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Reappraisal of digitalis. Part IV. Metabolism of the cardiac glycosides
Appraisalandreappraisalofcardiac therapy Edited by Arthur c. DoGraff and
Reappraisal Metabolism
Alan
F. Lyon
of digitalis. Part IV. of the cardiac glycosides
Alan F. Lyon, M.D.* Arthur C. DeGra$, M.D.** New York, N. Y.
T
here are two major reasons why the use of digitalis remains empirical. The first concerning the uncertainty of its precise physiologic effects has already been reviewed in this series. The second reason is incomplete knowledge of its absorption, distribution, metabolism, and excretion. Although there is information concerning a few glycosides in a few animal species, differences between glycosides, differing responses to the same glycosides in different species, and differing responses even in different individuals of the same species are known to exist and cannot be adequately explained. The lack of detailed information, despite much ingenious and tedious investigation, is due to the difficulty in the identification of the digitalis glycosides and their metabolites in tissue. The total amount of any glycoside in therapeutic dosage in the body at any time is very small, and most of this is fixed to tissue. The quantities of digitalis in the blood are, therefore, infinitesimal, and blood levels are of little value in the study of its metabolism. Since digitalis glycosides are steroid compounds, quite similar to many natural substances in the body, chemical separation is difficult. Although there are a number of reagents, both acidic and basic, which combine Received for publication Sept. 19. 1966. *Chief, Cardiology Section, Veterans Administration **Professor of Therapeutics. New York University ministration Hospital, Bronx, N. Y.
838
with the digitalis glycosides and allow precise quantitative determination, none of these is unaffected by other tissue substances, and they cannot be used for direct assay in biological systems. On the other hand, bioassay can be accomplished by measuring the effect of a test substance on contractility of cat papillary muscle or on the cardiac rhythm of chick or duck embryo. Finally, isotope assay has been accomplished with two glycosides, digitoxin and digoxin. Digitoxin has been prepared as the Cl4 isotope by isolation from the plant, Digitalis pur+rea grown in an atmosphere containing C1402. Digoxin is available in the tritiated form, that is, with tritium substituted for hydrogen. Both the bioassays and isotope assays are extremely sensitive, but cannot be used on unprepared tissue samples, because of the interference or the toxicity of other substances in the case of the bioassays, and because of uncertainty about the persistence of the isotope tag on a cardioactive glycoside in the case of the isotope assays. Therefore, in all cases the tissue sample, whether blood, urine, or tissue homogenate, must first be prepared by some kind of separation, usually chromatographic, using one or more of the chemical reagents mentioned above, and then Hospital. Bronx, N. Y. College of Medicine, and Consultant
in Cardiology,
Veterans
Ad-
Reappraisal
elution and measurement. A tremendous amount of work is involved in such studies; hence, only limited data are available. Although these data agree in trend, there are many presently unreconciled discrepancies in the results obtained by various assay methods. Therefore, only an outline of the metabolism of the digitalis glycosides can be presented at this time with any degree of reliability. There is a marked difference in the metabolism of the clinically used cardiac glycosides, depending on their degree of polarity or water solubility. Digotoxin is the most-studied example of the relatively nonpolar, nonwater-soluble, lipid-soluble glycosides; ouabain at the other extreme is more polar, less lipid soluble, and more water soluble. Intermediate between these compounds is digoxin, on which a fair amount of information is available. It is generally agreed that digitoxin is almost completely absorbed from the gastrointestinal tract. Ouabain and lanatoside C are poorly absorbed, presumably because they are less lipid soluble. Another factor that may be operating to interfere with gastrointestinal absorption of many of the strophanthus group, and of gitoxin, is the destruction of the drugs in the gastrointestinal tract because of greater susceptibility to gastrointestinal enzymes. Information about the absorption of digoxin is less clear. Prior to the availability of isotope assay there were various clinical studies, some of which showed digoxin to be equally potent orally and intravenously, and others which seemed to show as much as a 2:l difference. Studies of tritiated digoxin show that about 90 per cent of digoxin is absorbed but that 20 per cent can be recovered from the stool, the additional 10 per cent resulting from biliary excretion. In one patient who required a large amount of digoxin clinically, 35 per cent of a single dose was found in the stool. Whether this was due to decreased absorption or increased biliary excretion is not known. Such individual variation may account for the discrepancies in previous clinical studies. Once absorbed into the circulation, all digitalis preparations are widely distributed through the body and rapidly fixed
of digitalis.
