Drug Disposition

Clinical Pharmacokinetics 15: 165-179 (1988) 0312-5963/88/0009-0165/$07.50/0 © ADIS Press Limited All rights reserved.

Digitalis

An Update of Clinical Pharmacokinetics, Therapeutic Monitoring Techniques and Treatment Recommendations

Arshag D. Mooradian Geriatric Research. Education and Clinical Center. Sepulveda Veterans Administration Medical Center. and The Department of Medicine. UCLA School of Medicine. Los Angeles. California. USA

Contents

Summary .................... .......................... .............. ............ ................................. .............. ............. 165 1. Pharmacokinetics ................. ............................. .................................................... ................. 166 1. 1 Absorption ... .......... ... ... ................. ................. ............................... .. ...... .............. ............. 167 1.2 Distribution ..... .. .............................................................................................................. 168 1.3 Elimination ..................... ................................................................................................. 169 2. Effect of Disease States ..... ....... ........ ........ .......... .. ............................................ ...... ............... 170 3. Effect of Pregnancy ....... ......... ............................................................................................... 172 4. Effect of Age ........... .................. .. ................... ............................................. ........................... 172 5. Drug-Drug Interactions .......... ................ ...... .......................... ............................................... 173 6. Serum Concentration Monitoring ............................................................... ........................... 174 7. Treatment Recommendations ................... ........................................................................... 175

Summary

The intestinal absorption of digoxin is essentially a passive non-saturable diffusion process, although a saturable carrier-mediated component also plays an important role. The bioavailability varies between 40 and 100%: the presence offood may reduce the peak serum concentration. but does not reduce the amount of digoxin absorbed. Recent development of a capsule containing a hydroalcoholic vehicle may reduce interindividual variations in absorption. Pharmacokinetic analysis of the distribution of digoxin suggests 3 compartments. the slow distribution phase accounting for the lag time between the inotropic effects and the plasma concentration profile. Digoxin is extensively bound to tissues such as myocardium, renal. skeletal muscle as well as red blood cells. but not to adipose tissue. Plasma protein binding varies between 20 and 30%: displacement of digoxin from protein binding sites does not cause sign{ficant clinical effects. As expected. haemodialysis or exchange transfusions do not significantly alter the body load of digoxin. The apparent volume of distribution of digox in varies between 5 and 7.3 L/kg; this may be reduced by. for example, electrolyte abnormalities which reduce digoxin binding to the myocardium. The elimination half-We of digoxin is 36 hours, with 60 to 80% being excreted unchanged. by passive glomerular filtration and active tubular secretion. The remainder is excreted non-renally. Clearance is therefore dependent on renal function and declines in renal disease and in elderly patients. Digoxin interacts with other drugs at any stage of absorption (e.g. cholestyramine). distribution (e.g. quinidine). metabolism (e.g. phenytoin) or elimination (e.g. diltiazem).

Digitalis: An Update

166

Patients should. therefore. be car~fully monitored when changing a therapeutic regimen which includes any drugs known to interact with digoxin. Clinical monitoring is more important than therapeutic drug monitoring which should be reserved for suspected toxicity. doubts about efficacy. or in cases of poor compliance. With the advent of newer treatment modalities. digoxin is no longer the treatment of .first choice in supraventricular arrhythmias and congestive heart failure. Howel'er. with careful monitoring. digoxin remains an important therapeutic option.

Since the elegant description of the medical uses of the foxglove plant by William Withering in 1785 (Withering 1941), the use of digitalis glycosides for the treatment of congestive heart failure has received mixed reactions ranging from uncritical acceptance to withholding of therapy for fear of possible adverse effects, and now to reluctant acceptance by most practising physicians. Nevertheless, the common use of digitalis over 2 centuries indicates that the drug has truly passed the test of time. Major advances in our understanding of pharmacokinetics and pharmacodynamics of digitalis have been made over the past 25 years. With this knowledge and a better targeting of the patient population likely to respond to digitalis, it is expected that this drug, if used judiciously, will continue to be a viable therapy for congestive heart failure. Two excellent reviews on digoxin pharmacokinetics have been previously published in this journal (Aronson 1980; lisalo 1977). This review discusses the pharmacokinetics of digoxin, the most commonly prescribed digitalis glycoside, and compares it with the other cardiac glycosides. In addition, the available techniques for monitoring serum concentrations are discussed and the determinants of patient response to therapy are delineated.

1. Pharmacokinetics The term 'digitalis' generally refers to a family of compounds which share a steroid nucleus and have characteristic electrophysiological and inotropic effects on the heart. At present, digoxin is the most commonly used digitalis compound, but others, such as digitoxin, ouabain (strophanthin),

medigoxin (metildigoxin), lanatoside C and desacetyl-lanatoside C, are still available. Although the pharmacokinetics of some of these compounds have been studied extensively, the differences among them are not completely appreciated. Table I summarises the pharmacokinetic parameters of 3 representative digitalis compounds: ouabain, a polar compound; digitoxin, a non-polar compound; and digoxin, a compound with inter-

Table I. Pharmacokinetic parameters of 3 digitalis compounds with different degrees of polarity

Parameter

Ouabain (polar)

Intestinal absorption Highly variable Intestinal secretion?

