Antiarrhythmic drugs

In anesthesia and resuscitation practice, antiarrhythmic drugs that have a rapid stopping effect, which can be administered parenterally and which do not have a large number of long-term side effects, have found application in the first place.

Heart rhythm disturbances are quite often encountered in cardioanesthesiological practice, some of which have important prognostic significance 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 arrhythmias of ventricular origin, can develop with ischemia and myocardial infarction, increased myocardial excitability due to various causes, heart failure and even at a superficial level of anesthesia and cardiac manipulation. In the latter case, to stop ventricular extrasystole, an anesthesiologist can sufficiently deepen anesthesia and analgesia by administering 0.1 or 0.2 mg of fentanyl.

Clinical conditions predisposing to the development of rhythm disturbances are the introduction of inhalational anesthetics, changes in acid-base and electrolyte balance (hypokalemia, hypocalcemia, hypomagnesia, acidosis), temperature disorders (hypothermia), hypoxia. Thus, as a result of an intensive transition of potassium into cells under the influence of an elevated plasma catecholamine level, hypokalemia may develop, which, with ischemia and acute myocardial infarction, as well as with 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 (AAS). According to the most widespread classification of Vaughan Williams (Vaughan Williams) allocate 4 classes of AAS. AAS are classified according to a set of electrophysiological properties, due to which they cause changes in the rate of depolarization and repolarization of the cells of the conduction system of the heart.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]

Antiarrhythmic drugs: a place in therapy

In the treatment of rhythm disorders in the practice of an anesthesiologist, first of all, the establishment of the cause of the development of rhythm disturbances in the patient, and then the correct choice of a particular medicine, as well as the optimal treatment tactics, are of great importance.

An anesthesiologist should exclude inadequacy of anesthesia, the presence of electrolyte balance disorders, the occurrence of heart failure in the patient, conduction disorders due to various reasons (ischemia, excess amount of cardioplegic solution injected, residual effects of cold cardioplegia) and then develop tactics of treatment.

With intracardiac manipulations during heart operations, patients may develop extrasystole, often polytopic. The prophylactic use of lidocaine solution in these cases in combination with the transfusion of 20% glucose solution with potassium, the so-called "polarizing" mixture, allows, if not to exclude their development (this is impossible), in any case, to reduce the risk of VF development or the occurrence of ciliary arrhythmias. The mechanism of the stabilizing action 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 the metabolism from lipolytic to glycolytic, reducing the level of free fatty acids and minimizing the disturbance of mitochondrial function. These properties are supplemented by a positive inotropic effect of insulin added to the solution. Its positive inotropic effect is equated to dopamine infusion at a dose of 3-4 μg / kg / min.

The most effective drugs for stopping the paroxysmal supraventricular tachycardia developed during surgery is the use of a short-acting beta-blocker of esmolol, and in patients with coronary heart disease during the operation of CABG, adenosine administration, especially in patients with hypovolemia, because it reduces myocardial oxygen consumption by 23%. Only in extreme cases, in the absence of the effect of drug therapy, they resort to defibrillation. When the patient develops atrial fibrillation or atrial flutter during an operation (rarely), the treatment strategy is determined by the level of blood pressure. If the patient retains a stable blood pressure, a correction of the water-electrolyte balance should be made, the potassium solution or a "polarizing" mixture must be poured; in the presence of signs of heart failure to enter digoxin. In the case of a reduction in blood pressure, cardioversion should be immediately performed.

Adenosine is effective in paroxysmal supraventricular tachycardias due to pulse recurrence, incl. With paroxysms in patients with Wolff-Parkinson-White syndrome (WPW). Earlier it was thought that adenosine is the drug of choice for emergency therapy of paroxysmal supraventricular tachycardia, but now in anesthetic practice in most cases it is advisable to use short-acting beta-blockers like esmolol, since the use of adenosine for these purposes in doses that arrest rhythm disturbance can cause pronounced hypotension, for the correction of which may require vasopressors. A single adenosine administration allows one to establish the origin of a tachycardia with a wide QRS complex on the ECG (ie ventricular or supraventricular with impaired conductivity). In the case of the last atrioventricular blockade, adenosine reveals beta waves and allows diagnosis.

