Antiarrhythmic drugs

In anesthesiology and resuscitation practice, antiarrhythmic drugs that have a rapid stopping effect, can be administered parenterally and do not have a large number of long-term side effects have been primarily used.

Heart rhythm disturbances are quite common in cardiac anesthesiology practice, and some of them have important prognostic value and can lead to serious complications. Therefore, understanding the etiology and treatment of rhythm disturbances that occur during surgery is of great importance for the patient's safety. Heart rhythm disturbances, the most important of which are ventricular arrhythmias, can develop in myocardial ischemia and infarction, increased myocardial excitability due to various reasons, heart failure, and even with too superficial anesthesia and manipulations on the heart. In the latter case, to stop ventricular extrasystole, the anesthesiologist may only need to deepen the anesthesia and analgesia by administering 0.1 or 0.2 mg of fentanyl.

Clinical conditions predisposing to the development of rhythm disturbances are the administration of inhalation anesthetics, changes in acid-base and electrolyte balances (hypokalemia, hypocalcemia, hypomagnesemia, acidosis), temperature disturbances (hypothermia), hypoxia. Thus, as a result of the intensive transfer of potassium into cells under the influence of an increased level of plasma catecholamines, hypokalemia may develop, which in ischemia and acute myocardial infarction, as well as in heart failure, contributes to the development of cardiac rhythm disturbances. Therefore, it is important for the anesthesiologist to identify and treat the underlying cause of rhythm disturbances.

Classification of antiarrhythmic drugs (AAD). According to the most widely used classification by Vaughan Williams, there are 4 classes of AAD. AAD are classified depending on the set of electrophysiological properties due to which they cause changes in the rate of depolarization and repolarization of the cells of the cardiac conduction system.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ]

Antiarrhythmic drugs: place in therapy

When treating rhythm disturbances in the practice of an anesthesiologist, it is of great importance to first of all establish, if possible, the cause of the development of rhythm disturbances in the patient, and then the correct choice of one or another drug, as well as the optimal treatment tactics.

The anesthesiologist must rule out inadequacy of anesthesia, the presence of electrolyte imbalance, the occurrence of heart failure in the patient, conduction disturbances due to one reason or another (ischemia, excessive amount of administered cardioplegic solution, residual effects of cold cardioplegia) and only then develop treatment tactics.

During intracardiac manipulations during cardiac surgery, patients may develop extrasystole, often polytopic. In these cases, prophylactic use of lidocaine solution in combination with transfusion of 20% glucose solution with potassium, the so-called "polarizing" mixture, allows, if not to exclude their development (this is impossible), then, in any case, to reduce the risk of developing VF or the occurrence of atrial fibrillation. The mechanism of the stabilizing effect of glucose in this case consists in increasing the glycogen content for the potential use of glucose as an energy material, improving the function of the K + -Na + pump necessary for stabilizing the cell membrane, reducing the formation of free radicals, shifting metabolism from lipolytic to glycolytic, reducing the level of free fatty acids and reducing mitochondrial dysfunction to a minimum. These properties are complemented by the positive inotropic effect of insulin added to the solution. Its positive inotropic effect is equivalent to dopamine infusion at a dose of 3-4 mcg/kg/min.

The most effective drug for stopping paroxysmal supraventricular tachycardia that develops during surgery is the use of the short-acting beta-blocker esmolol, and in patients with ischemic heart disease during CABG surgery, the administration of adenosine, especially in patients with hypovolemia, since it reduces myocardial oxygen consumption by 23%. Only in extreme cases, when drug therapy is ineffective, defibrillation is used. If atrial fibrillation or atrial flutter develops during surgery (rarely), the treatment tactics are determined by the blood pressure level. If the patient's blood pressure remains stable, the water-electrolyte balance should be corrected, a potassium solution or a "polarizing" mixture should be transfused; if there are signs of heart failure, digoxin should be administered. If blood pressure drops, cardioversion should be performed immediately.

Adenosine is effective in paroxysmal supraventricular tachycardias caused by impulse reentry, including paroxysms in patients with Wolff-Parkinson-White syndrome (WPW). Previously, adenosine was considered to be the drug of choice for emergency therapy of paroxysmal supraventricular tachycardias, but currently in anesthesiological practice in most cases it is advisable to use short-acting beta-blockers such as esmolol, since the use of adenosine for these purposes in doses that stop rhythm disturbances can cause severe hypotension, for the correction of which vasopressors may be required. A single administration of adenosine allows establishing the origin of tachycardia with a wide QRS complex on the ECG (i.e. ventricular or supraventricular with impaired conduction). In the case of the latter, atrioventricular block with adenosine reveals beta waves and allows making a diagnosis.