Part IV
839
to tissue. Nearly complete disappearance from the blood is rapid. The concentration of labeled digitoxin given intravenously has been reported to fall to 12 per cent of the initial level at 15 minutes, and to less than 5 per cent at 3 hours. Tritiated digoxin given in a single dose intravenously falls to 10 per cent of the initial level after 3 minutes, and to 2.8 per cent at 1 hour. The more polar, short-acting glycosides have not been identified one-half hour after a single dose. With the use of precise techniques, a small amount of digoxin continues to be found in the serum with a half life of 23 hours. This is at a very low level, one fortieth of the tissue concentration, but appears to be in equilibrium with it. Small amounts of digitoxin are more easily identifiable in the serum and persist for even longer times. This is due to protein binding, probably to albumin, and may be an important factor in the long duration of action of digitoxin. The distribution of digitalis glycosides to tissues is fairly uniform and does not show any predilection for cardiac muscle. If anything, higher concentrations are recorded in the liver and organs of excretion. C14-digitoxin concentration in the heart has been found to be from 0.5 to 2 times lo-* molar. A partial blood-brain barrier to distribution has been demonstrated; at least for digoxin. The fate of the various digitalis glycosides varies widely. The more polar, and clinically shorter-acting, ouabain and lanatoside C are excreted rapidly through the bile. It has been reported that 83 to 93 per cent of a single intravenous dose of ouabain, and 60 to 8.5 per cent of a similar dose of lanatoside C could be identified in the bile 5 hours after administration. At the opposite extreme is digitoxin, which persists for a long time in the body both as unchanged digitoxin (with a half life of 9 days) and as cardioactive metabolites. About 70 per cent of digitoxin is metabolized prior to excretion. A considerable portion of this is via hydroxyation to compound G, which has now been identified to be digoxin. Another metabolite, not yet identified, is called compound C. It is identical to compound B, formed from administered digoxin. About 70 per
840
Am. Heart 1. December, 1966
Lyon and DeQra$
cent of digitoxin and its metabolites can be recovered from the urine, about 20 per cent in the first 3 days and the rest over a period of 40 days. About 10 per cent of digitoxin is excreted in the bile; some of this is probably reabsorbed, but some appears in the stool. Further evidence of the long duration of digitoxin in the body is the persistence of S-T segment and T-wave abnormalities in the postexercise electrocardiogram of some normal subjects for up to 6 weeks after a single dose of digitoxin. Digoxin is intermediate in rate of excretion and metabolic degradation. Only about 5 to 10 per cent of digoxin is transformed prior to excretion. Unlike digitoxin, which is probably degraded in the liver, the metabolic alteration of digoxin takes place primarily in extrahepatic sites. The biologic half life of digoxin is only 1.5 days. About 80 per cent of an intravenous dose is finally excreted in the urine, and the remainder in the stool. Thirty-seven per cent of a single dose has been reported to be excreted in the urine in the first 3 days, and essentiallyall is excreted in 10 days. This correlates with the electrocardiographic findings that S-T segment and T-wave abnormalities persist in the postexercise electrocardiogram for only 4 days after a single dose of digoxin. Clinical importance is attached to the effect of three conditions on the metabolism of digitalis glycosides: these are uremia, severe liver disease, and cardiopulmonary bypass. In each instance, the present evidence is either fragmentary or, to some extent, contradictory. In the case of uremia, it would appear, at least in the case of digoxin, that patients with severe renal insufficiency have a reduced rate of excretion. On the basis of these data, with some extrapolation, it has been suggested that,
in patients with blood urea nitrogen of 50 mg. per cent or more, the maintenance dose of digoxin be reduced to one half or one third of the usual dose. There is no information on the effect of renal insufficiency on the initial loading doses. Studies with tritiated digoxin in patients having hepatic insufficiency have shown no change in the rate of its excretion in the urine or feces or in the partition of metabolites. On the other hand, animal studies employing partial hepatectomy showed slow disappearance of ouabain because of interference with excretion, and slow disappearance of digitoxin because of slower degradation. The clinical significance of these observations is not clear. The effect of cardiopulmonary bypass on stores of digitalis is also uncertain. It has been shown that no significant amount of digitalis is removed by hemodialysis in uremic patients. Investigators differ about the effect of cardiopulmonary bypass, with reports of either no significant change or a modest loss of digitalis. The problem is further complicated by the observation that tritiated digoxin is handled differently from the normal in the post-bypass state, with a faster turnover initially and then slower turnover. REFERENCES 1. Okita, G. T.: Pharmacology of digitalis, Fed. Clin. North America 11:229,1964. 2. Wright, S. E.: The metabolism of cardiac glycosides, Springfield, Ill., 1960, Charles C Thomas. 3. Doherty, J. E., Perkins, W. H., and Mychell, G. K.: Tritiated digoxin studies in human subiects. Arch. Int. Med. 108~531. 1961. 4. Marcus,’ F. I., and Kapadia, G: G.: The metabolism of tritiated digoxin in cirrhotic patients, Gastrcenterology47:517, 1964. 5. Doherty, J. E., and Perkins, W. H.: Tissue concentration and turnover of tritiated digoxin in dogs, Am. J. Cardiol. 17:47, 1966.