Yes

tma.

Digoxin Digitoxin (intermediate (non-polar) polarity) 40-100%·

90-100%

Yes

Yes

45-60 min

1-2h

Plasma protein binding (%)

10

20-30

95

Vd (L/kg)

14-18

5-7.3

0.5-0.73

Therapeutic plasma concentration VtQ/L)

0.25-1.0

0.5-2.0

10-30

18-25h

36

4-6 days

Major route of elimination

Renal. gastrointestinal

Renal, gastrointestinal

Hepatic: metabolites in urine

Enterohepatic circulation (%)

Unlikely to occur

6.8

26

Placental transfer?

Not known

Yes

Yes

tV./1

a Dependent on dosage form. Abbreviations: tm •• = time to maximum plasma concentration; Vd = volume of distribution; tV./1 = elimination half-life.

167

Digitalis: An Update

Brain

~

c •• = 1 pg/ L Free C••

tv>"

= 0.8 .«9/L

~

= O.SSh

= 37h A. s = 420pg t",~

Digoxin tablet O.25mg

•

Heart

~ 16.8.«9

Skeletal muscle

excretion

Fig. 1. Schematic representation of the steady-state distribution of digoxin and the fate of a 0.2Smg digoxin tablet in an adult with a bodyweight of 70kg. Calculations are based on a volume of distribution of 6 L/kg and digoxin absorption of 80%. The amount of drug in the body at steady-state (Ass) and in different tissues is shown. Abbreviations: DRP = digoxin reduction products ; Css

= steady-slate serum concentration; I",,, = distribution half-life; t'hi = elimination

mediate polarity. Since the polarity of a digitalis compound is an important determinant of its absorption, distribution and elimination characteristics, the pharmacokinetics of any digitalis compound will approximate whichever of those in table I has a polarity characteristic similar to it. It should be emphasised , however, that this schema is only an approximation , since polarity is not the sole determinant of the pharmacokinetics of a drug. The average kinetic parameters of digoxin in a typical individual are schematised in figure I. 1.1 Absorption The intestinal absorption of digoxin is a passive, non-saturable diffusion process (Caldwell et al. 1969; Greenberger & Caldwell 1972: Haass et

half-life.

al. 1972), although a saturable, carrier-mediated component also plays a significant role (Lauterbach 1981). The proximal part of the small intestine is the predominant site of absorption, with the stomach playing a minor role. The rate of gastric emptying and the acidity of gastric contents do not seem to alter digoxin absorption (Beermann et al. 1972). Extensive intestinal disease resulting in malabsorption would reduce the bioavailability of oral digoxin (Heizer et al. 1971), but partial gastrectomy (Beermann et al. 1973) or jejunoileal bypass (Marcus et al. 1976) has minimal effect. The presence of food in the gut may reduce peak serum concentrations (White et al. 197Ia), but would probably not alter the total absorption of the drug. In contrast, concomitant ingestion of other drugs, such as phenytoin, sulphasalazine (saJicyl-

Digitalis: An Update

azosulfapyridine), neomycin and, particularly, antacids or kaolin-pectin, significantly decreases the bioavailability of orally administered digoxin tablets (Brown & Juhl 1976). As intestinal absorption of digitalis is predominantly a passive diffusion process, it is not surprising that the more lipophilic the compound, the better it is absorbed. However, to correlate the polarity of a digitalis glycoside with its absorption rate is to oversimplify a transport process with complex kinetics, which include passive diffusion, a carriermediated component and active secretion (Lauterbach 1981). Because the intestinal absorption of the polar compounds, such as ouabain and desacetyllanatoside C, is unreliable, they should only be administered intravenously. Digitoxin, a lipid-soluble compound, is 90 to 100% absorbed, and recent studies using a specific assay of digitoxin have found that it has a bioavailability of only 81.5% (MacFarland et aI. 1984). Cholesterol-binding resins such as cholestyramine and colestipol substantially reduce digitoxin absorption (Caldwell & Greenberger 1971). The absorption of digoxin, a more polar digitalis compound, varies between 40 and 100%, depending on the type of preparation used and as a result of marked interindividual variability in absorption capacity. In earlier studies, digoxin in solution (i.e. elixir) was found to be more bioavailable than in the tablet form (Huffman & Azarnoff 1972; Wagner et aI. 1973). Because of differences in the dissolution rate of different tablets, however, there is marked variability in the bioavailability of digoxin in this form (Lindenbaum et aI. 1971; Shaw et aI. 1972). In 1 study the variation in peak serum digoxin concentration following intake of different tablets reached as high as 7-fold (Lindenbaum et aI. 1971). Substantial differences were also seen in steady-state serum digitoxin concentrations, indicating the clinical relevance of the variability in peak concentration (Shaw et aI. 1972). With the recent introduction of digoxin in a capsule form containing a hydroalcoholic vehicle, the interindividual variability of digoxin absorption was reduced, so that the bioavailability of oral digoxin now approaches that of digitoxin. It would

