Cardiac glycoside poisoning

Cardioactive steroidal compounds of a number of plants - cardiac glycosides - are the basis of medicinal preparations, overdose of which leads to toxic effects, that is, causes cardiac glycoside poisoning.

Epidemiology

According to some estimates, the incidence of digitalis toxicity ranges from 5-23%. Moreover, chronic intoxication is much more common than acute poisoning.

Domestic statistics of poisoning by cardiac glycosides are not available. And according to the data of toxicological centers of the USA, in 2008 there were 2632 cases of digoxin poisoning with 17 fatalities, which was 0.08% of all deaths due to overdoses of pharmacological drugs.

According to the National Network of Poison Control Centers of Brazil, during 1985-2014, 525 poisonings with cardiotonic and hypotensive agents were reported in the country, representing 5.3% of all drug toxicities.

A decline in the number of cases of toxic exposure to cardiac glycosides - from 280 in 1993-94 to 139 in 2011-12 - has been observed, according to experts from the Australian Institute of Health (AIH). - noted by experts from the Australian Institute of Health (AIH).

Causes of the cardiac glycoside poisoning

Medical professionals attribute the causes of cardiac glycosides poisoning to exceeding therapeutic doses of cardiotonic drugs containing them, which are used in the treatment of cardiovascular diseases, in particular, chronic heart failure and atrial fibrillation. Drugs belonging to cardiac glycosides (ATX code - C01A) increase inotropy (force of contractions) of myocytes, which leads to improved blood flow in all tissues of the body.

What drugs are these? First of all, it is Digoxin (other trade names - Dilanacin, Digofton, Cordioxil, Lanikor), which contains cardiac glycosides of the leaves of the poisonous plant foxglove (Digitalis lanataa Ehrh) - digoxin and digitoxin. In addition, D. Lanata contains, chitoxin, digitalin and gitaloxin. Foxglove has a low therapeutic index or narrow therapeutic range (the ratio of the amount of a drug that causes a therapeutic effect to the amount that has a toxic effect), so the safety of using its preparations requires medical supervision; digoxin is usually used in daily doses of 0.125 to 0.25 mg.

Glycosides of this plant are the main active ingredient of Dilanizide solution for injection; Lantoside drops; tablets, drops and solution Celanide. And Cordigit tablets contain glycosides of foxglove purpurea (Digitalis purpurea L.). Moreover, glycosides of both species of this plant - with prolonged use of drugs - accumulate in the body and are removed slowly.

Strophanthin K, a product for parenteral use in emergency cases, includes almost a dozen cardioactive glycosides of the tree strophanthus liana (Strophanthus), including: strophanthin G, cimarin, glucocimarol, K-strophanthoside.

Active substances of tablets Adonis-brom are cardiac glycosides of goricetum or spring adonis (Adonis vernalis): adonitoxin, cymarin, K-strophanthin-β, acetyladonitoxin, adonitoxol, vernadigine.

Cardiovalen drops contain extracts of jaundice (Erysimum diffusum) of the cruciferous family and spring goricolor, i.e. A mixture of glycosides erysimine, erysimoside, adonitoxin, cimarin, etc.

Korezid, a drug for intravenous administration, contains glycosides of the jaundiced leucaemia (Erysimum cheiranthoides).

Corglycone (Corglycard) acts on the myocardium due to the convallatoxin, convallatoxol, convalloside, and glucoconvalloside it contains, which are cardiac glycosides derived from the May lily of the valley (Convallaria majalis).

The mechanism of action of therapeutic doses of these drugs is: inhibition of membrane transport enzyme - sodium-potassium adenosine triphosphatase (Na+/K+-ATP-ase) or sodium-potassium ATP-ase pump; inhibition of active movement of calcium (Ca2+) and potassium (K+) ions across the membranes of heart cells; local increase in Na+ concentration. This increases the level of Ca2+ inside cardiomyocytes, and the contraction of cardiac muscles increases.

Excessive dosage disrupts the pharmacodynamics of cardiac glycosides and they begin to act as cardiotoxins, altering the processes of membrane potential regulation and causing disruption of heart rhythm and conduction. [1]

Risk factors

There is an increased risk of intoxication with preparations of cardiac glycosides:

• in old age;
• with prolonged bed rest;
• In individual hypersensitivity to cardioactive plant steroids;
• if you don't have enough muscle mass;
• in the presence of ischemic heart disease and pulmonary heart disease;
• with kidney failure;
• in cases of acid-base imbalance in the body;
• if diuretics, antiarrhythmic drug Amiodarone, calcium channel blockers, antibiotics of macrolide group, sulfonamides, antifungal agents (Clotrimazole, Miconazole) are taken;
• when there is a deficiency of thyroid hormones (hypothyroidism);
• when serum potassium levels are low (hypokalemia);
• in case of increased calcium content in the blood (which occurs in hyperparathyroidism and malignant neoplasms).

While chronic toxic effects of cardiac glycosides are more common in elderly patients as a result of decreased clearance, renal function failure, or concomitant administration of other drugs, acute poisoning may have an iatrogenic etiology (due to errors in treatment) or be the result of accidental or intentional (suicidal) exceeding of a single dose.

Pathogenesis

The mechanism of toxicity, the pathogenesis of cardiac glycoside poisoning, is due to a number of electrophysiologic effects, as cardioactive steroidal compounds affect the sodium-potassium ATP-ase pump in cardiac muscle cells, altering their function.

