Frank I. Marcus

is Professor of Medicine and Chief, Section of Cardiology at the University of Arizona Health Sciences Center, Tucson. He received his M.D. from the Boston University School of Medicine and did his internship and residency at the Peter Bent Brigham Hospital, Boston. Dr. Marcus’ special areas of interest are clinical cardiology and clinical pharmacology.

I wish it was as easy to write upon the Digitalis-I despair of pleasing myself or instructing others, in a subject so difficult. It is much easier to write upon a disease than upon a remedy. The former is in the hands of nature, and a faithful observer with an eye of tolerable judgement, cannot fail to delineate a likeness. The latter will ever be subject to the whims, the inaccuracies, and the blunders of mankind. -William Withering, M.D.: An Account of the Foxglove, 1785 Knowledge of digoxin pharmacokinetics (absorption, distribution, biotransformation and elimination) has resulted in several major changes in its use. Among the most important are the general use of lower doses for maintenance therapy and the initiation of digoxin therapy without a loading dose with the assurance that drug accumulation will occur and reach a plateau in 5- 7 days. Knowledge of digoxin pharmacokinetics should result in a decreased incidence of digitalis toxicity; nevertheless, cases of digitalis toxicity are not a rarity, even at a university hospital where serum digoxin levels are easily monitored and the house staff is regularly instructed regarding the proper use of this agent. Since dosage determinations in the individual patient must be guided by the principles of pharmacokinetics of digoxin, it is important to review current knowledge of them. This review will also summarize information regarding the efficacy and indications for the use of digoxin in various clinical situations.

DIGOXIN

ABSORPTION

GASTRIC ABSORPTION There is minimal but measurable absorption of digoxin from the stomach. Essentially all of the digoxin recovered from the stomach after 30 minutes can be identified as unchanged by thin 8

layer chromatography, but when given in tablet form, it may remain in the stomach sufficiently long to undergo some hydrolysis.’ Digoxin and its derivatives are not stable in acidic buffer solutions; they are nearly completely hydrolyzed at pH 1 after a 2-hour period, but are stable above pH 3. Since extensive intragastric hydrolysis of digoxin may occur if the gastric acidity approaches a pH of l- 2, it is conceivable that a considerable amount of digoxin may be hydrolyzed to active as well as to inactive metabolites in patients who have peptic ulcer with markedly delayed gastric emptying.“’ 3x’ ABSORPTION FROM THE SMALL AND L,ARGE BOWEL

Digoxin is absorbed by a passive (nonenergy dependent), nonsaturable transport process.“. fi It is well appreciated that digitoxin is completely absorbed. Cardiac glycosides that are more polar than digitoxin (those that have a greater number of hydroxyl groups) are less well absorbed. Ouabain, which has many hydroxyl groups and is quite water soluble, essentially is not absorbed.7 Digoxin appears to be absorbed throughout the small intestine and colon,H but mostly in the proximal part of the small intestine. However, the lower small intestine is also capable of digoxin absorption.H Digoxin has been found to be slowly but well absorbed from the transverse as well as the sigmoid colon.v-10 The extent of absorption appears to be similar whether the drug is taken in the fasting state or after meals,” but a high fat intake appears to result in a lower steady-state serum concentration, even allowing for the effect of body weight, serum creatinine and sex.12 The enterohepatic circulation (intestinal reabsorption) of digoxin does not appear to be a significant factor in its metabolism and has been calculated to represent about 6.5% of the administered dose in man.‘” MALABSORPTION

There is some dispute as to whether digoxin is well absorbed in malabsorption syndromesl+‘” The problem of malabsorption was investigated in our laboratory before and an average of 2 months after jejunoileal bypass was performed for morbid obesity.17 This procedure leaves only 12 in. of the jejunum anastomosed to 6 in. of the distal ileum; the rest of the small intestine is excluded from the absorptive process. Malabsorption of fat and nxylose was demonstrated in these patients. Despite this severe diminution of the surface available for absorption, the average digoxin bioavailability in these patients after surgery

was 87% of that prior to surgery. This study was done utilizing digoxin tablets with a dissolution rate of 69% in one hour. It would appear that when the dissolution rate of digoxin is greater than 65%, which is the minimum standard stipulated by the Food and Drug Administration (FDA), malabsorption of digoxin should be unusual in malabsorption states. ) ROBERTA. O’ROURKE:Earlier investigations suggesting decreased digoxin absorption in patients with celiac disease, sprue and pancreatic insufficiency were performed prior to the FDA minimum standard of a >65% digoxin dissolution rate. Therefore, these studies were most likely not applicable to oral digoxin preparations administered since 1974.

DRUG INTERFERENCE WITH DIGOXIN

ABSORPTION

Possible interference with digoxin absorption has been demonstrated when a single dose of digoxin is given concomitantly with antidiarrheal agents such as kaolin-pectin (Kaopectate), or with antacidsIR-‘” but it is not clear whether the concomitant administration of antacids significantly decreases steady serum concentrations.2()-21 Other drugs that can decrease bioavailability when given concomitantly with digoxin include cholestyramine z-*~ sulfasalazine (Azulfidine)24 and neomycin.“” The mechanism of the decreased absorption of these agents is not known. Lindenbaum et al. found that the inhibitory effect of neomycin was not related to alteration of the dissolution rate of digoxin tablets.z5 It was suggested that the absorption deficit is due either to an intralumenal effect, such as precipitation or complex formation, or an interference at the level of the cell membrane. It is not thought to be a direct effect of neomycin adsorption of digoxin. Similarly, the adsorption of digoxin by antacids is probably not an adequate explanation for the decrease of digoxin bioavailability. The information that certain drugs interfere with digoxin absorption is of clinical importance. Patients should be instructed to take digoxin at least 2 hours before taking any of the above preparations. DIGOXIN

BIOAVAILABILITY

Bioavailability is defined as the percentage of a drug that enters the systemic circulation in an unchanged form after oral administration of a drug product. 26 The digoxin bioavailability story is a fascinating one. It was initiated by the discovery by Lindenbaum and co-workers that different generic preparations of digoxin tablets do not have the same bioavailability.27 The fact that changes in the manufacturing process can alter bio10

availability was well illustrated when the bioavailability of digoxin from Lanoxin tablets produced in the United Kingdom was reduced in 1969 and was restored in 1972, even though established quality control of the amount of digoxin in the tablets was maintaimdZA The bioavailability of the digoxin produced in 1972 appeared to be double that in 1969. This indicated that a major change in bioavailability could occur without a dramatic reduction in content uniformity of the digoxin tablets. It would appear that a number of patients in the United Kingdom were “under-digitalized” using the standard doses of the tablets produced from 1969 to 1972. When the increase in biologic potency was discovered the practitioners were alerted to this change. Alteration in bioavailability of digoxin tablets is of more than academic interest. A recent outbreak of digoxin intoxication occurred in a foreign country after an increase in bioavailability of digoxin went unannounced by a manufacturer.2CJ The lack of relation among tablet content, uniformity of digoxin and its bioavailability posed quite a problem to the prescribing physician. However, it was soon discovered that in vitro tests of tablet dissolution rate (not necessarily disintegration rate) correlated well with bioavailability.30, 31 Subsequently, in 1974, the FDA required that all dosage forms of digoxin have a dissolution rate of greater than 65% when tested by methods detailed in the U.S. Pharmacopeia, and must meet USP requirements for content uniformity. In addition, any company marketing digoxin tablets must submit results of an in vivo comparative bioavailability study performed in cross-over design. These requirements have given the physician reassurance that digoxin can now be prescribed by generic name and that its bioavailability regardless of the manufacturer, should be equivalent. It has now been determined that digoxin tablets which have a dissolution rate of greater than 65% will have an equivalent absorption to an oral solution, such as the elixir.“’ Therefore, interchangeable doses of the rapid dissolution tablets and liquid preparations of digoxin can be used in most clinical situations. The problem of absolute bioavailability has not yet been resolved. Absolute bioauailability is defined as the percentage of unchanged drug which is absorbed as compared to the same dose of the drug given intravenously. Methods of determination of absolute bioavailability include measurement of the area under the serum concentration time curve or the 6-day total urinary excretion of digoxin after a single dose is given orally and intravenously to the same subjects. However, it has been shown that the amount of digoxin excreted, as well as the area under the serum concentration curve, is greater when digoxin is given over a one-hour period, rather than as a rapid bolu~.~” Indeed, urinary excretion is increased when a specific amount of digoxin 11

