Part I Digitalis glycosides: Mechanisms and manifestations of toxicity

PART I

Digitalis Glycosides: Manifestations Thomas W. Smith, Elliott M. Antman,

Peter L. Friedman,

“I gave him the Infusum Digitalis stronger than usual, viz. two drams to eight ounces. Finding himself relieved by this, he continued to take it, contrary to the directions given, after the diuretic effects had appeared. The sickness which followed was truly alarming; it continued at intervals for many days, his pulse sank down to forty in a minute, every object appeared green to his eyes,and between the exertions of retching he lay in a state approaching to syncope.” William Withering 1785

T

HE ABOVE QUOTATION was cited by Irons and Orgain in their excellent review of digitalis-induced arrhythmias and their management, published in Progress in Cardiovascular Diseasesin 1966.’ Since then, this journal has been a rich source of information regarding the cardiac glycosides, with additional reviews of selected aspects of the study of digitalis provided by Seizer’ in 1968, Mason et al3 and Wilson4 in 1969, Fisch and Knoebel’ and Kassebaum and Griswold6 in 1970, Butler7 in 1972, Ferrier’ in 1977, and Doherty et al9 in 1978. Although our review will approach the problem of digitalis toxicity from a clinical perspective, we will also consider information recently available about the basic mechanisms of digitalis action, since insights into the effects of the drug on such fundamental cellular functions of the heart as ion transport, contraction, and impulse formation and conduction will most likely have eventual clinical implications. Our citation of references to the literature is not intended to be all inclusive; for purposes of both timeliness and brevity, we have concentrated on selected contributions to the literature since 1975. Recent detailed reviews of specific areas of knowledge regarding the digitalis glycosides will be cited appropriately throughout this discussion. Before delving into current areas of progress and controversy, let us reflect-at least brieflyon the colorful past from which our present thinking about digitalis has evolved. The classic monograph by Withering on the “foxglove,“‘o published in 1785 after nine years of careful clinical observations, contains many penetrating comments but none more astute than Progress in Cardiovascular

Diseases,

Vol. XXVI,

Mechanisms of Toxicity

No. 5 (March/April),

and

Charles M. Blatt, and James D. Marsh

the following: “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 judgment, cannot fail to delineate a likeness. The latter will ever be subject to the whims, the inaccuracies, and the blunders of mankind.” Withering’s observations almost immediately met with lively controversy. After a century of continuing debate, clinicians in the early 1900s appear to have been in general agreement with Sir James Mackenzie, who believed that digitalis was of value primarily in patients with atria1 fibrillation and who did not advocate its use in patients with congestive heart failure and normal sinus rhythm. In The Oxford Medicine, he wrote “The best effect of digitalis is seen in cases of heart failure with dilatation of the heart and dropsy. Eighty or ninety percent of such cases suffer from auricular fibrillation. . . . If we scrutinize the published records of cases that have benefited by the drug, we find that the great majority of these results occur in one condition, auricular fibrillation, or its allied condition, auricular flutter.“” Henry Christian, then physician-in-chief of the Peter Bent Brigham Hospital, took exception to the view that digitalis was of value only in patients with supraventricular tachyarrhythmias. In 1922, he wrote: “My views evidently differ from those of my fellow editor of The Oxford Medicine. The views of Sir James Mackenzie . . . have been concurred in by numerous observers, with the result that there is a growing feeling that, unless the pulse is absolutely irregular and rapid, little is to be gained from digitalis therapy. My own experience is so directly contrary to this that it seems worth while to restate From the Cardiovascular Division, Brigham and Women’s Hospital, and the Departments of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. Address reprint requests to Thomas W. Smith, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. 0 1984 by Grune & Stratton, Inc. 0033-0620/84/2605-0003$05.00/0 1984

413

414

the views already expressed by me. . . . My own view with regard to digitalis is that digitalis, as a rule, has a striking effect on those changes in the patient which are brought about by cardiac insufficiency, and this effect appears irrespective of whether or not the pulse is irregular.“‘* Lest it appear that Sir James Mackenzie overlooked important aspects of the action of digitalis, however, elsewhere in his writings can be found a clear awareness of salutary effects of the drug in patients with cardiac rhythms other than atria1 fibrillation. The following statement, published in 1911, serves today as an astute summary of the state of the art: “Many years ago I was struck with the variability in the action of digitalis in different patients, and a careful grouping of cases which presented similar effects led me to realize that, to a great extent, the different reactions obtained in different people are due to a difference, not in the drug, but in the nature of the lesion from which the patients suffer.“13 In any event, Henry Christian must have been a convincing teacher, since the use of digitalis in patients with signs and symptoms of congestive heart failure, irrespective of the presence or absence of atria1 fibrillation, became standard and was not seriously questioned-at least in the United States-for the next 50 years. Between 1969 and 1979, however, a substantial body of literature accumulated that, taken together, convincingly made the point that many patients on chronic maintenance digitalis were not benefiting from the drug commensurate with the known risks of toxicity. In 1969, Starr and Luchi14 questioned the efficacy of chronic maintenance digitalis treatment on the basis of a placebo-controlled double-blind study of 11 elderly patients with normal sinus rhythm. Later studies of several populations of patients from the United Kingdom on maintenance digoxin therapy showed that a substantial majority of those with normal sinus rhythm showed no deterioration in clinical status upon withdrawal of the drug (see below).‘5-‘* Similar conclusions have been drawn from studies of geriatric patients in the United States” and in Denmark.*’ McHaffie et al*’ studied six patients in sinus rhythm with congestive heart failure resulting from myocardial infarction or cardiomyopathy, and the

SMITH

ET AL

patients showed no benefit from digoxin over that achieved with diuretic alone, as judged from their response on submaximal exercise testing. It will come as no surprise to the experienced clinician that a substantial number of patients on maintenance digoxin, including a sizable fraction of those in normal sinus rhythm, do not derive obvious benefit from the use of the drug beyond the extent to which it may offer some enhanced cardiac reserve during periods of stress, such as may be imposed by an episode of anemia, infection, or other intercurrent illness. At the same time, it is clear that there are subsets of patients, including some with normal sinus rhythm, who derive appreciable benefit from long-term digitalis therapy.22y23 The challenge to the clinician is to determine which individual patients have a favorable risk/ benefit ratio for digitalis use, recognizing that few if any therapies are good for all patients while most are useful in at least selected subsets. In short, then, a critical appraisal of the anticipated benefits of starting or continuing digitalis treatment will ensure that the well-known risks of toxicity are appropriately counterbalanced by the likelihood of such benefits. “Digitalis treatment is one of the most important and serious duties of the general physician: it demands a great deal of skill, power of observation, keen interest, and experience. A long life is too short to learn enough about this wonderful drug.” K. F. Wenckebach 1864-1940

Pharmacokinetics and Bioavailability of Digitalis Glycosides Digitalis and related cardiac glycosidescompounds found naturally in several plants and in the venom and skin of certain toads-exert potent inotropic and electrophysiologic effects on the myocardium. Clinically useful preparations are derived from the leaves and seeds of plants in the genera Digitalis and Strophanthus. Additional flora containing cardiac glycosides that are potential sources of toxicity but are not used clinically include Convalfaria majalis (lily of the valley), Thevetia neriifolia (yellow oleander), and members of the Helleboros family.24 Each cardiac glycoside consists of a combina-

DIGITALIS

TOXICITY

415

tion of an aglycone (or genin) with one to four glycoside moieties. Pharmacologic activity resides in the aglycone, while water solubility and pharmacokinetic properties are influenced by the particular sugars attached to the aglycone.24 The derivation of the clinically relevant digitalis preparations is shown in Fig 1. Leaves of the plant Digitalis lanata contain “native” precursor glycosides termed lanatosides (or digilanids) A, B, and C. Upon mild alkaline hydrolysis (loss of an acetyl group) and enzymatic hydrolysis (loss of glucose), these yield digitoxin and digoxin, respectively.** The leaves of Digitalis purpurea have precursors that lack acetyl groups, and there is no analogue of lanatoside C; enzymatic hydrolysis of desacetyldigilanid A yields digitoxin. Lanatoside C (Cedilanid) is available commercially for clinical use. Removal of glucose from lanatosides A and C produces acetyldigitoxin (Acylanid) and acetyldigoxin, while alkaline hydrolysis of lanatoside C results in desacetyl lanatoside C (Cedilanid-D, deslanoside, Sandoz Pharmaceuticals, East Hanover, NJ), which may also be employed clinically. Ultimately, the more familiar compounds digitoxin and digoxin are derived via the routes indicated.

Finally, the seeds of Strophanthus gratus contain G-strophanthin (ouabain), while 5’. kombt seeds provide the precursor for the semisynthetic compound acetylstrophanthidin.25 Both of these latter compounds are of clinical interest because of their rapid onset of action and, especially in the case of acetylstrophanthidin, the relatively rapid offset of effect when they are administered intravenously.2”28 A review of Fig 1 in conjunction with Table 1 should clarify the often confusing terminology used in the literature concerning these compounds. When these drugs cause toxicity, the clinical profiles are similar, but the time courses are dissimilar, reflecting their pharmacokinetic differences.29-3’ Individual cardiac glycosides are discussed in detail below, with clinically relevant data summarized in Table 2. DIGOXIN

Administration

In the United States digoxin is the cardiac glycoside used most frequently in both hospital and office practice,32 owing to the flexibility of its route of administration, its intermediate dura-

DIGITALIS (leaf I

\

l

(Digilonid

= composite

l

Lanatosidc

A -

l

Lonotoside

B

Lonotoside ( 37%) (Cedilanid)

C

l

of lanatorides

/ s.g’atus

Acetyldigoxin \Cedilonid 1 Deslanoside

D )

A, 8. C 1

-G.

Strophanthin

-K.

Strophanthin

= [m]

Strophonlhus ( seed 1 S. komb; Fig 1.

Derivation

of clinically

B -Strophanthidin relevant

digitalis

---+Acetylstrophanthidin preparations.

*One

mole

Strophanthus

Digitalis

of sugar

or acetic

acid

is split

S. kombh (seed) S. gratus (seed1

0. lanata (leaf)

D. purpurea (leaf)

B 61 C

A)

A

off, unless

the number

of moles

A)

Glycosides

indicated

Glucose

Glucose acetic

Glucose

of Clinical

in parentheses.

+ acid

Split Off by Enzymatic and Mild Alkaline Hydrolysis*

of Cardiac

is otherwise

1. Sources

(digilanid C: Cedilanid) K-strophanthin-fl

(digilanid Lanatoside tdigilanid Lanatoside

Purpurea-glycoside ldesacetyl-digilanid Lanatosida A

Table

Ouabagenin

Rhamnose Ouabain (G-strophanthin)

(G-strophanthidin)

Strophanthidin

Digoxigenin

Digitoxigenin

Digitoxigenin

Aglycone. or Genin

Cymarose

Digitoxose(3)

Digitoxos43)

Digitoxose(3)*

Split Off by Acid Hydrolysis

Cymarin

Digoxin

Digitoxin

Digitoxin

Glycoside

Importance

f I rl e

P t

About

Digitalis leaf Lanatoside C Gitalin* l Acetyldigitoxin

- 100%)

70%

40% -

20-30

8-10

-

-

4-12

25-120

1-2 1 ‘h-5

‘k-2

Peak Effect Ihr)

days

hr

Principle Metabolic Route (Excretory Pathway)

by severe

hepatic

to digitoxin to digitoxin

#Enterohepatic cycle exists. +*Gitalin is a mixture of cardiac glycosides, the principal one of which is digitoxin. ttApproximately 20% lower maintenance doses are required if gel solution in capsules (Lanoxicaps) Modified from Smith Tw: Drug therapy: Digitalis glycosides. N Engl J Med 288:7 19-722, 1973.

disease

is used.

medical

mg

g

mg

mg

DOS

and

Average

digoxin

supervision.

with

6mg

1.20 10mg

1.20

1.50

-

oTd$

2.0-3.0

0.80-

metabolites Similar to digitoxin Renal Similar Similar

0.70-

1.25-

tion Hepatic; renal excretion of

Renal Renal; some gastrointestinal excre-

Renal; some gastrointestinal excretion

Preparations

increments as necessary. patients and requires close with poor bioavailability).

and probably

4-6 days Similar to digitoxin

4-6 days Similar to dig&n

4-6

33 hr 36-48

21 hr

Glycoside

Average Half-Lifef

Cardiac

and deslanoside

2.

fjGiven in increments for initial subcomplete digitalization, to be supplemented by further small 11Average for adult patients without renal or hepatic impairment: varies widely among individual nFor tablet form of administration (may be less in malabsorption syndromes and in formulations

*For intravenous dose. tFor normal subjects (prolonged by renal impairment with digoxin, ouabain, SDivided doses over 12 to 24 hours at intervals of six to eight hours.

