while the second represents the dominant TIh of 31.3 hr and is attributed to the metabolism and excretion (primarily the latter) of tritium-labeled digoxin. There is obvious clinical correlation with the early onset of action of digoxin seen in the human subject. The dominant TIh also correlates with the disappearance of pharmacologic activity when the drug is withdrawn and is consistent with the term "short duration of action" frequently applied to this glycoside. The excretion of digoxin is primarily in the urine as unchanged digoxin and is shown in Figure 4 along with excretion by other routes of administration. DIGOXIN TURNOVER KINETICS AFTER INTRAMUSCULAR ADMINISTRATION
Tritiated digoxin was given to ten patients with congestive heart failure by the intramuscular route (10) and differences in the serum turnover curve are shown in Figure 2. Intramuscular administratKm reveals a dominant TIh of 38 hr, a figure not statistically different from that obtained by oral administration. Note, however, that th� peak serum concentration is later and somewhat lower than that found by the
162
DOHERTY & KANE
100,0
Annu. Rev. Med. 1975.26:159-171. Downloaded from www.annualreviews.org Access provided by San Diego State University on 01/28/15. For personal use only.
10,0
I'0
l'\
__�________
\
\\
\c \
_.,'.-\\ '-----�---_.,�---____._----__,_---____
Further
Quick links to online content
Copyright 1975. All rights reserved
CLINICAL PHARMACOLOGY
.7139
Annu. Rev. Med. 1975.26:159-171. Downloaded from www.annualreviews.org Access provided by San Diego State University on 01/28/15. For personal use only.
OF DIGITALIS GLYCOSIDES1 James E Doherty, MD., F.A.G.P', F.A.G.G. and James 1. Kane, MD. Division of Cardiology. Department of Medicine. Veterans Administration Hospital. and University of Arkansas School of Medicine. Little Rock. Arkansas 72206 INTRODUCTION
The clinical importance of digitalis glycosides in American medicine is illustrated by the fact that in 1971 digoxin was fourth on the list of most frequently prescribed drugs; digitoxin. sixteenth; and digitalis leaf. nineteenth (1). The first botanical with documented inotropic properties. the squill (urginea maritima or sea onion). was used by Egyptian physicians about 1500 B.C. (2). Continuing scientific interest is demonstrated by the listing of more than 600 citations for digitalis and similar products in the 1972 Index Medicus (3). The purpose of this review will be to apply appropriate clinical pharmacologic principles to these very commonly used prepara tions which possess the narrowest therapeutic:toxic ratio of almost any drug in common use today. PHARMACODYNAMICS OF DIGITALIS PREPARATIONS
The pharmacodynamic properties of digitalis glycosides inclUde the following: I. Inotropic effect-the induction of increased increments of contractile force of cardiac muscle. 2. Chronotropic effect-the "slowing" effect on heart rate. 3. Toxic and/or side effects-undesirable reactions to the drugs brought about by excessive concentration of the glycoside at the myocardial receptor site and/or extracardiac binding sites. Idiosyncracy to digitalis. although rare. may also be included here.
Inotropic Effect of Digitalis Glycosides The ability of the glycoside to cause increased myocardial fiber shortening is pre sumably related to inhibition of the sodium-potassium ATPase enzyme which sec'Supported in part by National Institutes of Health Grant 5ROI HL 06642-12 and Veterans Administration Medical Research Information System Grant 1887--01. 159
160
DOHERTY & KANE
ondarily alters the amount of calcium ion available for binding to specific myocardial proteins (4). The recent work of Okita (5) questions the role of Na-K ATPase in this area and it may be hoped that further work will resolve this contro versy.
Annu. Rev. Med. 1975.26:159-171. Downloaded from www.annualreviews.org Access provided by San Diego State University on 01/28/15. For personal use only.
