Poisoning by cardiac glycosides

Cardioactive steroid compounds of a number of plants – cardiac glycosides – are the basis of drugs, an overdose of which leads to a toxic effect, that is, causes poisoning with cardiac glycosides.

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 on cardiac glycoside poisoning are unavailable. But according to data from US poison control centers, in 2008 there were 2,632 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 in Brazil, 525 cases of poisoning with cardiotonic and antihypertensive drugs were recorded in the country between 1985 and 2014, representing 5.3% of all cases of drug toxicity.

A reduction in the number of cases of toxic effects from cardiac glycosides – from 280 in 1993-1994 to 139 in 2011-12 – is noted by experts from the Australian Institute of Health (AIH).

Causes cardiac glycoside poisoning

Doctors associate the causes of poisoning with cardiac glycosides with 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 related to cardiac glycosides (ATX code - C01A) increase the inotropy (strength of contractions) of myocytes, which leads to improved blood flow in all tissues of the body.

What are these drugs? First of all, it is Digoxin (other trade names are Dilanacin, Digofton, Cordioxyl, 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 a narrow therapeutic range (the ratio of the amount of the drug that causes a therapeutic effect to its amount that has a toxic effect), so the safety of using its drugs requires medical supervision; digoxin is usually used in daily doses from 0.125 to 0.25 mg.

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

The agent for parenteral use in emergency cases – Strophanthin K – includes almost a dozen cardioactive glycosides of the woody vine strophanthus (Strophanthuss), including: strophanthin G, cymarin, glucocymarol, K-strophanthoside.

The active ingredients of Adonis-brom tablets are cardiac glycosides of Adonis vernalis: adonitoxin, cymarin, K-strophanthin-β, acetyladonitoxin, adonitoxol, vernadigin.

Cardiovalen drops contain extracts of Erysimum diffusum of the cruciferous family and Adonis vernalis, i.e. a mixture of glycosides of erysimin, erysimoside, adonitoxin, cymarin, etc.

The composition of Coresid, a drug for intravenous administration, includes glycosides of yellow celandine (Erysimum cheiranthoides).

Korglikon (Korglikard) acts on the myocardium due to the convallatoxin, convallatoxol, convalloside and glucoconvalloside it contains – cardiac glycosides obtained from lily of the valley (Convallaria majalis).

The mechanism of action of therapeutic doses of the indicated drugs consists of: inhibition of the membrane transport enzyme – sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) or sodium-potassium ATPase pump; suppression of active movement of calcium (Ca2+) and potassium (K+) ions through the membranes of cardiac cells; local increase in Na+ concentration. In this case, the level of Ca2+ inside cardiomyocytes increases, and contraction of the cardiac muscles intensifies.

Exceeding the dosage disrupts the pharmacodynamics of cardiac glycosides, and they begin to act as cardiotoxins, changing the processes of regulation of membrane potential and causing disturbances in cardiac rhythm and conduction. [ 1 ]

Risk factors

There is an increased risk of intoxication with cardiac glycoside drugs:

• in old age;
• with prolonged bed rest;
• in case of individual hypersensitivity to cardioactive plant steroids;
• if there is insufficient muscle mass in the body;
• in the presence of ischemic heart disease and pulmonary heart disease;
• in case of kidney failure;
• in cases of acid-base imbalance in the body;
• if you are taking diuretics, the antiarrhythmic drug Amiodarone, calcium channel blockers, macrolide antibiotics, sulfonamides, antifungal agents (Clotrimazole, Miconazole);
• in case of deficiency of thyroid hormones (hypothyroidism);
• with low serum potassium levels (hypokalemia);
• in case of increased calcium levels in the blood (which occurs with hyperparathyroidism and malignant neoplasms).

While chronic toxic effects of cardiac glycosides are more often observed in elderly patients due to decreased clearance, renal insufficiency, 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) overdose.

Pathogenesis

The mechanism of toxicity – the pathogenesis of poisoning with cardiac glycosides – is caused by a number of electrophysiological effects, since cardioactive steroid compounds affect the sodium-potassium ATPase pump in cardiac muscle cells, changing their function.

Thus, due to blocking of Na+/K+-ATPase by increased doses of glycosides, the level of extracellular potassium (K+) increases. At the same time, intracellular accumulation of sodium (Na+) and calcium (Ca2+) ions occurs, as a result of which the automaticity of the impulses of the myocytes of the atria and ventricles increases, causing spontaneous depolarization of the membranes of the cells of the heart muscle and ventricular extrasystole.

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

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

Symptoms cardiac glycoside poisoning

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

The first signs of acute poisoning when taking digitalis preparations orally – cardiac glycosides digoxin or digitoxin – are gastrointestinal (occur after 2-4 hours), including: complete loss of appetite, nausea, vomiting, stomach cramps and intestinal upset.

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

In severe cases, stupor, convulsions, confusion, hallucinogenic delirium, and shock are possible.

Chronic digitalis intoxication is accompanied by dizziness, increased diuresis, lethargy, fatigue, muscle weakness, tremor, and visual impairment (scotoma, changes in color perception). Hyper or hypokalemia may be observed.

Complications and consequences

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

The main consequences and complications of decreased atrioventricular conduction are complete atrioventricular block, in which a person loses consciousness and – in the absence of urgent medical care – dies from cardiac arrest.

Diagnostics cardiac glycoside poisoning

The diagnosis is based on a history of recent overdose of cardiotonic drugs containing cardiac glycosides, clinical picture and analysis of plasma potassium level. Instrumental diagnostics includes electrocardiography.

Since the first signs are gastrointestinal in nature, differential diagnostics are carried out similarly to the diagnostics of acute poisoning. In addition, doctors take into account the possibility of bradycardia or conduction disturbances in the underlying cardiac disease, as well as when using other drugs, such as beta-blockers.

Laboratory testing of serum digoxin levels may be used to differentiate digitalis cardiac glycosides from other cardioactive glycosides. Acute poisoning becomes clinically evident when serum digoxin concentrations exceed 2 ng/mL.

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

Treatment cardiac glycoside poisoning

Emergency care in case of acute poisoning with cardiac glycosides - with the use of enterosorbents (activated carbon) and saline laxatives and gastric lavage - is carried out in full compliance with the rules for providing emergency care.

However, gastric lavage requires premedication with atropine, since this procedure additionally increases the tone of the vagus nerve and can accelerate heart block.

In a medical institution, symptomatic intensive therapy is carried out for poisoning with constant cardiac monitoring, in particular, drips with solutions of potassium chloride, glucose and insulin are administered; in case of bradycardia and atrioventricular block, m-anticholinergics (Atropine, Metoprolol) are administered intravenously; a magnesium solution is administered to maintain the activity of the sodium-potassium ATPase pump.

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

Complete heart block requires pacing and cardiopulmonary resuscitation.

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

In domestic toxicology, intoxication is carried out with ethylenediaminetetraacetic acid (EDTA), which has chelating properties, or sodium dimercaptopropanesulfonate monohydrate (trade names Dimercaprol, Unithiol). Side effects of mercaptan derivatives include nausea, vomiting, increased blood pressure, and tachycardia. [ 3 ]

Prevention

If it is necessary to take cardiac glycosides, prevention of poisoning with them consists of following the regimen and prescribed dosage (sometimes up to 60% of the lethal dose). And also taking into account all contraindications and the functional capabilities of the patients' kidneys.

Forecast

In cases of poisoning with cardiac glycosides, in particular, acute intoxication with digitalis preparations, the prognosis correlates with mortality. With a potassium level of more than 5 mg-eq/l, without the introduction of an antidote, mortality can reach 50% of cases.