The most effective drug for the treatment of ventricular extrasystoles is lidocaine, which has become essentially the only drug in widespread anesthesiology practice used for the rapid and effective treatment of ventricular extrasystoles. A good preventive effect in patients with a tendency to ventricular arrhythmia is provided by the use of lidocaine in a solution of potassium preparations or a "polarizing" mixture. In the event of ventricular extrasystoles (more than 5 per minute), multifocal, group, it is necessary to ensure the adequacy of anesthesia and, if necessary, deepen anesthesia and analgesia by administering 0.2-0.3 mg of fentanyl. In the presence of hypokalemia, it is necessary to correct it by transfusing a glucose-potassium mixture with insulin or by slow administration of potassium and magnesium preparations. Lidocaine is administered at a dose of 1 mg / kg (usually 80 mg) in 20 ml of physiological solution, if there is no effect, the administration of the drug is repeated in the same dose. At the same time, 200 mg of lidocaine is added to the glucose-potassium mixture or Ringer's lactate (500 ml) and administered intravenously by drip at a rate of 20-30 mcg/kg/min to prevent a “therapeutic vacuum” formed as a result of rapid redistribution of the drug.

Lidocaine is the drug of choice for the treatment of VF after cardioversion. In case of unsuccessful attempts at defibrillation, preliminary intravenous administration of lidocaine at a dose of 80-100 mg against the background of a more rapid transfusion of glucose-potassium mixture often has a good effect. Lidocaine is successfully used to prevent the occurrence of ventricular arrhythmia during intracardiac operations during manipulations on the heart, diagnostic intracardiac studies, etc.

Currently, bretylium tosylate is recommended as a second-choice drug for the treatment of VT and VF when countershock and lidocaine are ineffective, with the development of repeated VF despite the administration of lidocaine. It can also be used for persistent ventricular tachyarrhythmias. However, in these cases, beta-blockers, in particular esmolol, may be the drug of choice. Antiarrhythmic drugs are used as a single intravenous injection at a dose of 5 mg/kg or continuous infusion at a rate of 1-2 mg/70 kg/min. Bretylium tosylate is often effective for arrhythmias caused by glycoside intoxication.

Amiodarone is an effective antiarrhythmic drug for various rhythm disorders, including supraventricular and ventricular extrasystoles, refractory supraventricular tachycardia, especially associated with WPW syndrome, and VF, atrial fibrillation, atrial flutter. Amiodarone is most effective in chronic arrhythmias. In atrial fibrillation, it slows the ventricular rhythm and can restore sinus rhythm. It is used to maintain sinus rhythm after cardioversion in atrial fibrillation or flutter. The drug should always be used with caution, since even short-term use can lead to serious intoxication. In anesthesiology, this drug is practically not used largely due to the long time required to achieve the effect and the long-term persistence of side effects. It is most often used in the postoperative period in cardiac surgery patients.

Propafenone is used to stop ventricular extrasystole, paroxysmal VT, atrial fibrillation, to prevent relapses, atrioventricular reciprocal tachycardia, recurrent supraventricular tachycardia (WPW syndrome). This drug has not found application in anesthesiology practice due to the availability of other, more effective and fast-acting drugs.

Nibentan is used for the prevention and treatment of persistent ventricular tachycardia and fibrillation, treatment of supraventricular and ventricular arrhythmias, treatment of persistent ventricular tachyarrhythmias, and treatment of acute or persistent atrial flutter and fibrillation. It was less effective in treating atrial extrasystole. The drug is mainly used in resuscitation and intensive care.

The main indication for the use of ibutilide is acutely developed atrial flutter or fibrillation, in which it ensures restoration of sinus rhythm in 80-90% of patients. The main property limiting its use is the relatively frequent arrhythmogenic effect (ventricular arrhythmia of the "pirouette" type develops in 5%) and, in connection with this, the need to monitor the ECG for 4 hours after administration of the drug.

