The question of cumulation of digoxin metabolites in renal failure

Gibson, Thomas; Nelson, Howard A.

doi:10.1038/clpt.1980.34

Cited by 35 publications

(10 citation statements)

References 3 publications

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“…11 Interestingly, many different clinical assays for cardiac glycosides have detected an endogenous interfering substance in the plasma from patients with cardiovascular or renal disease. 12 " 14 In addition, the presence of a receptor for cardiac glycosides suggests the existence of an endogenous ligand.…”

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confidence: 99%

Increased circulating levels of an endogenous digoxin-like factor in hypertensive monkeys.

Gruber¹,

Rudel²,

Bullock³

1982

Hypertension

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SUMMARY An endogenous, immunoreactive digoxin-like factor (endoxin) was measured in the plasma of nonhuman primates with hypertension. Both normotensive and hypertensive rhesus monkeys had levels of endoxin that significantly correlated with their systolic or diastolic blood pressure. Vervet monkeys with experimentally produced chronic Goldblatt hypertension had significantly elevated endoxin, but not plasma renin. These data suggest that increased plasma endoxin may be a contributing factor in the development of hypertension. (Hypertension 4: 348-354, 1982) KEY WORDS • digitalis-like factor natriuretic hormone sodium-potassium ATPase inhibition S EVERAL investigators have proposed that a circulating inhibitor of cardiovascular sodium-potassium adenosine triphosphatase ([Na + + K + ] ATPase) may be a causative factor in some forms of hypertension.1 " 4 The initial evidence for a (Na + + K + ) ATPase defect came from data indicating a blunted vasodilatory effect of potassium infusions in both experimental 516 and clinical essential hypertension. 7 This was followed by direct measurement of the cardiovascular enzyme in models of renovascular hypertension. 1These experiments revealed an inhibition of cardiovascular (Na + + K + ) ATPase, an effect that could be duplicated in vitro by application of cardiac glycosides. These data suggested the presence of a circulating inhibitor of the enzyme.

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mentioning

confidence: 99%

Increased circulating levels of an endogenous digoxin-like factor in hypertensive monkeys.

Gruber¹,

Rudel²,

Bullock³

1982

Hypertension

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“…Metabolites of digoxin may accumulate in renal fail ure [14]. However, the HPLC-radioactivity studies of serum and urine rule out the possibility that metabolites cross-reacting with antibody to digoxin [7] accounted for an appreciable component of the serum digoxin concen tration measured by RIA.…”

Section: Discussionmentioning

confidence: 99%

Rising Serum Digoxin without Further Dosage in Acute Renal Failure

Gault¹,

Gallway²,

Fine³

et al. 1984

Nephron

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A 73-year-old man was given a total of 1 mg of digoxin intravenously over 3 days, close to the time that he developed acute renal failure with oligo-anuria. He received no cardiac glycosides before or after this 3-day period. 2 days after the last dose, the serum digoxin concentration (SDC) was 2.9 ng/ml, yet a peak value of 4.2 ng/ml was reached only 11 days later. The SDC remained above 2 ng/ml for another week, until urine output began to increase appreciably. As renal function improved, the SDC gradually fell to become undetectable 32 days after the last dose. Values for apparent volume of distribution calculated from the total dose, and also determined after injection of tritiated digoxin, suggest that the rise in SDC in the absence of additional doses was due in large part to a decrease in the apparent volume of distribution. Dosage and parameters of toxicity should be carefully monitored in patients receiving digoxin who develop acute renal failure.

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“…At least for EMIT, this overestimation appears to be due largely, though possibly not entirely (Toseland et aI., 1983), to reagent cross-reactivity with 5-p-hydroxyphenyl-5-phenyl-hydantoin-glucuronide, a metabolite which accumulates extensively in the serum of uraemic patients (Aldwin and Kabakoff, 1981;Nandedkar et aI., 1980;Sawchuk and Matzke, 1984). Impaired analytical reliability in uraemic samples due to interference by metabolites and/or other immunoreactive substances has been observed in several other assays for various drugs, including the radioimmunoassay (RIA) for digoxin (Gibson and Nelson, 1980;Graves et aI., 1983a, b) and the fluorescence polarisation immunoassay (TDx®) for phenobarbitone (Bridges and Jennison, 1984;Patel et aI., 1984) and theophylline Elin and Ruddell, 1983;Patel et aI., 1984). Of course, metabolite interference may also be seen with nonimmunological methods, as exemplified by the overestimation of quinidine levels by certain fluorometric assays in samples from patients with poor renal function (Pape, 1981).…”

Section: Disease-related Errors In Drug Assaymentioning

confidence: 96%

Interpretation of Drug Levels in Acute and Chronic Disease States

Perucca

Grimaldi

Crema

1985

Clinical Pharmacokinetics

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Serum drug concentration monitoring can be an invaluable aid to patient management, particularly in certain pathological conditions when individualisation of dosage is particularly critical. To be clinically useful, however, drug levels must be interpreted in the context of all factors that could influence the correlation between the concentration of the drug in plasma and the intensity of action. Several such factors may be operating in acute and chronic disease states. For example, a number of pathological conditions are associated with marked changes in the fraction of free, pharmacologically active drug in plasma and this will result in disruption of the normal relationship between total serum drug level and effect, as seen for phenytoin in uraemia. An altered response to a given serum drug level in disease states may also be caused by changes in tissue distribution, by abnormal accumulation of pharmacologically active metabolites in plasma or by changes in end-organ responsiveness. The latter are best illustrated by the altered sensitivity to digoxin in patients with various conditions, including hypokalaemia and thyroid disease. In addition to the factors listed above, consideration should also be given to potential interactions with concomitantly used drugs and to the possibility of analytical errors, especially in view of the evidence that the performance of otherwise reliable drug assays may be grossly impaired in certain diseases (e.g. uraemia), due to abnormal plasma composition and/or accumulation of interfering metabolites. In view of these complexities, a correct interpretation of serum drug levels requires a good knowledge of clinical pharmacology and a close collaboration between physician and laboratory. In any case, serum drug concentrations, like other laboratory tests, are not a substitute for careful patient observation, and any decision about drug treatment should be primarily based upon evaluation of the clinical state and, whenever possible, direct measurement of drug effects.

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The question of cumulation of digoxin metabolites in renal failure

Cited by 35 publications

References 3 publications

Increased circulating levels of an endogenous digoxin-like factor in hypertensive monkeys.

Increased circulating levels of an endogenous digoxin-like factor in hypertensive monkeys.

Rising Serum Digoxin without Further Dosage in Acute Renal Failure

Interpretation of Drug Levels in Acute and Chronic Disease States

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