is given intravenously over 3 hours, as compared to when the same amount is given intravenously over a l-hour period.s4 Therefore, the calculation of absolute bioavailability depends on whether the intravenous dose is given as a bolus, a l-hour intravenous infusion or a 3-hour infusion. The best estimate available indicates that the average absolute bioavailability of digoxin tablets is between 60% and 80%. If one uses the value of 70% as the mean absorption, a 0.5 mg oral dose of digoxin should be equivalent to 0.35 mg of digoxin given intravenously. This ratio of 1.5 mg digoxin orally to 1.0 mg intravenously is similar to that obtained after biological titration by Wayne35 and by Gold et a1.36 many years ago. INFLUENCE PLACENTAL

OF AGE ON DIGOXIN TRANSFER

AND FETAL

DISPOSITION

CONCENTRATION

OF DIGOXIN

The serum concentration in the fetus appears to be equal to that in maternal blood after daily chronic administration of digoxin in the ewe and in the dog.37, 38 Hernandez and associates found that the concentration of digoxin in the fetal organs, including the heart, was considerably lower than in the maternal organs. The fetal-maternal ratio after chronic dosing was less than 0.25 in all instances. These investigators concluded that there is a decrease in myocardial binding of digoxin in the nearterm fetus, since the myocardial-serum concentration ratio was less in the fetus than in the ewe.* Digoxin, given acutely to the ewe, did maintain fetal cardiac output during the stress of exteriorization of the fetus.40 Allonen et al. administered 0.5 mg digoxin 24 and 4 hours prior to therapeutic abortion in 12 healthy women.41 They found a maternal-fetal serum concentration ratio of 0.6 and could not measure any digoxin in the fetal organs. On the basis of their data, they suggested that there was a lower body affinity for digoxin in the fetus, a conclusion similar to that found by Hernandez. Nevertheless, digoxin can measurably affect the fetus, as demonstrated by Fouron who showed digitalis effect on the fetal electrocardiogram of the dog at the same time that the maternal dog showed multiple ectopic beats consistent with digitalis intoxication. This information - that digoxin, in usual therapeutic doses, has an effect on the fetus- has been used successfully to treat supraventricular tachycardia detected in the fetus. The decrease in the myocardial-to-serum digoxin concentration ratio in the fetus apparently cannot be attributed to a de*The findings of Berman et aLTJ9are not in agreement with those of Hemandez. Berman infused digoxin into both ewes and fetuses until steady state and found that the myocardialiplasma concentration ratios were similar.

crease in the activity of Na-K-ATPase, the presumed digitalis receptor site, since the activity of this enzyme in the fetus and newborn appears to be greater t,han that in the mature mongrel dog.42 PHARMACOKINETICS

OF DIC~XIN

IN THE INFANT

Considerable investigation of the pharmacokinetics of digoxin in premature and full-term infants as compared to the adult has resulted in only partial clarification.4:S* 44 The absorption, serum half-life and excretion of digoxin in urine and stool were found to be similar in infants and adults in some of the earlier studies by Hernandez et al.*” and by Dungan et a1.46 More recent studies have found an increased mean serum half-life of 57 hours in premature newborns as compared to a mean of 35 hours in the mature newborns.47 This increased half-life in the premature infant has been attributed, in part, to a decrease in the renal clearance of digoxin.4X, 4R There appears to be an increase in the volume of distribution in the newborn.50, j* Glantz et al. attributed this increased volume of distribution to an increase in the plasma volume and in the interstitial volume of digoxin in puppies as compared with adult animals.50 Contributory to this increase in the volume of distribution may be an increased tissue and red cell binding in the newborn.s2, s3 The pharmacokinetic findings have been summarized in Table 1. The observation of an increased volume of distribution in the newborn has been used to explain the relatively lower serum concentrations per unit digoxin administered and the need for higher doses of digoxin per kilogram body weight in infants (Table 21. The increase in biologic half-life TABLE

l.-PHARMACOKINETICS AS COMPARED

OF DIGOXlN WITH ADULTS

IN INFANTS

Larger plasma and intestinal volume Increased tissue and RBC binding Decreased skeletal muscle mass Net effect Increased volume of distribution

!

Factor Decreased glomerular filtration rate in premature infants Increased digoxin-creatinine clearance ratio Net effect Increase in half-life (premature infants) No change in half-life (full-term infants)

t w

TABLE

2. -RECOMMENDED IN PEDIATRIC

Oral

0.03-0.05

Intravenous

0.02-

0.04-

0.04

DOSAGE PATIENTS

0.06

0.03-0.05

OF

0.04-

0.02-0.06

0.06

DIGOXIN

VlO - 115 of loading dose in premature5 and newborns; v5 - ‘I3 of loading dose in 2 divided doses in infants and children.

As above

may explain the increased serum concentration of digoxin per dose in premature infants. The pediatrician recognizes that both the loading and the maintenance dose must be decreased in the premature infant to avoid toxicity (see Table 2). RESISTANCE TO DIGITALIS FETUS AND NEWBORN

TOXICITY

IN THE

The serum concentration may have to be interpreted differently in the infant than in the adult, since it has been found at post mortem that the myocardial-serum concentration ratio was twice as high in the former as in the latter.52, 53 In these studies, both the infants and the adults received digoxin for at least 5 days and therefore could be said to be in a steady state. There was no evidence of toxicity in any of these infants. Experimental evidence to support the hypothesis of myocardial resistance to digitalis toxicity in the newborn has been provided by Rosen and co-workers.54 They performed electrophysiologic studies on cardiac Purkinje fibers from neonatal (l- 7 days), young (4- 7 weeks) and adult dogs, and found that ouabain induced smaller changes in the action potential of Purkinje fibers taken from the younger animals; this occurred despite the fact that the ouabain uptake in the Purkinje fibers from the younger animals was higher than in the adult dogs. These results suggest that Purkinje fiber sensitivity to ouabain effects increases with age. These studies may explain why infants are more resistant to digitalis toxicity than the adult. Kelliher and Roberts have shown that the dose of ouabain necessary to produce ventricular tachycardia and death in l -4-week-old rabbits is significantly greater than that required in older animals.“” The age-dependent decrease in the dose of ouabain necessary to produce ventric14