Ibutilide is used to treat and prevent supraventricular, nodal and ventricular rhythm disturbances, especially in cases that do not respond to lidocaine therapy. For this purpose, the drug is administered intravenously slowly at a dose of 100 mg (about 1.5 mg/kg) at 5-minute intervals until the effect is achieved or a total dose of 1 g, under constant monitoring of blood pressure and ECG. It is also used to treat atrial flutter and paroxysmal atrial fibrillation. In the event of hypotension or widening of the QRS complex by 50% or more, the drug is discontinued. If necessary, vasopressors are used to correct hypotension. To maintain an effective therapeutic concentration in plasma (4-8 mcg/ml), the drug is administered dropwise at a rate of 20-80 mcg/kg/min. However, due to the pronounced negative inotropic effect and the frequently observed hypersensitivity reaction of patients to this drug, as well as the availability of more easily controlled and less toxic drugs in anesthesiological practice, it is used relatively rarely.

[ 10 ], [ 11 ], [ 12 ], [ 13 ], [ 14 ], [ 15 ], [ 16 ]

Mechanism of action and pharmacological effects

The exact mechanisms and sites of action of many antiarrhythmic drugs have not yet been fully elucidated. However, most of them work in a similar way. Antiarrhythmic drugs bind to channels and gates that control ion flows across cardiac cell membranes. As a result, the speed and duration of the action potential phases change, and the basic electrophysiological properties of cardiac tissue change accordingly: conduction velocity, refractoriness, and automaticity.

During phase 0, rapid depolarization of the cell membrane occurs due to the rapid influx of sodium ions through channels that selectively pass these ions.

• Phase 1 is characterized by a short initial period of rapid repolarization, mainly due to the release of potassium ions from the cell.
• Phase 2 reflects a period of slow repolarization, which occurs mainly due to the slow flow of calcium ions from the extracellular space into the cell through calcium channels.
• Phase 3 is the 2nd period of rapid repolarization, during which potassium ions move out of the cell.
• Phase 4 characterizes the state of complete repolarization, during which potassium ions reenter the cell and sodium and calcium ions leave it. During this phase, the contents of the cell, which discharges automatically, gradually become less negative until a potential (threshold) is reached that allows rapid depolarization to occur (phase 0), and the entire cycle is repeated. Cells that are not themselves automatic depend on the passage of action potentials from other cells to initiate depolarization.

The main characteristic of class I AAS is their ability to block fast sodium channels. However, many of them also have a blocking effect on potassium channels, although weaker than class III antiarrhythmic drugs. According to the severity of the sodium and potassium blocking effect, class I drugs are divided into 3 subclasses: IA, IB and 1C.

Class IA antiarrhythmics, by blocking fast sodium channels, slow phase 0 of the action potential and moderately slow the impulse conduction velocity. Due to the blockade of potassium channels, the action potential and refractoriness are prolonged. These electrophysiological effects are manifested in both atrial and ventricular tissues, therefore class IA antiarrhythmics have potential effectiveness in atrial and ventricular tachyarrhythmias. Antiarrhythmic drugs are able to suppress the automaticity of the sinus node, which is more often manifested in its pathology.

Class IB antiarrhythmics have relatively little effect on fast sodium channels at normal heart rates and, therefore, on conduction velocity. Their main effect is to decrease the duration of the action potential and, as a result, to shorten refractory periods. However, at high heart rates, as well as in the presence of ischemia, hypokalemia, or acidosis, some antiarrhythmics, such as lidocaine, can significantly slow depolarization and conduction velocity. Class IB antiarrhythmics have little effect on the atria (with the exception of phenytoin) and are therefore useful only for the treatment of ventricular arrhythmias. Antiarrhythmics suppress the automaticity of the sinus node. Thus, lidocaine is capable of suppressing both normal and abnormal automaticity, which can lead to asystole when it is administered against the background of a ventricular escape rhythm.

Class 1C drugs are characterized by a pronounced effect on fast sodium channels, since they have slow binding kinetics, which determines a significant slowdown in the conduction velocity even at normal heart rates. The effect of these drugs on repolarization is insignificant. Class 1C antiarrhythmic drugs have a comparable effect on atrial and ventricular tissues and are useful in atrial and ventricular tachyarrhythmias. Antiarrhythmic drugs suppress the automaticity of the sinus node. Unlike other class 1C antiarrhythmic drugs, propafenone contributes to a slight increase in refractory periods in all cardiac tissues. In addition, propafenone has moderately pronounced beta-blocking and calcium-blocking properties.

Class II drugs include beta-blockers, the main antiarrhythmic action of which is to suppress the arrhythmogenic effects of catecholamines.