Reappraisal Metabolism
Alan
F. Lyon
of digitalis. Part IV. of the cardiac glycosides
Alan F. Lyon, M.D.* Arthur C. DeGra$, M.D.** New York, N. Y.
T
here are two major reasons why the use of digitalis remains empirical. The first concerning the uncertainty of its precise physiologic effects has already been reviewed in this series. The second reason is incomplete knowledge of its absorption, distribution, metabolism, and excretion. Although there is information concerning a few glycosides in a few animal species, differences between glycosides, differing responses to the same glycosides in different species, and differing responses even in different individuals of the same species are known to exist and cannot be adequately explained. The lack of detailed information, despite much ingenious and tedious investigation, is due to the difficulty in the identification of the digitalis glycosides and their metabolites in tissue. The total amount of any glycoside in therapeutic dosage in the body at any time is very small, and most of this is fixed to tissue. The quantities of digitalis in the blood are, therefore, infinitesimal, and blood levels are of little value in the study of its metabolism. Since digitalis glycosides are steroid compounds, quite similar to many natural substances in the body, chemical separation is difficult. Although there are a number of reagents, both acidic and basic, which combine Received for publication Sept. 19. 1966. *Chief, Cardiology Section, Veterans Administration **Professor of Therapeutics. New York University ministration Hospital, Bronx, N. Y.
838
with the digitalis glycosides and allow precise quantitative determination, none of these is unaffected by other tissue substances, and they cannot be used for direct assay in biological systems. On the other hand, bioassay can be accomplished by measuring the effect of a test substance on contractility of cat papillary muscle or on the cardiac rhythm of chick or duck embryo. Finally, isotope assay has been accomplished with two glycosides, digitoxin and digoxin. Digitoxin has been prepared as the Cl4 isotope by isolation from the plant, Digitalis pur+rea grown in an atmosphere containing C1402. Digoxin is available in the tritiated form, that is, with tritium substituted for hydrogen. Both the bioassays and isotope assays are extremely sensitive, but cannot be used on unprepared tissue samples, because of the interference or the toxicity of other substances in the case of the bioassays, and because of uncertainty about the persistence of the isotope tag on a cardioactive glycoside in the case of the isotope assays. Therefore, in all cases the tissue sample, whether blood, urine, or tissue homogenate, must first be prepared by some kind of separation, usually chromatographic, using one or more of the chemical reagents mentioned above, and then Hospital. Bronx, N. Y. College of Medicine, and Consultant
in Cardiology,
Veterans
Ad-
Reappraisal
elution and measurement. A tremendous amount of work is involved in such studies; hence, only limited data are available. Although these data agree in trend, there are many presently unreconciled discrepancies in the results obtained by various assay methods. Therefore, only an outline of the metabolism of the digitalis glycosides can be presented at this time with any degree of reliability. There is a marked difference in the metabolism of the clinically used cardiac glycosides, depending on their degree of polarity or water solubility. Digotoxin is the most-studied example of the relatively nonpolar, nonwater-soluble, lipid-soluble glycosides; ouabain at the other extreme is more polar, less lipid soluble, and more water soluble. Intermediate between these compounds is digoxin, on which a fair amount of information is available. It is generally agreed that digitoxin is almost completely absorbed from the gastrointestinal tract. Ouabain and lanatoside C are poorly absorbed, presumably because they are less lipid soluble. Another factor that may be operating to interfere with gastrointestinal absorption of many of the strophanthus group, and of gitoxin, is the destruction of the drugs in the gastrointestinal tract because of greater susceptibility to gastrointestinal enzymes. Information about the absorption of digoxin is less clear. Prior to the availability of isotope assay there were various clinical studies, some of which showed digoxin to be equally potent orally and intravenously, and others which seemed to show as much as a 2:l difference. Studies of tritiated digoxin show that about 90 per cent of digoxin is absorbed but that 20 per cent can be recovered from the stool, the additional 10 per cent resulting from biliary excretion. In one patient who required a large amount of digoxin clinically, 35 per cent of a single dose was found in the stool. Whether this was due to decreased absorption or increased biliary excretion is not known. Such individual variation may account for the discrepancies in previous clinical studies. Once absorbed into the circulation, all digitalis preparations are widely distributed through the body and rapidly fixed
of digitalis.
