Pharmacological aspects of acute treatment glycoside intoxication

Despite the active introduction of surgical treatments for cardiac pathology and new synthetic cardiotonic drugs, cardiac glycosides (CG) remain an important component of the pharmacological treatment of heart diseases. Moreover, interest in this group of drugs is only increasing with the discovery of new pharmacological effects, such as antitumor and antiviral. However, despite many years of experience, the issue of managing patients with symptoms of both acute and chronic poisoning with cardiac glycosides remains one of the leading ones. The literature review provides a brief historical outline of cardiac glycoside poisoning and comprehensively describes the pharmacokinetics and pharmacodynamics of this group of drugs. The clinical picture of intoxication is described. We analyzed modern ideas and limitations of using antidote therapy such as digoxin immune Fab-antibody fragments, as well as the features of pathogenetic and symptomatic treatment of patients with acute glycoside poisoning.

Free and Total Digoxin in Serum During Treatment of Acute Digoxin Poisoning With Fab Fragments: Case Study

A woman ingested 10 mg of methyldigoxin in a suicide attempt and presented 19 hours after ingestion with clinical signs of glycoside intoxication. Her serum level of digoxin was 7.4 ng/mL, and antidotal therapy with Fab antibody fragments was started. The manufacturer’s recommended dosing scheme was modified, with 80 mg Fab administered intravenously within 15 minutes followed by a continuous infusion at 30 mg/h. Total serum concentration of digoxin increased markedly within minutes after Fab therapy was started, while the level of free digoxin immediately decreased into the nontoxic range without recrudescent toxic effects of digoxin. The cumulative amounts of free and bound digoxin that were excreted in urine within 30 hours after ingestion were 900 μg and 1600 μg, respectively. Half-life of bound digoxin in urine was 9.9 hours; mean rate of clearance of bound digoxin in the urine was 7.0 mL/min. On the basis of these kinetic data, a smaller initial bolus dose of Fab followed by a continuous infusion may be a more tailored, cost-effective, and relatively safe therapy for patients who have overdosed on cardiac glycosides.

Turnover and regulation of Na-K-ATPase in HeLa cells

HeLa cells in log growth have 10(6) surface Na-K-ATPase molecules as estimated by the specific binding of [3H]-ouabain. Studies utilizing ouabain as a label show that the ligand is internalized at a rate corresponding to the turnover of three sets of Na-K-ATPase enzymes per generation. The label is taken up exclusively into a particulate cell compartment where it is codistributed with beta-hexosaminidase, identifying the internal compartment as lysosomal. Turnover is an important parameter in the recovery of the cells from glycoside intoxication. The unmetabolized glycoside is subsequently released by exocytosis. 13C-density-labeled Na-K-ATPase has been identified by specific phosphorylation of its catalytic subunit with [32P]ATP or [33P]ATP, and the rate of turnover of the density label is shown to be the same as the internalization of the ouabain-labeled site. There is a transit time of about 4 h from the onset of synthesis of the catalytic subunit to its insertion in the surface membrane; 2,800 catalytic subunits are synthesized per minute per cell, and 2,100 are turned over K+-starved cells respond to the stress in 24-30 h with modulation of the surface density of Na-K-ATPase the synthetic rate remains constant; the number of functional enzymes per cell is controlled by change in the rate constant for turnover.