Poisoning with cardiac glycosides (Digitalis intoxication)

Content:

1. Effects of pentobarbital
2. Overdose prevalence
3. Risk factors
4. Overdose symptoms
5. Complications
6. Causes of death
7. First aid
8. Specialized treatment

Pentobarbital sodium is a drug from the group of barbiturates. It has a rapid hypnotic effect, the effect begins within 15–35 minutes after administration and lasts for approximately 6 hours. In Russia it is included in the list of medicines with restricted circulation. Illegally used to achieve a state of drug intoxication. Sometimes used to commit suicide attempts.

Publications in the media

Intoxication with cardiac glycosides (CG) is a condition that develops as a result of the toxic effects of CG. Intoxication can occur both against the background of an overdose and with normal concentrations of digitalis drugs in the blood plasma (for example, with hypoproteinemia, most of the SG circulates in a free state, which causes a more rapid development of toxic effects). Usually the course is acute, less often - chronic. Statistical data. Frequency: 5–23% of patients taking digitalis and other FH medications.

Etiology • Overdose of SG (including during suicide attempts) • Poisoning by plants containing SG.

Risk factors • Hypoxia • Hypokalemia (including when taking diuretics that remove potassium from the body and GCs) • Hypercalcemia • Hypomagnesemia • MI • Post-infarction cardiosclerosis • Previous cardiac surgery • Liver or renal failure • Hemodialysis • Hypothyroidism • Electrical cardioversion • Older age • Hypoproteinemia (including due to insufficient protein intake from food) • Co-administration of SG and quinidine, verapamil, amiodarone, propafenone.

Clinical manifestations

• Symptoms of rhythm disturbances: •• tachycardia (especially non-paroxysmal tachycardia from the atrioventricular node), occurring after a period of normalization of heart rate or bradycardia •• bradycardia, ventricular extrasystole (especially bigeminy) •• ventricular tachycardia (including multifocal) •• atrial fibrillation (rare). It must be remembered that if tachycardia persists in a patient taking SG, it is necessary to exclude their overdose.

• Symptoms of conduction disorders: •• AV block of various degrees •• Sinoatrial block.

• Symptoms of gastrointestinal dysfunction: •• anorexia •• abdominal pain •• nausea, vomiting •• diarrhea.

• Symptoms of central nervous system dysfunction: •• headache •• dizziness •• nightmares •• depression •• hallucinations •• delirium •• decreased visual acuity •• impaired color vision (yellow or green spots before the eyes) •• blindness.

ECG signs • Trough-shaped depression of the ST segment • Prolongation of the P–Q interval >0.20 s • Decreased amplitude, inversion of the T wave • Shortening of the Q–T interval • Sudden disturbance of heart rhythm while taking SG: •• sinus bradycardia •• atrial extrasystoles -ventricular, atrial or ventricular (often allorhythmia in the form of bigeminy or trigeminy) •• non-paroxysmal tachycardia from the atrioventricular node •• atrial flutter (rare) •• AV block of the second degree in the Samoilov-Wenckebach periodicity •• bundle branch block • • atrial tachycardia with AV block •• bidirectional ventricular tachycardia (QRS complexes on the ECG are alternately positive and negative).

Laboratory tests • Increased levels of SG in the blood (for digoxin >2 ng/ml [>5.1 nmol/l], for digitoxin >35 ng/ml) • Hypokalemia.

TREATMENT

Management tactics • Regime - stationary with limitation of physical activity • Cancellation of SG • Maintaining optimal concentration of plasma electrolytes (potassium - at the upper limit of normal: 5.5 mmol/l) • Avoid the use of quinidine, which increases the concentration of digitalis in plasma by releasing it from associated condition and a decrease in renal and extrarenal excretion of the drug, as well as b-blockers and b-agonists • Temporary transvenous pacemaker if necessary (in cases of severe bradycardia, complete AV block with Morgagni–Adams–Stokes attacks).

Drug therapy

• For bradycardia - atropine.

• In case of intoxication due to hypokalemia - potassium preparations, for example, potassium chloride orally or intravenously as part of a polarizing mixture (potassium chloride 2 g, insulin 6 units, 5% glucose solution 350 ml; potassium chloride 4 g, insulin 8 units , 10% glucose solution 250 ml). When taking the drug orally to patients with left atrium dilatation or when treated with anticholinergic drugs, the risk of ulceration of the mucous membrane of the esophagus and stomach is increased.

• For tachycardia, in addition to potassium supplements, beta-blockers may be prescribed.