The general mechanism of the antiarrhythmic effect of class III drugs is to prolong the action potential by blocking potassium channels that mediate repolarization, thereby increasing the refractory periods of cardiac tissue. All representatives of this class of drugs have additional electrophysiological properties that contribute to their effectiveness and toxicity. The drug is characterized by an inverse frequency dependence, i.e. at a slow heart rate, the prolongation of the action potential is most pronounced, and with an increase in heart rate, the effect is reduced. This effect, however, is weakly expressed in amiodarone. Unlike other class III antiarrhythmic drugs, amiodarone is capable of moderately blocking sodium channels, causing non-competitive blockade of beta-adrenergic receptors, and also to some extent causing blockade of calcium channels.

Bretilium tosylate by its pharmacodynamic properties refers to peripheral sympatholytics. Antiarrhythmic drugs have a biphasic effect, stimulates the release of norepinephrine from presynaptic nerve endings, which explains the development of hypertension and tachycardia immediately after its administration. In the 2nd phase, antiarrhythmic drugs prevent the release of the mediator into the synaptic cleft, causing peripheral adrenergic blockade and chemical sympathectomy of the heart. The 3rd phase of action consists of blocking the reabsorption of catecholamines. For this reason, it was previously used as an antihypertensive agent, but tolerance quickly develops to it, and at present the drug is not used to treat hypertension. Bretylium tosylate lowers the fibrillation threshold (reduces the discharge power required for defibrillation) and prevents recurrence of ventricular fibrillation (VF) and ventricular tachycardia (VT) in patients with severe cardiac pathology.

Sotalol has both non-cardioselective beta-blocker and class III antiarrhythmic properties because it prolongs the cardiac action potential in the atria and ventricles. Sotalol causes a dose-dependent increase in the QT interval.

Nibentan causes an increase in the duration of the action potential by 2-3 times more pronounced compared to that of sotalol. At the same time, it does not have a significant effect on the force of contraction of the papillary muscles. Nibentan reduces the frequency of ventricular extrasystole, increases the threshold for the development of VF. In this regard, it is 5-10 times more effective than sotalol. Antiarrhythmic drugs do not affect the automaticity of the sinus node, intra-atrial, AV and intraventricular conduction. It has a pronounced antiarrhythmic effect in patients with atrial flutter or fibrillation. Its effectiveness in patients with persistent atrial flutter or fibrillation is 90 and 83%, respectively. It has a less pronounced effect in stopping atrial extrasystole.

Ibutilide is a new and unique Class III drug because it prolongs the action potential primarily by blocking inward sodium currents rather than outward potassium currents. Like sotalol, ibutilide causes a dose-dependent prolongation of the QT interval. Ibutilide slightly slows sinus rhythm and slows AV conduction.

Class VI AAS include verapamil and diltiazem. These antiarrhythmic drugs inhibit slow calcium channels responsible for depolarization of two main structures: the SA and AV nodes. Verapamil and diltiazem suppress automaticity, slow conduction, and increase refractoriness in the SA and AV nodes. As a rule, the effect of calcium channel blockers on the myocardium of the atria and ventricles is minimal or absent. However, slow calcium channels are involved in the development of both early and late after-depolarizations. Class VI antiarrhythmic drugs are able to suppress after-depolarizations and the arrhythmias they cause. In rare cases, verapamil and diltiazem are used to treat ventricular arrhythmias.

The mechanism of the antiarrhythmic action of adenosine, a drug not included in the Vaughan Williams classification, is associated with an increase in potassium conductivity and suppression of cAMP-induced Ca2+ entry into the cell. As a result, pronounced hyperpolarization and suppression of calcium-dependent action potentials develop. With a single administration, adenosine causes direct inhibition of conductivity in the AV node and increases its refractoriness, having an insignificant effect on the SA node.

Arrhythmogenic effect. Antiarrhythmic drugs, in addition to the antiarrhythmic effect, can cause an arrhythmogenic effect, i.e. they can provoke arrhythmias themselves. This property of AAS is directly related to their main mechanisms of action, namely, changes in the conduction velocity and duration of refractory periods. Thus, changes in the conduction velocity or refractoriness in different parts of the reentry loop can eliminate critical relationships at which reciprocal arrhythmias are initiated and maintained. Most often, class 1C antiarrhythmic drugs cause aggravation of reciprocal arrhythmias, since they significantly slow down the conduction velocity. This property is expressed to a slightly lesser extent in class IA drugs, and even less in class IB and III drugs. This type of arrhythmia is more often observed in patients with heart disease.