About

lO%-40%

90%-100%

Digitoxin

90%

10-30 15-30

Unreliable

Deslanoside Digoxin

55%-75%ll (Lanoxicaps

5-10

Unreliable

Agent

Onset Of Action* Imin)

Ouabain

Gastrointestinal Absorption

Table

1.4-1.6

digitalis

mg

leaf).

-

-

mg

mg

mg

1 .OO mg

0.80 0.76-1.00

0.30-0.50

lntravenous§

Digit&zing

mg

0.10 g 1.5 mg

mgtt

0.251.25 mg 0.1-0.2 mg

0.5-

0.10

0.25-0.50

Usual Daily Oral Maintenance Dose//

SMITH

418

tion of action, and the readily available techniques for assaying serum digoxin levels. The drug may be administered orally (in tablet or elixir form), intravenously, or intramuscularly. For the intramuscular preparation, propylene glycol (lo%), ethyl alcohol (40%), and water (50%) act as a vehicle; in addition to being very painful, this route of administration significantly increases serum creatine kinase enzyme levels. 33,34Doherty and colleaguesgV35compared the pharmacokinetics of digoxin administered by these three routes in volunteers with normal renal function. As expected (Fig 2) the serum concentration rises most rapidly after intravenous administration, followed by oral, and then intramuscular administration. Intramuscular use of digoxin is not recommended, because it results in greater pharmacokinetic variability than does oral or intravenous use. Ext.-etion

Irrespective of the route of administration, digoxin is excreted exponentially, with an average half-life of 36 hours in healthy individuals with normal renal function.36 This results in the loss of approximately 37% of total body stores daily. In older patients with normal BUN and creatinine levels but a reduced glomerular filtration rate (GFR) as a consequence of age, a half-life of 48 hours is probably a better estimate. 6ERlJM

33hn

36hn

34hn

7 MY

1%

‘v

EXCR2mN

ET AL

Usually renal excretion of digoxin is independent of the rate of urine flow in patients with reasonably intact renal function, since it is proportional to the GFR (and hence to creatinine clearance).37’38Renal tubular reabsorption of digoxin may increase with low urinary flow rates and conversely may be decreased by acute vasodilator therapy in patients with congestive heart failure.3g*40 Digoxin is predominantly excreted in unchanged form, although occasional patients may excrete measurable quantities of relatively inactive metabolites4’A3 (see subsequent discussion). Equilibrium (steady state) conditions are achieved when daily losses are matched by daily intake. When daily maintenance therapy is begun in patients not previously digitalized, steady-state plateau concentrations occur after four to five half-lives, corresponding to about seven days in subjects with normal renal function.44 If the half-life of elimination is prolonged, the time required to reach the steady state on a daily maintenance schedule is correspondingly prolonged. Hence, when prompt onset of effect is required, clinical administration involves a loading dose followed by daily maintenance therapy. In massively obese patients, digoxin pharmacokinetics are essentially the same before and after the loss of large amounts of adipose tissue, suggesting that lean body mass should be considered when dosage is being calculated.45*46 This is ““FM

m92,

4&m&~

~!!!z

Rmmpu

Fig 2. Comparison of the pharmacokinetics of digoxin given by the intravenous. oral, and intramuscular routes. As expected, serum concentration rises most rapidly by the intravenous form of administration. [Reprinted from Doherty JE. de Soyza N, Kane JJ. et al: Clinical pharmacokinetics of digitalis glycosides. Prog Cardiovasc Dis 21:141-158, 1978. With permission.]

DIGITALIS

TOXICITY

419

important when designing dosage regimens in order to avoid toxicity. Calculating

Dosage

A nomogram for calculating the total oral loading dose and daily maintenance dose of digoxin based on body weight and renal function has been devised by Jelliffe and Brooker47 (Fig 3). Such nomograms are helpful for an initial estimate of digoxin dosage requirements but may

iai. 30 .

Toti iidj 25 . 20

-3erui

Oigox~n

tii5oZi .15

,lb. .5

(nan&a~s.ml)

Risk of Adverse Reactions (Number per patlent - year)

be inaccurate in elderly patients.48 Clinicians should recall that a number of factors influence an individual’s resistance or sensitivity to digitalis (Table 3). Changes in renal tubular secretion, tubular absorption, and biliary secretion of digoxin are possible factors that lead to difficulties in predicting digoxin clearance by renal and nonrenal means in patients with cardiac failure.4q Therefore, careful monitoring of the patient’s clinical status supplemented by

t 1 -Oral

--. Daily

.,--. :: Maintenanca

CC ol4Digox~n

Pedfatric

_-: Dose

Zxir

(mg:)

gO5

:

mglcc)

Fig 3 Nomogram for digoxin dosage. The central vertical scale represents the total oral loading dose. The fan-shaped group of lines on the left, leading from body weight and converging at zero, represents the effect of body weight upon this loading dose, adjusted for oral absorption. The fan of lines thus yields the lower left scale of maximum total body digoxin [Max. Total Body Digoxin (nglkg)], showing the dilutional relationships that both the 85% effectiveness of oral digoxin (assumed to occur) and the body weight of the patient exert upon the oral loading dose and providing a computed overall peak total body concentration of glycoside, expressed in micrograms of glycoside per kilogram of body weight. To use the nomogram for adult euthyroid patients with reasonably normal hepatic function, who have a normal electrolyte balance, normal gastrointestinal absorption, and have received no previous digitalis therapy of any type, the physician must first decide what risk of arrhythmias or risk of adverse reactions per patient-year are acceptable for that patient, depending upon the urgency of the patient’s clinical situation and an estimate of his or her possible sensitivity to digoxin. (In eneral, most patients with normal sinus rhythm have done well with a maximum total body digoxin concentration of 10 pg B kg.) If hypokalemia is present, the selected level should be revised somewhat downward. The series of arrows shown in the nomogram represents the determination of a dosage regimen for the hypothetical example of a 150-lb (58-kg) patient whose Cc, is 1 mL/min, for whom a therapeutic goal corresponding to a maximal total body digoxin concentration of 10 pglkg was selected, corresponding to a risk of adverse reactions of 0.2 episodes per patient-year, as shown in the lower left scale at the start of the upward vertical series of arrows. The user then looks upward vertically from the chosen maximum total body digoxin concentration, as shown by the sample vertical arrow, until the line corresponding to the patient’s body weight is encountered. Once that point is found, the user proceeds horizontally rightward to obtain the suggested total oral loading dose. Here, as shown by the arrow, a loading dose of 0.8 mg is found. This total dose is divided into two or three parts to be given six hours apart, checking carefully for toxicity before giving each new increment. Once the increments of loading dose have been administered, and the patient has been shown to tolerate them, the maintenance dose is determined by continuing horizontally rightward from the point of the loading dose to the line corresponding to the patient’s measured or estimated C,. or to the patient’s serum creatinine level, on the nomogram. In this example, C,, is assumed to be 100 mL/min. From this point, the user continues vertically downward to find the appropriate suggested single oral daily maintenance dose. which in this case is 0.27 mg. If the amount shown is difficult to achieve with tablets. the user may continue downward to find the appropriate corresponding dose of digoxin pediatric elixir (0.05 mg/mL). [Reprinted from Jelliffe RW, Brooker G: A nomogram for digoxin therapy. Am J Med 57:54,1974. With permission.]

SMITH

420

Table

3.

Factors

Influencing

Individual

Sensitivity

to

Digitalis Typa and severity Serum electrolyte

of underlying derangements

cardiac

disease

Hypokalemia or hyparkalemia Hypomagnesemia Hypercalcemia Hyponatremia Acid-base imbalance Concomitant Anesthetics

drug administration

Catecholamines Antiarrhythmic

and sympathomimetics agents

Thyroid status Renal function Autonomic Respiratory

nervous disease

system

tone

measurement of the serum digoxin concentration when needed remain the physician’s essential tools for appropriately managing digoxin therapy and cannot be replaced even by a sophisticated nomogram like that shown in Fig 3. Absorption

Gastrointestinal absorption of all cardiac glycosides is a passive process; the rate and completeness of absorption decreases with increasing polarity of the cardiac glycoside mo1ecule.SD,5’In patients with normal gastrointestinal function, absorption of digoxin by the oral route is 85% for the elixir form and 60% to 75% for tablet formulations that meet current Food and Drug Administration and United States Pharmacopeia guide1ines?2 A number of factors known to alter the degree of absorption will be discussed later in the section on bioavailability. Protein Binding

Reports of the amount of digoxin bound to plasma proteins range from 10% to 40%, but there is general agreement on values in the 20% to 25% range under clinically relevant circumstances.53-55 Only the unbound drug is active. Protein binding of digoxin is a minor pharmacokinetic factor, reducing glomerular filtration of the drug to about 80% of that of creatinine under normal circumstances. Distribution

The time course of distribution of digoxin in the body can be characterized by a two-compart-

ET AL

ment mode1.g Prompt distribution from the central compartment to peripheral sites (alpha phase), with a half-time of about 30 minutes, is followed by a slower phase of clearance (beta phase). Although distribution of digoxin in skeletal muscle is low in comparison to kidney and heart, total digoxin content is greatest in this tissue group because skeletal muscle constitutes as much as 40% of normal lean body mass.56 Several studies have shown a reasonably constant relationship between the amount of digoxin bound to heart muscle and its concentration in serum, which is one reason why serum digoxin values are used for monitoring patient status.5G5g Electrolyte derangements may exert clinically significant effects on myocardial uptake and distribution of cardiac glycosides. Hyperkalemia and hyponatremia reduce myocardial binding of digoxin and probably other glycosides as well. 37*6M2The fact that hypomagnesemia may contribute to digitalis toxicity63”6 may not be solely a result of a direct effect of serum magnesium concentration on myocardial digoxin binding but rather may also involve an indirect effect through the net myocardial potassium efflux that coincides with magnesium depIetion.‘j’ Finally, an important interaction between digoxin and quinidine exists.‘j8 On average, the addition of conventional quinidine doses to a standard digoxin maintenance regimen results in about a twofold increase in serum digoxin concentration. Total body clearance and volume of distribution of digoxin were found to be reduced significantly in studies of this interaction.68 Its clinical implications will be discussed further below; however, it should be emphasized that maintenance digoxin dosage should be reduced when quinidine is given concurrently. Pediatric Dosage

Although infants and children absorb and excrete digoxin in a fashion similar to adults, digoxin doses in neonates and infants characteristically are larger than those in adults when calculated on the basis of milligrams per kilogram of body weight or per square meter of body surface area.6g-73 Such higher doses result in higher serum digoxin concentrations, which are usually well to1erated.71-74 Digoxin has been found to cross the placental barrier, as indicated

DIGITALIS

TOXICITY

421

by the observation that fetal umbilical cord digoxin concentrations at term are similar to those found in the venous blood of the mother.”

100% bioavailability of the drug.76 This stands in contrast to digoxin,.for which the tablet form has a bioavailability of 60% to 80% for currently available preparations.”

Metabolism

As noted above, renal excretion of digoxin is the predominant mode of elimination and is independent of the route of administration. Although digoxin is excreted largely unchanged in the urine, it is metabolized to some degree to digoxin reduction products (DRPs) such as dihydrodigoxin and dihydrodigoxigenin.’ In about 10% of individuals receiving digoxin, such metabolism accounts for 30% to 40% of the total urinary excretion of digoxin and its metabolites.42.43 Lindenbaum et a175 have reported that the extent of metabolism of digoxin to reduced derivatives varies markedly with bioavailability of the drug. Digoxin reduction products are formed by the bacterial flora in the gastrointestinal tract. Antibiotic therapy that alters gut flora reverses this tendency to metabolize digoxin to cardioinactive products and can result in striking alterations in the state of digitalization. It should be kept in mind that these metabolic considerations apply to approximately 10% of the population who form substantial amounts of DRPs.

