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New Information Regarding Digitalis Metabolism
CRITICAL REVIEW New Information Regarding Digitalis Metabolism* James E . Doherty, M.D.;'" William H . Hall, hl.D.;t Marvin L. Murphy, M.D.;$ and Owen W . Beard, M.D.B
The digitalis glycosides, digoxin and digitoxin, have been examined in the Ught of new information regarding absorption, excretion, and metabolism. Digitoxin is completely absorbed, extensively recycled in the intestine, protein-bound, metabolized, and excreted largely in the urine as metabolites. It possesses, as a result, a long half-time of five to seven days. Factors governing its excretion and metabolism are incompletely studied in human subjects. Digoxin is 80 percent to 90 percent absorbed, little recycled, relatively little protein-bound, relatively little metabolized, and excreted largely unchanged in the urine. As a result it hm a shorter half-time of 1.5 days and its excretion may be directly related to creatinine clearance. These properties of the commonly used glycosides should assist In clinical management of patients with congestive heart failure. Smaller doses of either glycoside than usually prescribed appear to suffice for adequate digitalization, and the dangerous complication of digitalis toxicity may then be avoided.
1mportant
new knowledge regarding the clinical
a pharmacology of the digitalis glycosides has be-
come available in the past decade. This -paper outlines and summarizes the advances of clinical value. This effort will be directed toward the major glycosides in clinical use today, digoxin and digitox- . in. An attemut is made to correlate the knowns, unknowns, and variables to be considered in clinical therapy. 'From the Medical Service, Veterans Administration Hospital, and the Department of Medicine and Division of Cardiology, University of Arkansas School of Medicine, Little Rock, Arkansas. Supported in part by USPHS grant HE 06642, the Burrou hs Wellcome Company (USA), Inc., Tuckahoe, NY, an8 the Arkansas Heart Association. *'Professor of Medicine, University of Arkansas School of Medicine, and Director, Division of Cardiology, University and Veterans Hospitals. +Assistant Professor of Medicine, University of Arkansas School of Medicine, and Chief, Gastroenterology Section, Veterans Administration Hospital. :Associate Professor of Medicine, University of Arkansas School of Medicine, and Chief, Cardiology Section, Veterans Administration Hospital. §Professor of Medicine, University of Arkansas School of Medicine, and Assistant Chief, Medical Service, Veterans Administration Hospital.
Absorption Digitoxin has been shown in clinical studies to be virtually 100 percent absorbed,' and except for a mechanism to explain this fact,*,:{ little has been added to existing knowledge in this area. Digoxin, on the other hand, originally thought to be only about 50 to 60 percent absorbed,4 has been shown by radioactive tracer techniques to be 80 to 90 percent absorbed." These differences in absorption are best explained by the polar structure of the two compounds, as they are chemically very similar (digoxin is 12hydroxydigitoxin). Figure 1 shows graphically the similar structure of these compounds, the only difference being a hydroxyl group at position 12 on the digitoxin molecule. This minor difference creates a real metabolic difference between the glycosides, digitoxin being a nonpolar compound and digoxin a polar compound. Any polar compound is more readily absorbed and exchanged by the human body and nonpolar compounds are less likely to be
DOHERTY ET AL
FIGURE1. S t n ~ c h ~ rchemical al formula of digitoxin and digoxin ( 12-hydroxydigitoxin). The only difference in the molecule is noted at position 12 on the steroid nucleus, where a hydroxyl group replaces a hydrogen ion.
absorbed, thus an important difference is already extant. This feature lends itself to further analysisenterohepatic recycling of the drugs and their metabolic products. Digitoxin (and its metabolites ), therefore, is extensively recycled through the bowel. It is excreted largely in the bile and then reabsorbed to perpetuate its own body stores. Calculations by Okita2 indicate that 26 percent of a given amount of digitoxin is recycled in the intestine, and Katzung and Meyers:' have shown that biliary fistula surgically induced in dogs will significantly reduce the digitoxin half-time (the time required for one-half of the drug present in the body at a given time to be excreted or metabolized ) . Caldwell and GreenbergerG demonstrate a modest but similar reduction in the serum half-time in human subjects given cholestyramine, a compound which binds digitoxin in the small intestine and thus prevents recycling. This demonstrates that the human subject receiving digitoxin recycles the drug (and its metabolites) rather extensively. Digoxin has been shown in human subjects with surgically induced biliary fistula to lack extensive recycling, only 6.8 percent of a given dose being recycled through the bowel as determined by Okita's f o r m u l a . T h e serum T % of these patients did not differ from those without biliary fistula,7-8 indicating that this factor is of minor importance in digoxin metabolism. It appears that polar characteristics may contribute greatly to absorption and half-time of these digitalis glycosides.