The most effective drugs for treatment of ventricular extrasystoles is lidocaine, which has become essentially the only drug in a wide anesthetic practice, used for rapid and effective treatment of ventricular extrasystoles. A good preventive effect in patients with a predilection for ventricular arrhythmias is the use of lidocaine in a solution of potassium preparations or a "polarizing" mixture. When ventricular extrasystoles occur (more than 5 per minute), multifocal, group, it is necessary to verify the adequacy of anesthesia and, if necessary, deepen anesthesia and analgesia with the addition of 0.2-0.3 mg of fentanyl. In the presence of hypokalemia, it is necessary to correct it by transfusion of glucose-potassium mixture with insulin or slow administration of potassium and magnesium preparations. Lidocaine is administered at a dose of 1 mg / kg (usually 80 mg) in 20 ml of saline, in the absence of effect, the administration of the drug is repeated in the same dose. At the same time, 200 mg of lidocaine is added to the solution of the glucose-potassium mixture or Ringer's lactate (500 ml) and injected intravenously at a rate of 20-30 μg / kg / min to prevent the "therapeutic vacuum" resulting from the rapid redistribution of drugs.

Lidocaine is the drug of choice in the treatment of VF after cardioversion. With unsuccessful attempts at defibrillation, a good effect is often provided by preliminary iv injection of lidocaine in a dose of 80-100 mg against a background of faster transfusion of the glucose-potassium mixture. Lidocaine is successfully used to prevent the occurrence of ventricular rhythm disturbances during intracardiac operations during cardiac manipulation, diagnostic intracardiac studies, and others.

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

Amiodarone is an effective antiarrhythmic drug for various rhythm disturbances, including supraventricular and ventricular extrasystoles, with refractory supraventricular tachycardia, especially associated with WPW syndrome, and FF, with atrial fibrillation, atrial flutter. The most effective amiodarone in chronic arrhythmias. With atrial fibrillation, it slows the ventricular rhythm and can restore the sinus rhythm. It is used to maintain sinus rhythm after cardioversion with flicker or atrial flutter. The drug should always be used with caution, since even a brief use of it can lead to serious intoxication. In anesthesia practice, this drug is not used in practice, in large part because of the long time required to achieve the effect and prolonged maintenance of side effects. More often it is used in the postoperative period in cardiosurgical patients.

Propaphenone is used to stop ventricular extrasystole, paroxysmal VT, atrial fibrillation, for the prevention of recurrence, atrial-ventricular reciprocal tachycardia, recurrent supraventricular tachycardia (WPW syndrome). In anesthesia practice, this medicine has not found application due to the presence of other, more effective and quick-acting drugs.

Nibentan is used for the prevention and relief of persistent VT and fibrillation, suppression of supraventricular and ventricular rhythm disturbances, treatment of persistent ventricular tachyarrhythmias, and also for the management of acute developing or persistent flutter and atrial fibrillation. Less effective, he was at the relief of atrial extrasystole. The drug is mainly used in the practice of resuscitation and intensive care.

The main indication for the use of ibutilide is acute flutter or atrial fibrillation, in which it provides recovery of sinus rhythm in 80-90% of patients. The main limiting property of the application is the relatively frequent arrhythmogenic effect (5% develops pirouette-type ventricular arrhythmia) and therefore the need to monitor the ECG within 4 hours after drug administration.

Ibutilid is used for the treatment and prevention of supraventricular, nodular and ventricular rhythm disturbances, especially in cases not responding to lidocaine therapy. To this end, the drug is injected / slowly in a dose of 100 mg (about 1.5 mg / kg) at 5-minute intervals until the effect or total dose of 1 g is reached, under constant monitoring of blood pressure and ECG. It is also used to treat atrial flutter and paroxysmal atrial fibrillation. In the case of development of hypotension or expansion of the QRS complex by 50% or more, administration of the drug is stopped. If necessary, for the correction of hypotension resorted to the introduction of vasopressors. To maintain an effective therapeutic concentration in plasma (4-8 μg / ml), LS is administered dropwise at a rate of 20-80 μg / kg / min. However, due to the pronounced negative inotropic effect and often observed reaction of the patients' hypersensitivity to this drug, as well as the availability of more easily administered and less toxic drugs in anesthetic practice, it is used comparatively rarely.

[13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]

Mechanism of action and pharmacological effects

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

During phase 0, a rapid depolarization of the cell membrane occurs, due to the rapid intake 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 delayed repolarization, occurring mainly due to the slow flow of calcium ions from the extracellular space into the cell through the calcium channels.
• Phase 3 is the second period of rapid repolarization, during which the potassium ions leave the cell.
• Phase 4 characterizes the state of complete repolarization, during which the potassium ions re-enter the cell, and the sodium and calcium ions exit it. During this phase, the contents of the cell that is discharged automatically gradually become less negative until the potential (threshold) is reached, which will allow rapid depolarization (phase 0) to pass, and the entire cycle repeats. Cells that do not themselves have automaticity depend on the transition of the action potential from other cells in order for depolarization to begin.

The main characteristic of AAS class I is their ability to block fast sodium channels. At the same time, many of them have a blocking effect on potassium channels, although weaker than anti-arrhythmic drugs of the third class. According to the severity of the sodium and potassium blocking effect of drugs class I class are divided into 3 subclasses: IA, IB and 1C.