• For ventricular arrhythmias - lidocaine 50-100 mg IV over 3-4 minutes, if necessary, repeat every 5 minutes up to a total dose of 300 mg/hour, or its infusion at a rate of 20-50 mcg/kg/min.

• Magnesium preparations are indicated for every patient with suspected digitalis intoxication in the absence of hypermagnesemia and without impaired renal function.

• To accelerate the excretion of the glycoside - activated carbon 25 g every 4 hours for 40 hours.

• Correction of acidosis.

The course and prognosis are favorable after 24 hours from the first signs of intoxication.

Observation • Frequent ECG, determination of potassium and SG concentrations in the blood plasma • Monitoring of kidney functions.

Prevention • Careful monitoring of the patient taking SG • Monitoring the concentration of potassium in the blood plasma • Good nutrition.

Reduction. CG - cardiac glycosides.

ICD-10 • T46.0 Poisoning with cardiac glycosides and drugs with similar effects.

Application. Hypermagnesemia is an increase in serum magnesium concentration of more than 2.2 mEq/L. Etiology. Because the kidneys have the ability to excrete several hundred mEq of magnesium daily, hypermagnesemia is usually iatrogenic and persists only in patients with decreased renal function who consume magnesium either as laxatives or antacids. Acute magnesium intoxication can occur in women receiving intravenous magnesium salts in excessive doses for toxicosis of pregnancy. Clinical picture. When the magnesium level is above 4 mEq/l, depression of cardiovascular activity is observed (arterial hypotension, bradycardia, on the ECG - prolongation of the P-Q, QRS and Q-T intervals, complete AV block and asystole), deterioration of neuromuscular excitability (areflexia, drowsiness, weakness, paralysis, respiratory failure) and central nervous system functions. Treatment • Calcium gluconate (10 ml of 10% solution) IV • Furosemide or ethacrynic acid (IV, orally) with adequate hydration and preservation of kidney function - to increase magnesium excretion • In case of severe hypermagnesemia, hemodialysis is performed (if it is possible to maintain blood pressure) or peritoneal dialysis. ICD-10. E83.4 Magnesium metabolism disorder.

Effects of pentobarbital

Barbiturates have a depressant effect on the central nervous system, speed up sleep, and eliminate convulsions. In doses exceeding therapeutic ones, they cause mental and physical relaxation, a feeling of calm and tranquility. After taking the medication, the addict feels confident in a prosperous future.

Existing problems seem insignificant, your own strengths seem limitless. It seems to a person that he has reached the state of nirvana, that he has approached enlightenment. The perception of visual images, sounds and tactile sensations changes, the real world is covered with a mystical flair.

Overdose prevalence

Poisoning with drugs belonging to the group of barbiturates is diagnosed in almost a quarter of patients admitted to specialized toxicology centers. Fatal overdoses reach 3% in the structure of mortality from intoxication . These statistics take into account not only pentobarbital, but also other barbituric acid-based drugs. However, the data looks alarming and indicates the high danger of taking the drug for the purpose of drug intoxication.

Interactions with drugs

Convincing evidence has been provided for changes in plasma concentrations of digoxin when used in combination with other drugs [26, 27, 29]. A decrease in the absorption of digoxin occurs when taken simultaneously with antacids, cholestyramine, sorbents, metoclopramide, sulfasalazine, and cytotoxic drugs.

An increase in the concentration of digoxin in plasma occurs when antiarrhythmic drugs are prescribed (quinidine, amiodarone, propafenone, procainamide, verapamil), drugs with cholinergic properties (atropine, metacin), and angiotensin-converting enzyme inhibitors. The use of non-steroidal anti-inflammatory drugs is associated with the risk of a decrease in GFR, which leads to a decrease in renal excretion of digoxin by 20–30%, and consequently to an increase in its plasma level [26, 29, 31].

The combined use of digoxin with diuretics increases the risk of developing DTI due to their inherent side effects: hypokalemia, hypomagnesemia (loop and thiazide diuretics), hyperkalemia (potassium-sparing diuretics), hypercalcemia (thiazide diuretics), metabolic alkalosis (loop and thiazide diuretics). In this regard, in patients receiving digoxin and diuretic therapy, it is necessary to monitor plasma levels of electrolytes and electrocardiographic parameters [25–27].