Part IV
839
to tissue. Nearly complete disappearance from the blood is rapid. The concentration of labeled digitoxin given intravenously has been reported to fall to 12 per cent of the initial level at 15 minutes, and to less than 5 per cent at 3 hours. Tritiated digoxin given in a single dose intravenously falls to 10 per cent of the initial level after 3 minutes, and to 2.8 per cent at 1 hour. The more polar, short-acting glycosides have not been identified one-half hour after a single dose. With the use of precise techniques, a small amount of digoxin continues to be found in the serum with a half life of 23 hours. This is at a very low level, one fortieth of the tissue concentration, but appears to be in equilibrium with it. Small amounts of digitoxin are more easily identifiable in the serum and persist for even longer times. This is due to protein binding, probably to albumin, and may be an important factor in the long duration of action of digitoxin. The distribution of digitalis glycosides to tissues is fairly uniform and does not show any predilection for cardiac muscle. If anything, higher concentrations are recorded in the liver and organs of excretion. C14-digitoxin concentration in the heart has been found to be from 0.5 to 2 times lo-* molar. A partial blood-brain barrier to distribution has been demonstrated; at least for digoxin. The fate of the various digitalis glycosides varies widely. The more polar, and clinically shorter-acting, ouabain and lanatoside C are excreted rapidly through the bile. It has been reported that 83 to 93 per cent of a single intravenous dose of ouabain, and 60 to 8.5 per cent of a similar dose of lanatoside C could be identified in the bile 5 hours after administration. At the opposite extreme is digitoxin, which persists for a long time in the body both as unchanged digitoxin (with a half life of 9 days) and as cardioactive metabolites. About 70 per cent of digitoxin is metabolized prior to excretion. A considerable portion of this is via hydroxyation to compound G, which has now been identified to be digoxin. Another metabolite, not yet identified, is called compound C. It is identical to compound B, formed from administered digoxin. About 70 per
840
Am. Heart 1. December, 1966
Lyon and DeQra$
cent of digitoxin and its metabolites can be recovered from the urine, about 20 per cent in the first 3 days and the rest over a period of 40 days. About 10 per cent of digitoxin is excreted in the bile; some of this is probably reabsorbed, but some appears in the stool. Further evidence of the long duration of digitoxin in the body is the persistence of S-T segment and T-wave abnormalities in the postexercise electrocardiogram of some normal subjects for up to 6 weeks after a single dose of digitoxin. Digoxin is intermediate in rate of excretion and metabolic degradation. Only about 5 to 10 per cent of digoxin is transformed prior to excretion. Unlike digitoxin, which is probably degraded in the liver, the metabolic alteration of digoxin takes place primarily in extrahepatic sites. The biologic half life of digoxin is only 1.5 days. About 80 per cent of an intravenous dose is finally excreted in the urine, and the remainder in the stool. Thirty-seven per cent of a single dose has been reported to be excreted in the urine in the first 3 days, and essentiallyall is excreted in 10 days. This correlates with the electrocardiographic findings that S-T segment and T-wave abnormalities persist in the postexercise electrocardiogram for only 4 days after a single dose of digoxin. Clinical importance is attached to the effect of three conditions on the metabolism of digitalis glycosides: these are uremia, severe liver disease, and cardiopulmonary bypass. In each instance, the present evidence is either fragmentary or, to some extent, contradictory. In the case of uremia, it would appear, at least in the case of digoxin, that patients with severe renal insufficiency have a reduced rate of excretion. On the basis of these data, with some extrapolation, it has been suggested that,
in patients with blood urea nitrogen of 50 mg. per cent or more, the maintenance dose of digoxin be reduced to one half or one third of the usual dose. There is no information on the effect of renal insufficiency on the initial loading doses. Studies with tritiated digoxin in patients having hepatic insufficiency have shown no change in the rate of its excretion in the urine or feces or in the partition of metabolites. On the other hand, animal studies employing partial hepatectomy showed slow disappearance of ouabain because of interference with excretion, and slow disappearance of digitoxin because of slower degradation. The clinical significance of these observations is not clear. The effect of cardiopulmonary bypass on stores of digitalis is also uncertain. It has been shown that no significant amount of digitalis is removed by hemodialysis in uremic patients. Investigators differ about the effect of cardiopulmonary bypass, with reports of either no significant change or a modest loss of digitalis. The problem is further complicated by the observation that tritiated digoxin is handled differently from the normal in the post-bypass state, with a faster turnover initially and then slower turnover. REFERENCES 1. Okita, G. T.: Pharmacology of digitalis, Fed. Clin. North America 11:229,1964. 2. Wright, S. E.: The metabolism of cardiac glycosides, Springfield, Ill., 1960, Charles C Thomas. 3. Doherty, J. E., Perkins, W. H., and Mychell, G. K.: Tritiated digoxin studies in human subiects. Arch. Int. Med. 108~531. 1961. 4. Marcus,’ F. I., and Kapadia, G: G.: The metabolism of tritiated digoxin in cirrhotic patients, Gastrcenterology47:517, 1964. 5. Doherty, J. E., and Perkins, W. H.: Tissue concentration and turnover of tritiated digoxin in dogs, Am. J. Cardiol. 17:47, 1966.