Class IA antiarrhythmic drugs, blocking fast sodium channels, slow down the phase 0 of the action potential and moderately slow the rate of impulse conduction. Thanks to blockade of potassium channels, the action potential and refractoriness are lengthened. These electrophysiological effects appear at both the atrial and ventricular tissues, so class IA antiarrhythmics have potential efficacy in atrial and ventricular tachyarrhythmias. Antiarrhythmic drugs are able to suppress the automatism of the sinus node, which is more often manifested in its pathology.

Antiarrhythmic drugs of class IB have a relatively small effect on the fast sodium channels at normal heart rate, and therefore, on the speed of the conduct. Their main effect consists in decreasing the duration of the action potential and, as a consequence, shortening the refractory periods. However, at a high heart rate, as well as against ischemia, hypokalemia or acidosis, some antiarrhythmic drugs, for example lidocaine, can significantly slow the depolarization and the rate of impulse conduction. Atrial antiarrhythmic agents IB influence slightly (except for phenytoin) and therefore are useful only for the treatment of ventricular arrhythmias. Antiarrhythmic drugs suppress the automatism of the sinus node. Thus, lidocaine is able to suppress both normal automatism and anomalous, which can lead to asystole when administered against the background of a ventricular slipping rhythm.

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

Class II drugs are beta-adrenoblockers, the main antiarrhythmic effect of which is to suppress the arrhythmogenic effects of catecholamines.

The general mechanism of the antiarrhythmic effect of class III drugs is to extend the action potential by blocking the potassium channels that mediate repolarization and thereby increasing the refractory periods of the cardiac tissue. All representatives of this class of drugs have additional electrophysiological properties, contributing to their effectiveness and toxicity. LS is characterized by an inverse frequency dependence, i.e. With a slow heart rate, the elongation of the action potential is most pronounced, and with increasing heart rate, the intensity of the effect decreases. This effect, however, is weakly expressed in amiodarone. Unlike other antiarrhythmic drugs of class III, amiodorone is able to moderate block sodium channels, cause non-competitive blockade of beta-adrenoreceptors, and also to some extent cause blockade of calcium channels.

Bretilia tosilate in its pharmacodynamic properties refers to peripheral sympatolytic. Antiarrhythmic drugs have a two-phase effect, stimulates the release of norepinephrine from the presynaptic nerve endings, which explains the development of hypertension and tachycardia immediately after its administration. In the second phase, antiarrhythmic drugs prevent the mediator from reaching the synaptic cleft, causing peripheral adrenergic blockade and chemical sympathectomy of the heart. The third phase of the action is to block the re-absorption of catecholamines. For this reason, it was previously used as an antihypertensive drug, but tolerance is developing rapidly, and at present, drugs are not used to treat hypertension. Brethilia tosylate lowers the threshold of fibrillation (reduces the discharge power needed for defibrillation) and prevents the recurrence of ventricular fibrillation (VF) and ventricular tachycardia (VT) in patients with severe cardiac pathology.

Sotalol has both the properties of a non-cardioselective beta-blocker and antiarrhythmic drugs of class III, since it extends the cardiac potential of action in the atria and ventricles. Sotalol causes a dose-dependent increase in the Q-T interval.

Nibentan causes an increase in the duration of the action potential 2 to 3 times more pronounced than that of sotalol. In this case, 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 of VF development. In this respect, it is 5-10 times higher than that of sotalol. Antiarrhythmic drugs do not affect the automatism of the sinus node, atrial, AV and intraventricular conduction. He has a pronounced antiarrhythmic effect in patients with flutter or atrial fibrillation. Its effectiveness in patients with persistent flutter or atrial fibrillation is 90 and 83%, respectively. Less pronounced effect it has at the relief of atrial extrasystole.

Ibutilid is a new unique class III drug. It extends the action potential mainly by blocking the incoming sodium streams, rather than the outgoing potassium ones. Like sotalol, ibutilide causes a dose-dependent lengthening of the Q-T interval. Ibutilide moderately reduces the frequency of the sinus rhythm and slows the AV conductivity.

Class VI AAS are verapamil and diltiazem. These antiarrhythmic drugs inhibit the slow calcium channels responsible for the depolarization of the two main structures: CA and AB nodes. Verapamil and diltiazem suppress automatism, slow down conduction and increase refractoriness in CA 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 trace depolarization. Class VI antiarrhythmics can suppress the trace depolarization and arrhythmia that they cause. In rare cases, verapamil and diltiazem are used to treat ventricular arrhythmias.