Excretion Digitoxin, reported to be excreted largely in the
urine," is excreted primarily in the bile as metabolites, recycled, and is ultimately excreted as cardioinactive metabolites in the urine. Digoxin has been shown to be excreted mostly in the urine as the unchanged glycoside, and excretion is predictably related to the creatinine clearance.*-" Digoxin clearance is virtually unity with creatinine and, although less specific because of prerenal azotemia, is inversely related to the level of the blood urea nitrogen. It follows that digoxin excretion (and by extension, half-time and therapeutic activity) is prolonged in renal insufficiency and dosage should be curtailed accordingly. Digitoxin excretion has not been reported to be reduced in liver disease, as might be expected because of the biliary recycling and extensive hepatic metabolism. Digitoxin blood levels also appear to be somewhat higher than usual in renal insufficiency, although T % does not appear to be unduly prolonged." As a smaller fraction of digitoxin is excreted unchanged in the urine, excretion cannot be predictably related to renal function. Digitoxin dosage in these clinical situations continues to be governed by the clinical judgment of the physician, and errors should be made on the conservative side.
Metabolism Digitoxin is extensively metabolized by the human body, and digoxin is relatively little metabolized. The "normal" metabolic end products of digitoxin are, in general, much less cardioactive than the parent compound. The principal cardioactive metabolite is digoxin ( 12-hydroxydigitoxin ) which represents only 7.7 percent of the total daily excreCHEST, VOL. 59, NO. 4, APRIL 1971
Ii
NEW INFORMATION REGARDING DIGITALIS METABOLISM
DIG ITOX lN
( Nonpolar)
Serum T V t = 5doys
r 1"
2% Stool Dally
DAY8
-
= 15 20% of total body stores
16% Urine Doily
excreted per day 2 % as Dlgltoxln 18% or metobolitrs 9 2 % inactive 8% octivo
tory losses of the glycoside estimated by Jelliffe and co-workers. 1 :{ Under unusual circumstances, it appears that both digoxin and digitoxin may follow abnormal metabolic pathways. Luchi and Gruberl4 have reported an instance of abnormal metabolism of digoxin resulting in the production of dihydrodigoxigenin, a cardioinactive metabolite, and a concomitant increase in digoxin requirements. Solomon and coworkers1: report drug induction of digitoxin metabolism by phenylbutazone (Butazolidin) with increased conversion of digitoxin to digoxin and an appropriate shortening of the serum T X which resulted in increased digitoxin dosage requirements. The nonpolar structure of digitoxin leads to protein binding" and conversely, polar digoxin is virtually nonprotein-boundlVn the blood serum. The native antigenic potential of either of these compounds appears to be slight; however, binding to protein might produce an antigen complex with resultant development of antibodies. This is the basis for the digoxin-antibody serum assay described by Butler and C h e n l i and Smith and associates.'s This technique is a major advance in determination of digitalis serum levels which correlate with myocardial concentration and toxicity to the glycoside, as well as the state of "underdigitalization." Other methods of serum digoxin assay appear less specific, but seem to be clinically useful and deserve further
CHEST, VOL. 59, NO. 4, APRIL 1971
2a. Pharmacokinetics of FIGURE digitoxin. The graph is self-explanatory and summarizes the disci~ssionin the text regarding absorption, recycling, and routes of excretion. The graph at the upper right represents the long dominant senlm half-life of the drug which is related to metabolism and excretion of the dnlg.
