Human serum and myocardium digoxin

Härtel, Gottfried; Kyllönen, K. E. J.; Merikallio, E; Ojala, Kaarina; Manninen, Vesa; Reissell, Pentti

doi:10.1002/cpt1976192153

Cited by 43 publications

(5 citation statements)

References 4 publications

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“…In fact, no simple relation seemed to exist between serum and myocardial concentrations of digoxin. This agrees with findings in some studies in adults and infants (Coltart et aI., 1972;Weintraub and Lasagna, 1973;Kim et aI., 1975), but is in conflict with others (Karjalainen et al, 1974;Gorodischer et al, 1976a;Hartel et al, 1976). The reasons for this discrepancy in result are unclear, but differences in experimental and methodological approaches may be of importance.…”

Section: 2 Distributionsupporting

confidence: 91%

Clinical Pharmacokinetics of Digoxin in Infants

Wettrell

Andersson

1977

Clinical Pharmacokinetics

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Based on clinical experience, infants with congestive heart failure are given larger doses of digoxin than adults, whether calculated on the basis of body weight or surface area. The reasons for this difference in dosage are not clear. The myocardium of the infants might be more resistant to the effects of digoxin than that of adults, and/or differences might exist between infants and adults concerning the absorption, distribution and elimination of the glycoside. Infants have been found to absorb digoxin in solution at the same rate and to the same extent as adults. The relative distribution of the glycoside to different tissues is also similar in the two age-groups. However, the binding of digoxin to several tissues seems to be more extensive in infants than in adults. In agreement with this, the apparent volume of distribution of the glycoside is larger in infants than in adults. As no enhanced urinary excretion has been found in infants there might be a non-renal elimination of the glycoside. With most prevailing dose schedules for digoxin, serum concentrations higher than those considered optimum for adults are often obtained in infants. It is known that infants tolerate higher serum digoxin concentrations than adults without developing signs of toxicity. However, it is not known whether such high concentrations are necessary for obtaining an adequate inotropic effect on the myocardium of the infants. If the relation between serum concentration and effect is the same in infants and adults, the loading (digitalising) dose generally given to infants is unnecessarily high.

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Section: 2 Distributionsupporting

confidence: 91%

Clinical Pharmacokinetics of Digoxin in Infants

Wettrell

Andersson

1977

Clinical Pharmacokinetics

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“…In patients with normal renal function digoxin concentrations were even higher in the kidney than in the myocardium, though with those in renal failure this did not occur. However, in myocardial samples devoid of fibrous tissue, Hartel et al (1976) have shown a linear correlation between serum digoxin and papillary muscle digoxin concentrations from 12 adults undergoing mitral valve replacement, confirming an earlier similar finding by Gillner et al (1974). Kim et al (1975) obtained tissue from 7 prema-ture infants, 4 full-term newborn infants, and 4 older children who had received digoxin for cardiac failure.…”

supporting

confidence: 84%

Relation between concentrations of digoxin in the myocardium and in the plasma.

Malcolm¹,

Coltart²

1977

Heart

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It soon becomes apparent to those who use cardiac glycosides clinically that the relation between the amount of drug administered and the therapeutic effect is highly variable. The correlation of dose and effect of the drug is influenced by a number of factors including bioavailability, completeness of absorption, apparent volume of distribution, rate of elimination, degree of plasma protein binding, diffusion and active transport to the site of action, and local factors at the side of action (Koch-Weser, 1972;Sjoqvist and Bertilsson, 1973). KochWeser (1972) effect depended on the drug itself and not on metabolites, (2) protein binding was minimal, (3) the concentration/response graph followed a known and readily definable form such as the linear or monoexponential, and (4) the functional state of the drug receptor responded predictably and instantaneously, or nearly so, to changes in plasma concentration. The first condition is satisfied by digoxin but the second and third conditions are only partially satisfied, and the fourth is not. The importance of the second and third points is crucial and may be illustrated by recourse to the conceptual device of mathematical modelling. The simplest practical model to consider in this situation is the two-compartment model first comprehensively described by Teorell in 1937(Vere, 1972. Administered drug rapidly enters a 'space' where thorough mixing soon occurs (first compartment f blood and some part of well-perfused tissues) and thereafter exchanges with a 'space' more remote from the outside world by virtue of relatively slower ingress and egress of drug across the intercompartmental boundary (second compartment t cells and most drug receptor sites). Intercompartmental transfer is treated as a two-way flux, and absorption and elimination of the drug as one-way fluxes according to the Fick equations for simple diffusion, a valid approach simply because most drugs are effectively non-electric in their transfer behaviour. Teorell showed that very soon after full absorption of a drug, all the terms in the mathematical description of the fluxes across the various boundaries become vanishingly small except for the one-way flux of drug removal from tissue. This leaves a single exponential for removal of drug from the blood and so, unless blood volume alters, plasma concentrations of the drug should follow this exponential form (Vere, 1972).