ular tachycardia, ventricular fibrillation and death showed an inverse correlation with the increase in ventricular norepinephrine content with increasing age.>: Further insight in the interpretation of serum digoxin levels was provided by Berman et al.:!!’ These investigators infused digoxin into fetuses, and found a mean steady-state plasma digoxin concentration of 4.5 rig/ml. AV dissociation occurred in only 1 of the 6 fetuses, and in that animal the serum concentration was 9.0 rig/ml. Arrhythmias occurred in 6 of 8 ewes infused with digoxin when the mean steady-state plasma digoxin concentration was 2.3 rig/ml. Myocardial-plasma concentration ratios were similar in the ewes and the fetuses. The above data are in agreement with the earlier studies of Wollenberger and associates, who showed that the susceptibility of the guinea pig to the toxic action of ouabain increases between the age of 3 weeks and 5’/2-?/2 months.“” This finding was made in the isolated heart, as well as in the intact preparation. These observations have been confirmed clinically, since digoxin levels in excess of 2 rig/ml are frequently found in infants receiving standard maintenance therapy without any ECG evidence of toxicity. Conversely, digoxin intoxication is unlikely to be present in infants when serum digoxin concentrations are less than 2 rig/ml. Digoxin toxicity appears to be fairly common when the serum concentration is in excess of 3.5 ngiml. Serum digoxin levels up to and even in excess of 5 rig/ml have been reported in children who have shown no evidence of digitalis toxicity.57-“” The dosage of digoxin recommended for infants and children is given in Table 2. Wettrell and Andersson,“3 reported that in neonates (less than 1 month), a daily oral maintenance dose of 0.01 mg/kg body weight resulted in a serum concentration of digoxin between 1 - 2 rig/ml. In infants i I- 12 months), a daily oral maintenance dose of 0.015-0.020 mg/kg body weight yielded a serum concentration in the same range. DIGOXIN DOSE-RESPONSE FETUS AND NEWBORN

REI,ATION

IN THE

The question of whether higher serum levels are needed to obtain the necessary inotropic effect of digoxin in the fetus was studied by Berman et al.:‘” The decrease in pre-ejection periodleft ventricular ejection time ratio was less in the fetus than in the ewe at similar plasma concentrations of digoxin, indicating less responsiveness to digitalis in the fetus. A decrease in responsiveness of rabbit papillary muscle to ouabain from the newborn has been reported.fi” Levy and co-worker#l determined the systolic time intervals in normal neonates and in those with congestive heart failure before and after administration of digoxin. Maximal inotropic effects, as measured by shortening of 15

the left ventricular pre-ejection period (PEP), were observed at digoxin doses of 30 wglkg body weight and no further shortening of PEP was observed when much larger loading doses, 80 pg/kg body weight, were used. Therefore, it appears reasonable to use the lower dosage recommended in Table 2, or those suggested by Wettrell and Andersson,“” for digoxin dosing in infants. CONCLUSIONS:

DIGOXIN

IN THE NEWBORN

The literature on the kinetics of digoxin in infants, although confusing, indicates that in comparison to adults the absorption of digoxin is no different and the volume of distribution is increased. Data are conflicting regarding the myocardial-serum concentration ratio of total digoxin. There is a decreased rate of urinary excretion and increased half-life of digoxin in the premature infant. The increased tolerance of the infant for digitalis is indicated by the observation that serum concentrations of digoxin of 2- 3 rig/ml are usually well tolerated. Nevertheless, there are some data to suggest that these higher serum concentrations are necessary for a therapeutic inotropic effect. Until these data are confirmed, doses sufficient to achieve serum concentrations similar to that in the adult should generally be used. USE OF DIGOXIN

IN THE AGED

It is common knowledge that elderly patients develop digitalis intoxication if they are maintained on doses of digoxin that are well tolerated in younger individuals. There are conflicting data on whether the myocardium in the elderly is more sensitive to digitalis glycosides. In a study of the inotropic response of the aged rat myocardium to ouabain, it was found that the peak increase in active tension over the entire range of ouabain concentrations was the same in the old and young. However, the young muscles exhibited contracture more frequently than those of the aged group at high concentrations of ouabain.G2 Baskin et a1.63 found that ATPase activity was markedly decreased in the purified microsomal fraction of rat heart between 135 and 840 days of age. Enzymatic activity was inversely related to cardiac toxicity. Pharmacokinetic studies provide an additional explanation for digitalis intolerance in the aged. Ewy et a1.‘j4 found that a single dose of tritiated digoxin injected intravenously into elderly patients resulted in a higher serum concentration than in the younger control subjects (Fig 1). The higher serum concentration of digoxin in the elderly is due primarily to two factors. The first is a decrease in renal function, as measured by decrease in glomerular filtration rate, that regularly accompanies the aging process. This is associated with a concomitant decrease in digox16

--em-.

9 Young Subjects

-

5 Old Pmants

DIGOXIN NANOGRAMS PER MI. WHOLE BLOOD

1 !--l---r----: 2

6

12

1

2

%lURS

Fig I.-Concentration of dlgoxin at intervals after digoxin to young subjects and elderly patients. (Reprinted Digoxin metabolism in the elderly. Circulation 39:449. the American Heart Association. Inc !

3

4

5

6

DAYS

the

injection of 0.5 mg from Ewy, G. A.. et al.: 1969. By permission of

in renal clearance. Therefore, the half-life of the drug is increased in the aged. In addition, elderly patients are smaller and have a decreased skeletal muscle mass, and it would be anticipated that they would have a decrease in the apparent volume of distribution (Fig 2). Since the half-life of elimination is increased and the volume of distribution is probably decreased, the steady-state serum levels should be increased as compared to serum levels in younger patients given the same dose of digoxin. Thus, the daily maintenance dose given to elderly patients should be in the range of 0.125 mg to 0.25 mg/day. Elderly patients frequently are confused by complicated directions regarding their medications; therefore, it is best to avoid the administration of a loading dose, since they may continue it with resultant toxicity. The physician should be aware that a normal serum creatinine in the elderly does not exclude a decrease in creatinine clearance or in digoxin clearance, since there may be a decrease in creatinine production which would result in a decrease in serum creatinine. In the studies of Ewy et a1.,“4 the serum creatinine in the young was 1 mg% and the mean creatinine clearance was 122 ml/minute/l.73 m’. In the elderly, the mean serum creatinine was 1.24 and the creatinine clearance was 56 I ‘7

Fig 2.-Changes in body weight composition due to aging: as fluid parameters decrease relative to total weight, the percentage of fat increases. Such changes may significantly affect drug distribution and half-life. Data illustrated are from Dittmer, D. S. (ed.), Blood and other body fluids, FASEB, 1961. More recent studies suggest, however, that in healthy elderly individuals, these body-composition changes may not be so pronounced. (Drawing by Lyn Van Eick from Lamy, P. P. Drug prescribing for the elderly, Hosp. Prac., 11(l): January, 1976. Used by permission.)

ml/minute/l.73 m2. The digoxin clearances were also diminished. It has been found that the serum creatinine in 9 subjects below the age of 50 was 0.89, with a creatinine clearance of 98.7 mg/minute/l.73 m2. In 18 patients over the age of 70, the mean serum creatinine was 1.07 and the mean creatinine clearance was 44.2 mg/minute/l.73 m2. THE EFFECT OF KIDNEY KINETICS OF DIGOXIN