study.l"20 Figure 2 is designed to summarize the pharmacokinetic behavior of the digitalis glycosides digitoxin and digoxin. DISCUSSION Utilization of this new pharmacokinetic knowledge regarding the digitalis glycosides should and does lead to a more enlightened concept of digitalis usage in arrhythmias and congestive heart failure. It should be appreciated that the effects of digitalis on the conduction system of the heart (control of the ventricular rate in atrial fibrillation) and inotropic effects of the drug are not the same." Larger doses of digitalis are usually required to control arrhythmia than for salutory effect in congestive failure. Evidence for this difference includes the "unmasking" of digitalis intoxication following electrical conversion of the heart rhythm, reported by Kleiger and Lown,'%nd the subsequent reduced requirements of digitalis once normal sinus rhythm is attained. This fact enables the physician to use smi~ll doses of the glycoside with benefit and maintain a greater margin of safety in patients with sinus rhythm. Morris and colleagues2:' have demonstrated that 60 percent of the toxic dose of ouabain determined during a control period results in digitalis toxicity following induction of myocardial infarction in the same animals. The patient with con-
DOHERTY ET AL
DIGOXIN (Polar) ( 12-Hydroxydigitoxin)
/
FIGURE 2b. Pharmacokinetics of digoxin ( 12-hydroxydigitoxin). This figure reveals the same data as Figure 2a, plotted for digoxin. Note the increased excretion compared to digitoxin and the shorter dominant half-time of digoxin compared to digitoxin.
8 5 % Absorbed:
Stool Daily
gestive heart failure and acute myocardial infarction should receive small doses of digitalis to avoid this dangerous complication. Knowledge of the pharmacokinetics of the drug, plus its inotropic and dromotropic effects, forces us to reevaluate digitalis dosage regimens. It appears that with current knowledge we should be able to attain optimal effects of the glycoside with smaller doses, avoid toxicity ( a dangerous complication in the patient with congestive failure and arrhythmia or both), and achieve better control of the clinical disease state.
Dosage Schedules Doses of digitalis (digitoxin and digoxin) recommended by us are outlined in Table 1. It should be remembered that these are "average" doses, and that there is really no such thing. Each patient has a highly individual dose requirement based upon renal function (digoxin) and probably hepatic function (digitoxin), as well as other factors, and these schedules are only guidelines. Errors, should they be made, should be on the minus or low side for avoidance of toxicity. Remember: a small amount of digitalis does help increase inotropic effect. Schema proposed by Jelliffel"z4~25 offer clinically useful guidelines for therapy. Table 2 outlines the factors affecting sensitivity or resistance to therapy with digitalis.
/n
30% Urine Dally
Serum T
Ih
= 1.6 days
of total body stores excreted per day 3 0 % as Digoxin 3% as metabolites
Digitalis Zntoxication The use of low sodium diets, powerful diuretics, rest, and intelligent control or recognition of "other factors" (infections, renal complications, liver dysfunction, thromboembolic disease, electrolytes, etc) make the complication of digitalis toxicity avoidable, inexcusable, and unwise. The concept of induction of digitalis toxicity and "backing off' to a smaller dose regimen for maintenance of digitalization is no longer tenable. Smaller doses are dictated, particularly for digoxin, and a plea is made for reduced dosage regimens for all glycosides. Treatment of digitalis intoxication remains largely one of control of cardiac arrhythmias and awaiting the excretion or metabolism of the glycoside (notably shorter with digoxin). The suggestion that Table
1-Digitalb
Sensitivity and Reaiatanee.
A Increased Sensitivity to Digitalis 1 Prolonged excretion 2 Electrolyte imbalance-K+, Mg+,Ca++ 3 Increased end-organ response 4 "Overdosage" 5 Combinations of the above
B Decreased Sensitivity to Digitalis 1 Poor absorption 2 Abnormal metabolism 3 Decreased end-organ response 4 "Underdosage" 6 Combinations of the above
CHEST, VOL. 59, NO. 4, APRIL 1971
NEW INFORMATION REGARDING DIGITALIS METABOLISM Table 2-Recommended Oral Digitoxin Digoxin
IV
Doses I R.1
1.0 - 1.5 mg 1.0 - 1.5 mg 1.0 - 1.5 mg given during a single 24-hour period 1.0 - 2.5 1.0 - 2.0 1 .O - 2.0 given during a single 24-hour prriod
of
437 Digitalis. Maintenanre 0.1 - 0.15 mg 0.125 - 0.75 mg
No Loading Dose 0.1 - 0.15 mg for 25 - 30 days 0.125 0.75 mg* daily for 5 - 7 days
-
'Dosage depends on renal function, end organ response, absorption and excretion (see text).