Protein Binding

Digitoxin differs most importantly from digoxin in that it binds avidly to human serum albumin; 97% of the serum or plasma content of digitoxin is bound to albumin at clinically relevant concentrations.78 Metabolites of digitoxin tend to have a similarly high binding affinity for albumin.’ Theoretically, a low serum albumin concentration as a result of renal, hepatic, or gastrointestinal disease could free more digitoxin for tissue binding or excretion at a given total serum digitoxin level. However, this has never been demonstrated to be an important factor clinically.’ A number of drugs has been reported to displace digitoxin from its serum albumin binding sites. This includes high concentrations of phenylbutazone, warfarin, tolbutamide, sulfadimethoxine, and clofibrate.” These potential drug interactions are probably not of major consequence at plasma concentrations encountered in clinical use.79*80 Distribution

DIGITOXIN

Digitoxin is the second most frequently used cardiac glycoside in the United States. It is the least polar of the cardiac glycosides in common use, so that it binds to serum proteins and is the most slowly excreted,’ and it constitutes the principal active agent in the leaf of the digitalis plant. The half-time of elimination of digitoxin varies little among patients and is usually from four to six days, irrespective of renal function.32 Thus, with initiation of a daily maintenance program of digitoxin without a prior loading dose, steady-state plateau levels will develop after three to four weeks of oral administration. Several decades ago, Gold et a176examined the relative efficacy of cardiac glycosides given by oral and parenteral routes. Control of the ventricular rate in patients with atria1 fibrillation was used as a quantitative estimate of digitalis effect. Digitoxin was almost equally effective when given by either route, indicating essentially

Because of the high degree of protein binding, the distribution (alpha) phase for digitoxin lasts significantly longer than that for digoxin and has been calculated to be as long as four to ten hours.8’ Careful double-isotope dilution studies suggest that the tissue distributions of digitoxin and digoxin are similar, with significant concentration in the kidney, myocardium, liver, and skeletal muscle.82 Metabolism and Excretion

Renal clearance of unchanged digitoxin is relatively minor compared with digoxin; extensive metabolism of digitoxin occurs, presumably in the liver.’ Lukas reported that a mean of 3.8% of the total body pool of digitoxin per day was excreted as unchanged digitoxin in the urine and 1.9% was excreted in the stool.” Eight percent of the body pool of digitoxin per day is believed to undergo biotransformation to a variety of metabolites.83

SMITH

422

Enterohepatic recycling of digitoxin is reported to average 6.6% per day.84 This enterohepatic cycle can be interrupted-at least partially-by nonabsorbable resins, such as cholestyramine, that bind digitoxin within the gut lumen.@ However, administration of cholestyramine to patients suffering from digitoxin intoxication only modestly enhances the clearance rate, and the clinical efficacy of this approach remains to be proved. The major route of elimination of digitoxin is via metabolic change to a number of poorly characterized products. Digoxin, however, is ordinarily a quantitatively unimportant metabolic product of digitoxin in humans.’ The exact metabolic degradation pathways are poorly understood; available information is summarized in recent reviews.‘**’ Drugs such as phenobarbital and phenylbutazone can accelerate the metabolism of digitoxin in some patients.79 DESLANOSIDE

Deslanoside (desacetyl lanatoside C; Cedilanid-D) is structurally similar to digoxin except for the presence of an additional terminal glucose residue. Because of this additional glycoside moiety, it is poorly absorbed from the gastrointestinal tract and is recommended only for parenteral use.86 Its half-life is similar to that of digoxin.87 An average of 30% of the body stores of deslanoside are excreted in the urine daily in subjects with normal renal function, while about 3% is eliminated via the stool. Of the total body stores eliminated per day, 25% are excreted as deslanoside, 5% as digoxin,’ and 3% as other metabolites. 9*80Except for its somewhat more rapid onset of action, deslanoside offers no substantial advantages over parenteral digoxin.32 When rapidity of onset of action is critical, ouabain may be preferable. OUABAIN

AND ACETYLSTROPHANTHIDIN

Ouabain and acetylstrophanthidin are derived from the seeds of plants in the genus Strophanthus. Ouabain is the most polar of the commonly used cardiac glycosides and is used parenterally for rapid digitalization. Its excretion from the body follows first-order pharmacokinetics, with a fixed proportion of the residual drug in the body being excreted daily. In patients with normal renal function, the mean dominant serum half-

ET AL

life is estimated to be 21 hours,26 which is similar to the half-life of the positive inotropic effect and slowing of ventricular rate in patients with atria1 fibrillation. (It should be noted that this half-life is considerably longer than some earlier published estimates.) The total body content of ouabain and the risk of digitalis toxicity in a patient begun on a regular maintenance schedule without a loading dose will continue to rise for four to five half-lives (four to five days) until a steady state is achieved. Disturbances of renal function can prolong the half-life of ouabain and thus extend the period during which accumulation will continue. Although ouabain is predominantly excreted unchanged by the renal route, recent findings indicate that gastrointestinal excretion of the drug after intravenous administration is appreciable in both dogs and humans.29 Ouabain is poorly absorbed from the gastrointestinal tract and is not available for oral use.‘* Acetylstrophanthidin is a rapidly acting semisynthetic C, acetyl ester of the aglycone strophanthidin that has been used extensively in both experimental and clinical investigations.88-90 Its clinical use at present remains investigational. A sensitive radioimmunoassay for acetylstrophanthidin developed by Selden et al*’ has delineated the pharmacokinetics of this drug. In humans, the principal exponential decline of plasma acetylstrophanthidin commences ten to 30 minutes after intravenous infusion, and its mean half-life in plasma is 2.3 hours, which is consistent with its known short duration of clinical effect. Urinary excretion has been estimated to be only 22% of the intravenous dose; other pathways of elimination remain to be elucidated. LANATOSIDE

C AND ACETYLDIGITOXIN

Lanatoside C (Cedilanid) is a precursor glycoside obtained from D. lanata. Although marketed for oral administration, it is poorly absorbed, and we cannot recommend its use. Acetyldigitoxin (Acylanid) is a crystalline glycoside obtained from D. lanata. It is available as O.l-mg tablets for oral use only and is well absorbed by this route. Clinical studies suggest a loading dose of 2.0 mg and a maintenance dose of 0.1 to 0.2 mg daily.” With pharmacokinetic features similar to those of digitoxin, acetyldigitoxin has no known advantage over digitoxin but

DIGITALIS

423

TOXICITY

has the disadvantage of having been studied and used less extensively. BIOAVAILABILITY

Events occurring in both the United States and Great Britain in the 1970s rendered the bioavailability of digoxin a newsworthy item. This resulted from observations that occasional patients had low serum digoxin concentrations and responded poorly to the drug despite relatively large oral doses.92This prompted investigation of the bioavailability of various digoxin preparations. Pharmaceutical formulations of a drug that meet chemical and physical standards established by governmental or regulatory agencies are termed chemically equivalent. They are termed biologically equivalent if they result in similar concentrations of drug in blood and tissues and are considered therapeutically equivalent if they show equal therapeutic benefit in a clinical trial. Preparations that are chemically equivalent but lack biologic or therapeutic equivalence are said to differ in bioavailability. Bioavailability is often expressed mathematically: F = WJGo)

# WJGv)

where F represents bioavailability and AUCw and AU& are the areas under the serum concentration curve following oral and intravenous administration, respectively. Examples from the digoxin bioavailability literature serve to illustrate these points.93 Although tablets may contain chemically equivalent amounts of digoxin, careful studies have indicated a wide range of dissolution rates of available marketed digoxin tablets from several manufacturers.90*94 Coupled with individual patient variation and varying circumstances of drug administration, this can result in considerable inconsistency in digoxin bioavailability. Patients with malabsorption syndromes sometimes absorb digoxin poorly and erratically,95 although patients with maldigestion because of pancreatic insufficiency usually continue to absorb the drug normally. Administration of digoxin along with or shortly after meals may decrease the peak serum levels obtained, but total absorption is not affected to any substantial degree.96 Absorption of digoxin may be enhanced by drugs that decrease gastrointestinal motility and can be

reduced by drugs that increase motility, particularly if the preparation has limited bioavailability.9’ In addition, certain nonabsorbable substances such as cholestyramine, colestipol hydrochloride, kaolin-pectin (Kaopectate; The Upjohn Co, Kalamazoo, MI), and nonabsorbable antacids when taken concurrently with digoxin can interfere with gastrointestinal absorption9*-I”” The antibiotic neomycin also interferes with digoxin absorption.“’ Such considerations of bioavailability are not merely theoretical constructs but can have an important effect on the incidence of glycoside toxicity. For example, in 1969 and 1972, Burroughs Wellcome UK, the major manufacturer of digoxin in Great Britain, altered its manufacturing process.92 This produced a change in the bioavailability of digoxin, initially resulting in tablets with substantially reduced bioavailability. Later, tablets with relatively high biologic availability were marketed. In order to prevent repetition of this problem, various techniques for assessing the bioavailability of digoxin preparations have been evaluated. Methods for measuring clinically relevant concentrations of the cardiac glycosides in serum, plasma, and other biologic fluids are now widely available and have led to a greater appreciation of the variation in the bioavailability of different preparations of digoxin. Current FDA and USP guidelines on bioavailability specifications include a defined permissible range of tablet dissolution rates and the demonstration in human subjects that such data on dissolution rate translate into clinically reliable bioavailability.lo2 This latter point is established by such techniques as measurement of cumulative urinary excretion of digoxin following infusion of an intravenous dose. Under present FDA guidelines, all digoxin tablets marketed in the United States must have in vitro dissolution rates of at least 65% in one hour and no greater than 90% in 15 minutes. A new drug application must be filed for preparations exceeding these maximal dissolution rates. The digoxin elixir currently marketed by Burroughs Wellcome Co. (Lanoxin) is more bioavailable (70% to 85% of the intravenous dose) than the tablet form (60% to 80% of the intravenous dose).‘03-‘0’ Intramuscular digoxin is also more bioavailable (75% to 85% of the intrave-

424

SMITH

Table

4.

Interactions

Mechanism of Interaction

Involving

Cardiac

Glycosides

Interacting Drugs/Conditions

Digoxin

Digitoxin

Pharmacokinetic GI absorption Decreased

Cathartics

+

7

Antacids Neomycin

+ +

+ 7

Cholestyramine Colestipol

+ +

+ + 7

Activated

charcoal

Tablets with bioavailability

+

low

Metoclopramide Phenytoin Propantheline Atropine Trapping

of glycosides

in enterohepatic

tion (increased fecal Metabolism of glycoside Increased

excretion)

circula-

+ +

Cholestyramine Colestipol Phenobarbital Phenytoin Phenylbutazone lsoniazid Ethambutol Rifampin Spironolactone Hyperthyroidism

Decreased Protein binding

Antibiotic

Decreased

therapy

+

Phenylbutazone Sulfadimethoxine Phenobarbital Clofibrate Tolbutamine

Renal

excretion

Increased Decreased

Hyperthyroidism

GFR GFR

Hydralazine Guanethidine Alpha-methyldopa Debrisoquine Thiazide diuretics Ethacrynic Furosemida

Increased

urine

flow

Saline Ethacrynic

acid + acid

+

Furosemide Binding

to cardiac

Decreased Increased Volume of distribution Decreased

+

tissues Reserpine Hyperkalemia

+

? ?

Hypokalemia

+ +

Quinidine Quinine Verapamil

+ + ?

? 7 ?

Amiodarone

7

7

Quinidine Spironolactone

+ +

7

?

Clearance Decreased

?

ET AL

DIGITALIS

425

TOXICITY

Table

4.

Continued

Mechanism of Interaction

Interacting Drugs/Conditions

Digoxin

Digitoxin

Pharmacodynamic Alteration

of swum

electrolytes Diet

Hypokalemia

Desoxycorticosterone Insulin/glucose Diuretics Hyperkalemia

Potassium

salts

Spironolactone Triamterene Amiloride Hypercalcemia

Calcium

Alteration of cardiac Increased

sympathetic

salts

tone Beta adrenergic agonists Reserpine Theophylline Cyclopropane Succinylcholine Beta adrenergic blockers Halothane Reserpine Bretylium Guanethidine

Reprinted toxicity.

Semin

and modified Drug

from

Treatment

Bigger 2: 147-

JT Jr, Strauss 177,

1972.