168

be of interest to determine if the coingestion of antacids or kaolin-pectin interferes with the absorption of digoxin in this newer preparation. The luminal factors that alter digoxin absorption may also alter the rate of digitoxin absorption without affecting its bioavailability. Digoxin-inactivating bacteria in human gut flora may have a significant effect on the bioavailability of digoxin, thus explaining the rare cases of apparent resistance to this drug (Dobkin et aI. 1983). An anaerobic saprophyte, Eubacterium len tum, can convert digoxin to reduced cardioinactive metabolites both in vivo and in vitro. However, neither the presence of these organisms alone nor their concentration within the gut flora is an indicator of whether digoxin will undergo inactivation in an individual, as additional factors, peculiar to the individual, also influence the inactivation process. These factors are not known at present. A course of antibiotics in subjects who are excretors of digoxin reduction products exposes them to potential drug toxicity (Lindenbaum et aI. 1981 b) by eliminating intraluminal degradation of digoxin. Two precursors of digoxin have been used clinically, but have not received wide acceptance. Conversion of t/-methyl digoxin (medigoxin) to digoxin occurs after absorption, whereas the gut is the site of conversion of lanatoside C to digoxin. The absorption of medigoxin is greater than that of digoxin, and the absorption of lanatoside C is lower. In general, however, the greater the absorption of a compound, the less likely is there to be interindividual variability in absorption. It remains to be seen whether the improvement of digoxin bioavailability by cyclodextrin complexation will be widely utilised (Uekama et aI. 1983). Inclusion of drug molecules in the relatively hydrophobic cavity of cyclodextrins would change the water solubility and instability of the drug in acidic media. 1.2 Distribution After an intravenous bolus dose of digoxin or ouabain, plasma concentration decay is biphasic. The first phase, which lasts 4 to 8 hours, represents

Digitalis: An Update

the time required for drug distribution to the tissues, and the subsequent phase comprises the elimination of the drug from the body. Kinetic analysis of plasma concentration data obtained with frequent blood sampling suggested 3 drug compartments (Schenck-Gustafsson et al. 1981; Sumner & Russel 1976): I large peripheral compartment, and 2 small compartments representing plasma water or extracellular fluid spaces and highly vascularised tissues. The slow drug distribution phase accounts for the delay between the inotropic effects of the drug and the plasma concentration profile. The use of the recently described skin blistering technique has allowed measurement of tissue fluid concentrations of digoxin. After an intravenous dose the inotropic effects of digoxin were closely related to cantharides blister fluid concentrations of the drug (Schafer-Korting et al. 1987). Peak digoxin concentration in blister fluid occurred I hour after intravenous injection. In contrast, the maximal effect of digoxin on heart rate appears in less than I hour after intravenous injection, before tissue distribution is completed, suggesting that the receptors for this action are located in extracardiac sites, probably in the autonomic nervous system (Pedersen et al. 1983a; Rosen et al. 1975). At steady state digoxin and digitoxin are extensively bound to tissues, particularly myocardium, kidney, skeletal muscles and red blood cells (Doherty 1968; Jogestrand 1980). Body adiposity, on the other hand, has no effect on digoxin pharmacokinetics, as adipose tissue binding to digoxin is poor (Ewy et al. 1971). The ratios of myocardial to plasma concentrations of digoxin and digitoxin are 50: I, and approximately 10: 1, respectively. The plasma protein binding of digoxin ranges from 20 to 30%, but is more than 95% for digitoxin (Lukas & De Martino 1969). The ability of some drugs, e.g. warfarin, phenylbutazone and clofibrate, to displace digitoxin from plasma protein binding sites does not have significant clinical implications (Solomon & Abrams 1972). Since the vascular compartment comprises 0.5% of the total body digoxin content, it is not surprising that dialysis (Ackerman et al. 1967) or exchange transfusions (Coltart et al.

169

1972) have only minor effects on plasma digoxin concentrations. In pregnant women maintained on digoxin, the maternal and fetal plasma concentrations across the placental unit are similar (Lingman et al. 1980; Rogers et al. 1972). Other studies, however, in which fetal supraventricular tachycardia was treated with maternal digoxin, found lower serum digoxin concentrations in cord blood than in maternal plasma (Kerenyi et al. 1980; King et al. 1984; Spinnato et al. 1984). These observations should be interpreted with caution, as elevated concentrations of digoxin-like immunoreactive substances have been found in premature and mature newborn infants (Pudek et al. 1983; Valdes et al. 1983). The apparent volume of distribution of digoxin is usually 5 to 7.3 L/kg (Koup et al. 1975a; Leakey et al. 1975), while that of digitoxin is 0.5 to 0.73 L/kg (Graves et al. 1984a; Lukas 1971,1973). The volume of distribution of ouabain ranges between 14 and 18 L/kg (Selden & Smith 1972). A variety of factors alter distribution volume by interfering with drug binding to tissues (for review see Smith & Haber I 973a). For example, electrolyte abnormalities such as hyperkalaemia or hyponatraemia reduce digoxin binding to the myocardium. The effect of acute changes in serum magnesium concentrations on tissue digoxin binding is usually minor. Some drugs, notably quinidine, can displace digoxin from tissue binding sites and reduce the apparent volume of distribution of digoxin (Pedersen 1985). On the other hand, hyperthyroidism is associated with a modest increase in digoxin distribution space (Doherty & Perkins 1966). It is not clear whether this increase can be totally attributed to the increased Na+-K+-ATPase units (digoxin binding sites) in hyperthyroidism. 1.3 Elimination The plasma half-lives and excretory pathways of digitalis compounds differ. Digitoxin has the longest half-life (4 to 7 days) and ouabain has the fastest elimination rate, with a half-life of approximately 18 to 21 hours. Digoxin and deslanatoside have an intermediate rate of elimination, with a