digitalis toxicity may be ultimately controlled by digitalis antibodies which will bind the glycoside in an antigen-antibody complex seems feasible; however, many technical problems remain, some of which are: (1) Assuming the digitalis toxicity is reversed, will all inotropic effect be removed? ( 2 ) How and in what quantity should digitalis be replaced? ( 3 ) Antibody protein binding of excessive digitalis may effectively remove digitalis as an immediate problem; however, proteins have a finite half-life, and is the digitalis then released to again produce toxicity? One may see that with the ultimate availability of digitalis antibodies for management of toxicity, many problems remain. Conventional therapy with potassium salts, antiarrhythmic agents (particularly diphenylhydantoin, lidocaine, and propanolol), cautious use of diuretics if indicated, and withholding the drug still appear to form the basis of treatment of digitalis intoxication. The use of digitalis-specific binding antibodies, "induction," and drug interference with enterohepatic recycling show promise for the future in the management of digitalis toxicity. For the present, cautious dosage, careful electrolyte monitoring, and awareness of renal and hepatic function appear to be the best methods for prevention (and management) of our present epidemic of digitalis intoxication. ACKNOWLEDGhfENTS: Jacquelyn Gammill, BS, hIT (ASCP) and Joyce Sherwood, BS, MT (ASCP) gave technical nssistance.
REFERENCES
1 Gold H, Cattell McK, Modell W, et al: Clinical studies on digitoxin (Digitaline nativelle). J Pharmacol Exp Ther 82: 187-195, 1944 2 Okita CT: Species difference in duration of action of cardiac glycosides. Fed Proc 26: 1125-1130, 1967 3 Katzung BG, hleyers FH: Excretion of radioactive digitoxin by the dog. J Pharmacol Exp Ther 149:257-262, 1965 4 Gold H, Cattell hIcK, Greiner T, et al: Clinical pharmacology of digoxin. J Pharmacol Exp Ther 109:45-57, 1953 5 Doherty JE, Flanigan WJ, hlurphy XIL, et al: Studies with tritiated digoxin XIV: Enterohepatic circulation, absorption, and excretion studies in human volunteers. Circulation, in press 6 Caldwell JH, Creenberger NJ: Cholestyramine enhances digitalis excretion and protects against lethal intoxication. J Clin Invest 49:16a, 1970
CHEST, VOL. 59, NO. 4, APRIL 1971
7 Doherty JE, Perkins WH: Studies with tritiated digoxin in human subjects after intravenous administration. Amer Heart J 63:528-536, 1962 8 Doherty JE, Perkins WH, Mitchell GK: Tritiated digoxin studies in human subjects. Arch Intern Med 108351-539, 1961 9 Doherty JE, Perkins WH, Wilson hlC: Studies with tritiated digoxin in renal failure. Amer J bled 37:536-544, 1964 10 Jelliffe RW: A mathematical analysis of digitalis kinetics in patients with normal and reduced renal function. Math Biosci 1:305-325, 1967 11 Bloom Pht, Nelp FVB: Relationship of the excretion of tritiated digoxin to renal function. Amer J Med Sci 251: 133-144, 1966 12 Lukas DS, Peterson RE: Double isotope dilution derivative assay of dik~toxin in plasma, urine, and stool of patients maintained on the drug. J Clin Invest 45:782795, 1966 13 Jelliffe RW, Buell J, Kalaba R, et al: An improved method of digitoxin therapy. Ann Intern bled 72:453-464, 1970 14 Luchi RJ, Gruber JW: Unusually large digitalis requirements. Amer J hled 45:322-328, 1968 15 Solomon HM, Abrams WB, Reich SD: Interactions between digitoxin and other drugs in vitro and in vivo. Clin Res 18:344, 1970 16 Doherty JE, Hall WH: Tritiated digoxin XV: Serum protein binding in human