Thus, due to blocking of Na+/K+-ATP-ase by increased doses of glycosides, the level of extracellular potassium (K+) increases. This results in intracellular accumulation of sodium (Na+) and calcium (Ca2+) ions, as a result of which the automatism of impulses of atrial and ventricular myocytes increases, causing spontaneous depolarization of cardiac muscle cell membranes and ventricular extrasystole.

Cardiac glycosides act on the vagus nerve, increasing its tone, resulting in a decrease in atrial and ventricular effective refractory period and a slowing of sinus rhythm - sinus bradycardia.

Ventricular excitation progresses to ventricular fibrillation of the heart, and a decrease in the rate of conduction of impulses from the atria to the ventricles can progress to life-threatening atrioventricular (AV) node block. [2]

Symptoms of the cardiac glycoside poisoning

Since cardiac glycosides can have toxic effects on the cardiovascular, central nervous and digestive systems, the symptoms of poisoning by them will be divided into cardiac, neurological and gastrointestinal.

The first signs of acute poisoning with ingestion of foxglove preparations - cardiac glycosides digoxin or digitoxin - are gastrointestinal (occurring in 2-4 hours), including: complete loss of appetite, nausea, vomiting, stomach cramps and intestinal upset.

After 8-10 hours, cardiovascular symptoms appear: heart rhythm disturbance with premature contraction of the heart; atrial arrhythmias; cardiac conduction delays (bradyarrhythmia); strong but slow pulse (bradycardia); ventricular tachycardia up to fibrillation, drop in BP, generalized weakness.

In severe cases, stupor, convulsions, confusion, hallucinogenic delirium, and shock may occur.

In chronic intoxication with digitalis, dizziness, increased diuresis, lethargy, fatigue, muscle weakness, tremor, visual impairment (scotoma, color perception changes) are observed. Hyper or hypokalemia may be observed.

Complications and consequences

Toxic effects of cardiac glycosides can lead to fatal arrhythmias, atrial flutter, and worsening of intracardiac hemodynamics.

The main consequences and complications of reduced atrial-ventricular conduction are manifested by complete atrioventricular block, in which the person loses consciousness and - in the absence of urgent medical attention - dies of cardiac arrest.

Diagnostics of the cardiac glycoside poisoning

Diagnosis is based on a history of recent overdose of cardiotonic drugs containing cardiac glycosides, clinical presentation, and plasma potassium level testing. Instrumental diagnosis includes electrocardiography.

Since the first signs are gastrointestinal in nature, differential diagnosis is carried out similarly to diagnosis of acute poisoning. In addition, physicians take into account the possibility of bradycardia or conduction disturbances in the underlying cardiac disease, as well as in the use of other drugs, such as beta-adrenoblockers.

To differentiate foxglove cardiac glycosides from other cardioactive glycosides, laboratory testing of Digoxin serum levels can be performed. Acute poisoning becomes clinically evident when the serum concentration of digoxin exceeds 2 ng/mL.

Although determination of digoxin concentrations can help confirm the diagnosis, serum levels correlate poorly with toxic effects and must be interpreted in conjunction with clinical symptoms and ECG readings.

Treatment of the cardiac glycoside poisoning

Emergency treatment of acute poisoning with cardiac glycosides - with administration of enterosorbents (activated charcoal) and saline laxative and gastric lavage - is carried out in full accordance with the rules of emergency care.

However, gastric lavage requires premedication with atropine, as this procedure further increases vagus nerve tone and may accelerate heart block.

In a medical facility, symptomatic intensive therapy for poisoning with constant cardiac monitoring, in particular, drips with potassium chloride, glucose and insulin solutions are administered; in case of bradycardia and atrial-ventricular block, m-choline blockers (Atropine, Metoprolol) are administered intravenously; magnesia solution is administered to maintain the activity of sodium-potassium ATP-ase pump.

Medications such as Lidocaine and Phenytoin, class 1B antiarrhythmic drugs, are also used.

Complete heart block requires electrocardiostimulation and cardiopulmonary resuscitation.

There is an antidote for poisoning with cardiac glycosides, more specifically digostin - Digoxin-specific antibody (Fab) fragments, Digibind or DigiFab, produced by foreign pharmaceutical companies from fragments of sheep immunoglobulin immunized with digoxin derivative (DDMA). This antidote is administered in acute digoxin poisoning when its serum level is above 10 ng/mL.

In domestic toxicology intoxication is carried out with chelating properties of ethylenediaminetetetraacetic acid (EDTA) or sodium dimercaptopropanesulfonate monohydrate (trade names Dimercaprol, Unithiol). The side effects of mercaptan derivatives include nausea, vomiting, increased BP, tachycardia. [3]

Prevention

If it is necessary to take cardiac glycosides, prevention of poisoning by them consists in compliance with the regimen and the prescribed dosage (sometimes amounting to 60% of the lethal dose). As well as taking into account all contraindications and functional capacity of the kidneys of patients.

Forecast

In cases of poisoning with cardiac glycosides, particularly acute intoxication with foxglove preparations, the prognosis correlates with mortality. When potassium levels exceed 5 mg-eq/L without antidote administration, lethality may be up to 50% of cases.