Torsades de pointes (pirouettes) are another type of arrhythmogenic action of AAS. This type of arrhythmia manifests itself as polymorphic VT caused by prolongation of the Q-T interval or other repolarization abnormalities. The cause of these arrhythmias is considered to be the development of early after-depolarizations, which may result from the use of AAS classes IA and III. Toxic doses of digoxin can also cause polymorphic VT, but due to the formation of late after-depolarizations. Heart disease is not required for this type of arrhythmia to manifest. They develop if some factor, such as antiarrhythmic drugs, prolongs the action potential. Torsades de pointes (pirouettes) most often occurs in the first 3-4 days of treatment, which requires ECG monitoring.

Hemodynamic effects. Most AAS affect hemodynamic parameters, which, depending on their severity, limits the possibilities of their use, acting as side effects. Lidocaine has the least effect on blood pressure and myocardial contractility. The introduction of lidocaine at a dose of 1 mg/kg is accompanied by only a short-term (at the 1-3 minute) decrease in SOS and MOS, LV work by 15, 19 and 21% of the initial level. Some decrease in HR (5 ± 2) is observed only at the 3rd minute. Already at the 5th minute, the above indicators do not differ from the initial ones.

Antiarrhythmic drugs of class IA have a pronounced hypotensive effect, especially when administered intravenously, and bretylium tosylate, to a lesser extent this is characteristic of drugs of other classes. Adenosine dilates coronary and peripheral arteries, causing a decrease in blood pressure, but these effects are short-lived.

Disopyramide has the most pronounced negative inotropic effect, which is why it is not recommended for patients with heart failure. Procainamide has a significantly weaker effect on myocardial contractility. Propafenone has a moderate effect. Amiodarone causes dilation of peripheral vessels, probably due to the alpha-adrenergic blocking effect and calcium channel blockade. When administered intravenously (5-10 mg/kg), amiodarone causes a decrease in myocardial contractility, expressed in a decrease in the LV ejection fraction, the first derivative of the rate of pressure increase in the aorta (dP/dUDK), mean aortic pressure, LVED, OPS, and SV.

Pharmacokinetics

Procainamide is easily absorbed in the stomach, its effect manifests itself within an hour. When administered intravenously, the drug begins to act almost immediately. The therapeutic level of the drug in plasma is usually from 4 to 10 μg / ml. Less than 20% of the drug binds to plasma proteins. Its T1 / 2 is 3 hours. The drug is metabolized in the liver by acetylation. The main metabolite N-acetylprocainamide has an antiarrhythmic effect (prolongs repolarization), has a toxic effect and is excreted by the kidneys. T1 / 2 N-acetylprocainamide is 6-8 hours. In patients with impaired liver or kidney function or with reduced blood supply to these organs (for example, with heart failure), the excretion of procainamide and its metabolite from the body is significantly slowed down, which requires a decrease in the dose of the drug used. Intoxication develops when the concentration of the drug in the plasma is more than 12 μg / ml.

The antiarrhythmic effect of lidocaine is largely determined by its concentration in the ischemic myocardium, while its content in venous or arterial blood and in healthy areas of the myocardium is not significant. The decrease in the concentration of lidocaine in the blood plasma after its intravenous administration, as with the administration of many other drugs, has a two-phase nature. Immediately after intravenous administration, the drug is mainly in the blood plasma and then transferred to the tissues. The period during which the drug moves to the tissues is called the redistribution phase, its duration for lidocaine is 30 minutes. Upon completion of this period, a slow decrease in the drug content occurs, called the equilibration phase, or elimination, during which the levels of the drug in the blood plasma and tissues are in an equilibrium state. Thus, the effect of the drug will be optimal if its content in the myocardial cells approaches its concentration in the blood plasma. Thus, after the introduction of a dose of lidocaine, its antiarrhythmic effect manifests itself in the early period of the distribution phase and ceases when its content falls below the minimum effective. Therefore, to achieve an effect that would be maintained during the equilibration phase, a large initial dose should be administered or repeated small doses of the drug should be administered. T1/2 of lidocaine is 100 min. About 70% of the drug binds to plasma proteins, 70-90% of the administered lidocaine is metabolized in the liver to form monoethyl-glycine-xylidide and glycine-xylidide, which have an antiarrhythmic effect. About 10% of lidocaine is excreted in the urine unchanged. Metabolic products are also excreted by the kidneys. The toxic effect of lidocaine after intravenous administration is due to the accumulation of monoethyl-glycine-xylidide in the body. Therefore, in patients with impaired liver or kidney function (patients with chronic renal failure), as well as in patients with heart failure, elderly people, the dose of intravenous drugs should be approximately 1/2 of that in healthy people. The therapeutic concentration of lidocaine in plasma ranges from 1.5 to 5 μg/ml, clinical signs of intoxication appear when its content in plasma is above 9 μg/ml.