subjects. Amer J Cardiol, submitted for publication 17 Butler VP, Chen JP: Digoxin-specific antibodies. Proc Nat Acad Sci USA 57:71-78, 1967 18 Smith TW, Butler VP, Haber E: Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassay. New Eng J Med 281:1212-1216, 1969 19 Lowenstein Jhl, Corrill EM: An improved method for measuring plasma and tissue concentrations of digitalis glycosides. J Lab Clin &led 67:1048-1952, 1968 20 Burnett GH, Conklin RL: The enzymatic assay of plasma digitoxin levels. J Lab Clin Med 71:1040-1044, 1968 21 Ogden PC, Selzer A, Cohn KE: The relationship between the inotropic and dromotropic effects of digitalis: The modulation of these effects by autonomic influences. Amer Heart J 77:628-635, 1969 22 Kleiger R, Lown B: Cardioversion and digitalis. 11. Clinical studies. Circulation 33:878-887, 1966 23 Morris JJ, Taft CV, Whalen RE, et al: Digitalis and experimental myocardial infarction. Amer Heart J 77:342355, 1969 24 Jelliffe RW: Administration of digoxin. Dis Chest 56:5660, 1969 25 Jelliffe RW: An improved method of digoxin therapy. Ann Intern hled 69:703-717, 1968 Reprint requests: Dr. Doherty, 300 East Roosevelt Road, Little Rock 72206.
The digitalis glycosides, digoxin and digitoxin, have been examined in the Ught of new information regarding absorption, excretion, and metabolism. Digitoxin is completely absorbed, extensively recycled in the intestine, protein-bound, metabolized, and excreted largely in the urine as metabolites. It possesses, as a result, a long half-time of five to seven days. Factors governing its excretion and metabolism are incompletely studied in human subjects. Digoxin is 80 percent to 90 percent absorbed, little recycled, relatively little protein-bound, relatively little metabolized, and excreted largely unchanged in the urine. As a result it hm a shorter half-time of 1.5 days and its excretion may be directly related to creatinine clearance. These properties of the commonly used glycosides should assist In clinical management of patients with congestive heart failure. Smaller doses of either glycoside than usually prescribed appear to suffice for adequate digitalization, and the dangerous complication of digitalis toxicity may then be avoided.
1mportant
new knowledge regarding the clinical
a pharmacology of the digitalis glycosides has be-
come available in the past decade. This -paper outlines and summarizes the advances of clinical value. This effort will be directed toward the major glycosides in clinical use today, digoxin and digitox- . in. An attemut is made to correlate the knowns, unknowns, and variables to be considered in clinical therapy. 'From the Medical Service, Veterans Administration Hospital, and the Department of Medicine and Division of Cardiology, University of Arkansas School of Medicine, Little Rock, Arkansas. Supported in part by USPHS grant HE 06642, the Burrou hs Wellcome Company (USA), Inc., Tuckahoe, NY, an8 the Arkansas Heart Association. *'Professor of Medicine, University of Arkansas School of Medicine, and Director, Division of Cardiology, University and Veterans Hospitals. +Assistant Professor of Medicine, University of Arkansas School of Medicine, and Chief, Gastroenterology Section, Veterans Administration Hospital. :Associate Professor of Medicine, University of Arkansas School of Medicine, and Chief, Cardiology Section, Veterans Administration Hospital. §Professor of Medicine, University of Arkansas School of Medicine, and Assistant Chief, Medical Service, Veterans Administration Hospital.