DISEASE

ON THE

Digoxin is excreted principally by the kidneys. It is filtered at the glomerulus. 65 Both tubular reabsorption and secretion have been demonstrated.@6H Steiness”* demonstrated that digoxin serum levels may rise when tubular secretion is blocked by concomitant administration of spironolactone. A linear correlation between creatinine clearance and digoxin clearance has been shown by numerous investigators.““, 6g, ‘O Gault et al.‘O found a linear relation between creatinine clearance and the elimination constant of digoxin (r = .94). From this relation, they constructed a nomogram with which to predict digoxin half-life. Marcus, utilizing accumulated data from his laboratory as well as those of Doherty and co-vvorkers, was not able to predict digoxin half-life from creatinine clearance.‘” The utility of the nomogram ap18

preach to digoxin dosage remains controversial. At present, it is logical to estimate the dose ofdigoxin necessary and alter it after measurement of serum digoxin level during steady state. Nevertheless, the nomogram illustrates the importance of renal function as a major determinant of serum digoxin levels. For example, 25 of 32 consecutive patients who had values for serum digoxin levels of over 2.5 rig/ml had creatinine clearance estimated to be less than 45 ml/minute. A total of 210 patients had serum digoxin levels assayed during this per&x17” The serum half-life is prolonged from 1%/z-2 days in the individual with normal renal function to 4- 10 days in dialysis-dependent patients.70s 72 The variability in the half-life of elimination of digoxin under these circumstances may be partly due to differences in nonrenal elimination.73 Another factor that may account for the wide variation in the half-life is a decrease in the volume of distribution in digoxin in severe renal disease.74-7fi The variability in elimination of digoxin may be better understood if one realizes that the body clearance of digoxin (total of renal excretion, biotransformation and stool excretion) is directly related to the volume of distribution and inversely related to the body clearance of digoxin as follows: x volume of distribution total body clearance -= -0.693 -- ------half-life This formula

can be transposed

to read:

volume of distribution x .693 -t& = __-‘total body clearance As has been mentioned, the volume of distribution may be decreased in azotemia. The degree of diminution in volume of distribution appears to be unpredictable and not necessarily related to the degree of azotemia. The decrease in the volume of distribution of digoxin in renal disease was recently verified in our laboratory by comparing the volume of distribution in the same dog before and after experimentally induced chronic azotemia.i7 The reason for the decrease in volume of distribution has not been elucidated. It has been speculated that this may be due to a decrease in the affinity of the receptor site for digoxin.7fi The knowledge that there is a decreased volume of distribution in patients with severe renal impairment has clinical significance, since administration of the loading dose should be decreased under these circumstances. It has been observed that in 9 patients with end stage renal disease, an intravenous dose of 0.7 mg resulted in a 24-hour level of serum digoxin of 1.43 rig/ml (range 1.0-2.1~ with none of the patients showing evidence of toxicity.70 Patients with end stage renal disease who weigh 40 kg can 19

tolerate a maintenance dose of 0.0625 mg daily, while the 90 kg patient usually requires 0.1 mg/day (0.125 mg 5 days a week) to maintain a serum digoxin level in the therapeutic range. Digoxin is not removed to any significant extent by hemodialysis, since most of the drug is distributed rapidly into tissue stores. Less than 3% of an intravenously administered dose of digoxin remains in the blood after 1 hour.78 The average amount of digoxin removed during a single 6- 10 hour hemodialysis has been reported as 17 pug, or 4% of body stores.7”v RoThus, it is not necessary to adjust the dose of digoxin on dialysis days. THE EFFECT OF CHANGES IN POTASSIUM BALANCE ON THE SENSITIVITY AND INOTROPIC EFFECT OF DIGITALIS In 1952, Lown and co-workers made dogs hypokalemic by hemodialysis and found that there was a 60% decrease in the dose of acetylstrophanthidin required to produce toxicity.E1 The intimate relationship between myocardial loss of potassium and digitalis toxicity was demonstrated by Seller et al.?* who showed that pretreatment with triamterene decreased the coronary AV difference of potassium during digitalization with acetylstrophanthidin and resulted in an increased dose of acetylstrophanthidin required to produce toxicity. In turn, this allowed an increase in the inotropic effect over and above that seen before triamterene was administered. These experiments were all performed in normokalemic dogs. The question of whether digitalis sensitivity in acutely hypokalemic animals is relevant to the clinical situation in which hypokalemia is produced more gradually has been the subject of a number of investigations dating back to 1954. At that time, Zeeman et a1.8sproduced potassium depletion in dogs over a 2- 3 week period by the daily injection of desoxycorticosterone acetate and addition of 0.3% NaCl in the drinking water. They found that animals so treated were more sensitive to Lanatoside than were appropriate controls. Kleiger et a1.84 documented that puppies made hypokalemic by being fed a potassium deficient diet had a 40% decrease in tolerance to acetylstrophanthidin as compared to normokalemic controls. However, Kleiger et a1.85 could not document digitalis sensitivity in similarly potassium depleted adult dogs, although they found that the digitalis toxic arrhythmias were of longer duration in the hypokalemic adult animals. The argument as to whether or not chronic potassium depletion results in digitalis sensitivity was recently raised by Binnion,“” who found no difference in digitalis tolerance induced by acute or chronic hypokalemia. These results were challenged by Hall et al.,X7 who documented digitalis sensitivity in dogs acutely depleted by glucose and insulin infusion, as well as by 20

Gelbert et al.,8x in dogs chronically depleted by a low potassium diet and daily furosemide administration. It can be concluded that acute hypokalemia results in a dramatic digitalis sensitivity and that chronic hypokalemia is also associated with some degree of such sensitivity. This implies that the suddenness of the rate of decrease of serum potassium is related to digitalis sensitivity. It is of note that even though concentration of potassium in skeletal muscle is decreased during acute and chronic hypokalemia, there is no evidence that the myocardial concentration of potassium is diminished during chronic hypokalemia. The inotropic response to digitalis in hypokalemia was studied by GoldmanS in chronic depleted dogs. He found that their response to digoxin as well as to isoproterenol was markedly attenuated as compared to the controls, despite a decrease in NaK-ATPase activity and an unchanged rate of uptake of specifically bound digoxin. He postulated that there was a hypokalemia induced cardiomyopathy which was not evident by electron microscopy. The mechanism of the enhanced sensitivity associated with hypokalemia is still unsettled. Marcus et al. did not find an enhanced myocardial uptake of digoxin with acute hypokalemia at the onset of toxicity in dogs. HI However, Hall et alx7 interpreted their data as showing an enhanced uptake of digoxin after glucose-insulin induced hypokalemia in dogs. The inotropic response to digitalis is also greatly diminished in the presence of hyperkalemia. Yt-PBThis may be due to an inhibition of the rate of uptake or total uptake of digoxin by the myocardium because of a competition for similar binding sites by potassium.Y4-Yfi Thus, in both hypokalemia and hyperkalemia, digitalis may have less of an inotropic response as compared to the normokalemic state. The clinical significance of hypokalemia in patients receiving digitalis was recently verified by Steiness,Y’ who demonstrated that 6 of 12 patients developed ventricular and atria1 premature beats after being made hypokalemic while receiving digoxin. All 12 were in chronic congestive heart failure during the period of close observation while potassium supplementation was withdrawn and the patients were given a low potassium diet. THE EFFECT OF ALTERATIONS OF THE SERUM CONCENTRATION OF CALCIUM AND MAGNESIUM DIGITALIS EFFECT AND SENSITIVITY

ON

The literature of the 1930s and 1940s contains several reports of adverse effects - including death - following the injection of calcium to digitalized patients. This led to the admonition against the use of digitalis in patients with hypercalcemia due to the fear of inducing arrhythmias thought to be related to syn21

ergism between calcium and digitalis. Subsequently, several investigators infused digitalis to hypercalcemic dogs. Lown et alsK showed that digitalis sensitivity could not be demonstrated by infusion of acetylstrophanthidin to dogs previously treated with calcium to levels as high as 23 mEq/L. Later, Nola et alss were able to show some increased digitalis sensitivity in dogs, but only at serum calcium concentrations in excess of 15 mEq/L. It would appear that enhanced sensitivity of digitalis in the presence of hypercalcemia is probably not relevant clinically. Hypocalcemia can, however, nullify the effects of digitalis, as has been adequately demonstrated in man.‘“O In fact, digitalis may be ineffective until serum calcium is restored to normal.101 Hypomagnesemia, acutely or chronically induced in dogs, has been found to be associated with increased sensitivity to digitalis.‘O* The mechanism of enhanced sensitivity of digoxin in hypomagnesemia may be due to an increased myocardial uptake of digoxin.‘O” Hypomagnesemia was found to be present in 21% of patients with and 10% of patients without digitalis toxicity who had relatively low serum levels of digoxin.lo4 Other studies could not implicate hypomagnesemia as a factor in digitalis toxicity in manlo thus leaving its clinical significance unclear. Hypermagnesemia reverses digitalis induced arrhythmias, but does not reactivate digoxin inhibited Na-K-ATPase or decrease myocardial or microsomal digoxin binding.“)”