Propafenone is almost completely (85-97%) bound to blood and tissue proteins. The volume of distribution is 3-4 l/kg. The drug is metabolized in the liver with the participation of the cytochrome P450 system with the formation of active cleavage products: 5-hydroxypropafenone, N-depropylpropafenone. The overwhelming majority of people have a fast type of metabolization (oxidation) of this drug. T1/2 for them is 2-10 hours (on average 5.5 hours). In approximately 7% of patients, oxidation occurs at a slow rate. T1/2 in such people is 10-32 hours (on average 17.2 hours). Therefore, when equivalent doses are administered, the concentration of the drug in plasma is higher in them than in other people. 15-35% of metabolites are excreted by the kidneys, most of the drug is excreted with bile in the form of glucuronides and sulfates.

A peculiarity of amiodarone pharmacokinetics is a long T1/2, which is from 14 to 107 days. The effective concentration in plasma is approximately 1-2 μg/ml, while the concentration in the heart is approximately 30 times higher. A large distribution volume (1.3-70 l/kg) indicates that a small amount of the drug remains in the blood, which necessitates the administration of a loading dose. Due to the high solubility of amiodarone in fats, it accumulates significantly in the adipose and other tissues of the body. Slow achievement of an effective therapeutic concentration of the drug in the blood even with intravenous administration (5 mg/kg for 30 min) limits its effective use during surgery. Even with large loading doses, 15-30 days are required to saturate tissue depots with amiodarone. If side effects occur, they persist for a long time even after the drug is discontinued. Amiodarone is almost completely metabolized in the liver and excreted from the body in the bile and through the intestines.

Bretylium tosylate is administered intravenously only, as it is poorly absorbed in the intestine. Antiarrhythmic drugs are actively captured by tissues. Several hours after administration, the concentration of bretylium tosylate in the myocardium can be 10 times higher than its level in the serum. The maximum concentration in the blood is achieved after 1 hour, and the maximum effect after 6-9 hours. The drug is excreted by the kidneys by 80% unchanged. T1 / 2 is 9 hours. The duration of action of bretylium tosylate after a single administration ranges from 6 to 24 hours.

T1/2 of nibentan after intravenous administration is 4 hours, its clearance is 4.6 ml/min, and the circulation time in the body is 5.7 hours. In patients with supraventricular tachycardia, T1/2 from the vascular bed after administration of the drug at a dose of 0.25 mg/kg is about 2 hours, clearance is 0.9 l/min, and the distribution volume is 125 l/kg. Nibentan is metabolized in the liver to form two metabolites, one of which has a significant antiarrhythmic effect similar to that of nibentan. The drug is excreted with bile and through the intestines.

Due to low absorption when taken orally, ibutilide is used exclusively intravenously. About 40% of the drug in the blood plasma binds to plasma proteins. The small volume of distribution (11 l/kg) indicates its predominant storage in the vascular bed. T1/2 is about 6 hours (from 2 to 12 hours). Plasma clearance of the drug is close to the rate of hepatic blood flow (about 29 ml/min/kg body weight). The drug is metabolized mainly in the liver by omega-oxidation followed by beta-oxidation of the heptyl side chain of ibutilide. Of the 8 metabolites, only the omega-hydroxy metabolite of ibutilide has antiarrhythmic activity. 82% of the drug metabolization products are excreted mainly by the kidneys (7% unchanged) and about 19% with feces.

Adenosine after intravenous administration is captured by erythrocytes and vascular endothelial cells, where it is rapidly metabolized by adenosine deaminase to form electrophysiologically inactive metabolites of inosine and adenosine monophosphate. Since drug metabolism is not associated with the liver, the presence of liver failure does not affect the T1/2 of adenosine, which is approximately 10 sec. Adenosine is excreted by the kidneys as inactive compounds.

Classification of antiarrhythmic drugs

• Class I - fast sodium channel blockers:
  • 1a (quinidine, procainamide, disopyramide, primalium butartrate);
  • 1b (lidocaine, bumecaine, mexiletine, phenytoin);
  • 1c (propafenone, etacizine, lappaconitine, moricizine);
• class II - beta-adrenergic receptor blockers (propranolol, esmolol, etc.);
• class III - potassium channel blockers (amiodarone, bretylium tosylate, sotalol, ibutilide, nibentan);
• class IV - calcium channel blockers (verapamil, diltiazem).