Digitalis: An Update

half-life of 36 and 33 hours, respectively (Smith & Haber 1973a). The principal route of ouabain elimination is the kidney, which accounts for the excretion of 47% after an intravenous dose, although up to 33% of an intravenous dose can be excreted in the gastrointestinal tract by a primarily nonhepatic route, presumably intestinal secretion (SeIden et al. 1974). Digitoxin, on the other hand, is primarily eliminated through the hepatic route. At least 50% of a dose is metabolised in the liver to cardioinactive and cardioactive metabolites, including digoxin, which are excreted in the bile and, to a lesser extent, the urine. Digitoxin excreted in the gut is subsequently reabsorbed into the enterohepatic circulation (Lukas 1971, 1973; Okita 1969); only a small fraction is eliminated in the gut in unaltered form. Drugs that stimulate hepatic microsomal enzymes, such as phenytoin, phenobarbitone, phenylbutazone and rifampicin (rifampin), can accelerate the hepatic metabolism of digitoxin and alter plasma concentrations (Solomon & Abrams 1972). One of the metabolites of digitoxin, digitoxigenin bisdigitoxoside, may have therapeutic advantages, since it has pharmacokinetic and pharmacodynamic properties similar to the parent compound, except for an elimination half-life of only 15 hours (Graves et al. I 984a). Digoxin, like ouabain, is excreted by a predominantly renal route. Approximately 60 to 80% of bioavailable digoxin is excreted unchanged, by passive glomerular filtration and active tubular secretion (Steiness 1974; Sumner & Russel 1976), although there is also some reabsorption of digoxin from the tubular fluid. The remaining one-third (approximately) of the drug is eliminated by an extrarenal route (fig. I). In approximately 10% of patients digoxin reduction products constitute 30 to 40% of total urinary excretion of digoxin and its metabolites (Lindenbaum et al. 1981a,b; Peters et al. 1978). Inactivation of digoxin by gut flora may substantially reduce the availability of oral digoxin tablets. A variety of digoxin reduction products have been identified of which dihydrodigoxin is the major one.

170

In individuals who are digoxin reduction product excretors the use of highly bioavailable digoxin capsules may minimise drug inactivation (Rund et al. 1983), as the metabolism of oral digoxin is partly accomplished by gut flora. Gut flora, however, appear to have an insignificant role in the metabolism of intravenous digoxin (Schenck-Gustafsson et al. 1981), suggesting that biliary or intestinal excretion of unaltered drug, rather than metabolism, is usually responsible for 20 to 40% of total body clearance. A small amount of digoxin undergoes hepatic metabolism to various compounds, including 3iJ-digoxigenin and its mono- and bis-digitoxosides, 3-keto and 3a(epi)-digoxigenin and their conjugated polar end-metabolites (Gault et al. 1983). Of interest is that the intestinal secretion of digoxin and digitoxin, unlike absorption, appears to be an active, energy- and temperature-dependent transport process. The question of which intestinal site has maximal digitalis glycoside secretory capacity is controversial. In vivo studies in guineapigs found that the jejunum and the colon had similar digitoxin secretory capacity, while digoxin excretion was higher in the jejunum (Schafer et al. 1985). In studies with isolated intestinal mucosa preparation, the colon had up to IO-fold higher secretory capacity of digitoxin (Misra 1983) and digoxin (Lauterbach 1981) than the jejunum. Irrespective of the site of major secretory capacity, it appears that this route is an important elimination pathway of cardiac glycosides.