Chronotropic Effect of Digitalis Glycosides
The chronotropic or "slowing" effect of digitalis glycosides is thought to have two phases: 1. a "vagal" effect which is operative very shortly after administration of the drug, and 2. a direct myocardial effect which relates to (a) improved cardiac performance in the intact subject and (b) slowing of impulse propagation from the atria to the ventricles in the atrio-ventricular nodal area (6). Toxic and/or Side Effects of Digitalis Glycosides
Digitalis intoxication as a clinical entity seems to be increasing in incidenc� in the hospitalized cardiac patient. It probably represents the most frequent adverse drug reaction (as well as the most dangerous) physicians observe. A full scale discussion of digitalis toxicity will follow the section on pharmacokinetics of the various glycosides, as duration of intoxication is dependent on kinetic properties of the various preparations. PHARMACOKINETICS OF DIGITALIS GLYCOSIDES
Much of the recent scientific data regarding the kinetic behavior of digitalis glyco sides has been generated through turnover studies with a radioactive label (14C, 3H) applied to the compound. These studies are supplemented by later studies of serum levels and excretory products by inhibitions of red cell rubidium uptake by the sample (7) or radioimmunoassay (8). Kinetic behavior is well described for the purified glycosides: digoxin, digitoxin, ouabain, deslanoside, and the similar product lanatoside C. Digitalis leaf is a mix ture of glycosides containing mostly digitoxin and is probably closest in its kinetic behavior to that glycoside. An attempt will be made to discuss in depth the kinetics of digoxin and digitoxin. Digoxin Pharmacokinetics
Digoxin ( l 2-hydroxydigitoxin) is now the most popular glycoside used in the United States by both oral and parenteral routes of administration. Tritium labeled digoxin was given by mouth to 12 human subjects who were in congestive heart failure. Digoxin was recovered from serum, urine, and stool for a 7-day period and digoxin extracted by a technique previously reported (9). Figure 1 is a composite graph of the serum turnover of these patients. Radioactivity representing digoxin appears in the serum almost immediately and rises to a peak level at 45-60 min and then falls more gradually to a plateau level at 5-6 hr after administration of the drug. DIGOXIN TURNOVER KINETICS AFfER ORAL ADMINISTRATION
DIGITALIS PHARMACOLOGY ;;-
100
161
\
�
.. .. ... , .. � O!: >:: '"
�
10
Annu. Rev. Med. 1975.26:159-171. Downloaded from www.annualreviews.org Access provided by San Diego State University on 01/28/15. For personal use only.
�
\e ., ,.. ,, ,, ,, ,, ,
O!: �
O!:
�
.. Q
B
\
O!:
I
12
0
Figure 1
24
36
48
HOURS
Composite
(12
patients) serum concentration of digoxin following oral administra
tion. Serum concentration is plotted on the vertical axis; time on the horizontal axis on a semilogarithmic scale. Although studies were continued for seven days, only the first two days are shown in order to demonstrate the important early differences in the serum turnover curves. Note that serum concentration reaches a peak 45 to 60 min after being administered. Line B is the best straight line that can be drawn back to zero time and represents the dominant T� of digoxin (31.3 hr) and is associated with metabolism and excretion of the glycoside. Line C is derived by subtracting line B from the descending limb of curve A, thus eliminating metabolism and excretion. This exponential function now represents distribution and binding of the glycoside to the tissue and has a T� of 60 min (reproduced with permission from Doherty, J. E., Perkins, W. H., Mitchell, G. D. 1961. Arch. Intern. Med. 108:351).
Two exponential functions may be derived from this disappearance curve. The first of these is attributed to the distribution and binding of the glycoside and has a half time (TIh) of 60 min, while the second represents the dominant TIh of 31.3 hr and is attributed to the metabolism and excretion (primarily the latter) of tritium-labeled digoxin. There is obvious clinical correlation with the early onset of action of digoxin seen in the human subject. The dominant TIh also correlates with the disappearance of pharmacologic activity when the drug is withdrawn and is consistent with the term "short duration of action" frequently applied to this glycoside. The excretion of digoxin is primarily in the urine as unchanged digoxin and is shown in Figure 4 along with excretion by other routes of administration. DIGOXIN TURNOVER KINETICS AFTER INTRAMUSCULAR ADMINISTRATION
Tritiated digoxin was given to ten patients with congestive heart failure by the intramuscular route (10) and differences in the serum turnover curve are shown in Figure 2. Intramuscular administratKm reveals a dominant TIh of 38 hr, a figure not statistically different from that obtained by oral administration. Note, however, that th� peak serum concentration is later and somewhat lower than that found by the
162
DOHERTY & KANE
100,0
Annu. Rev. Med. 1975.26:159-171. Downloaded from www.annualreviews.org Access provided by San Diego State University on 01/28/15. For personal use only.
10,0
I'0
l'\
__�________
\
\\
\c \
_.,'.-\\ '-----�---_.,�---____._----__,_---____