Other medications that cannot be classified into any of the Vaughan Williams classification groups due to their electrophysiological properties are also used in practice as antiarrhythmic agents. These include cardiac glycosides, magnesium and potassium salts, adenosine, and some others.

[ 19 ], [ 20 ], [ 21 ], [ 22 ], [ 23 ]

Contraindications

General contraindications for almost all antiarrhythmic drugs are the presence of AV block of varying degrees, bradycardia, weakness of the sinus node, prolongation of the Q-T interval more than 440 msec, hypokalemia, hypomagnesemia, heart failure and cardiogenic shock.

The use of drugs is contraindicated in case of increased individual sensitivity to them. Procainamide, propafenone, amiodarone and adenosine are not prescribed for bronchial asthma and COPD.

Procainamide is contraindicated in patients with impaired liver and kidney function, systemic lupus erythematosus, and myasthenia. Lidocaine is not indicated if the patient has a history of epileptiform seizures. Propafenone should not be used in patients with myasthenia, severe electrolyte disturbances, and impaired liver and kidney function.

Bretylium tosylate is contraindicated in patients with fixed cardiac output, pulmonary hypertension, aortic valve stenosis, acute cerebrovascular accident, and severe renal failure.

[ 17 ], [ 18 ]

Tolerability and side effects

The least number of side effects is observed when using lidocaine. When used in therapeutic doses, antiarrhythmic drugs are usually well tolerated by patients. Lidocaine intoxication (drowsiness and disorientation, followed by the development of muscle twitching, auditory hallucinations and seizures in severe cases) is practically not encountered in the practice of cardiac anesthesiology and is observed mainly when using lidocaine for regional anesthesia. Adenosine side effects are insignificant due to the short duration of its action. Serious side effects are extremely rare.

Most of the side effects of antiarrhythmic drugs are related to their main electrophysiological actions. Due to the prolongation of AV conduction, many antiarrhythmic drugs can cause bradycardia. The probability of its development increases with increasing dose. Thus, adenosine, with an increase in dose, can cause pronounced bradycardia, which quickly passes after stopping the infusion of the drug or intravenous administration of atropine. Bradycardia rarely occurs with the administration of nibentan. Lidocaine and bretylium tosylate do not cause the development of bradycardia, since they do not prolong AV conduction.

Many antiarrhythmic drugs are characterized to a greater or lesser extent by an arrhythmogenic effect, which can manifest itself in the development of dangerous ventricular arrhythmias, such as torsades de pointes. This arrhythmia most often develops when prescribing drugs that prolong the Q-T interval: drugs of classes IA and III. Although amiodarone, like other drugs of class III, causes a blockade of potassium channels and, accordingly, prolongs the Q-T interval, the development of VT is rarely observed with its intravenous administration. Therefore, a slight prolongation of Q-T is not an indication to stop its administration. Lidocaine, like other antiarrhythmic drugs that cause a blockade of sodium channels, slows ventricular excitation, and therefore in patients with AV block, dependent only on the idioventricular rhythm, asystole may develop when using lidocaine. A similar situation can be observed with the prophylactic use of lidocaine after removal of the aortic clamp in order to restore sinus rhythm after a single defibrillation. Propafenone has a depressant effect on the sinus node and can cause weakness of the sinus node, and with rapid administration - cardiac arrest. In rare cases, AV dissociation is possible. The use of adenosine in large doses can cause depression of sinus node activity and ventricular automatism, which can lead to transient loss of cardiac cycles.

All antiarrhythmic drugs are capable of reducing blood pressure to a greater or lesser extent. This effect is most pronounced in bretylium tosylate, which is a sympatholytic agent by its mechanism of action. Bretylium tosylate accumulates in peripheral adrenergic nerve endings. Initially, the sympathomimetic effect predominates due to the release of norepinephrine. Subsequently, bretylium tosylate blocks the release of norepinephrine, which is associated with adrenergic blockade of the neuron. This may manifest itself in the development of severe hypotension.

Class I antiarrhythmic drugs and amiodarone can aggravate or even cause heart failure, especially against the background of reduced LV contractility due to the negative inotropic effect of these drugs. Lidocaine has a pronounced negative inotropic effect only at high concentrations of the drug in the blood plasma.