DIGITALIS

IN ACUTE

MYOCARDIAL

INFARCTION

Several questions will be discussed in this section. The first is, “Does digitalis exert a positive inotropic effect in the presence of an acute myocardial infarction?’ The second is, “Does the use of digitalis in acute infarction extend infarct size?” Third, “What is the overall net hemodynamic result of digitalis in acute infarction?” Finally, “Does digitalis sensitivity exist in acute infarction, and is it of clinical significance?” Let us first consider whether digitalis exerts an inotropic effect in the presence of myocardial infarction. Hood et a1.1°7 compared the effects of acetylstrophanthidin to that of isoproterenol in experimentally induced infarction in dogs. There was a diminished inotropic effect to both agents when the infarct size of the left ventricular mass exceeded 20%. Most studies have confirmed that digitalis exerts a positive inotropic effect in acute myocardial infarction. Digitalis was found to increase the contraction of the nonisehemic and borderline ischemic portion of the myocardium after coronary arterial ligation in the dog.lO”-l10 An increase in the peak first derivative of the left ventricular pressure was documented in patients with acute myocardial infarction and congestive heart failure after ouabain administration.“’ With the information that the cardiac glycosides increase 22

cardiac contractility following a myocardial infarction, why then is there controversy as to its use under these circumstances? Digitalis has a well-documented effect of increasing peripheral vascular resistance.1’2-‘14 This increase may occur prior to the inotropic effect and may be accentuated if the drug is given in large doses, and especially if given as a bolus. The increase in peripheral vascular resistance can further impair left ventricular function, resulting in a decrease in cardiac output. The increased peripheral resistance increases myocardial oxygen consumption. Since oxygen delivery is impaired in patients with acute infarction, there could be an increase in ischemia and infarct size. Therefore, the balance is a delicate one. The results of experiments to define whether digitalis is beneficial in acute myocardial infarction must be interpreted in view of the above factors. For example, if digitalis is given to the non-failing heart with resultant increase in mean arterial pressure, the extent of the ischemic injury may be increased.“” However, after experimentally induced coronary occlusion in dogs followed by acute pharmacologic depression of the dog heart by administration of phenylephrine, digitalis appears to decrease the area of ischemia as judged by decrease in the mean S-T segment elevation. Further evidence of myocardial functional improvement was seen by a decrease in left ventricular filling pressure. In man, there is evidence that digitalis preparations given to patients who are not in cardiac failure may increase infarct size, as evidenced by enhanced creatine phosphokinase (CPK) efflux,‘lR whereas preliminary data have been reported indicating that there is a decrease in CPK efflux in patients who have large infarcts and high pulmonary art.ery wedge pressures when given digoxin.“’ The hemodynamic effects of digitalis in patients with acute myocardial infarction and congestive heart failure have been variable.lJx Recently, Mason et allI reported the results of intravenous digoxin in patients with left ventricular failure and acute myocardial infarction. They found that the drug reduced a high end diastolic pressure in approximately two-thirds of the patients. Further, the cardiac output was raised substantially in over half of these patients in whom the cardiac output was below normal. Both the experimental and clinical studies of digitalis in acute myocardial infarction were reviewed by Rahimtoola and Gunnar.‘“” They concluded that digitalis is recommended in patients who have acute myocardial infarction and cardiac failure, especially if the patients have supraventricular tachyarrhythmias. Finally, there is the question of whether digitalis is hazardous to use in acute infarction because of undue sensitivity to this drug. Morris et al.“’ demonstrated digitalis sensitivity in pigs after acute infarction as compared with sham operated ani-

mals. However, these experimental data do not have significant clinical relevance in doses that are generally used and currently recommended. The fact that patients with acute myocardial infarction can tolerate digitalis well was documented by Lawn.‘** It is the author’s conclusion that digitalis can be administered safely in proper doses to patients who have acute myocardial infarction and left ventricular failure, and that moderate improvement in left ventricular function and overall hemodynamits may be expected in the majority of these patients. The drug should not be given in large doses, and especially not as a bolus. The concern that cardiac glycosides may increase infarct size in patients who have infarction and left ventricular failure has not been demonstrated and, in fact, there is evidence to the contrary. Digitalis is of greatest benefit in the patient with acute myocardial infarction who has congestive failure associated with atria1 fibrillation or atria1 flutter. Under these circumstances, the dual action of digitalis of slowing ventricular response as well as its modest inotropic effect act concomitantly to improve ventricular performance. ) ROBERT A. O'ROURKE: I agree completely with the author’s comments concerning the use of moderate doses of digoxin in patients with persistent heart failure during hospitalization for acute myocardial infarction. In the patient with cardiomegaly areas of hypokinesis and diminished left ventricular performance, digoxin will favorably influence the balance between myocardial oxygen demands and coronary blood flow, and thus possibly diminish “infarct size.” However, in patients with severe

pump failure and cardiogenic shock, digitalis adds little to more potent inotropic agents such as dopamine for its antiarrhythmic effects.

THE USE OF DIGITALIS ANGINA PECTORIS

or norepinephrine

IN PATIENTS

and is useful

only

WITH

Patients who have angina without evidence of heart failure do not generally respond to digitalis with a decrease in the frequency of angina, nor do they have an increase in exercise tolerance.123-125However, when the patient with angina has cardiomegaly or nocturnal angina, or if his exercise is limited primarily by dyspnea, the use of digitalis may be beneficial in decreasing the frequency of angina, eliminating nocturnal angina and increasing exercise tolerance. 126Whether to use digitalis in patients receiving beta blocking agents for treatment of angina depends on the state of the left ventricular function prior to the use of the beta blocking agents. If the patient with angina responds to beta blocking drugs by decreasing exercise tolerance, the addition of digitalis may improve his duration of exercise.127 In other words, patients who have abnormal left ventricular function may benefit by the combination of these two drugs. 24

F ROBERT A. O’ROURKE: In patients with angina pectoris and normal left ventricular performance, the administration of oral digoxin alone may significantly increase the angina1 attack rate as compared to treatment with an oral placeho.*Z7 ..- .-... ---____

THE USE OF DIGITALIS PULMONARY DISEASE

IN CHRONIC

OBSTRUCTIVE

There are several factors that the physician must consider in deciding whether to utilize digitalis as part of his armamentarium in treating patients with chronic obstructive pulmonary disease. The first is whether the drug is effective, and the second is whether there is an increased hazard of digitalis sensitivity in the use of this drug under the circumstances. A recent complete review of the literature by Green and Smith is highly recommended.12H Digitalis was shown by Vatner and Braunwald to have a definite inotropic effect in the conscious dog in whom heart failure was produced by a tricuspid evulsion and pulmonary stenosis.lZY These investigators noted only relatively minor positive inotropic responses in the nonfailing right heart as compared to the failing heart. In patients who have pulmonary disease without heart failure, digitalis does not appear to have any beneficial clinical effect.130 Ferrer et al.‘:” showed significant hemodynamic improvement with digitalization in patients with overt right heart failure due to car pulmonale. Acute digitalization resulted in a decrease in right ventricular end diastolic pressure and an increase in systolic pulmonary arterial pressure and cardiac output. Jezek and SchrijerP found that deslanoside given to patients with right heart failure due to chronic bronchitis improved cardiac performance; specifically, there was a significant decrease in right ventricular end diastolic pressure and an increase in cardiac output. They could not document changes in vascular resistance. There was a slight but significant decrease in the mean arterial wedge pressure after administration of the glycoside. The wedge pressure before digitalis was 13 mm Hg and rose to 21 mm Hg after exercise. This finding of an elevated filling pressure raises the question of whether these patients had concomitant left heart failure. It is well recognized, however, that pulmonary artery wedge pressures may be inaccurate in patients with chronic obstructive lung disease, It is also well appreciated that patients with severe obstructive lung disease may have evidence of left ventricular hypertrophy, possibly due to chronic hypoxemia. Thus, if these 9 patients with chronic obstructive lung disease and right heart failure are representative of a larger group, the beneficial effects of digitalis may be explained partially on the basis of improvement of left heart hemodynamics.

