Poisoning with 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 frequency of digitalis toxicity ranges from 5-23%. Moreover, chronic intoxication is much more common than acute poisoning.

Domestic statistics of poisoning with cardiac glycosides is not available. And according to US poison control centers, in 2008 there were 2632 cases of digoxin poisoning with 17 deaths, which accounted for 0.08% of all deaths due to drug overdoses.

According to the National Network of Poison Control Centers of Brazil, during 1985-2014. 525 poisonings with cardiotonic and antihypertensive drugs were recorded in the country, which is 5.3% of all cases of toxic effects of drugs.

Reducing the number of cases of toxic effects of cardiac glycosides - from 280 in 1993-1994. To 139 in 2011-12 - experts from the Australian Institute of Health (AIH) say.

Causes of the poisoning with cardiac glycosides

Doctors attribute the causes of poisoning with cardiac glycosides to the excess of therapeutic doses of cardiotonic drugs containing them, which are used in the treatment of diseases of the cardiovascular system, in particular, chronic heart failure and atrial fibrillation. Drugs related to cardiac glycosides (ATC code - C01A) increase the inotropy (strength of contractions) of myocytes, which leads to an improvement in blood flow in all tissues of the body.

What are these drugs? First of all, it is  Digoxin  (other trade names are Dilanacin, Digofton, Cordioxil, Lanicor), which contains cardiac glycosides of the leaves of the poisonous plant digitalis woolly (Digitalis lanataa Ehrh) - digoxin and digitoxin. In addition, D. Lanata contains chitoxin, digitalin and gitaloxin. Digitalis has a low therapeutic index or a narrow therapeutic range (the ratio of the amount of a 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 of 0.125 to 0.25 mg.

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

A remedy for parenteral use in urgent cases - Strofanthin K - includes almost a dozen cardioactive glycosides of the strophanthuss tree liana (Strophanthuss), including: strophanthin G, cymarin, glucocimarol, K-strophanthoside.

The active substances of  Adonis-bromine tablets  are cardiac glycosides of Adonis or spring Adonis (Adonis vernalis): adonitoxin, cymarin, K-strophanthin-β, acetyladonitoxin, adonitoxol, vernadigin.

Drops of Cardiovalen contain extracts of common jaundice (Erysimum diffusum) of the cruciferous family and spring adonis, that is, a mixture of glycosides eryzimin, erysimoside, adonitoxin, cymarin, etc.

The composition of Corezid - a drug for intravenous administration - includes glycosides of icterus levkoin (Erysimum cheiranthoides).

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

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

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

Risk factors

The risk of intoxication with drugs of cardiac glycosides is increased:

• in old age;
• with prolonged bed rest;
• with individual hypersensitivity to cardioactive plant steroids;
• if there is insufficient muscle mass of the body;
• in the presence of coronary heart disease and cor pulmonale;
• with kidney failure;
• in cases of acid-base imbalance in the body;
• if diuretics, the antiarrhythmic drug Amiodarone, calcium channel blockers, macrolide antibiotics, sulfonamides, antifungals (Clotrimazole, Miconazole) are taken;
• with a lack of thyroid hormones (hypothyroidism);
• with low serum potassium levels (hypokalemia);
• in case of increased calcium content in the blood (which happens with hyperparathyroidism and malignant neoplasms).

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

Pathogenesis

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

So, due to the blocking of Na + / K + -ATP-ase by increased doses of glycosides, the level of extracellular potassium (K +) increases. In this case, intracellular accumulation of sodium (Na +) and calcium (Ca2 +) ions occurs, as a result of which the automaticity of the impulses of the atrial and ventricular myocytes increases, causing spontaneous depolarization of the membranes of the heart muscle cells 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 a reduction in the rate of conduction of impulses from the atria to the ventricles can progress to life-threatening blockade of the atrioventricular (AV) node.[2]

Symptoms of the poisoning with cardiac glycosides

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

The first signs of acute poisoning when digitalis preparations are ingested - 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: heart rhythm disturbance with premature contraction of the heart; atrial arrhythmias; delays in cardiac conduction (bradyarrhythmia); strong but slow heart rate (bradycardia); ventricular tachycardia up to fibrillation, drop in blood pressure, generalized weakness.

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

With chronic intoxication with digitalis, dizziness, increased diuresis, lethargy, fatigue, muscle weakness, tremor, visual impairment (scotoma, change in color perception) are observed. Hyper or hypokalemia may occur.

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 a decrease in atrioventricular electrical conductivity are manifested by complete  atrioventricular block , in which a person loses consciousness and - in the absence of urgent medical care - dies from cardiac arrest.

Diagnostics of the poisoning with cardiac glycosides

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

Since the first signs are gastrointestinal in nature, differential diagnosis is carried out similarly to the  diagnosis 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.

To differentiate cardiac digitalis glycosides from other cardioactive glycosides, a laboratory study of the content of  Digoxin in the blood serum can be carried out . Acute poisoning becomes clinically apparent when the serum concentration of digoxin exceeds 2 ng/mL.

Although digoxin levels can help confirm the diagnosis, serum digoxin levels do not correlate well with toxic effects and should be interpreted in conjunction with clinical symptoms and ECG findings.

Treatment of the poisoning with cardiac glycosides

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

However, gastric lavage requires premedication with atropine, as this procedure further increases vagal tone and may precipitate heart block.

In a medical institution,  symptomatic intensive therapy is carried out for poisoning  with constant cardiac monitoring, in particular, they put droppers with solutions of potassium chloride, glucose and insulin; with bradycardia and atrioventricular blockade, m-anticholinergics (Atropine, Metoprolol) are administered intravenously; to maintain the activity of the sodium-potassium ATP-ase pump, a solution of magnesia is introduced.

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

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

Prevention

If it is necessary to take cardiac glycosides, the prevention of poisoning by them consists in observing the regimen of administration and the prescribed dosage (sometimes up to 60% of the lethal dose). And also in taking into account all contraindications and functionality of the kidneys of patients.

Forecast

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