Absorption Digitoxin has been shown in clinical studies to be virtually 100 percent absorbed,' and except for a mechanism to explain this fact,*,:{ little has been added to existing knowledge in this area. Digoxin, on the other hand, originally thought to be only about 50 to 60 percent absorbed,4 has been shown by radioactive tracer techniques to be 80 to 90 percent absorbed." These differences in absorption are best explained by the polar structure of the two compounds, as they are chemically very similar (digoxin is 12hydroxydigitoxin). Figure 1 shows graphically the similar structure of these compounds, the only difference being a hydroxyl group at position 12 on the digitoxin molecule. This minor difference creates a real metabolic difference between the glycosides, digitoxin being a nonpolar compound and digoxin a polar compound. Any polar compound is more readily absorbed and exchanged by the human body and nonpolar compounds are less likely to be
DOHERTY ET AL
FIGURE1. S t n ~ c h ~ rchemical al formula of digitoxin and digoxin ( 12-hydroxydigitoxin). The only difference in the molecule is noted at position 12 on the steroid nucleus, where a hydroxyl group replaces a hydrogen ion.
absorbed, thus an important difference is already extant. This feature lends itself to further analysisenterohepatic recycling of the drugs and their metabolic products. Digitoxin (and its metabolites ), therefore, is extensively recycled through the bowel. It is excreted largely in the bile and then reabsorbed to perpetuate its own body stores. Calculations by Okita2 indicate that 26 percent of a given amount of digitoxin is recycled in the intestine, and Katzung and Meyers:' have shown that biliary fistula surgically induced in dogs will significantly reduce the digitoxin half-time (the time required for one-half of the drug present in the body at a given time to be excreted or metabolized ) . Caldwell and GreenbergerG demonstrate a modest but similar reduction in the serum half-time in human subjects given cholestyramine, a compound which binds digitoxin in the small intestine and thus prevents recycling. This demonstrates that the human subject receiving digitoxin recycles the drug (and its metabolites) rather extensively. Digoxin has been shown in human subjects with surgically induced biliary fistula to lack extensive recycling, only 6.8 percent of a given dose being recycled through the bowel as determined by Okita's f o r m u l a . T h e serum T % of these patients did not differ from those without biliary fistula,7-8 indicating that this factor is of minor importance in digoxin metabolism. It appears that polar characteristics may contribute greatly to absorption and half-time of these digitalis glycosides.
Excretion Digitoxin, reported to be excreted largely in the
urine," is excreted primarily in the bile as metabolites, recycled, and is ultimately excreted as cardioinactive metabolites in the urine. Digoxin has been shown to be excreted mostly in the urine as the unchanged glycoside, and excretion is predictably related to the creatinine clearance.*-" Digoxin clearance is virtually unity with creatinine and, although less specific because of prerenal azotemia, is inversely related to the level of the blood urea nitrogen. It follows that digoxin excretion (and by extension, half-time and therapeutic activity) is prolonged in renal insufficiency and dosage should be curtailed accordingly. Digitoxin excretion has not been reported to be reduced in liver disease, as might be expected because of the biliary recycling and extensive hepatic metabolism. Digitoxin blood levels also appear to be somewhat higher than usual in renal insufficiency, although T % does not appear to be unduly prolonged." As a smaller fraction of digitoxin is excreted unchanged in the urine, excretion cannot be predictably related to renal function. Digitoxin dosage in these clinical situations continues to be governed by the clinical judgment of the physician, and errors should be made on the conservative side.