HC: Digitalis With

toxicity:

Drug

interactions

promoting

toxicity

and the management

of

permission.

nous dose) than the tablet form but consistently causes severe pain at the injection site33 and tends to exhibit a variable absorption pattern. The Burroughs Wellcome Co. has recently marketed a digoxin gel solution in capsules (Lanoxicaps) that have enhanced bioavailability (90% to 100%) compared with Lanoxin tablets, elixir, or intramuscular injection. Clinicians should be aware that this causes early high serum digoxin concentrations and usually warrants a change in the maintenance digoxin dose. Lanoxin tablets of 0.125 mg and 0.25 mg strength are equivalent to Lanoxicaps of 0.1 mg and 0.2 mg strength, respectively. In contrast to digoxin, oral absorption of digitoxin has generally been considered to be virtually 100%. Digitoxin tablets must have dissolution rates of not less than 60% in 30 minutes or 85% in 60 minutes. For patients receiving ion-exchange resins concurrently with either digoxin or digitoxin, it is advisable to ingest the cardiac glycoside two hours before the resin to minimize interference with intestinal absorption.32 Clinicians must constantly be alert to altera-

tions in a patient’s total medication program, since addition or discontinuation of substances such as ion-exchange resins or antibiotics can alter digoxin bioavailability or the amount of conversion to inactive metabolites and possibly precipitate digitalis toxicity or underdigitalization if the maintenance dose is not adjusted appropriately. DRUG INTERACTIONS WITH CARDIAC GLYCOSIDES

Drug interactions can present appreciable risks to patients unless clinicians are aware of potential interactions and take preventive or corrective measures when indicated. Three general types of drug interactions are possible (Table 4): (1) A pharmaceutical interaction consists of a chemical reaction between drugs that occurs in vitro and results in a change in the physicochemical nature of at least one of the drugs. An example is the precipitation of calcium carbonate crystals if solutions of calcium chloride and sodium bicarbonate are mixed in the same intravenous line. (2) A pharmacokinetic interaction occurs

426

SMITH

when one drug affects the action or effective concentration of a second drug at the site of action. Examples of pharmacokinetic drug interactions include absorption interference, proteinbinding alterations, and stimulation or inhibition of drug metabolism or drug excretion. (3) A pharmacodynamic interaction occurs when the pharmacologic effect of one drug influences the response to another. For example, diuretic-induced hypokalemia may predispose a patient to digitalis toxicity. Nontoxic serum levels of digoxin may become toxic when the ratio of intracellular to extracellular potassium is altered. Drug interactions involving digitalis glycosides are of the pharmacokinetic or pharmacodynamic type. These have been summarized in recent reviews’06q’07and will be discussed briefly here. In order to attack the problem of the seemingly limitless number of potential drug interactions, computer-based systems have been developed to aid the clinician. With regard to drug interactions involving cardiac glycosides, it is important to differentiate between effects on digoxin and those on digitoxin, since, as discussed above, the pharmacokinetic properties of these drugs differ. Pharmacokinetic

Interactions

Factors Aficting Glycosides

Absorption of Cardiac

Intestinal absorption of digoxin and digitoxin is a passive process. The polarity or lipid solubility of the glycoside determines its rate and extent of absorption. Absorption of digoxin may be impaired in patients with malabsorption syndromes caused by either mucosal defects or hypermotility. 95,97Individuals whose intestinal mucosa has been damaged by therapy with antineoplastic drugs such as cyclophosphamide or vincristine sulfate (Oncovin; Eli Lilly and Co, Indianapolis, IN) have been shown to have impaired gut absorption of a digoxin derivative.“’ Excessive laxative ingestion can result in lower steady-state serum digoxin concentrations than those found in normal subjects. Elderly patients often use cathartics without medical supervision, and the clinician should be aware that discontinuation of these agents might slow the gastrointestinal transit time and increase the absorption of digoxin.” Studies of digoxin tablets with high dissolution

ET AL

rates demonstrate no clinically important interaction between propantheline bromide, which diminishes intestinal motility, and the amount of digoxin absorbed.“’ Should digoxin tablets with low dissolution rates be used, however, concurrent administration of propantheline may increase serum levels of the glycoside.97 Fewer studies are available evaluating the effect of alterations of gut motility on the absorption of digitoxin. On a theoretical basis, such alterations should be of less clinical importance because gastrointestinal absorption of digitoxin is greater than that of digoxin. Drugs such as sulfasalazine,“’ cholestyramineIll-Ii3 and colestipol hydrochloride,99 kaolin and pectin,“2*“4 phenytoin,“’ activated charcoal,“6 and neomycin”’ are all known to decrease absorption of cardiac glycosides from the gut. For patients taking one of these preparations, glycoside therapy may require loading or maintenance doses that are higher than usual. Conversely, discontinuation of one of these agents might result in digitalis toxicity if the digoxin dosage is not adjusted downward.“’ Since antibiotic therapy that alters the gut flora can reduce the rate at which digoxin is converted to cardioinactive metabolites in some patients,75 maintenance digoxin doses may need to be adjusted upon initiation or discontinuation of antibiotic therapy. As noted earlier in this review, the timing of doses of digoxin relative to the agents mentioned above constitutes another important variable. One other factor that may influence absorption of digoxin is acidity of the gastric fluid. With increasing hydrogen-ion activity (and lowering of pH), digoxin is progressively hydrolyzed to digoxigenin and its mono- and bis-digitoxosides, which have reduced activity.“’ The frequency of clinically significant hydrolysis of digoxin is related to the frequency with which the patient population achieves intragastric pH below 2.5. While this drop in pH may occur under abnormal circumstances, such as in the Zollinger-Ellison syndrome or pentagastrin infusion,“’ its overall clinical significance remains to be established. Drugs Afecting Protein Binding of Cardiac Glycosides

The long duration of action of digitoxin is due in part to its extensive enterohepatic cycling and, probably to a greater degree, to its binding to

DIGITALIS

TOXICITY

427

serum albumin. Under normal circumstances, 97% of circulating digitoxin is in the bound state. High concentrations of phenylbutazone, warfarin, tolbutamide, sulfadimethoxine, and clofibrate have been shown to displace digitoxin from human serum albumin.78 However, the concentrations of these agents usually encountered clinically do not appear to result in any significant displacement of digitoxin from serum albumin. Since only a small fraction of the body stores of digoxin is bound to plasma proteins, drugs that alter protein binding have no significant effect on digoxin pharmacokinetics.9*‘07 Drugs A$ecting

Cardiac Glycoside Metabolism

Since digoxin is not extensively metabolized, agents that alter metabolism of cardiac glycosides are much more likely to interact with digitoxin.‘07 An exception is the recent observation by Lindenbaum and colleagues7’ that approximately 10% of patients convert digoxin to cardioinactive dihydro-reduction products in the gut. As noted previously, antibiotic therapy that alters gut flora will reduce the amount of conversion to inactive metabolites, which may leave more of the active parent compound available for tissue distribution. It is hoped that the recently developed radioimmunoassay for the digoxin metabolite dihydrodigoxin will elucidate this point in future studies.“’ Metabolism of digitoxin, presumably occurring via hepatic microsomal enzymes, can be induced by administration of drugs such as phenobarbital,‘*’ phenytoin7* and phenylbutazone.78 Clinical studies of patients receiving phenobarbital in doses of 180 to 240 mg/d for eight to 12 weeks have shown reductions in steady-state plasma digitoxin concentrations by as much as 50% accompanying a reduction in the plasma half-life of digitoxin; increased urinary excretion of digoxin and other metabolites of digitoxin has also been documented.79 Other drugs that appear to reduce plasma steady-state digitoxin levels include isoniazid, ethambutol hydrochloride, rifampicin, and spironolactone.‘22m’24 It should be recalled that the responses of patients to these potential enzyme-inducing agents vary markedly, so that it is difficult to predict the effect of initiating or terminating such an agent in the individual patient. Careful clinical observation of the patient and measurement of plasma digitoxin concentrations when indicated should permit

appropriate adjustments digitoxin program.*‘*

of the maintenance

Drugs AJecting Enterohepatic Cardiac Glycosides

Circulation

of

Unchanged digitoxin and its water-soluble and chloroform-soluble metabolites are excreted via the biliary tract into the duodenum. As the parent drug and its metabolites travel through the gastrointestinal tract, the amount of chloroform-insoluble metabolites progressively decreases. This may reflect their conversion to chloroform-soluble products as a result of the action of bacterial or pancreatic enzymes. Chloroform-soluble products exhibit enhanced absorption and may facilitate the enterohepatic cycling of digitoxin. If bacterial enzymes are indeed responsible for this conversion, changes in gut flora may alter the enterohepatic circulation of digitoxin.‘18 Interruption of the enterohepatic cycling of digitoxin and a consequent reduction in the biologic half-life of the compound may occur with the formation of biliary fistulas’25 or the administration of ion-exchange resins such as cholestyramineIll-" or colestipol hydrochloride.99 The clinical significance of glycoside trapping by binding resins is uncertain, since results of clinical investigations have been conflicting. For patients undergoing chronic treatment with binding resins, modification of digitoxin administration is appropriate.“* It may be necessary to increase the dosage for the period of time that the binding resin is administered, or, alternatively, to administer the usual maintenance dose of digitoxin two to four hours before ingestion of the binding resin. Since a smaller percentage of a given dose of digoxin undergoes enterohepatic cycling, the effect of these nonabsorbable anion-exchange resins on plasma digoxin concentrations is less marked. No adjustment in digoxin therapy appears to be necessary, provided that digoxin doses are ingested at least two hours after doses of the binding resin. Drugs Modifying Glycosides

Urinary

Excretion

of Cardiac

Any drug that modifies the glomerular filtration rate will similarly modify the renal clearance of digoxin. Thus, antihypertensive agents, particularly guanethidine, bethanidine, and debriso-

428

quine, will delay excretion of digoxin and increase the likelihood of digitalis toxicity.10’3”8 Changes in urine volume alone, however, are usually unimportant, since studies in humans and experimental animals show that excretion of tritiated digoxin does not appear to be related to the volume of urine excreted.37p38 Although digitoxin undergoes more extensive metabolism than digoxin, a small amount of unchanged digitoxin appears in the urine.g A substantial fraction of the digitoxin filtered at the glomerulus is reabsorbed in the tubules, so that renal excretion of this drug increases to some degree when urine flow increases. However, this response becomes clinically significant only with extreme increases in urine flow.“* Serum digitoxin concentration and digitoxin half-life in patients with uremia do not differ significantly from those in patients with normal renal function who are taking comparable doses.‘2”‘28 It is suggested that the uremic state may actually enhance the metabolic degradation of digitoxin by hepatic microsomal enzymes. Some authors have proposed that digitoxin may produce more stable serum glycoside concentrations than digoxin in patients with impaired or fluctuating renal function.‘18,‘2g Interactions Affecting Distribution, Tissue Binding, or Clearance of Cardiac Glycosides

Digoxin is excreted mainly as a result of glomerular filtration, but a small amount probably also undergoes renal tubular secretion.4g This aspect of digoxin elimination appears to be inhibitable by spironolactone. ” In both patients and healthy volunteers who received single intravenous injections of digoxin, five days of treatment with 100 mg of spironolactone twice daily was associated with increased plasma digoxin concentrations, reduced renal clearance, and a decreased volume of distribution of digoxin.13’ It would probably be wise to reduce loading and maintenance dosages of digoxin in patients who are receiving spironolactone and to follow the patient’s clinical status carefully by measuring serum digoxin levels as appropriate. Conversely, acute vasodilator therapy in patients with congestive heart failure increases renal digoxin clearance without changing the glomerular filtration rate, suggesting an increase in the renal tubular secretion of digoxin!’ If such changes occur during chronic vasodi-