Class IA antiarrhythmic drugs cause a number of side effects due to anticholinergic action, which are manifested by dry mouth, accommodation disorder, difficulty urinating, especially in elderly patients with prostatic hypertrophy. Anticholinergic action is less pronounced with the introduction of procainamide.

Propafenone, amiodarone and adenosine can cause bronchospasm. However, this action is based on different mechanisms. The bronchospastic action of propafenone and amiodarone is due to their ability to block beta-adrenergic receptors of the bronchi. Adenosine can provoke (rarely) the development of bronchospasm mainly in people suffering from bronchial asthma. The interaction of adenosine in these patients with the A2b-subtype of adenosine receptors leads to the release of histamine, which then causes bronchospasm through stimulation of H1 receptors.

Other adverse effects of adenosine include the ability to decrease pulmonary vascular resistance, increase intrapulmonary shunting, and decrease arterial oxygen saturation (SaO2) by suppressing pulmonary hypoxic vasoconstriction similar to NH and NNH, although to a much lesser extent. Adenosine can cause renal vasoconstriction, which is accompanied by a decrease in renal blood flow, glomerular filtration rate, and diuresis.

The use of propafenone, as well as procainamide, may be associated with the development of an allergic reaction.

Lidocaine, having the properties of local anesthetics, can cause side effects from the central nervous system (convulsions, fainting, respiratory arrest) only when toxic doses are administered.

Interaction

Antiarrhythmic drugs have a fairly wide range of drug interactions of both pharmacodynamic and pharmacokinetic nature.

Procainamide potentiates the action of antiarrhythmic, anticholinergic and cytostatic agents, as well as muscle relaxants. The drug reduces the activity of antimyasthenic agents. No interactions of procainamide with warfarin and digoxin have been noted.

The introduction of lidocaine with beta-blockers increases the likelihood of hypotension and bradycardia. Propranolol and cimetidine increase the concentration of lidocaine in plasma, displacing it from its protein binding and slowing its inactivation in the liver. Lidocaine potentiates the action of intravenous anesthetics, hypnotics and sedatives, as well as muscle relaxants.

Cimetidine inhibits the P450 system and may slow down the metabolism of propafenone. Propafenone increases the concentration of digoxin and warfarin and enhances their effect, which should be taken into account in patients who have received glycosides for a long time. Propafenone reduces the excretion of metoprolol and propranolol, so their doses should be reduced when using propafenone. Combined use with local anesthetics increases the likelihood of CNS damage.

The use of amiodarone in patients receiving digoxin simultaneously promotes the displacement of the latter from protein binding and increases its plasma concentration. Amiodarone in patients receiving warfarin, theophylline, quinidine, procainamide reduces their clearance. As a result, the effect of these drugs is enhanced. The simultaneous use of amiodarone and beta-blockers increases the risk of hypotension and bradycardia.

The use of bretylium tosylate with other antiarrhythmic drugs sometimes reduces its effectiveness. Bretylium tosylate increases the toxicity of cardiac glycosides, enhances the pressor effect of intravenous catecholamines (norepinephrine, dobutamine). Bretylium tosylate can potentiate the hypotensive effect of vasodilators used simultaneously.

Dipyridamole enhances the effect of adenosine by blocking its uptake by cells and slowing down its metabolism. The effect of adenosine is also enhanced by carbamazepine. In contrast, methylxanthines (caffeine, aminophylline) are antagonists and weaken its effect.

Cautions

All antiarrhythmic drugs should be administered under continuous ECG monitoring and direct recording of blood pressure, which allows for timely observation of possible side effects or drug overdose.

To correct possible hypotension, the anesthesiologist should always have vasopressors on hand. After the end of the ibutilide infusion, it is necessary to monitor the ECG for at least 4 hours until the normal Q-T interval is restored. In case of development of the arrhythmogenic effect of AAS, the patient is administered potassium and magnesium preparations intravenously; cardioversion or defibrillation is performed; if the rhythm slows, atropine and beta-adrenergic stimulants are prescribed.

Despite the fact that lidocaine in a therapeutic dose does not cause a significant decrease in myocardial contractility, it should be administered with caution to patients with hypovolemia (risk of developing severe hypotension), as well as to patients with severe heart failure with decreased myocardial contractility. Before using propafenone, the patient's electrolyte balance should be determined (especially the potassium level in the blood). In case of expansion of the complex by more than 50%, the drug should be discontinued.

Class I antiarrhythmic drugs should be used with caution in patients with liver and kidney damage, who are more likely to develop side effects and toxic effects.

[ 24 ], [ 25 ], [ 26 ], [ 27 ]