2. Effect of Disease States Table II summarises the effects of different disease states on the pharmacokinetics of digitalis. Although digitoxin is actively metabolised by the liver, the elimination kinetics are usually unaltered in hepatic disease because of the large reserve capacity of hepatic metabolism. Hypoalbuminaemia is associated with a lower therapeutic range of serum digitoxin concentrations, but does not cause clinically significant alterations in pharmacokinetics. Renal excretion of digitoxin is reduced in uraemia, but the volume of distribution

Digitalis:

An

Update

171

Table II. Effect of disease states on pharmacokinetics of digoxin and digitoxin Disease state Renal disease

Clinical implication

Altered pharmacokinetic variable

Reference

Decreased digoxin elimination and Vd

Loading and maintenance dose

Paulson & Welling

Unchanged digitoxin/tv", and Vd

of digoxin should be reduced

(1976) Doherty (1983) Storstein (1983) Graves et al. (1984b)

Low therapeutic serum digitoxin

Zilly et al. (1975)

Unaltered elimination kinetics of digitoxin (large metabolic reserve)

concentration (in

Congestive heart

Decreased digoxin elimination

Frequent monitoring of serum

Smith & Haber

failure

Increased Vd when patient is oedematous

concentrations

(1973b)

Thyroid disease

Increased renal elimination and Vd in

Increased dose is required in hyperthyroidism and reduced

(1966)

Hepatic disease

hypoalbuminaemia)

hyperthyroidism Reduced renal elimination and Vd

dose in hypothyroidism

Decreased absorption in those with

Increased dose may be required

Doherty & Perkins

Heizer et al. (1971)

Gastrointestinal disease

malabsorption syndromes

Diabetes insipidus

No significant changes

Bisset et al. (1972)

Obesity

No significant changes

Ewy et al. (1971)

Abbreviations: t'h"

= elimination half-life; Vd = volume of distribution.

and elimination half-life are unchanged due to enhanced extrarenal clearance. Absorption and steadystate serum concentration are also not altered (Graves et al. 1984b; Storstein 1983). Renal disease, on the other hand, substantially alters both the elimination half-life and volume of distribution of digoxin (Doherty 1983; Koup et al. 1975b; Paulson & Welling 1976). In general, there is a good correlation between creatinine clearance and the steady-state plasma digoxin concentration for a given maintenance dose. Digoxin clearance increases with creatinine clearance in hyperthyroidism (Bonelli et al. 1978; Croxson & Ibbertson 1975) and congestive heart failure treated with vasodilator therapy (Cogan et al. 1981). The reduction in volume of distribution and the prolongation of the elimination half time in uraemia is highly variable. The ratio of myocardial to plasma digoxin content is also decreased in renal failure (Jusko & Weintraub 1974), suggesting that the tissue effect of digoxin at a given serum concentration may be

reduced. Digoxin maintenance dose, as well as initial digitalising dose, should be adjusted in patients with renal failure. Various methods have been described for pharmacokinetic prediction of serum digoxin concentration in patients with renal failure (Gault et al. 1986; Paulson & Welling 1976); those which incorporate distribution volume change have best predictive value. The magnitude of error in the methods described to date, however, precludes their clinical application. Two other disease states, thyroid disease and congestive heart failure, alter digoxin pharmacokinetics primarily through changes in renal function. Despite some inconsistency in the reported studies, neither the intestinal absorption nor the volume of distribution of digoxin is altered in severe right heart failure (Ohnhaus et al. 1979). Acute vasodilator therapy increases renal blood flow, leading to a 50% increase in digoxin clearance. In hyperthyroidism, both the pharmacodynamics and pharmacokinetics of digoxin are altered. There is reduced myocardial responsiveness to dig-

Digitalis: An Update

oxin, and the serum concentrations following a given dose are reduced (Doherty & Perkins 1966). This is secondary to increased renal clearance and increased apparent volume of distribution of digoxin. Whether there is also an alteration in the extrarenal clearance of digoxin is not clear (Gilfrich 1976). Larger doses of digoxin may be required in hyperthyroidism, while hypothyroid patients require smaller doses (Doherty et al. 1983).

3. Effect of Pregnancy Studies of digoxin kinetics in pregnancy and newborn infants, like studies in patients with renal or hepatic failure, are complicated by the presence of digoxin-like serum immunoreactive substances (Barbarash 1984; Lackner & Valdes 1984). In general, digoxin clearance is increased with the pregnancy-related increase in creatinine clearance (Luxford & Kellaway 1985). In I study, serum digoxin was unexpectedly lower in the post partum period (Barbarash 1984). This was attributed to a possible increase in digoxin absorption in pregnancy, athough such an increase was not demonstrated experimentally, and the findings were inconsistent with a previous report demonstrating higher post partum serum digoxin concentrations (Rogers et al. 1972). Transplacental passive transport of digoxin and digitoxin occurs, and, occasionally, in utero fetal digitoxin intoxication has been documented (Shelman & Locke 1960).

4. Effect of Age The distribution volume of digoxin and digitoxin is slightly larger in children than in adults (I L/kg vs 0.57 L/kg) [Larsen & Storstein 1983; Morselli et al. 1975; Reuning et al. 1973]. Myocardial tissue concentrations of digoxin, in particular, are also higher in children less than 2 years old than in older children and adults (127 ng/g vs 86 ng/g) [Hastreiter & Van der Horst 1983]. Although renal clearance does not differ, total body clearance is significantly higher in children (0.085 ml/min/kg vs 0.036 ml/min/kg), presumably due to increased metabolic clearance (Larsen & Storstein 1983). In-