SMITH

ET AL

lator therapy, maintenance doses of digoxin may need to be increased. The concentration of cardiac glycosides in the heart far exceeds that in serum and skeletal muscle, indicating selective affinity of these agents for the myocardium. Increased concentrations of potassium reduce the binding of digoxin to cardiac sodium-potassium ATPase (NaKATPase).‘3’*132 Thus, elevated plasma levels of potassium can decrease the myocardial uptake of digoxin by as much as 40% under acute conditions; displacement of bound digoxin from the myocardium tends to be a slower process.133*‘34 Conversely, in potassium-depleted experimental animals, the myocardium is capable of taking up greater quantities of ouabain or digoxin in comparison to control animals.‘3s*‘36 In addition, recent experimental studies have shown a decrease in the number of ‘H-ouabain binding sites and reduced active Na+-K+ transport in skeletal muscle from rats chronically depleted of K+.137 This could favor redistribution of glycosides from the periphery to the myocardium and predispose K+-depleted patients to toxicity, especially since hypokalemia may increase NaKATPase levels and cardiac glycoside binding to myocardium. Thus, fluctuations in serum potassium levels modify the effect of a given myocardial glycoside concentration and directly alter these concentrations. Clinicians should be aware of the pharmacokinetic differences between the two glycosides when planning a transition from a maintenance digitoxin dosage to a maintenance digoxin dosage.‘18 Since digitoxin has a long half-life of elimination, clearance of this drug will proceed at a slower rate than will accumulation of digoxin. Thus, if digoxin is begun on the same day digitoxin is stopped, the total body store of cardiac glycosides will be increased for a period of time, and the risk of toxicity will increase accordingly. To avoid this risk, it is appropriate to discontinue digitoxin for two to four days before beginning digoxin and to consider using smaller than usual digoxin doses during the period of digitoxin elimination. Quinidine-Digoxin

Interaction

Leahey et al as well as other groups have demonstrated that the concurrent administration of quinidine to patients receiving digoxin

DIGITALIS

TOXICITY

increases the steady-state serum digoxin concentration.‘38-‘4’ In some individuals, the elevated serum digoxin level is associated with clinical or electrocardiographic evidence of digitalis toxicity. ‘38-‘42~‘55It is well established that quinidine decreases the renal clearance of digoxin,‘55 but it is not clear whether this is primarily related to an alteration in the intrarenal handling of digoxin. ‘43~‘44 Quinidine may decrease tubular secretion of digoxin, and this contributes an uncertain but normally small proportion of the amount of digoxin eliminated in urine. Studies in normal volunteers suggest that quinidine does not alter digoxin bioavailability, and, therefore, that altered absorption does not explain the rise in serum digoxin concentration in the presence of quinidine.‘45 Because digoxin is extensively bound to tissues, only a small proportion of the total-body content circulates in the blood. Some investigators have suggested that quinidine inhibits the binding of digoxin to tissue sites, since the mean apparent volume of distribution of digoxin is reduced by 30% during quinidine therapy.‘44 Such alterations in digoxin distribution may account in part for the increased plasma levels.“’ Evidence suggesting that decreased binding of digoxin to skeletal muscle contributes to the quinidine-induced reduction in the apparent volume of distribution of the glycosides has recently been provided by Swedish investigators.‘46 In addition to affecting the volume of distribution and renal clearance of digoxin, as noted above, quinidine may also alter its nonrenal clearance

‘44,147

Horowitz et a114’ reported a lack of direct interaction between digoxin and quinidine (to concentrations as high as 10m4mol/L) in isolated cultured heart cells.‘48 High concentrations of quinidine did not significantly alter the positive inotropic effects of digoxin or effects on monovalent cation transport (as judged by active uptake of the K+ analogue rubidium-86). Bigger68 has addressed the question of whether the increased serum digoxin concentrations seen during the quinidine-digoxin interaction can be translated into an increased effect of this drug in the myocardium of intact animals. Animal experimental studies suggest that the increase in serum digoxin concentration is accompanied by increased inhibition of NaK-ATPase and mono-

429

valent cation ion transport.‘49 Studies using tritiated digoxin have led to conflicting conclusions about alterations in digoxin tissue concentrations in dogs treated with quinidine and digoxin.‘50,‘5’ Clinical investigations suggest that the cardiac electrophysiologic effects of digoxin are increased during the quinidinedigoxin interaction, but less conclusive data are available regarding alterations in hemodynamic effects of digoxin. ‘38,‘42,‘50-‘53 To ascertain whether a similar interaction exists between digoxin and other orally active antiarrhythmics, Leahey et al carried out a prospective study in 63 patients before and during administration of quinidine, procainamide, disopyramide phosphate, or mexiletine.ls4 Quinidine increased digoxin concentration by at least 0.39 ng/mL in 21 of 22 patients; in some individuals, the serum digoxin concentration increased by as much as 2.50 ng/mL. Anorexia, nausea, and vomiting developed soon after quinidine therapy began in 10 of the 22 patients but in only one of the 41 patients who received procainamide, disopyramide phosphate, or mexiletine. Thus, if quinidine is found to be an effective antiarrhythmic agent in a given patient, it seems clinically wise to reduce the maintenance digoxin dosage when quinidine therapy is initiated and to monitor serum digoxin concentrations until a new equilibrium is established. Procainamide, disopyramide, or mexiletine may be considered as alternatives to quinidine therapy in’patients in whom the quinidine-digoxin interaction is of concern or becomes difficult to manage clinically. The calcium-channel blocking agent verapamil hydrochloride has been shown to decrease both the volume of distribution and the totalbody clearance of digoxin in healthy volunteers.‘56 Klein et al”’ found a dose-dependent increase in serum digoxin concentrations when patients with chronic atria1 fibrillation were treated with oral verapamil. Schwartz et a1’58studied ten patients with chronic atria1 fibrillation who were receiving maintenance digoxin therapy. After both intravenous and chronic oral verapamil (320 mg/d), resting and exercise ventricular rates were significantly reduced and mean serum digoxin concentrations increased [1.6 f 0.4 ng/ mL before verapamil and 2.7 f 0.9 ng/mL during verapamil (p < O.OOOl)]. Other calciumchannel blocking agents such as tiapamil and

SMITH

430

nifedipine have been reported to cause a similar increase in serum digoxin leveL.‘59~‘60 Finally, both short- and long-term therapy with the antiarrhythmic agent amiodarone has been found to increase steady-state serum digoxin concentrations.‘6’*‘62 Unanswered questions related to the quinidine-digitalis interaction as well as to interactions reported with other agents include further elucidation of the precise mechanisms of the interaction, the prevalence of the interaction clinically, the significance and risk of toxicity when elevation of steady-state serum digoxin levels occurs, and clinical guidelines for modifying digitalis therapy when the prescription of a drug that can potentially elevate serum digitalis levels is contemplated. Because quinidine appears to affect the distribution and elimination of digoxin, digitoxin might be considered an attractive alternative for patients receiving quinidine. Thus, the issue of whether the quinidine-cardiac glycoside interaction is confined to digoxin becomes an important clinical question. Unfortunately, because preliminary investigations into the question of a quinidine-digitoxin interaction have produced conflicting results, the issue remains unsettled for the time being.‘63-‘68 Alterations of thyroid function can have clinically significant effects in patients receiving digitalis glycosides. Hyperthyroid patients require more digoxin for clinical effect and comparable doses produce lower steady-state serum digoxin levels than in euthyroid patients,169X’70whereas the opposite response is seen among hypothyroid patients.“’ A similar pattern is seen with digitoxin.‘72 Although the mechanism underlying this phenomenon is unclear, evidence for altered tissue distribution, renal excretion, and drug metabolism has been presented. Of particular interest is the finding that left atria1 and left ventricular homogenates from T,-treated guinea pigs show enhanced myocardial NaK-ATPase activity, monovalent cation active transport, and ouabain binding.‘73 These results are consistent with thyroid hormone-induced increases in the number of functional NaK-ATPase complexes. Since the cardiac effects of thyroid hormone influence the response to all digitalis glycosides,

ET AL

thyroid status must be carefully considered when digitalis dosage is formulated. Thyroid replacement in a patient with a history of hypothyroidism may imply a need for an increase in digitalis maintenance doses. Control of hyperthyroidism by antithyroid medication will likely increase the patient’s responsiveness to digitalis and thus will require a reduction in dosage. Pharmacodynamic

Interactions

Interactions Resulting From Alteration of Plasma Electrolyte Concentrations Hypokalemia resulting from a potassiumdepleted diet, corticosteroid therapy, insulin and glucose therapy, or diuretic therapy increases the cardiac effects of digitalis glycosides and enhances the potential for digitalis toxicity. Risk of digitalis toxicity may be related to the rate at which serum potassium is lowered.“’ In addition, myocardial uptake of digoxin increases in the presence of hypokalemia.‘74 Inhibition of renal tubular secretion of digoxin in the presence of hypokalemia is probably not of clinical importance.“’ Although definitive clinical proof is lacking, it is probably wise to correct moderate hypokalemia in patients receiving chronic diuretic therapy, corticosteroids, amphotericin B, or lithium salts. Although electrophysiologic studies of isolated tissue preparations indicate that elevated concentrations of extracellular calcium potentiate digitalis toxicity, the administration of calcium salts under usual clinical conditions probably has a minimal effect upon digitalis therapy. In experimental animals, the risk of digitalis toxicity increased only at serum calcium levels exceeding 15 mEq/L.‘76 Interactions Involving Alteration of Autonomic Nervous System Activity Many of the cardiac effects of digitalis are mediated indirectly through enhanced vagal tone. The effects of augmented vagal tone on the heart rate and atrioventricular (AV) conduction system are ordinarily opposed by sympathetic nervous activity. In patients receiving catecholamine-depleting drugs such as reserpine, the vagal effects of digitalis thus may be relatively

DIGITALIS

431

TOXICITY

unopposed, resulting in sinus bradycardia, sinus pauses, sinus arrest, sinoatrial exit block, or AV block.‘07,“85’77 Marked bradycardia may occur even at usual therapeutic serum concentrations of digitalis glycosides. Other catecholaminedepleting drugs such as bretylium tosylate or guanethidine may be expected to have similar effects. Beta adrenergic blocking agents also reduce the physiologic antagonist of the vagal effects of digitalis on the heart. This property may be of therapeutic value when an attempt is made to control the ventricular rate in atria1 fibrillation. Interrelationships among catecholamines, sympathomimetic drugs, and cardiac glycosides are intriguing but incompletely understood. The available literature on the subject is discussed in detail elsewhere in this review. A considerable body of experimental evidence indicates that some electrophysiologic manifestations of glycoside toxicity are mediated in large part by release of myocardial catecholamines.“’ Clinical observations include precipitation of ventricular arrhythmias by reserpine administration in digitalized patients-presumably reflecting a sudden release of myocardial catecholamines.“’ It is reasonable for the clinician to assume that sympathomimetic agents increase the likelihood of enhanced automaticity of ectopic pacemakers in patients receiving digitalis. Thus, beta adrenergic stimulants, theophylline derivatives, the inhalation anesthetic cyclopropane, and neuromuscular blocking agents such as succinylcholine carry the potential for precipitating toxic arrhythmias in digitalized patients.“8,‘78*‘79 Beta adrenergic blocking agents have been suggested in the treatment of sympathomimetic-induced cardiac toxicity; however, the risks of severe bradycardia or asystole must be assessed carefully. It is of interest that the inhalation anesthetic halothane, in contrast to cyclopropane, has been reported to inhibit digitalis-induced arrhythmias.17* Miscellaneous

Drug Interactions

Patients treated with doxorubicin hydrochloride or other anthracyclines for the treatment of neoplasms are at risk of developing cardiac failure as the course of chemotherapy proceeds. Digitalis glycosides may reduce this risk by vir-

tue of their inotropic action and possibly by reducing myocardial uptake of doxorubicin.‘*’

Serum and Plasma Cardiac Glycoside Concentrations: Clinical Use and Misuse ASSESSING DIGITALIS GLYCOSIDE CONCENTRATIONS

As will be discussed later, the narrow margin between therapeutic and toxic doses of digitalis results in a high incidence of toxicity among patients seen in clinical practice. This problem has stimulated the development of several methods for determining circulating cardiac glycoside concentrations. Measurements of serum or plasma concentration* have substantial clinical utility, but inappropriate use or interpretation of these laboratory values can limit their usefulness and potentially can lead to suboptimal decisions in patient management. In this section emphasis will be placed on the proper use and interpretation of serum cardiac glycoside levels in the clinical context. Assay

Methods

A comprehensive review of the various methods used for quantitating cardiac glycoside concentrations and a list of the relevant literature can be found in Smith and Curfman.“’ Although each method was found to have its own particular advantages and disadvantages, the radioimmunoassay method’** or related competitive binding assay systems, with enzymatic rather than radioactivity readout, are now used in almost all clinical laboratories. Small volumes of serum or plasma are assayed directly, without the need for previous extraction steps.* Because antibody populations that have a high affinity and specificity for the compound under study can be obtained, the concentrations of digoxin and digitoxin in serum can be determined even if the glycoside that the patient has received is not known at the outset. When properly selected antisera are used, sensitivities in the

*For the cardiac glycosides studied to date, serum and plasma levels are equivalent, and the term serum will therefore be used for convenience to denote either.