Metabolism Digitoxin is extensively metabolized by the human body, and digoxin is relatively little metabolized. The "normal" metabolic end products of digitoxin are, in general, much less cardioactive than the parent compound. The principal cardioactive metabolite is digoxin ( 12-hydroxydigitoxin ) which represents only 7.7 percent of the total daily excreCHEST, VOL. 59, NO. 4, APRIL 1971
Ii
NEW INFORMATION REGARDING DIGITALIS METABOLISM
DIG ITOX lN
( Nonpolar)
Serum T V t = 5doys
r 1"
2% Stool Dally
DAY8
-
= 15 20% of total body stores
16% Urine Doily
excreted per day 2 % as Dlgltoxln 18% or metobolitrs 9 2 % inactive 8% octivo
tory losses of the glycoside estimated by Jelliffe and co-workers. 1 :{ Under unusual circumstances, it appears that both digoxin and digitoxin may follow abnormal metabolic pathways. Luchi and Gruberl4 have reported an instance of abnormal metabolism of digoxin resulting in the production of dihydrodigoxigenin, a cardioinactive metabolite, and a concomitant increase in digoxin requirements. Solomon and coworkers1: report drug induction of digitoxin metabolism by phenylbutazone (Butazolidin) with increased conversion of digitoxin to digoxin and an appropriate shortening of the serum T X which resulted in increased digitoxin dosage requirements. The nonpolar structure of digitoxin leads to protein binding" and conversely, polar digoxin is virtually nonprotein-boundlVn the blood serum. The native antigenic potential of either of these compounds appears to be slight; however, binding to protein might produce an antigen complex with resultant development of antibodies. This is the basis for the digoxin-antibody serum assay described by Butler and C h e n l i and Smith and associates.'s This technique is a major advance in determination of digitalis serum levels which correlate with myocardial concentration and toxicity to the glycoside, as well as the state of "underdigitalization." Other methods of serum digoxin assay appear less specific, but seem to be clinically useful and deserve further
CHEST, VOL. 59, NO. 4, APRIL 1971
2a. Pharmacokinetics of FIGURE digitoxin. The graph is self-explanatory and summarizes the disci~ssionin the text regarding absorption, recycling, and routes of excretion. The graph at the upper right represents the long dominant senlm half-life of the drug which is related to metabolism and excretion of the dnlg.
study.l"20 Figure 2 is designed to summarize the pharmacokinetic behavior of the digitalis glycosides digitoxin and digoxin. DISCUSSION Utilization of this new pharmacokinetic knowledge regarding the digitalis glycosides should and does lead to a more enlightened concept of digitalis usage in arrhythmias and congestive heart failure. It should be appreciated that the effects of digitalis on the conduction system of the heart (control of the ventricular rate in atrial fibrillation) and inotropic effects of the drug are not the same." Larger doses of digitalis are usually required to control arrhythmia than for salutory effect in congestive failure. Evidence for this difference includes the "unmasking" of digitalis intoxication following electrical conversion of the heart rhythm, reported by Kleiger and Lown,'%nd the subsequent reduced requirements of digitalis once normal sinus rhythm is attained. This fact enables the physician to use smi~ll doses of the glycoside with benefit and maintain a greater margin of safety in patients with sinus rhythm. Morris and colleagues2:' have demonstrated that 60 percent of the toxic dose of ouabain determined during a control period results in digitalis toxicity following induction of myocardial infarction in the same animals. The patient with con-
DOHERTY ET AL
DIGOXIN (Polar) ( 12-Hydroxydigitoxin)
/
FIGURE 2b. Pharmacokinetics of digoxin ( 12-hydroxydigitoxin). This figure reveals the same data as Figure 2a, plotted for digoxin. Note the increased excretion compared to digitoxin and the shorter dominant half-time of digoxin compared to digitoxin.
8 5 % Absorbed:
Stool Daily
gestive heart failure and acute myocardial infarction should receive small doses of digitalis to avoid this dangerous complication. Knowledge of the pharmacokinetics of the drug, plus its inotropic and dromotropic effects, forces us to reevaluate digitalis dosage regimens. It appears that with current knowledge we should be able to attain optimal effects of the glycoside with smaller doses, avoid toxicity ( a dangerous complication in the patient with congestive failure and arrhythmia or both), and achieve better control of the clinical disease state.
Dosage Schedules Doses of digitalis (digitoxin and digoxin) recommended by us are outlined in Table 1. It should be remembered that these are "average" doses, and that there is really no such thing. Each patient has a highly individual dose requirement based upon renal function (digoxin) and probably hepatic function (digitoxin), as well as other factors, and these schedules are only guidelines. Errors, should they be made, should be on the minus or low side for avoidance of toxicity. Remember: a small amount of digitalis does help increase inotropic effect. Schema proposed by Jelliffel"z4~25 offer clinically useful guidelines for therapy. Table 2 outlines the factors affecting sensitivity or resistance to therapy with digitalis.