172

fants require higher digitoxin doses by bodyweight or body surface area (3.1 J.Lg/kg/day vs 1.4 J.Lg/kg/ day), and steady-state serum concentrations are substantially higher than in adults (30 J.LgfL vs 24 J.Lg/L), but do not lead to overt cardiac toxicity (Giardina et al. 1975). The mechanism for this relative digoxin insensitivity in infants is not clear. In contrast, the incidence of digoxin toxicity in hospitalised geriatric patients has been reported to be as high as 20% (Williamson & Chopin 1980), a reflection of age-related alterations in the pharmacokinetics of digoxin. In contrast to digitoxin (Donovan et al. 1981), digoxin undergoes decreased clearance with deterioration of renal function with age. In addition, the volume of distribution of digoxin is reduced due to a decrease in lean body mass (Chellingsworth 1986), but intestinal absorption and biliary excretion of digoxin metabolites are usually not altered. Studies in laboratory animals, however, have suggested an age-related decrease in hepatic biotransformation of digitalis glycosides (van Bezooijen et al. 1984). There appear to be some age-related alterations in digoxin pharmacodynamics. Tissue uptake is reduced in older guinea-pigs and mice (Kroening & Weintraub 1980), as is the sensitivity of human red blood cell Na+ -K+ -ATPase inhibition by ouabain (Platt & Schoch 1974). Katano et al. (1985), on the other hand, found that the sensitivity of aged left myocardium to cardiac glycosides was increased. However, the clinical significance of these observations is not clear, as the elderly are probably not more sensitive to the therapeutic and toxic effects of digoxin at a given serum concentration (Chamberlain et al. 1970; Cokkinos et al. 1980). One form of extracardiac toxicity, however, manifesting as lethargy, depression and confusion, appears to occur almost exclusively in the elderly (Portnoi 1979). Since the accessibility of digitalis glycosides to the central nervous system is not increased with age (Krakauer & Steiners 1978), it is not clear why older patients are more susceptible to this form of toxicity.

173

Digitalis: An Update

Table III. Agents affecting the pharmacokinetics of digitalis

Alteration

Agents

Decreased absorption

Activated charcoal, antacids, cholestyramine. colestipol, cytotoxic agents [cyclophosphamide, doxorubicin (adriamycin)), dietary fibre, kaolin-pectin, metoclopramide, neomycin, sulphasalazine

Increased absorption

Antibiotics (by inhibiting gut flora), anticholinergics (propantheline)

Inhibition of serum protein binding

Clofibrate, phenobarbitone, phenylbutazone, prazosin, sulphonamides, tolbutamide, warfarin

Enhanced hepatic metabolism

Phenobarbitone, phenylbutazone, phenytoin, rifampicin (rifampin)

Enhanced renal excretion

Hydralazine, levodopa. nitroprusside

Inhibition of renal tubular secretion

Quinidine, spironolactone, triamterene, trimethoprim, verapamil

Inhibition of extrarenal clearance

Diltiazem, quinidine, verapamil

Decreased volume of distribution

Quinidine

Increased serum digoxin concentrations (mechanism unknown)

Amiodarone, aspirin, bepridil, diltiazem, flecainide, ibuprofen, indomethacin, nifedipine, nicardipine, nisoldipine, nitrendipine. propafenone

5. Drug-Drug Interactions The interaction of cardiac glycosides with other drugs has been extensively discussed in numerous papers. Interactions can occur at any phase of absorption, distribution, metabolism and elimination. Table III summarises the list of commonly used drugs that alter serum digoxin concentration by interfering with the usual pharmacokinetics (Aronson 1980; Pedersen 1985; Solomon & Abrams 1972). The absorption of digoxin is decreased by chole-

styramine, neomycin, sulphasalazine, metoclopramide, dietary fibre, activated charcoal, antacids and kaolin-pectin. Although the rate of absorption of digitoxin may also be altered, with the exception of cholesterol binding resins and antacids, the abovementioned substances do not significantly inhibit total absorption. The dosage form of the cardiac glycoside influences the extent of any drugdrug interaction. The bioavailability of the tablet form of digoxin, for example, is more likely to be reduced by other agents than preparations with hydroa1cohol as the solvent. Antibiotics may increase the bioavailability of digoxin in a subset of patients with digoxinmetabolising bacteria in their gut. Drugs such as phenobarbitone, phenytoin, and rifampicin that induce the hepatic microsomal metabolising system reduce plasma concentrations of digitoxin by accelerating its hepatic metabolism. Tubular secretion of digoxin can be reduced by triamterene and spironolactone, and a metabolite of spironolactone, canrenoate, interferes with the tissue binding sites of digoxin. Sulphonamides, tolbutamide, and phenobarbitone can displace digitoxin from albumin binding sites, and thereby temporarily increase the serum concentration of free drug, but without significant clinical consequences. The effect of antiarrhythmic drugs, particularly quinidine and, to a lesser extent, verapamil, on digitalis pharmacokinetics has been extensively studied (Pedersen 1985). A loading dose of quinidine causes a large increase in plasma digoxin concentration within 24 hours, followed by a minor increase over I to 2 weeks, after which equilibrium is achieved. The initial rise is probably related to displacement of digoxin from its binding sites. In addition to reducing the apparent volume of distribution, quinidine reduces renal excretion of digoxin by 25 to 40%, probably by inhibiting its active tubular secretion. Extrarenal clearance of digoxin is also attenuated by quinidine, either by inhibition of biliary excretion of unaltered drug or interference with intestinal secretion. The metabolic pathways of digoxin are not altered by quinidine (Pedersen et al. I 983a). Moreover, quinidine appears to enhance the net intes-