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“…The majority of these have suggested that myocardial digoxin concentration is approximately 70 times higher than plasma concentration at steadystate (Carroll et al 1973;Carruthers et al 1975;Hartel et al 1976), although atrial drug concentrations may be somewhat lower than ventricular. A possible technical problem is raised by the use of conventional, direct radioimmunoassays which also detect digoxin metabolites.…”

Section: Uptake Of Digoxinmentioning

confidence: 96%

“…Direct myocardial biopsy is available under only very limited circumstances, such as in association with open heart surgery (Hartel et al 1976). The use of indirect methods is therefore essential in most circumstances, and radionuclide or nuclear magnetic resonance imaging might therefore be regarded as potentially suitable methods for both short and long term studies.…”

Section: Perioperative Biopsy and Imaging Techniquesmentioning

confidence: 99%

Myocardial Uptake of Drugs and Clinical Effects

Horowitz

Powell

1986

Clinical Pharmacokinetics

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The process of uptake of cardioactive drugs into the myocardium is a major determinant of the efficacy and potential toxicity of such agents. Evaluation of responses to anti-arrhythmic and positive inotropic agents is best performed with reference to their concentration in the myocardium, and the potential toxicity of drugs such as tricyclic antidepressants and anthracycline antineoplastics is likely to be related to peak myocardial drug concentrations. Although it has been appreciated for many years that even during long term drug administration the myocardial drug content may not be readily predictable on the basis of estimation of plasma drug concentrations, methodology for direct assessment of myocardial drug content has remained limited. The results of in vitro experiments, utilising tissue culture preparations of myocardial cells or isolated atria, have shed some light on the role of local factors as determinants of myocardial drug uptake. For many agents, attainment of maximal cardiac drug content in vitro is a very slow process (taking up to 3 hours), although maximal inotropic and electrophysiological effects may occur more rapidly. The prolonged time course of drug washout from these preparations also reflects their extensive and slow intracellular accumulation. Mechanical activity of the myocardium appears to accelerate drug uptake, particularly for otherwise slowly equilibrating agents, but the major determinant of the extent of drug uptake into isolated myocardial preparations is lipophilicity, perhaps reflecting the passage of drugs through the sarcolemma. In intact animals, assessment of myocardial drug content after acute drug administration has been performed utilising serial myocardial biopsy or sacrifice of animals. Studies in open-chested dogs suggest that acute accumulation of agents may be most closely predicted from the second compartment of a 3-compartment pharmacokinetic model, and that there is a variable correlation between changes in plasma and myocardial drug concentrations. For example, bretylium concentrations within the myocardium continue to increase for up to 6 hours after drug administration. Factors which may influence drug uptake into the myocardium in intact animals include ischaemia, which usually results in a delay in both drug uptake and subsequent clearance. This change can also be inferred from the time course of onset of antiarrhythmic drug effects in some models of myocardial ischaemia. Anoxia may also inhibit myocardial drug uptake.(ABSTRACT TRUNCATED AT 400 WORDS)

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Human serum and myocardium digoxin

Cited by 43 publications

References 4 publications

Clinical Pharmacokinetics of Digoxin in Infants

Clinical Pharmacokinetics of Digoxin in Infants

Relation between concentrations of digoxin in the myocardium and in the plasma.

Myocardial Uptake of Drugs and Clinical Effects

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