/n
30% Urine Dally
Serum T
Ih
= 1.6 days
of total body stores excreted per day 3 0 % as Digoxin 3% as metabolites
Digitalis Zntoxication The use of low sodium diets, powerful diuretics, rest, and intelligent control or recognition of "other factors" (infections, renal complications, liver dysfunction, thromboembolic disease, electrolytes, etc) make the complication of digitalis toxicity avoidable, inexcusable, and unwise. The concept of induction of digitalis toxicity and "backing off' to a smaller dose regimen for maintenance of digitalization is no longer tenable. Smaller doses are dictated, particularly for digoxin, and a plea is made for reduced dosage regimens for all glycosides. Treatment of digitalis intoxication remains largely one of control of cardiac arrhythmias and awaiting the excretion or metabolism of the glycoside (notably shorter with digoxin). The suggestion that Table
1-Digitalb
Sensitivity and Reaiatanee.
A Increased Sensitivity to Digitalis 1 Prolonged excretion 2 Electrolyte imbalance-K+, Mg+,Ca++ 3 Increased end-organ response 4 "Overdosage" 5 Combinations of the above
B Decreased Sensitivity to Digitalis 1 Poor absorption 2 Abnormal metabolism 3 Decreased end-organ response 4 "Underdosage" 6 Combinations of the above
CHEST, VOL. 59, NO. 4, APRIL 1971
NEW INFORMATION REGARDING DIGITALIS METABOLISM Table 2-Recommended Oral Digitoxin Digoxin
IV
Doses I R.1
1.0 - 1.5 mg 1.0 - 1.5 mg 1.0 - 1.5 mg given during a single 24-hour period 1.0 - 2.5 1.0 - 2.0 1 .O - 2.0 given during a single 24-hour prriod
of
437 Digitalis. Maintenanre 0.1 - 0.15 mg 0.125 - 0.75 mg
No Loading Dose 0.1 - 0.15 mg for 25 - 30 days 0.125 0.75 mg* daily for 5 - 7 days
-
'Dosage depends on renal function, end organ response, absorption and excretion (see text).
digitalis toxicity may be ultimately controlled by digitalis antibodies which will bind the glycoside in an antigen-antibody complex seems feasible; however, many technical problems remain, some of which are: (1) Assuming the digitalis toxicity is reversed, will all inotropic effect be removed? ( 2 ) How and in what quantity should digitalis be replaced? ( 3 ) Antibody protein binding of excessive digitalis may effectively remove digitalis as an immediate problem; however, proteins have a finite half-life, and is the digitalis then released to again produce toxicity? One may see that with the ultimate availability of digitalis antibodies for management of toxicity, many problems remain. Conventional therapy with potassium salts, antiarrhythmic agents (particularly diphenylhydantoin, lidocaine, and propanolol), cautious use of diuretics if indicated, and withholding the drug still appear to form the basis of treatment of digitalis intoxication. The use of digitalis-specific binding antibodies, "induction," and drug interference with enterohepatic recycling show promise for the future in the management of digitalis toxicity. For the present, cautious dosage, careful electrolyte monitoring, and awareness of renal and hepatic function appear to be the best methods for prevention (and management) of our present epidemic of digitalis intoxication. ACKNOWLEDGhfENTS: Jacquelyn Gammill, BS, hIT (ASCP) and Joyce Sherwood, BS, MT (ASCP) gave technical nssistance.
REFERENCES
1 Gold H, Cattell McK, Modell W, et al: Clinical studies on digitoxin (Digitaline nativelle). J Pharmacol Exp Ther 82: 187-195, 1944 2 Okita CT: Species difference in duration of action of cardiac glycosides. Fed Proc 26: 1125-1130, 1967 3 Katzung BG, hleyers FH: Excretion of radioactive digitoxin by the dog. J Pharmacol Exp Ther 149:257-262, 1965 4 Gold H, Cattell hIcK, Greiner T, et al: Clinical pharmacology of digoxin. J Pharmacol Exp Ther 109:45-57, 1953 5 Doherty JE, Flanigan WJ, hlurphy XIL, et al: Studies with tritiated digoxin XIV: Enterohepatic circulation, absorption, and excretion studies in human volunteers. Circulation, in press 6 Caldwell JH, Creenberger NJ: Cholestyramine enhances digitalis excretion and protects against lethal intoxication. J Clin Invest 49:16a, 1970
CHEST, VOL. 59, NO. 4, APRIL 1971
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