Digitalis: An Update

tinal absorption of digoxin, although results are still inconclusive. In general, the digoxin maintenance dose should be halved before initiation of quinidine therapy, and in a patient who is on quinidine, one-third of the usual digitalising dose should be used. The effect of verapamil on serum digoxin concentrations is modest compared with that of quinidine. Verapamil does not alter digoxin distribution volume, but reduces both renal and extrarenal clearance (Klein et al. 1982; Pedersen 1985; Pedersen et al. 1983b). Thus, the maintenance dose of digoxin should be reduced in patients on verapamil, but the digital ising dose need not be altered. Less well-studied drugs that have been shown to be occasionally associated with increased plasma digoxin concentrations include diltiazem (Chaffman & Brogden 1985; North et al. 1986), nisoldipine (Friedel & Sorkin 1988), nifedipine (Kirch et al. 1986; Sorkin et al. 1985), nicardipine (Sorkin & Clissold 1987), nitrendipine (Goa & Sorkin 1987; Kirch et al. 1984), bepridil (Belz et al. 1986), amiodarone (Moysey et al. 1981), flecainide (Holmes & Heel 1985; Weeks et al. 1986), propafenone (Harron & Brogden 1987; Salerno et al. 1984), and ibuprofen (Quattrocchi et al. 1983). Tocainide, ethmozine, mexiletine and alprazolam do not seem to affect plasma digoxin concentrations (Kennedy et al. 1986; Ochs et al. 1985; Weber & Takemoto 1986). The effects of other drugs on serum digitoxin concentrations are less well studied than for digoxin. Quinidine increases serum concentrations by primarily decreasing extrarenal clearance without altering renal clearance. The apparent volume of distribution is slightly (16%) decreased (Kuhlmann et al. 1986). Similarly, verapamil and, to a lesser extent, diltiazem reduce the extrarenal clearance of digitoxin and thereby slightly increase steady-state serum concentrations (Kuhlmann 1985). Nifedipine, on the other hand, does not alter digitoxin kinetics (Sorkin et al. 1985).

6. Serum Concentration Monitoring In general, routine periodic measurements of serum digoxin concentrations are not recommended, even in frail, elderly nursing home resi-

174

dents (Dimant & Merrit 1978). Measurements are indicated, however, either when toxicity is suspected, or drug efficacy or patient compliance is doubtful. Since there is a significant overlap in serum concentrations of patients with or without digoxin toxicity, each test result should be interpreted within the context of the overall clinical status of the patient. It should be noted that digitalis toxicity can be difficult to detect, especially in the elderly (Joy & Higbee 1985: Stults 1982), and compliance in ambulatory patients is quite poor. Physicians should therefore remain alert and request serum concentration measurements if they are doubtful about toxicity or patient compliance. None of the methods used to predict serum digoxin concentrations is accurate enough to replace serum concentration monitoring (Mooradian & Wynn 1987), which has proved its clinical worth as an adjunct to patient management (Goldstein et al. 1986). Despite concerns raised about the diagnostic value of serum digoxin concentration monitoring, it is a useful diagnostic tool if used with good clinical judgement based on patient age, clinical status, electrocardiograms, and serum electrolyte and arterial blood gas measurements. A number of tests are available for measuring digoxin concentrations in biological fluids (table IV). Methods based on physicochemical separation of digoxin and its metabolites are highly specific, but technically complicated and often not sufficiently sensitive. A recently described method using high performance liquid chromatography followed by radioimmunoassay (Plum & Daldrup 1986) is highly sensitive and reproducible, but is still not widely available for clinical use. Methods based on Na+-K+-ATPase inhibition, such as rubidium (radiolabelled or non-radioactive) uptake measurement, are also not suitable for clinical laboratory use. Methods based on competitive protein binding, such as the various types of immunoassays, have been extensively used. Automatic immunoassays that either use fluorescence or are enzyme linked are now available; examples include: fluorescence energy transfer immunoassay (FETI) [Syva Advance System]; fluorescence polarisation immunoassay (FPIA) [Ab-

Digitalis: An Update

175

Table IV. Common assay methods for determination of serum digitalis concentrations Assay method

Reference

Clinical laboratory methods Immunoassays Radioimmunoassay Fluorescence energy transfer immunoassay

Pudek et al. (1985); Smith & Haber (1973b) Plebani & Burlina (1985)

Fluorescence polarisation immunoassay

Clark et al. (1986)

Enzyme-linked immunoassay

Clark et al. (1986)

High performance liquid chromatography (HPLC)

Plum & Daldrup (1986)

Research methods Na+-K+-ATPase inhibition assays Microsomal enzyme inhibition Red cell rubidium uptake inhibition

