Plasma and tissue digoxin concentrations in patients undergoing cardiopulmonary bypass.

Carruthers, S. George; Cleland, John G.F.; Kelly, J G; Lyons, Seán; McDevitt, DG

doi:10.1136/hrt.37.3.313

Cited by 21 publications

(7 citation statements)

References 19 publications

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“…The mean ratios of myocardium to plasma digoxin concentrations from different studies corresponded to each other. The value reported by Carruthers et al [109] [111] stated that the myocardial digoxin concentration averaged 30 times higher than the serum concentration. Being much higher than in plasma, concentrations of digoxin in the myocardium underwent no significant change before and after the period of bypass [112].…”

Section: Cardiac Pharmaceutical Agentsmentioning

confidence: 86%

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Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Tylutki

Polak

2015

Biopharm & Drug Disp

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ABSTRACT:Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart.

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Section: Cardiac Pharmaceutical Agentsmentioning

confidence: 86%

“…to sodium-potassium activated membrane adenosine triphosphatase. Thus, the total myocardial concentration may be of limited value [105,109]. It is even more complicated with regard to digitoxin which has few metabolites.…”

Section: Cardiac Pharmaceutical Agentsmentioning

confidence: 99%

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Tylutki

Polak

2015

Biopharm & Drug Disp

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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: 97%

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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“…Four papers (Carruthers et al 1975;Coltart et al 1971;Krasula et al 1974;Morrison & Killip 1973) on digoxin have already been discussed by Holley et al (1982). In 3 of the 4 studies, digoxin concentrations fell significantly at initiation of cardiopulmonary bypass, which can be explained by 16 dilution; digoxin binding in serum is too low to be of importance in this process.…”

Section: Digitalismentioning

confidence: 99%

Cardiopulmonary Bypass and the Pharmacokinetics of Drugs

Buylaert¹,

Herregods²,

Mortier³

et al. 1989

Clinical Pharmacokinetics

119

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Cardiopulmonary bypass is accompanied by profound changes in the organism that may alter the pharmacokinetics of drugs. Drug distribution can be altered, for example, by changes in blood flow and by haemodilution, with a decrease in protein binding; a decrease in the elimination of some drugs can be caused by impairment of renal or hepatic clearance, due, for example, to lowered perfusion and hypothermia. The subject was reviewed in the Journal in 1982, and the emphasis of the present review is on new data related to specific drugs. The following substances are dealt with: benzodiazepines, cephalosporins, digitalis glycosides, general anaesthetics, glyceryl trinitrate (nitroglycerin), lignocaine (lidocaine), muscle relaxants, nitroprusside, opiates, papaverine and propranolol. For many of these substances an abrupt decrease has been observed in serum concentration upon initiation of bypass, which is explained by haemodilution and an increase in distribution due to decreased protein binding. For nitrates and some opiates, adsorption to the bypass apparatus was shown to be important. The gradual increase in serum concentrations seen during cardiopulmonary bypass with some drugs after the initial fall is usually explained by redistribution of the drug and/or decrease in its elimination. The same phenomena are thought to explain why in the post-bypass period a concentration increase occurs, or at least a slower decrease than expected. However, drug elimination has been directly measured in only a few studies. The short duration of the bypass procedure and the continuous changes during the process hamper a rigorous pharmacokinetic evaluation. Studies allowing more precise understanding of the mechanisms underlying the observed concentration changes are needed, but are difficult to design. Similarly, more data are awaited on the pharmacodynamic and clinical consequences of the concentration changes.

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Plasma and tissue digoxin concentrations in patients undergoing cardiopulmonary bypass.

Cited by 21 publications

References 19 publications

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Myocardial Uptake of Drugs and Clinical Effects

Cardiopulmonary Bypass and the Pharmacokinetics of Drugs

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