432

SMITH

subnanogram range are readily obtainable. However, the radioimmunoassay is fraught with pitfalls for the technician who is inexperienced or not adequately trained or supervised, so that the clinical usefulness of serum level data is limited by the degree of accuracy of the reported value. Selection of antisera, accuracy of standards, purity of tracers, and appropriate use of counting equipment are all factors of critical importance. With the widespread use of nuclear medicine scanning techniques the presence of diagnostic radioisotopes in the serum sample is a frequent problem. Once recognized, this problem can be dealt with in a variety of ways.18’ Furthermore, the clinician must be certain that adequate time has elapsed since the previous cardiac glycoside dose to permit full equilibration of the drug between the plasma and peripheral compartments. A safe time for sampling of serum is generally five to six hours after either an oral or an intravenous dose. Rationale Levels

for Determining

Serum

Digitalis

Evidence indicates that a useful relationship exists between serum levels of cardiac glycosides and their pharmacologic effect. First, both therapeutic and toxic effects are known to be doserelated phenomena. Since it is clear from numerous studies that serum digitalis levels rise with increasing dosage, correlation between serum level and clinical state (at least in the statistical sense) would be expected. In the case of digoxin, experimental and clinical studies have shown a relatively constant ratio of serum to myocardia158259*‘83-‘87 or other tissue’88*‘89 concentrations after full equilibration between the vascular and peripheral compartments has taken place. In addition, the cardiac glycoside binding site of the putative digitalis receptor NaK-ATPase faces the outer cell surface,“’ providing a basis for the translation of serum level to myocardial effect. Finally, studies in experimental animals have demonstrated a significant relationship between serum digoxin level and cardiac electrophysiologic effect.“’ Despite these considerations, many variables-in particular, the type and severity of existing heart disease-interact to determine the individual patient’s response to a given serum cardiac glycoside concentration. This is demon-

ET AL

strated in the study by Klein et a1,90 in which serum digoxin concentrations were correlated with the response to incremental doses of the rapidly acting cardioactive aglycone acetylstrophanthidin in 133 patients with diverse cardiac disorders. Severe pulmonic, coronary, and aortic valvular disease, as well as old age, tended to predispose the patients to unusual acetylstrophanthidin sensitivity for a given serum digoxin level. Although relevant regulatory agencies regard the acetylstrophanthidin tolerance test as being too hazardous for broad clinical application, this study serves to highlight some of the factors that contribute to the variability in clinical responses to digitalis. Studies Correlating Clinical State

Serum

Digitalis

Levels With

Results of many studies designed to define the relationship between serum cardiac glycoside concentration and clinical effect are now available and are summarized in Table 5, including data from well over 1,000 patients. The mean serum digoxin level in patients judged to be receiving a therapeutically appropriate dose is about 1.4 ng/mL (1.8 nmole/L), while mean levels in patients with clinically overt toxicity (usually defined on the basis of characteristic cardiac rhythm disturbances) are generally twoto threefold higher. Although this difference is statistically significant in nearly all these reports, overlap of serum digoxin levels between groups of patients with and without evidence of toxicity is the rule in such studies and tends to be more marked with prospective, blind study design than in retrospective, unblinded studies.‘93 Data from series involving patients who received digitoxin are summarized in Table 6. Values are about tenfold higher than analogous serum digoxin concentrations because of serum protein binding of digitoxin, as discussed previously. As in the case of digoxin, mean values for groups of patients considered to be receiving optimal therapeutic doses are significantly less than mean values for patients with symptoms and signs of toxicity, but appreciable overlap between the two groups is the rule. Despite these reservations, use of serum digoxin measurement is reportedly associated with a lower incidence of digoxin intoxication in clinical practice.“’ For the clinician dealing with an

DIGITALIS

TOXICITY

433

Table

5.

Serum

Concentrations-Patients

or Plasma With

and

Digoxin Without

Toxicity

Mean Concentration (ng/mL) Patients Without Toxiciw

Patients Wifh Toxicity

Aronson et al”* Belier et alls3

1.60 1 .oo

2.60 2.30

Bernabei et a1”’ Bertler and Redfors””

1 .oo 0.90

2.90 2.40

Bertler Brooker

1.40 1.40

3.10 3.10

Burnett and Conklin”’ Carruthers et al”*$

1.20 1.21

5.70 2.76

Chamberlain et al’99 Doering et alzoo

1.40 1.02

3.10

Evered

1.38

6ource

et al’85* and Jelliffe’sst

and Chapmar?

Fogelman et a?‘*§ Follath et a1203

3.07 3.36

1.40 1.20 2.40

1.70 3.20

2.80 1.30

4.40 3.40

O.BO- 1.30 0.97

2.80 0.91

Huffman et a1208 lisalo et aIT

1.49 1.20

3.32 3.10

Johnston Krasula

1.00

3.15

1.70

3.60

1.10 1.10

2.90 2.20

N.S.11 N.S.11

2.73

Grahame-Smith Hayes et a1205

and Evere.stzO”*

Infants Children Hoeschen Howard

and Provedazm et al”‘$

et alZOg et al*”

Infants Children Lader et al*” Lehmann et a1*12 Normokalemic

patients

Hypokalemic Lichey et al*‘”

patients

Lees et al’” McCredie et aI”’ Infants Children Morrison et al2’6n Oliver et al*” Park et al”’ Ritzmann et a12’9*

5.70

1.20

1.76 2.50

1.10

4.90

3.45

-

1.41

3.81

0.76 1.60 1.10

3.35 3.00

1.20

5.5011

N.S./(

3.68 1.13

3.80

Shapiro**O Normckalemic Hypokalemic

patients patients

Scherrmann and Singh et aI”* Smith et alls2

Bourdon”’

N.S.11 1.37 2.91

4.58 4.79

Smith Suzuki

and Habe? and Ogawazz4

1.30 1.40 1.20

3.30 3.70 3.20

Waldorff Weissel Whiting

and Buch”’ et alz2’ et al*”

1.00 1.38 1.40

2.30

Zeegers

et al**’

1.60

Radioimmunoassay +%b uptake. tEnzymatic

used displacement.

in all instances

except

2.97 3.50 4.40 as noted:

individual patient, however, it is clear that no specific serum level can be chosen to define the separation between toxic and nontoxic states. This is what would be predicted in view of the many factors known to influence individual patient sensitivity to the toxic effects of digitalis (see subsequent discussion). Establishment of an accurate diagnosis of digitalis toxicity presents another difficulty, since any abnormality of cardiac impulse formation or conduction that can result from digitalis excess can be caused by intrinsic heart disease as well, even in patients without a history of having taken digitalis. For these reasons, we stress that serum glycoside concentration values must be taken into account along with all other relevant clinical data before one can arrive at appropriate management decisions, and they must not be considered in isolation and out of context. However difficult it may be to define digitalis toxicity in terms of single serum concentration values, it is still more difficult to correlate therapeutic effects with serum levels in humans. We have found-within relatively broad limits-a correlation between serum digoxin concentration and slowing of previously rapid ventricular rates in patients with atria1 fibrillation.‘99 As might be expected, this correlation is not seen in patients with relatively slow ventricular responses when not receiving digitalis, and the wide variation in serum levels needed to maintain control of the ventricular response to atria1 fibrillation (AF) and atria1 flutter is well recognized;199 under these circumstances, of course, the ventricular rate and clinical symptoms often serve as appropriate guides to dosage. Goldman et a1236have studied the relation between serum digoxin level and ventricular rate in patients with AF in a variety of clinical circumstances. Consistent with our own results, they found that “therapeutic” digoxin levels were often inadequate to control the ventricular rate in acutely ill patients with conditions such as hypoxia or infection or after recent thoracotomy. Serum levels of 2.5 to 6.0 ng/mL were required SATPase §Oifferences icant

inhibition. in mean

(P < 0.05) in all series I/ N.S. = not stated. TStatistical significance #Median

concentration.

concentration except

were these.

not stated.

statistically

signif-

434

SMITH

Table

6.

Serum

or Plasma

Concentrations-Patients

With

Digitoxin

and

Without

Toxicity

Meall Concentration klg/mL)

source Belier

et al’s3*

Bentley Brook

et allmt and Jelliffe’gs$

Chiche et.a1229* Dessaint’“’ Hillestad

et al”‘$

Lukas**[\ Morrison

and Killip’*‘*

25.0

Patients Without Toxicity

Patients With Toxicity

20.0

34.0

23.0 31.8

39.0 48.8

25.4

57.0

26.8 16.8

96.0 28.3 43.0-67.0

20.0 (0.1 mg/day)

Peters et al’s’* Rasmussen et a12s3§ Ritzmann et al”s§

28.8 16.6 20.57

Smith234’

17.0

53.0 56.4 48.7 37.01 34.0

*Radioimmunoassay. TATPase inhibition. *Enzymatic

displacement.

§%b uptake. ((Double isotope l/Median

dilution

derivative.

concentration.

to control the ventricular response in 15 of 39 such patients.236 Parenthetically, currently available beta adrenergic blocking agents and calcium-channel blockers such as verapamil will usually obviate use of such large digitalis doses to control ventricular responses. Halkin et alz3’ also noted considerable scatter in the relationship between serum digoxin concentration and ventricular response in a varied group of patients with AF but found that serum levels were valuable in about one third of patients for purposes of identifying inappropriate therapeutic responses and defining the subset of refractory cases, thought to allow prevention of digitalis intoxication. In patients with congestive heart failure and normal sinus rhythm, an even more difficult problem exists. Studies in experimental animals support the conclusion that increasing the dose of acutely administered cardiac glycoside will increase its inotropic effects, the limits of which are imposed by the emergence of overt rhythm disturbances.238s239 More recent findings, however, suggest that this conclusion may need to be modified somewhat in the context of clinical cardiac glycoside use. Carliner et al used systolic time intervals to assess the myocardial contractile state of eight

ET AL

patients with coronary or hypertensive disease.240 After receiving 0.25 or 0.50 mg/d of digoxin for 13 days, the patients experienced positive inotropic effects, with a lesser response evident with the 0.25mg dose than with the higher dose; however, mean steady-state serum levels reached only 0.50 and 0.88 ng/mL, respectively. Hoeschen and Cuddy24’ used the same two dosing regimens in 21 patients, producing mean serum digoxin concentrations of 0.56 and 1.18 ng/mL. Again, ventricular function showed greater improvement with the larger dose. Neither of these two clinical studies, however, evaluated responses to digoxin doses that would produce serum levels outside the lower limit of the conventional “therapeutic” range. One clinical study with potentially important results is that of Belz et a1,242 who explored higher portions of the conventional dosage range in a study of 120 healthy male volunteers given various doses of digitoxin or P-acetyldigoxin (which is metabolized to digoxin). Serum levels and systolic time intervals were measured 24 hours after completion of a three-day dosing period. Dose-dependent serum digoxin levels ranged from 0 to 2.4 ng/mL, as expected, but the positive inotropic effect reached a plateau at a /3-acetyldigoxin dose of 0.4 mg/d. Electrocardiographic changes in corrected Q-T intervals and T waves reflected progressive electrophysiologic changes over the full range of doses used, up to 0.6 mg/d. Analogous findings were reported for digitoxin.242 In a related study, Lampe et a1243correlated changes in systolic time intervals with serum digoxin levels over a range of 1 to 3 ng/mL in 15 patients on a three-day dosing regimen. The maximum effect on systolic time intervals was observed in the range of 1 ng/mL, with a tendency toward decreasing effects at the upper end of the serum concentration range studied. Serum concentration of digoxin in relation to its inotropic effects was also studied in eight patients with ischemic heart disease by Buch and Waldorff.244 Using systolic time intervals to assess the inotropic state of the myocardium, they found that the serum concentrationinotropic effect curve was decidedly flattened at serum digoxin levels above 1 to 2 ng/mL. Thus, despite the limitations of systolic time intervals in the evaluation of cardiac contractile state,