Risk factors

Most often, a pentobarbital overdose is diagnosed under the following circumstances:

• inappropriate use of medication (to achieve euphoria);
• combination with the use of alcoholic beverages;
• self-administration without a doctor’s prescription or as prescribed by a specialist, but not in accordance with the recommendations (changes in dosage and frequency of administration).

The risk group includes people with social adaptation disorders, neurotic disorders, and alcoholism. When taken over a long period of time, barbiturates cause addiction. Over time, tolerance occurs - previous doses no longer produce the desired effect, which entails the need to increase dosages and, as a result, increase the likelihood of poisoning.

Features of the pharmacokinetics of digoxin

An important factor determining the bioavailability of digoxin is the nature of its absorption. Digoxin absorption is incomplete and is characterized by wide individual fluctuations, which is one of the risk factors for the development of DTI. The bioavailability of digoxin when taken orally in a “tablet” dosage form is 50–80% of an identical dose administered intravenously. After oral administration of 0.25 mg of digoxin, the maximum concentration (Cmax) in the blood serum is established after 0.2–2 hours, and then gradually decreases as it is distributed into tissues. The distribution process takes 6–12 hours. Due to renal excretion, serum and tissue levels of digoxin gradually decrease. Normally, the half-life (t1/2) is 26–45 hours (average 36 hours), regardless of the route of administration [14, 26, 27].

In order to prevent DTI, the pharmacokinetics of digoxin should be taken into account in various clinical situations [28, 29]. Thus, with age, a decrease in glomerular filtration rate (GFR) is observed, and skeletal muscle mass, which is the main depot of SG, decreases, which leads to a decrease in the volume of distribution and, consequently, to higher plasma concentrations [16]. The presence of comorbidity and polypharmacy determines the need to reduce digoxin dosages in elderly people - usually to 0.125 mg.

The pharmacokinetics of digoxin does not change significantly in patients with hepatitis, liver cirrhosis and obese patients due to low concentration in adipose tissue. Therefore, in case of obesity, digoxin doses should be calculated not for total body weight, but for muscle mass [25, 30].

The nature of changes in the structure of the heart, their severity, and the presence of HF play an important role in approaches to prescribing SG, duration of use, the possibility and need for combinations with other drugs. Myocardial ischemia is associated with increased arrhythmogenic effects of digoxin even at low plasma levels. If, in the absence of severe organic heart damage, the boundary between therapeutic and toxic doses is relatively large, then the “therapeutic window” in the presence of such becomes significantly narrower, and therefore the risk of developing DTI increases [21].

Overdose symptoms

The first sign of poisoning is sleep, which makes it difficult to recognize a dangerous condition in a timely manner. In the initial phase of sleep, reflexes are preserved; subsequently, the ability to perceive external stimuli decreases: the person does not react to touch or pain, and does not hear sounds.

A simple way to determine the degree of overdose is to study the pupillary and corneal reflexes. Normally, the pupil dilates in the dark and contracts in the light. When the cornea of ​​one eye is irritated (for example, touched with a cotton swab), both eyelids abruptly close. The absence of these reflexes indicates severe intoxication.

Pentobarbital depresses the respiratory center located in the brain. Depending on the severity of poisoning, a decrease in the frequency of respiratory movements, shallow or intermittent breathing is possible. In case of a critical overdose, there is no breathing. Other objective signs of poisoning are a weak thread-like pulse and decreased blood pressure. There are four phases of poisoning:

• Falling asleep. Accompanied by drowsiness, indifference, sluggish reaction to external stimuli. With sufficient persistence, contact can be established with the patient.
• Superficial coma. Consciousness is impaired. The pupils are dilated, swallowing and cough reflexes are weakened. Possible tongue retraction and slight increase in body temperature.
• Deep coma. There are no reflexes, the functions of the main organs and systems are impaired. Worsening breathing problems are detected.
• Postcomatose state. Consciousness returns. Depression, loss of strength, moodiness, and sleep disturbances may occur. Sometimes mild motor excitation is detected.

If the dose is slightly exceeded, the second and third phases may be absent. If a deep coma develops and there is no qualified medical care, death occurs due to taking a lethal dose of pentobarbital.

Treatment of intoxication with cardiac glycosides

Treatment goals: adjustment of digitalis levels, correction of arrhythmia, prevention of complications.

The treatment regimen depends on the degree of poisoning.

1. Mild poisoning is treated with a temporary pause in taking the drug or reducing the dose.

2. Acute poisoning and stable conditions, e.g. S-digoxin <5 ng/ml requires gastric aspiration, use of activated charcoal, monitoring of S-potassium, correction of hypokalemia.