ROBERT A. O’ROURKE: In our experience, most patients with severe obstructive pulmonary disease resulting in dyspnea and hypoxemia have normal resting left ventricular performance and derive little, if any, symptomatic improvement from digoxin therapy unless supraventricular arrhythmias are present (Kline, L. E., et al.: Non-invasive assessment of left ventricular performance in patients with chronic obstructive pulmonary disease, Chest 72:558,1977).

)

Several investigators have found that acute digitalization causes a slight but consistent rise in pulmonary vascular resistance which will increase the after-load of the right ventricle. This reviewer concludes that although the right heart will respond with an inotropic effect in patients with obstructive lung disease, the net beneficial result from acute digitalization is difficult to demonstrate and therefore is probably not of major beneficial consequence. Digitalis sensitivity in patients who have acute car pulmonale with severe hypoxemia (0, saturation below 75%) has been documented by Baum et al. 133These investigators gave a total of 1.2 mg of acetylstrophanthidin in divided doses to 18 patients with chronic obstructive lung disease and car pulmonale. Six of the 18 patients could not tolerate this dose and developed electrocardiographic evidence of toxicity. Lown has reported that the majority of patients who are receiving maintenance doses of digoxin can tolerate a dose of 1.0 mg without evidence of toxicity. Thus, one third of the patients, especially those who had severe hypoxemia, showed evidence of digitalis toxicity. The mechanism for digitalis sensitivity under these conditions is not clear. Apparently it is not due to an increased half-life of digoxin in patients with pulmonary heart disease and congestive heart failure.134 Acute hypoxemia does cause a moderate increase in digitalis sensitivity in experimental animals,135, 136 but not to animals exposed to chronic hypoxemia.‘“’ The mechanism for the decreased sensitivity to digitalis in acute hypoxemia may be an increase in circulating catecholamines which, through its effects on ventricular automaticity, could contribute to the appearance of arrhythmias. Hypoxemia increases the release of catecholamines from cardiac adrenergic stores as well as from the adrenal glands. *Experimentally, catecholamines enhance ventricular automaticity. This effect is additive to the arrhythmogenic effects of digitalis.‘38 Therefore, there appears to be an added risk

in giving digitalis to patients with acute car pulmonale and right heart failure due to an increased sensitivity. If the drug is used under these conditions, smaller loading doses and smaller maintenance doses should be used.

26

THE INFLUENCE OF THYROID HORMONE ON THE PHARMACOKINETICS AND EFFECT OF DIGOXIN Several studies indicate that the early (up to 48 hours) serum digoxin concentration curve after the intravenous injection of a single dose of digoxin is higher in hypothyroid than in hyperthyroid patients.13”, ‘*O Among various mechanisms hypothesized to account for these findings are alteration of absorption, renal or extrarenal excretion and metabolism of the drug. All of these changes, except impaired absorption, have been found by at least one of the groups of experimenters who have studied this problem, but have not been confirmed by others.‘3Y-142 Patients who have hyperthyroidism tend to have lower steady-state levels of digoxin than patients who have hypothyroidism.143 Appropriate alterations in dosage of digoxin appear to be in order as a result of these observations. Since patients with either hyper- or hypothyroidism are not a homogeneous group with regard to age, weight or renal function, further studies comparing the kinetics of digoxin in groups of patients under these conditions would not appear fruitful. Rather, each patient must be studied before and after appropriate treatment for his thyroid condition. Gilfrich140 followed this design, studying 8 patients before and after treatment for thyrotoxicosis. Patients were given a single intravenous dose of digoxin. Plasma levels of digoxin declined more rapidly when the patients were thyrotoxic, and urinary half-lives were shorter for the thyrotoxic subjects before treatment for their thyroid condition. The cumulative urinary excretion of digoxin would be expected to be higher based on the above data, but actually was found to be lower (51% of the dose) during thyrotoxicosis than after normalization of thyroid function (78%) in the same patients. Digitalis produces an inotropic effect in the hyperthyroid as well as in the hypothyroid dog heart.L”“-14fi The percent increment of inotropic response has generally been found to be less in the hyperthyroid than in the hypothyroid animal. These findings are best explained by the thesis that digitalis administration produces a variable inotropic response which is inversely related to the intensity of the preexisting contractile state. There seems to be an inherent ceiling to the contractile response. Hyperthyroidism has been found by Thompson to increase the arrhythmogenic dose of cardiac glycosides in rabbits,147 but not by others studying dogs144 and cats.laH There is no longer a need to administer large doses of digitalis to control the rapid ventricular response to atria1 fibrillation in hyperthyroid patients, since beta adrenergic blocking agents in conjunction with modest doses of digoxin may be successfully used for this purpose.

SELECTION INDIVIDUAL

OF DOSE OF DIGOXIN PATIENT

FOR THE

Previous sections have reviewed the pharmacokinetics of digoxin, particularly digoxin absorption, bioavailability and the kinetics of digoxin in patients with heart disease who have additional organ system involvement such as renal failure. These sections serve as a guide for the physician to alter the dose of digoxin for the individual patient from the “average” loading and maintenance doses generally prescribed. Knowledge of the various factors that alter digoxin pharmacokinetics has tempted several investigators to assess whether the parameters that are known to alter digitalis dosing may be utilized in computer programs to provide a better estimate of the dose of digoxin needed for the individual. This approach has not, in my opinion, been successful, nor does it promise to be a fruitful endeavor for future studies. My pessimism is based on the fact that there are several factors, each difficult to predict accurately in the individual patient, that determine the steady-state serum concentration. The variables that determine steady-state serum digoxin concentration are as follows: Serum Concentration = fraction of dose absorbed x dose x half-life apparent volume of distribution x dosage interval x ,693 (the natural log of 2) The fraction of digoxin absorbed is quite variable from subject to subject, even in normal individuals. The biologic half-life of digoxin shows considerable variability between subjects and cannot be predicted accurately in the individual patient either by creatinine clearance or by urinary digoxin clearance. Little is known about the variation or determinants of apparent volume of distribution of digoxin in normal individuals or in disease states. The volume of distribution appears to be much larger per kilogram body weight in the infant and is reduced in patients with renal disease. There may be a considerable range in the volume of distribution in patients with cardiac disease. Proper dose adjustment of digoxin for the individual will remain a biologic titration. The difficulty in predicting the plasma concentration from the known determinants of digoxin dosing was emphasized by Wagner et al.,14y who stated that “predictability of plasma or serum digoxin in an individual patient from dose of digoxin, body weight, serum creatinine concentration, urinary excretion rate of creatinine, age, and height where the basic correlation data is from a panel of cardiac patients-is extremely low.” Using multiple linear regression analyses, Wagner and coworkers accounted for only 34% of the variance of the plasma concentration of digoxin. Dobbs et al.lsO concluded that prescrib28