Burnett & Conklin (1968) Gjerdrum (1970)

Chromatography Gas-liquid chromatography Thin layer chromatography HPLC Competitive binding assay using Na+-K+-ATPase enzyme as the

Watson & Kalman (1971) Hinderling et al. (1986) Plum & Daldrup (1986) Brooker & Jelliffe (1972)

binding protein Double-isotope dilution derivative assay

bott TDx]; and enzyme linked immunoassay (e.g. 'EMIT) [Syva Co., Dade Stratus, and Dupont aca]. However, when 3 automated methods of digoxin immunoassay were evaluated against a radioimmunoassay (RIA) similar to the Centers for Disease Control Candidate (CDCC) Reference Method, none was found to be satisfactory (Clark et al. 1986). It is possible that the recently recommended improvements in the 'FETI' assay (Lehmann 1985; Plebani & Burlina 1985) will increase its correlation with the aforementioned and CDCC Reference Method. The reliability and precision of digoxin radioimmunoassays have also been questioned (Molin 1986), and lack of specificity of the current antidigoxin antibodies has been recognised (Thong et al. 1985). However, some commercially available radioimmunoassays, such as 'Phadebas Digoxin RIA' (Pharmacia Norden AB, Uppsala, Sweden) appear to be quite specific for digoxin (Hinderling et al. 1986), although further research is required to determine relative advantages and disadvantages of individual assays. Discrepancies among different RIA kits are particularly likely in patients with liver disease or renal failure who have

Lukas & Peterson (1966)

digoxin-like immunoreactive substances in their serum. The fluorescence polarisation immunoassay is less likely than other methods to detect digoxin-like immunoreactive substances (Nanji & Greenway 1986). Moreover, changing assay conditions and using appropriate mathematical equations allows the calculation of digoxin-like immunoreactive substances in samples (Pudek et al. 1985). It is essential for each clinical laboratory measuring serum digoxin concentrations that the information for antibody specificity is available, the accuracy of the assay is periodically evaluated, and that the assay kit used is tested against a reference method.

7. Treatment Recommendations It is generally accepted that digitalis has an important role in the treatment of supraventricular arrhythmias, and probably in acute congestive heart failure also. With the availability of verapamil, however, digoxin is no longer the first drug of choice for treatment of supraventricular arrhythmias, especially in patients with chronic obstructive lung disease.

Digitalis: An Update

The role of digitalis in chronic heart failure with sinus rhythm has been questioned, and concerns about its ill effects on the survival of patients with a history of myocardial infarction have been raised. One study reported that a subset of patients with congestive heart failure and ventricular premature depolarisation who were maintained on digoxin therapy had a small but significant increase in mortality, compared with those who were not taking digoxin (Moss et al. 1981). All subsequent studies, however, found either no difference or a nonsignificant difference in mortality figures between digoxin- and non-digoxin-treated groups, when multiple logistic regression analysis was used to adjust for differences in risk factors between the 2 groups (Bigger et al. 1985; Byington et al. 1985; Madsen et al. 1984; Muller et al. 1986; Ryan et al. 1983). However, as pointed out by Yusuf et al. (1986), these statistical manipulations of data cannot ensure comparability ofthe groups. Until a large randomised prospective clinical trial is performed, the question of whether digoxin is hazardous in patients with myocardial infarction will remain unanswered. The role of digitalis in the treatment of congestive heart failure is still controversial. The inotropic effects of digoxin are maintained on long term treatment (Arnold et al. 1980; Griffiths et al. 1982), and it appears to be particularly useful in patients with dilated left ventricles and third heart sounds (Lee et al. 1982). A recent double-blind placebo-controlled study comparing digoxin to captopril treatment during maintenance diuretic therapy found digoxin to be superior to placebo in patients with mild to moderate heart failure (Captopril-Digoxin Multicenter Research Group 1988). On the other hand, discontinuation of digoxin therapy in patients with stable heart failure and sinus rhythm had no adverse clinical or haemodynamic effects (Reg et al. 1982; Gheorghiade & Beller 1983). In addition, digoxin withdrawal was successfully accomplished in 81 % (Boman et al. 1981) of geriatric patients without clinical or roentgenographic evidence of heart failure or a ventricular rate higher than 95 beats/min. Overprescription of digitalis is a widespread

176

problem (lmpivaara et al. 1986), and can be avoided only if the characteristics of heart failure patients who are likely to benefit from digitalis are identified. Patients who do not have atrial fibrillation, enlarged left ventricles or a third heart sound, and those in whom diastolic dysfunction is a major component of heart failure, are not likely to respond to digitalis therapy. For patients who are already on digitalis therapy, drug withdrawal should be tried if cardiac status is stable and the indications for maintenance of therapy are dubious. The patient with an episode of heart failure or tachycardia in the distant past (Carlson et al. 1985), and a subtherapeutic serum digitalis concentration (serum digoxin less than 0.5 J.Lg/L), can be successfully weaned from digitalis therapy.

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Digitalis: An Update

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Digitalis: An Update

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Digitalis: An Update

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