3. For severe poisoning, provide adequate ventilation and monitor serum potassium and heart rate. Provide symptomatic and antidote drug treatment.

Complications

The greatest threat to the life of the victim is respiratory disorders. The list of other negative consequences in the early period of poisoning includes:

• development of a coma;
• neurological disorders;
• cardiac dysfunction;
• suppression of kidney function.

After resuscitation and detoxification measures, 25% of patients develop respiratory failure due to tracheobronchitis or pneumonia. Due to trophic disorders, bullous dermatitis and necrodermatomyositis are formed, and there is an increased tendency to form bedsores.

Electrolyte disturbances

Imbalances in the balance of K+, Na+, Mg2+ and Ca2+ ions are associated with both changes in the effectiveness of SG and the development of DtI. Among these disorders, disturbances of K+ homeostasis occupy an important place. Experimental and clinical studies have shown an increased risk of developing DTI with hypokalemia. This phenomenon is due to a number of factors, including a decrease in the binding of SG to the Na+-K+-ATPase of the sarcolemma, a decrease in the content of Na+-K+-ATPase units in skeletal muscle, the direct effect of hypokalemia on the formation of ectopic foci in the myocardium and conduction disturbances. Electrophysiological mechanisms caused by hypokalemia contribute to an increase in the toxic effects of SG and significantly increase the risk of developing arrhythmias [16].

Unlike hypokalemia, hyperkalemia is not associated with an increased risk of developing DTI. An increase in the concentration of extracellular K+ leads to structural changes in Na+-K+-ATPase, disrupting the connection of SG with it. In addition, with hyperkalemia, stimulation of Na+-K+-ATPase activity is observed. An increase in plasma K+ levels (more than 5.5 mEq/L) stimulates depolarization of the conductive tissue of the heart (especially atrioventricular connections), which may result in a decrease in conductivity and the development of atrioventricular block [26–28].

Ca2+ ions play an important role in the development of DtI. One of the risk factors for DTI is an increase in intracellular Na+, which modifies the Na+-Ca2+ exchange, resulting in an increase in the intracellular Ca2+ content, leading to a slowdown in conduction processes [12]. The above argues for the need to determine plasma levels of electrolytes when using digoxin [32].

First aid

Even a mild overdose of pentobarbital is a reason to immediately call an ambulance team, since violations can worsen over time. The most important task at the first aid stage is the removal of toxic substances from the digestive tract. If the patient is conscious, he is given a mixture of water and adsorbent (activated carbon) to drink, and then vomiting is artificially induced. The procedure is repeated until clear water appears.

Other measures (cleansing the intestines, taking diuretics, correcting respiratory disorders) should be carried out by specialists, since an incorrect assessment of the victim’s condition and errors in selecting the type and dose of the drug are fraught with serious complications. The only action that needs to be performed before the ambulance arrives is mouth-to-mouth artificial respiration in case of paralysis of the respiratory system.

Etiology and pathogenesis

At the moment, cardiac glycoside poisoning is less common in medical practice than before, as fewer patients receive digoxin.

General effects:

· Digitalis paralyzes Na + -K + AT and has a strong vagotonic effect.

· Poisoning can be due to intentional acute or accidental chronic overdose.

· The toxic effects of digitalis are enhanced by electrolyte disturbances, especially hypokalemia, as well as cardiovascular and pulmonary disturbances.

· The plasma half-life of digoxin is approximately 36 hours but may be prolonged in renal failure due to delayed urinary excretion.

Specialized treatment

In stationary conditions, gastric intubation is performed, mechanical ventilation is performed, and infusion therapy is prescribed to remove toxins and restore acid-base and water-electrolyte balance. Diuretics are used. Hemodialysis and hemosorption are carried out. The effectiveness of treatment measures and the likelihood of a successful outcome are determined by the severity of the overdose and the time of initiation of therapy. Pentobarbital is deadly in large doses, but seeking medical help early increases your chances of recovery.

Therapeutic tactics for digitalis intoxication

The nature of therapeutic measures for DTI and their effectiveness are determined by a number of factors, including timely diagnosis, establishing the severity of the condition, the total amount of the drug taken and the time of taking the last dose, the presence of electrolyte imbalance, renal function, as well as the interaction of SG with other drugs [38– 41]. Thus, in case of DTI, manifested by sinus bradycardia, 1st degree atrioventricular block, rare ventricular or atrial extrasystoles, it is enough to temporarily cancel SG and monitor ECG and blood pressure. Subsequently, it is necessary to select adequate dosages of digoxin to prevent recurrent episodes of DTI [41, 42].