ing doses of digoxin based on creatinine clearance was similar to prescribing one fixed dose of 0.3125 mg for all male patients and 0.25 mg for all female patients to achieve a target serum digoxin concentration of 1 rig/ml. Dobbs and co-workers151 attempted to predict the standardized dose using both empirical prescribing methods and published nomograms. Although a maximum of 70% of the variance of the standard dose was explained, this corresponded approximately to I patient in 3 having a predicted dose outside the 95% confidence limits for the standardized dose. F RCIBERT A. O'ROURKE: In many young and middle-aged adults with

chronic congestive heart failure, the maintenance dose of oral digoxin prescribed produces low normal serum digoxin concentrations, and a slight, careful increase in the daily dosage improves symptoms without producing signs or symptoms of digitalis toxicity. As pointed out by the author, the maintenance dose is variable and use of a nomogram provides no magic answer for the individual patient. _EDITORIAL COMMENTS. -1 have requested editorial comments from Dr. Michael Mayersohn, associate professor and Dr. Donald G. Perrier, assistant professor of the Department of Pharmaceutical Sciences, College of Pharmacy, University of Arizona. They have kindly reviewed this paper and have a different view on the use of predictive methods in digoxin dosing. Their comments follow.

A number of methods have been reported in the literature for the estimation of digoxin dosing regimens. These predictions have been based on average pharmacokinetic parameters for digoxin and/or one or more patient parameters such as sex, age, body weight, body surface area, serum creatinine and creatinine clearance. It is unfortunate that few of the suggested approaches have been based on or evaluated in a sufficiently large patient population for a meaningful conclusion to be reached with respect to their utility, with the exception of a method proposed by Jelliffe.’ Kolendorf et al.* estimated digoxin maintenance doses employing the nomogram of Siersback-Nielsen et al.” for predicting creatinine clearance, plus the equation developed by Jelliffe. Creatinine clearance was estimated from the patient’s age, sex, body weight and serum creatinine. Of the 99 patients studied, only 5 demonstrated some symptom of toxicity. The use of average pharmacokinetic and patient parameters for the estimation of an initial digoxin maintenance dose has therefore been shown to be useful. Other investigators have demonstrated that this approach, in combination with one measured digoxin serum concentration for feedback, comes close to the best possible prediction of digoxin serum concentrations.* Such approaches to the design of an initial dosing regimen may be most useful for the relatively inexperienced physician, as this approach is not intended to replace clinical judgment but to complement it. 1. Jelliffe, R. W.: Therapeutic guidelines. Administration of digoxin, Dis. Chest 5656, 1969. 2. Kolendorf, K., Christiansen, N. J. B., Siersback-Nielsen, K., et al.: 29

Serum digoxin after dosage regimen based on body weight and renal function, Lancet 2:326, 1972. 3. Siersback-Nielsen, K., Molholm-Hansen, J., Kampmann, J., et al.: Rapid evaluation of creatinine clearance, Lancet 1:1133, 1971. 4. Sheiner, L. B., Melmon, K. L., and Rosenberg, B.: Instructional goals for physicians in the use of blood level data and the contribution of computers, Clin. Pharmacol. Ther. 16:260,1974.

Weintraub et a1.1s2 concluded that the most important determinant of serum digoxin concentration was patient compliance. It has been estimated that 30 - 40% of patients who are supposed to be taking digoxin regularly do not comply completely.1s2~ lS3 The average oral and digitalizing dose for an adult is l- 1.5 mg. This is frequently given as a loading dose of 0.5-0.75 mg followed by 0.25-0.5 mg every 6-8 hours until full digitalization is achieved. In elderly patients, the maintenance oral dose ranges from 0.125 mg to 0.5 mg. Although 0.25 mg is considered an average maintenance dose, a dose of 0.375 mg would be more appropriate for middle-aged males. In elderly patients, 0.125-0.25 mg should be considered the average maintenance dose. In previously undigitalized patients, institution of daily maintenance therapy without a loading dose results in the development of a steady-state plateau concentration in about 7 days in patients with normal renal function.‘s4 In patients with decreased renal function, an impaired excretion rate will prolong the serum half-life, and the process of accumulation to a plateau will require a longer period of time in the presence of renal failure. Therefore, a small loading dose is appropriate in patients with moderate to severe renal disease. It has been assumed that a person receiving two 0.125 mg tablets of digoxin would receive the equivalent of 0.25 mg. This was only recently verified.lZs Digoxin should not be given intramuscularly, since it may cause excruciating pain in the injected site.‘“” Greenblatt et al Is7 believe that digoxin itself must be an irritant, since diazepam is in a similar vehicle of 40% propylene glycol and 10% ethanol and the intramuscular injection of the vehicle and of this drug is not accompanied by the severe pain associated with the intramuscular injection of digoxin. The intravenous injection of cardiac glycosides should be performed over at least a 15-minute period to avoid the increase in peripheral vascular resistance that may precede the inotropic effect of the drug. Rapid intravenous injection of digoxin may temporarily exacerbate heart failure and has been shown to be of clinical significance. DeMots and co-workers1”8 showed that a lo-second or 2-minute infusion of ouabain caused an increase in mean arterial blood pressure and systemic vascular resistance, 30

but these effects were not seen when ouabain was infused over a 15-minute period. The ability to obtain serum concentrations of digoxin has proved invaluable in the management of selected patients with heart disease who are receiving digoxin. In particular, it has been of most benefit in patients with suspected digitalis intoxication. A level of greater than 2 rig/ml obtained 6 - 8 hours after the last dose of digoxin helps to substantiate digoxin toxicity in adults, whereas a level of less than 1 rig/ml tends to exclude this possibility. Determination of serum digoxin levels also has been found to be useful in patients who do not appear to be responding to therapy or in whom there is a suspicion of poor compliance. It is extremely useful as a guide to therapy in patients with severe renal impairment, in whom it is hazardous to estimate the appropriate dose from knowledge of creatinine clearance or other parameters of renal function. Once one has a serum level from a reliable laboratory, one can adjust the dose to the target serum level, since there appears to be a linear relationship between dose and serum concentration, at least in patients who do not have severe renal disease.l~+l”l In patients in the latter category, this relationship has not yet been established. There is reason to increase the dose of digoxin if it is felt that greater inotropic effect is needed, since it has been shown that there is an increase in effect during chronic therapy associated with an increase in dose and serum digoxin level.‘“’ THE EFFICACY OF LONG-TERM ADMINISTRATION IN PATIENTS HEART FUNCTION

DIGITALIS WITH ABNORMAL

Recent controversy has been generated by the failure to document improvement in some patients with left ventricular failure who are receiving digoxin, because of the meagerness of the hemodynamic changes, as well as the observation that arrhythmias temporally related to digoxin administration were seen in 5 of 8 patients.163 Also, the question has been raised as to whether the findings of improved left ventricular performance documented after acute digitalis administration applies equally with chronic drug administration. It is not known which patients with left ventricular failure associated with low output states will benefit on a long-term basis from the use of digitalis. It can be answered in the affirmative that the acute effects of digitalis do persist chronically. This has been demonstrated by utilizing systolic time intervals.1”2* lfi4 The persistence of digitalis effect has also been demonstrated by improvement in performance of hypertrophied right ventricular papillary muscles obtained from cats subjected to pulmonary artery banding and treated chroni-