DIGITALIS

TOXICITY

these last three studies suggest that, with regard to inotropic response, a point of diminishing returns is reached at serum digoxin levels of 1 to 2 ng/mL. Also of interest in this regard is the study by Arnold et al,** who observed the effect of supplemental doses of digoxin (0.25 or 0.50 mg) given intravenously to patients on conventional chronic maintenance doses. Despite well-documented positive inotropic effects of the maintenance regimen, no further augmentation of inotropic state occurred with these incremental doses. Taken together, these findings suggest that doses sufficient to maintain serum digoxin concentrations in the range of 1 to 2 ng/mL may yield nearmaximal or maximal effects on cardiac performance in patients with normal sinus rhythm. Since the risk of digitalis-toxic arrhythmias clearly increases at serum concentrations beyond this range,245 the risk/benefit ratio appears to be optimal in the intermediate serum digoxin concentration range of 1 to 2 ng/mL. It must be emphasized, however, that available data on this important issue are quite limited, particularly regarding patients with advanced heart failure. Still sorely needed are further studies in which the patient populations are stratified based on etiology, severity, and pathophysiologic manifestations of heart failure. Relatively limited data are available correlating noncardiac symptoms of toxicity with serum digitalis levels. Doering et a1200carried out an extensive study of 1,148 patients and found considerable overlap among serum digoxin levels in patients with and without extracardiac symptoms of toxicity, even though the mean digoxin levels of the two groups differed significantly. Of patients with serum digoxin concentrations of 2.0 ng/mL and above, 39.4% had nausea, 30.4% fatigue, 23.7% dizziness, 23.1% vomiting, 16.0% headache, 13.5% visual disturbances, 6.7% chromatopsia, 4.2% diarrhea, and 3.8% severe neuropsychiatric disturbances. In patients with digitalis-induced arrhythmias the relative frequency of symptoms was the same, but the percentages were somewhat higher. In accordance with broad clinical experience, only about half of the patients with arrhythmias thought to be caused by digitalis excess also showed extracardiac symptoms of toxicity.*” Ochs et a1246 evaluated the relationship

435

between serum digoxin concentration and subjective manifestations of toxicity in 300 patients with permanent transvenous pacemakers; the majority of these patients were taking maintenance doses of fi-acetyldigoxin or p-methyldigoxin, with a total of 34 on digoxin and ten on lanatoside-C. Subjective toxicity symptom scores tended to increase at higher serum digoxin levels but showed considerable scatter, emphasizing the multiplicity of factors that can produce symptoms similar to those of digitalis excess. Eraker and Sasse247have developed a Bayesian approach to using serum digoxin levels in clinical decision making. The relation between the estimated risk of toxicity in the patient population at risk and the predictive value of the serum digoxin concentration was established and was used to analyze the importance of the degree of elevation of the serum digoxin level. With a knowledge of a patient’s serum level, the probability of toxicity can be made to cross the threshold probability for treatment for toxicity for an intermediate range of pretest risk. This interesting study formalizes the approach we have long advocated in the use of serum digoxin concentration data, ie, that the values be used in the overall clinical context in formulating clinical decisions. “BIOASSAYS” FOR CARDIAC GLYCOSIDE EFFECTS: SALIVARY AND RED CELL ELECTROLYTE CONTENT

The interesting suggestion has been made that changes in the electrolyte content of salivary or red cell samples from patients receiving digitalis glycosides might serve as a clinically useful assay of the extent of digitalis effect in individual patients. Wotman et a1248collected saliva from 73 patients, 18 of whom were diagnosed as having overt digitalis toxicity. Three other groups were studied: patients on digitalis alone without toxicity, patients on digitalis and a diuretic without toxicity, and normal subjects. Salivary potassium and calcium concentrations were significantly higher in the group with digitalis toxicity than in the nontoxic groups. The product of potassium and calcium concentrations in saliva was particularly useful in distinguishing between toxic and nontoxic patients. The diagnostic value of the test was not influenced by the specific type of digitalis glycoside the patient had received. Presumably, changes in salivary electrolyte values

SMITH

436

represent a dose-related consequence of inhibition of monovalent cation transport; as such, they might be of particular value, when integrated over time, for assessing the effect of prolonged digitalis therapy. The test has not been widely used during the decade since its description, however, and to our knowledge no prospective studies have been carried out to assess its predictive accuracy. An analogous approach that uses a more conventional source of material for diagnostic analysis is measurement of red blood cell sodium and potassium concentrations. As would be expected, partial inhibition of monovalent cation transport by the highly glycoside-sensitive NaK-ATPase of the human erythrocyte reduces the rate of K+ or rubidium (Rb+) uptake, elevates intracellular Na+, and reduces intracellular K+ in red blood cells from patients receiving digitalis. Aronson et a1249measured the rate of x6Rb+ uptake by erythrocytes from patients treated with digoxin for AF and other tachyarrhythmias and reported that the therapeutic response in the 15 patients studied correlated better with changes in “Rb+ uptake than with plasma digoxin concentration.249 Loes et a1214measured red cell Na+ and K+ levels by flame photometry in samples from children on digoxin and from normal control patients of similar ages. Digoxin therapy was associated with an increase in red-cell Na+ from a pretreatment mean of 6.2 to 11.9 mEq/L and a decrease in K+ from 105.4 to 99.5 mEq/L. Red-cell sodium levels in patients with clinical evidence of digoxin toxicity were higher-and K+ levels lower-than levels in patients without toxicity. The mean ratio of red cell Na’ to K+ was 0.213 in the toxic group-substantially and significantly higher than the mean ratio of 0.085 for patients without toxicity. This interesting approach has not, to our knowledge, been applied to any large patient population, and its ultimate clinical usefulness remains to be determined.“’ CLINICAL

USE OF SERUM CARDIAC CONCENTRATIONS

GLYCOSIDE

Regarding the practical clinical use of serum digoxin measurements, we offer the following guidelines. Assessment of timing and magnitude of digoxin doses, renal function, and body mass will permit a first approximation of the total

ET AL

body stores of the drug. When a patient on digoxin develops fatigue, visual changes, anorexia, nausea, vomiting, or cardiac rhythm abnormalities, a toxic response should be suspected, and knowledge of the digoxin level is likely to be useful. Since metabolic abnormalities, including hypokalemia, hypomagnesemia, hypercalcemia, and severe acid-base imbalance, predispose a patient to digitalis toxicity, a digoxin level within the usual “therapeutic” range should not be considered to exclude toxicity under such circumstances. Table 3 lists additional important variables. As discussed elsewhere in this review, underlying heart disease is a critically important variable in determining the individual patient’s sensitivity to digitalis. Myocardial ischemia, myocardial infarction, and advanced cardiomyopathy may increase sensitivity to digitalis glycosides, and a digoxin level in the usual “therapeutic” range does not exclude digoxin toxicity in the presence of symptoms or signs consistent with digitalis excess. Hypothyroidism and pulmonary disease are also associated with an increased incidence of digoxin toxicity at any given serum digoxin concentration. Conversely, in the absence of clinical symptoms or signs of digoxin toxicity, a digoxin level in the range of 2 to 3 ng/mL should not dictate the withholding of digoxin when such levels are required to control the ventricular response to a supraventricular tachyarrhythmia. A frequently encountered clinical problem is failure to achieve an adequate therapeutic response in a patient receiving a conventional dose of digoxin. The clinician must decide whether the dose is inadequate (for example, because of noncompliance with the prescribed regimen or because of impaired absorption) or whether there are reasons why the patient may be resistant to usual doses and serum levels of digoxin (for example, occult thyrotoxicosis or mitral stenosis). In a compliant patient with a low serum digoxin concentration despite usually adequate dosage, the digoxin level may be a clue to other disorders or drug interactions. Hyperthyroidism tends to cause relatively low serum digoxin levels, in addition to true resistance to control of the ventricular response to supraventricular tachyarrhythmias. Malabsorption syndromes and preparations of digoxin with poor

DIGITALIS

TOXICITY

437

Table

7.

Causes

of Altered

Responsiveness

to Cardiac

Glycosides

Digitalis resistance Apparent: Tablets not taken as prescribed Inadequate bioavailability of tablets Inadequate Increased

intestinal metabolic

True end-organ Infancy With

absorption degradation

(eg, by gut flora)

resistance:

respect to control a. Fever b. Elevated congestive

of ventricular

response

sympathetic tone heart failure

from

in the presence

all causes,

including

of atrial

fibrillation

or atrial

flutter:

uncontrolled

c. Hyperthyroidism Digitalis sensitivity Apparent: Unsuspected Change from Decreased Drug-drug

use of digitalis poorly absorbed

True end-organ sensitivity Advanced myocardial

to toxic disease

Active myocardial ischemia Electrolyte imbalance [especially Acid-base

to well

absorbed

tablets

effects:

hypokalemia)

imbalance

Concomitant drug administration Hypothyroidism Hypoxemia (especially in setting Altered

tablets

renal excretion interactions (eg, quinidine)

autonomic

tone

leg, catecholamines) of acute

(eg, vagotonic

respiratory

failure)

states)

bioavailability will result in low serum digoxin values and clinical underdigitalization. Certain drugs, including cholestyramine, colestipol, kaolin-pectin, and certain antacids, will bind digoxin in the gut and result in clinical and laboratory evidence of subtherapeutic digitalization (see prior section). Table 7 lists relatively commonly encountered causes of altered responsiveness to digitalis, subdivided according to whether the alteration tends to be apparent or a true change in end-organ sensitivity. Finally, a healthy skepticism is warranted when a laboratory result conflicts with clinical judgment. Digoxin levels will never become substitutes for clinical judgment, and an isolated value should never be used as the sole criterion for determination of a drug’s toxicity or efficacy. We do not advocate routine measurement of serum digoxin levels for patients with a satisfactory therapeutic response to a conventional dosage regimen. Above all, neither serum digoxin concentration measurements nor any other laboratory test should diminish the essential role of clinical observation and follow-up by a vigilant physician.

Digitalis Toxicity Epidemiology

Had the therapeutic value of digitalis glycosides not been popularized at least 195 years ago, modern regulatory agencies would probably have judged this class of drugs too frequently toxic to approve their release for clinical use.” Withering, the British physician who wrote the first widely read treatise on the use of foxglove for medicinal purposes, was well aware of the drug’s potential for toxicity: “The foxglove, when given in very large and quickly repeated doses, occasions sickness, vomiting, purging, giddiness, confused vision, objects appearing green or yellow; increased secretion of urine, with frequent motions to pass it; slow pulse, even as low as 35 in a minute, cold sweats, convulsions, syncope and death.“” Since Withering’s time, countless patients suffering from dropsy as a consequence of congestive heart failure have been helped by cardiac glycoside preparations; no doubt the demise of countless others was hastened by this class of drugs.

SMITH

438

FACTORS AFFECTING INCIDENCE DIGITALIS TOXICITY

OF

In the late 1960s and early 1970s clinical interest focused on the incidence of digoxin toxicity among patients receiving either digoxin or digitoxin, the most frequently used forms of purified cardiac glycoside.‘93~‘98~20’~25’-256 Most agreed that the incidence of digitalis toxicity was high, although the percentage of patients taking digitalis glycosides in either a hospital or an ambulatory setting varies from study to study. As Ingelfinger and Goldman point out in a review of 27 publications dealing with this subject, it is easy to suspect digitalis toxicity in a patient but exceedingly difficult to be certain that digitalis excess is the cause of a given symptom or sign.257 When a cohort of hospitalized patients was intensively monitored for all adverse drug reactions, one study found an 18% overall incidence of such reactions, of which 21% were attributed to digoxin. 252In a related study,*” the number of patients taking digoxin who exhibited signs of toxicity was 19.8%. Using prospectively defined clinical criteria to screen a large number of medical admissions to a city hospital, Beller et a1’93 reported that 23% of 135 patients on maintenance digoxin or digitoxin had definite toxicity on the basis of electrocardiographic criteria, while an additional 6% had possible toxicity. Earlier studies from the late 1960s reported an incidence of 18% to 21%,24s*258 and the estimated incidence of overt toxicity in a group of Boston hospitals in about 1970 was 13% among patients taking a digitalis glycoside.2S5 Undoubtedly, the focus on digitalis toxicity during this time period was related to the fact that the formulation of the tablet had been changed by the leading manufacturer of digoxin over a period of four to five years, resulting in a major alteration in the bioavailability of the digoxin content of the tablet.*” This alteration was particularly marked in the product available in the United Kingdom. Other manufacturers used widely varying methods of tablet preparation, so that the bioavailability from manufacturer to manufacturer and from lot to lot varied five- to sevenfold.253 At times this caused a strikingly high incidence of clinically recognized digitalis toxicity (15 concurrent cases in a medi-