At the same time, serious life-threatening disturbances of heart rhythm and conduction require immediate treatment. Thus, with severe sinus bradycardia, bradyarrhythmia with AF or 2nd degree atrioventricular block, the use of atropine often provides a good clinical effect. In the absence of effect from atropine, as well as in cases of more severe sinus node dysfunction with 3rd degree atrioventricular block, installation of a pacemaker is necessary. This can be either a temporary measure - during a period of acute struggle with life-threatening cardiac arrhythmias, or a permanent measure - if a high degree of blockade remains [16, 18, 29].

The development of severe life-threatening arrhythmias serves as the basis for the prescription of special anti-digoxin antibody fragments (Fab fragments). Before prescribing Fab fragments or during their use, urgent implementation of other therapeutic measures is necessary, including correction of potassium and/or magnesium homeostasis and/or prescription of antiarrhythmic drugs (procainamide, propafenone, lidocaine, amiodarone) [38, 39, 43].

Fab fragments bind to intravascular digoxin, as well as to digoxin located in the interstitial space, where it enters by diffusion. As a result, the concentration of free digoxin in the extracellular space decreases to almost zero levels. The concentration gradient established in this case promotes the release of digoxin from tissues and rapid connection with Fab fragments. Due to this, there is a noticeable increase in the total concentration of extracellular digoxin, which is pharmacologically inactive, since it is in a bound state with Fab fragments. Digoxin bound to Fab fragments is eliminated primarily by the kidneys. Thus, Fab fragments of anti-digoxin antibodies quickly and effectively eliminate the manifestations of DTI [21, 39, 43]. According to E. Antman et al. (1990) [44], continuation of digitalis therapy is possible 7 days after elimination of DTI and correction of digoxin dosages. Hemodialysis and peritoneal dialysis are not able to significantly eliminate digoxin from the body, since it is in a bound state in various (primarily muscle) tissues [45].

Literature:

1. Medicines in the neurological clinic: handbook. for doctors / E. I. Gusev, A. S. Nikiforov, A. B. Gekht. — 2nd ed., erased. - Moscow: MEDpress-inform, 2006 (M.: Printing house "News"). — 405 p.
2. International legal framework for combating drug trafficking: collection of articles. doc. / comp. V. S. Ovchinsky, A. V. Fedorov. - Moscow: Infra-M, 2005. - 623 p.
3. Interoceptive effects of psychotropic drugs: dissertation ... Doctor of Biological Sciences: 14.00.25 / Kalinina Tatyana Sergeevna; [Place of protection: Scientific research. Institute of Pharmacology named after. V.V. Zakusov RAMS]. - Moscow, 2008. - 360 p.

Clinical manifestations of digitalis intoxication

The incidence of DTI varies significantly in different reports, which is explained by the heterogeneity of the studied groups of patients, the use of different doses of SG and diagnostic approaches. DTI can develop at different serum concentrations of digoxin (usually above 2.0 ng/ml, but also at lower levels). In this regard, to verify DTI in a particular patient, it is necessary to take into account not only the values ​​of serum digoxin concentrations, but also the clinical manifestations of DTI [13, 16–18, 28].

The wide range of manifestations of DTI, both cardiac and non-cardiac, significantly complicates its diagnosis. According to G. Ordog et al. (1987) [33], timely diagnosis of DTI is carried out in approximately 20% of cases.

According to the results of a study by M. Böhn et al. (1998) [34], with DTI, cardiac manifestations occur in 67–80% of cases, gastrointestinal manifestations in 20–25% of cases, and neurological manifestations in 5–10% of cases. Heart rhythm and conduction disturbances can often be the first (and sometimes the only) manifestations of DTI.

I. See et al. (2014) [19] published a detailed analysis of data from 5165 patients hospitalized in intensive care units from 2005 to 2010 in the United States due to side effects of drugs. Among them, 441 cases of DTI were identified. The majority were women (67.8% [95% CI 62.9–72.6%]) and persons ≥70 years of age (79.1% [95% CI 73.5–84.7%]). DTI was diagnosed in 5.9% (95% CI 4.0–7.9%) of hospitalizations in patients ≥85 years of age. Serum digoxin concentrations ≥2.0 ng/ml occurred in 95.8% of cases. These data give a real idea of ​​the frequency and severity of DTI, its structure and risk factors for its development in clinical practice (Table 1).