tally with digitalis. I65Persistence of digitalis effect has also been demonstrated by a variety of techniques in patients after myocardial infarction, but without clinical signs or symptoms of congestive heart failure. O’Rourke et al.‘“” utilized an increase in segmental left ventricular wall motion by videotracking. The left heart dimension decreased in patients with cardiomegaly, but not in patients with normal heart size. They were able to demonstrate a decrease in the extent of shortening in normal myocardial segments during chronic digoxin therapy. These changes were enhanced during the stress of handgrip exercise. They also demonstrated a decrease in the number of segments with abnormal wall motion at rest or with handgrip exercise during digoxin therapy. Vogel et al.lG7 also demonstrated an improvement in left ventricular performance with chronic digoxin therapy during the exercise of handgrip, but not at rest. They also showed that myocardial perfusion during handgrip was improved by chronic digoxin therapy, as measured by thallium 201 uptake in the patients with coronary disease and left ventricular dysfunction.l6R Thus, it appears well documented that digitalis is effective when administered chronically on a daily basis to patients with left ventricular impairment, but it is not entirely clear whether there is a subgroup of patients whose response to digitalis may be minimal. A frequent question that is raised by both patients and physicians is whether digoxin treatment must be continued indefinitely after an episode of heart failure. Dobbs et a1.16greported a controlled clinical trial of withdrawing digitalis in patients in whom digoxin therapy had been initiated for ventricular failure and who were clinically stable. Twenty-eight of the patients were receiving diuretics. Patients who had been clinically stable for 3 months on the selected dose were randomly allocated to either digoxin or a placebo, and after 6 weeks their treatment was crossed over. Diuretic therapy was continued throughout the study. Sixteen of the 46 patients deteriorated on the placebo. Some of the other patients who did not exhibit clinical evidence of failure had a decrease in FEV-1, which may have been a sign of clinical deterioration. If a patient has had a definite history of heart failure, it would appear prudent to continue digitalis indefinitely, unless failure occurred early in the course of an acute infarction or if the cause of heart failure were found and corrected. ) ROBERT A. O’ROURKE: With the justified optimism concerning the use of vasodilator therapy to improve left ventricular performance in patients with “refractory heart failure,” enthusiastic young investigators may be unaware of the large number of patients with severe congestive heart failure who have benefited from the use of oral digitalis preparations even before the advent of diuretic therapy. To quote Sir William Withering, ‘
unobserved in any other medicine, and this power may be converted to salutory ends.” The inotropic action of digitalis in normal as well as in dysfunctioning cardiac muscle has been well documented (Cattell, M., and Gold, H. J.: J. Pharmacol. Exp. Ther. 62116, 1938; Braunwald, E., et al., J. Clin. Invest. 40:52,1961; Mahler et al., Circulation 50:720,19741. The effects of the cardiac glycosides on left ventricular performance may vary depending on the pretreatment inotropic state and peripheral vascular resistance, the route of administration and the level of circulating catecholamines. For example, oral daily digoxin enhances left ventricular performance considerably in the awake pre-instrumented normal animal while intravenous digoxin does not (Mahler, et al., Circulation 50:720, 1974). Variations in experimental design or groups of patients treated may explain the differing results of several recent studies assessing the effects of digitalis glycosides on left ventricular performance. _I...---

ACKNOWLEDGMENTS I wish to thank Dr. Howard 3. Burchell of this paper. I am grateful to Miss Ann

the manuscript

and Mrs. Edith

Makler

for his initial

review

Vallefuoco for typing for secretarial assis-

tance. REFERENCES 1. Hall, W. H., and Doherty, J. E: Tritiated digoxin XVI. Gastric absorption, Am. J. Dig. Dis. 16:903, 1971. 2. Kuhlman, J., Abshagen, U., and Rietbrock, N.: Cleavage of glycoside bonds of digoxin and derivatives as function of pH and time, Naunyn Schmiedebergs Arch. Pharmacol. 276:149,1973. 3. Gault, M. H., Charles, J. D., Sugden, D. L., and Kepkay, D. C.: Hydrolysis of digoxin by acid, J. Pharm. Pharmacol. 29:27, 1977. 4. Kalra, J., Barrowman, J., Kepkay, D., and Gault, M. H.: Intragastric hydrolysis of digoxin (abstract), Clin. Res. 25:675A, Dec. 1977. 5. Caldwell, J. H., Martin, J. F., Dutta, S., and Greenberger, N. J.: Intestinal absorption of digoxin 3H in the rat, Am. J. Physiol, 217:1747,1969. 6. Forth, W., Furukawa, E., Rummel, W., and von Andres, H.: Intestinal resorption von herzglykosiden in vitro und in vivo. Naunyn Schmiedebergs Arch. Pharmacol. 26253, 1969. 7. Greenberger, N. J., et al.: Intestinal absorption of six tritium labeled digitalis glycosides in rats and guinea pigs, J. Pharmacol. Exp. Ther. 167:265, 1969. 8. Beermann, B., Hellstrom, K., and Rosen, A.: The absorption of orally administered (12 a - “H) digoxin in man, Clin. Sci. 43507, 1972. 9. Ochs, H., Bodem, G., Schafer, P. K., Kodrat, G., and Dengler, H. .I.: Absorption of digoxin from the distal parts of the intestine in man, Eur. J. Clin. Pharmacol. 9:95, 1975. 10. Andersson, K. E., Nyberg, L., Dencker, H., and Gothlin, J.: Absorption of digoxin in man after oral and intrasigmoid administration studied bv portal vein catheterization, Eur. J. Clin. Pharmacol. 9:39, 1975. 11. White. R. J.. Chamberlain. D. A., Howard. M.. and Smith, T. W.: Plasma concentration of digoxin after oral administration in the fasting and post prandial state, Br. Med. J. 1~380, 1971. 12. Turner, J.. Dobbs, S. M.. .Nicholson, P W.. McGill, A. P. I., and Rodgers, 33

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38

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39

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maintenance digoxin therapy on systolic time intervals and serum digoxin concentrations, Circulation 50194, 1974. Cohn, R., Selzer, A., Kersh, E. S., Karpman, L. S., Goldschlager, N.: Variability of hemodynamic responses to acute digitalization in chronic cardiac failure due to cardiomyopathy and coronary artery disease, Am. .I. Cardiol. 35461, 1975. Tomas-Dervera-Cosmelli, J., Garcia-DelPoso, J. M.. Lopez-Moralles, J., Palou-DeComasema, A., and Morey-Molina, A.: Effect of the chronic administration of digoxin on the systolic time intervals in healthy subjects, Rev. Esp. Cardiol. 3053, 1977 Williams, J. F.: Effect of chronic digitoxin administration on contractile state of non-failing myocardium, Clin. Res. 23(A):436, 1975. O’Rourke, R. A., Henning, H.. Theroux, P., Crawford, M. H., and Ross, J.: Favorable effects of orally administered digoxin on left heart size and ventricular wall motion in patients with previous myocardial infarction, Am. J. Cardiol. 37:708, 1976. Vogel, R., Frischknecht, ,J., and Steele. P.: Shortand long-term effects of digitalis on resting and post handgrip hemodynamics in patients with coronary artery disease, Am. J Clardiol. 40:171, 1977. Vogel, R., Kirch, D., LeFree, M.. Frischknecht, J., and Steele, P.: Effect of digitalis on resting and isometric exercise myocardial perfusion in patients with coronary artery disease and left ventricular dysfunction, Circulation

163.

164.

165. 166.

167.

168.

56:355,

169.

1977.

Dobbs, S. M., Kenyon, W. I., and Dobbs, episode of heart failure: Placebo-control 749.1977.

SELF-ASSESSMENT 1. 2. 3. 4. 5. 6.

d c b a

b b, d

7. 8. 9. 10. 11. 12.

b b b b b b

H. -1.: Maintenance trial in outpatients,

digoxin after an Br. Med. -1. 1:

ANSWERS 13. 14. 15. 16. 17.

h b b, c’. :t h 0

41