ET AL

cal ward of 30 beds in Israel),259 and it is rather remarkable that digitalis toxicity was not recognized even more frequently than it was. Perhaps mitigating the impact of digoxin’s altered bioavailability was the fact that many patients for whom digoxin or digitoxin was prescribed did not actually comply with the regimen; this was the case among 30% to 36% of patients in one British study,260 in which almost 50% of the women prescribed digoxin were thought to be noncompliant compared with only 5% of the men. There is no doubt that noncompliance regarding digoxin prescriptions is also common in North America.‘* ASSESSING

THE DEGREE OF DIGITALIZATION

In 1969, a sensitive radioimmunoassay to determine clinically relevant serum digoxin concentrations was introduced’** and soon became widely available to assist clinicians in assessing suspected digoxin toxicity. Although the ability to measure serum digoxin levels permitted heightened suspicion for digoxin toxicity,2s6V26’it was clear from the outset that these concentrations overlapped substantially between populations of patients with and without clinical signs or symptoms consistent with digoxin toxicity.223 Furthermore, correlation between serum digoxin concentrations and resting heart rate for patients with atria1 fibrillation who were taking digoxin was poor, unless heart rates obtained while the patient was off digoxin were taken into account; thus, the “bioassay” and the radioimmunoassay frequently yielded discordant results.‘99 Long before the advent of this technique for measuring serum digoxin concentration, astute clinicians had been well aware of how difficult it is to determine whether a patient is optimally digitalized. Cardiac arrhythmias and conduction disturbances as well as gastrointestinal and neurologic symptoms that might be attributable to digitalis toxicity occur frequently in patients with heart disease who are not taking a digitalis glycoside.235 To aid analysis of this conundrum, Lown and Levine262 and Klein et a19’ recommended using carotid sinus massage to assessthe degree of digitalization. Acetylstrophanthidin, a short-acting digitalis-like drug, has also been administered to determine whether a particular patient could safely tolerate additional doses of a cardiac glycoside.w With this approach it also

DIGITALIS

TOXICITY

became clear that the serum digoxin concentration is a limited predictor of whether a given patient is over- or underdigitalized, as would be expected in view of the many factors that bear on the individual patient’s response to cardiac glycosides.223 Thus, while there is evidence that systematic determination of serum digoxin levels can diminish the incidence of digitalis toxicity in certain groups of patients,235*263 this measurement alone should not be considered the final arbiter of the presence or absence of toxicity in each case. APPROACH TO PRESCRIBING CARDIAC GLYCOSIDES-CLINICAL CONSIDERATIONS

In the past ten years a number of more or less elaborate schemes have been introduced to assist the clinician in selecting the optimal digoxin dose for the individual patient. Peck et a1263introduced a computerized method of dose selection but concluded that both the computer and the clinician perform inadequately in arriving at a desirable serum digoxin concentration. Dobbs et a1264compared “clinical judgment,” a standard dose of 0.25 mg per day of digoxin, a pharmacokinetic model, and an elaborate clinical scoring system for prescribing digoxin. They found that to achieve a serum level of 1 to 2 ng/mL after three weeks no method was better than simply placing all patients on a daily regimen of 0.25 mg of digoxin.264 Most widely appreciated among the factors that contribute to the enormously complex approach to prescribing cardiac glycosides are altered renal clearance and hepatic metabolism. Other factors such as drugdrug interactions”’ and age198,265,266 are certainly important as well. Even when hepatic and renal function are accounted for in an older population, there is evidence that the properties of NaK-ATPase, the putative digitalis receptor, may be altered in the elderly. Zannad et a1266measured the extent to which digoxin inhibited the NaK-ATPasemediated uptake of the potassium analogue, rubidium, in erythrocytes from elderly patients. When they compared the results with those in younger patients, they found that erythrocytes from elderly patients were more sensitive to a given concentration of digoxin. In addition, experimental evidence indicates that stress may heighten an individual’s vulnerability to the

439

toxic, arrhythmogenic effects of a cardiac glycoside.267 As described elsewhere in this review, digitalis is a neuroexcitatory drug;268 therefore, to the extent that stress may also be neuroexcitatory, it is not surprising that these potential toxic effects may be additive. Although elderly patients are often more sensitive to digoxin, the very young patient, ie, the newborn, is relatively resistant to the effects of this drug.269 Kearin et a1269reported that neonatal erythrocytes contained about twice as many digoxin binding sites per cell and had a 50% lower affinity for digoxin than did erythrocytes from adults. Although their tissue may be less sensitive to digoxin than is that of adults, the plasma half-life for the drug is substantially longer in premature infants than in normal neonates because of slowed renal clearance,270927’so that smaller digoxin doses are recommended.270 Besides altered metabolism, age, and neurohumoral factors affecting sensitivity to digitalis glycosides, the common clinical syndrome of chronic obstructive pulmonary disease (COPD) may make a patient more susceptible to digitalis toxicity.272 Digoxin absorption in right ventricular failure has been reported to be unaltered,273 but the actual usefulness of digoxin for patients with right ventricular failure in the setting of COPD remains unclear. Green and Smith reviewed the often conflicting evidence for the safety and efficacy of cardiac glycoside use in COPD.*‘* In this setting several clinical observations are almost certainly correct: (1) cardiac glycosides may diminish the frequency of atria1 premature beats and lessen the patient’s risk of developing atria1 fibrillation; (2) when digoxin is used in high doses in an attempt to slow sinus tachycardia or control multifocal atria1 tachycardia, the risk of digoxin toxicity is substantial, and the chances of controlling the arrhythmia are small; (3) acutely administered digoxin does have a modest positive inotropic effect on the failing right ventricle and may also cause modest pulmonary vasoconstriction. Less certain is the clinical value of the mild increase in inotropic state of the right ventricle. In the absence of overt right heart failure, digoxin has little discernible benefit. The preponderance of evidence supports the long-held suspicion that sensitivity to the toxic effects of digitalis,

440

particularly ventricular automaticity, is heightened in patients with COPD. The precise underlying mechanisms, however, remain obscure. Factors contributing to the increased sensitivity include hypoxia, either as a direct effect or by way of catecholamine release; hypokalemia, which is frequently present in this syndrome; and therapy with sympathomimetic agents and methylxanthines (eg, aminophylline) that will potentiate the effects of catecholamines. Considering the narrow therapeutic-toxic ratio in this setting, it may be prudent to use a cardiac glycoside only during episodes of acute decompensation and in modest doses. Indeed, Mathur et a1274have suggested that only if left ventricular failure is a major element will digoxin be of therapeutic benefit in patients with severe chronic airflow obstruction and right ventricular failure. In the setting of acute left ventricular failure, considerable clinical experience indicates that the digitalis glycosides can be of substantial therapeutic benefit. However, for the clinical syndrome of chronic heart failure, some authors have expressed doubt about whether this potentially toxic class of drugs has a favorable risk/ benefit ratio in all patients.275 Many patients begun on digitalis for an episode of congestive heart failure (CHF) can no doubt be taken off digoxin without apparent ill effect.‘7S’8 Thus, in one series of 24 patients receiving digoxin in a general practice, 18 had no signs of overt CHF. Digoxin was discontinued in 17 of 18 patients in sinus rhythm; all tolerated withdrawal without adverse effects, and ten of the 17 reported that they felt better not taking digoxin.17 In a similar trial of digoxin withdrawal for patients in sinus rhythm without overt CHF, 34 patients had a serum digoxin concentration less than 0.8 ng/mL and an additional 22 had concentrations of 0.8 to 2.0 ng/mL. Eighty-six percent of patients tolerated digoxin withdrawal without evident deterioration; however, five patients developed atria1 fibrillation with a rapid ventricular response.‘* Furthermore, a recent double-blind study276 has identified subsets of patients with overt CHF who do and do not benefit from digoxin therapy. Lee et a1276studied 25 ambulatory patients and assessed the degree of CHF present during placebo treatment and during digoxin therapy (av-

SMITH

ET AL

erage dose 0.44 mg/d). Digoxin was of apparent benefit only in patients with chronic heart failure, a dilated heart, and a third heart sound. In 11 of 25 patients, withdrawal of digoxin had no adverse effects. Most of these nonresponders could have been predicted based on our current understanding of the actions of digitalis on the heart, since six of the 11 had hypertrophic cardiomopathy or ischemic disease with normal ejection fractions in the range of 52% to 67%, while another three had serum digoxin concentrations of only 0.5 ng/mL and, hence, were probably not on adequate doses or were noncompliant. Of note is that digoxin caused no measurable overall improvement in ejection fraction. However, in another recent study it has been unequivocally established for the first time that long-term digitalis treatment does improve left ventricular function in selected patients with chronic CHF.22 DIGITALIS AND SURVIVAL AFTER MYOCARDIAL INFARCTION

The impact of digitalis use on survival after myocardial infarction is currently an area of controversy that has major clinical importance but lacks clear resolution. Recently, Moss and co-workers277 analyzed 4-month mortality rates after hospital discharge of postinfarction patients treated with and without digitalis. Multiple logistic analysis was used to evaluate the independent effect of digitalis use on mortality. In the group of patients with CHF and complex ventricular arrhythmias on predischarge Holter monitoring, digitalis use appeared to be associated with excessive mortality. The majority of deaths occurred in the hospital and were not sudden, implicating further ischemia and not arrhythmias as the causative factor. The extent of coronary disease and severity of left ventricular dysfunction were not defined in this population. Of note is that the group with CHF and complex arrhythmias not treated with digitalis had an unusually low mortality rate. Bigger et a1278also recently reported that in the year following myocardial infarction, treatment with digoxin may increase mortality. In their series of 490 patients who survived the hospital phase of myocardial infarction, 46% were discharged on digoxin. During the year following, of all the deaths that occurred in these 490 patients,

DIGITALIS

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441

77% were among the patients receiving digoxin. The mortality was 22% in the group receiving digoxin versus 6% in the untreated group. A multiple logistic regression model was used to control for several variables which indicated that patients in the digoxin group were more seriously ill. Even when all additional identifiable risk factors were taken into account, however, there still appeared to be excess mortality in the digoxin-treated group. Importantly, because the extent of coronary disease in this study population was not known, it was not possible to correct for this factor, which is known to be a major determinant of prognosis. Data from the Coronary Artery Surgery Study (CASS) sheds a somewhat different light on this problem?79 In this large group of patients who underwent coronary angiography and thus had carefully defined coronary anatomy, it was possible to stratify patients on the basis of extent of coronary artery disease. Once this important factor was taken into account, digoxin use in the months after infarction did not appear to contribute to adverse outcome. Even in the high-risk group of patients who had had an infarct within two months, a prior cardiac arrest, manifest CHF, and were on antiarrhythmic drugs, digoxin use was not associated with increased mortality. Additional prospective studies are needed to resolve this important issue. CONCLUSION

What impact have the availability of serum digoxin concentration measurements and the heightened clinical suspicion of the possibility of digitalis intoxication had on the incidence of toxicity over the past ten years? Some evidence indicates that the incidence of digitalis toxicity is

lower than it was in the late 1960s and early 1970s. 225*280-283 A recent study of the prescribing of digoxin by family practitioners in Rochester, New York, showed that 1% of all prescriptions were written for digoxin; 63% of these were for 0.25 mgfd. For patients over 64 years of age, the average dose prescribed was slightly reduced. Compared with the data available for 1973, current dosing patterns appear to be more sophisticated. **’ Pedoe283 analyzed the digoxin-prescribing patterns of general practitioners in Great Britain from 1967 to 1977. Seventy-four percent of all prescriptions for digoxin were for patients over 65 years of age, and during this ten-year period the average daily dose for digoxin fell from 450 pug/d to 220 pg/d.283 Thus, we may surmise that there is greater awareness of the problem of digoxin toxicity as well as greater availability of other effective means of treating CHF. This conclusion is also directly supported by the data of Duhme et a1235regarding the impact of the availability of methods for measuring serum digoxin levels. Other epidemiologic aspects of digoxin toxicity may change more slowly. Apparently, red deer find the foxglove plant most appetizing. When these animals were raised commercially in a pasture that contained an abundance of this plant, an epidemic of digitalis intoxication occurred, manifest by anorexia, vomiting, and arrhythmias.284 Also, when amateur herbalists choose the leaves of Digitalis purpurea as ingredients for their herb tea, digitalis intoxication may result,285 as previously reported by Withering.” These “clinical” settings notwithstanding, digitalis intoxication probably occurs less often in 1983 than it did in the late 1960s.235*252*258

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