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

Arrhythmogenic effect. Antiarrhythmic drugs, in addition to antiarrhythmic drugs, can cause an arrhythmogenic effect, i.e. Can themselves provoke arrhythmias. This property of AAS is directly related to their basic mechanisms of action, namely, the change in the speed and duration of refractory periods. Thus, a change in the rate of conduction or refractoriness in different parts of the loop of the reentry can eliminate the critical relationships at which initiation and maintenance of reciprocal arrhythmias occurs. More often, aggravation of reciprocal arrhythmias is caused by antiarrhythmic drugs of class 1C, tk. They clearly slow down the speed of the exercise. To a somewhat lesser extent, this property is expressed in class IA drugs, even less in LS of IB and III classes. This type of arrhythmia is more common in patients with heart disease.

Tachyarrhythmias of the "pirouette" type are another kind of arrhythmogenic action of AAS. This kind of arrhythmia is manifested by polymorphic VT caused by prolongation of the Q-T interval or by other repolarization anomalies. The cause of these arrhythmias is the development of early trace depolarization, which may be a consequence of the use of AAS classes IA and III. Toxic doses of digoxin can also cause polymorphic VT, but due to the formation of late trace depolarization. For the manifestation of this type of arrhythmias, the presence of heart disease is not necessary. They develop if any factor, for example antiarrhythmic drugs, lengthens the action potential. Tachycardia such as "pirouette" often occurs in the first 3-4 days of treatment, which requires monitoring of the ECG.

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 in a dose of 1 mg / kg is accompanied only by a short-term (by the 1-3 rd minute) decrease in UOS and MOS, LV work at 15, 19 and 21% of the baseline level. Some decrease in heart rate (5 ± 2) is observed only in the 3 rd minute. Already in the 5th minute the above indicators do not differ from the initial ones.

The pronounced antihypertensive effect is possessed by antiarrhythmic preparations of class IA, especially with iv introduction, and brethilia tosylate, to a lesser degree it is characteristic of drugs of other classes. Adenosine dilates the coronary and peripheral arteries, causing a decrease in blood pressure, but these effects are short-lived.

Dysopyramide has the most pronounced negative inotropic effect, because of which it is not recommended to be prescribed to patients with heart failure. Prokainamide has a significantly weaker effect on myocardial contractility. Propafenone has a moderate effect. Amiodarone causes the expansion of peripheral vessels, probably due to a-adrenoblocking action and calcium channel blockade. With iv administration (5-10 mg / kg), amiodarone causes a decrease in myocardial contractility, which is expressed in a decrease in the LV ejection fraction, the magnitude of the first derivative of the rate of increase in aortic pressure (dP / dUDK), mean pressure in the aorta, CSDL, OPS, and CB .

Pharmacokinetics

Procainamide is easily absorbed in the stomach, its effect is manifested within an hour. With iv injection, the drug starts acting almost immediately. The therapeutic level of drugs in plasma is usually from 4 to 10 μg / ml. Less than 20% of drugs bind to plasma proteins. T1 / 2 it is 3 hours. Metabolization of drugs in the liver is carried out by acetylation. The main metabolite N-acetylprocainamide has antiarrhythmic action (prolongs repolarization), has a toxic effect and is secreted by the kidneys. T1 / 2 N-acetylprocainamide is 6-8 hours. In patients with impaired liver or kidney function or with a decrease in the blood supply of these organs (for example, with heart failure), the isolation of the procuring of the inamid and its metabolite from the body is significantly slowed down, which requires a decrease in the used dose of drugs . Intoxication develops when the concentration of drugs in the plasma is more than 12 μg / ml.

The antiarrhythmic effect of lidocaine largely determines its concentration in the ischemic myocardium, whereas its content in the venous or arterial blood and in healthy parts of the myocardium is not significant. Reducing the concentration of lidocaine in the blood plasma after its iv introduction, as well as with the introduction 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 is transferred to the tissue is called the phase of redistribution, its duration in lidocaine is 30 minutes. At the end of this period, there is a slow decrease in the level of the drug, 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 action of the drug will be optimal if its content in the cells of the myocardium will be close to its concentration in the blood plasma. So, after the administration of a dose of lidocaine, its antiarrhythmic effect is manifested in the early phase of the distribution phase and ceases when its content falls below the minimum effective. Therefore, in order to achieve an effect that would persist even during the equilibration phase, a large initial dose should be administered or repeated administration of small doses of drugs should be initiated. T1 / 2 lidocaine is 100 min. About 70% of drugs are associated with plasma proteins, 70-90% of the administered lidocaine is metabolized in the liver with the formation of monoethyl glycine-xylidide and glycine-xylidide having antiarrhythmic action. About 10% of lidocaine is excreted in the urine unchanged. Metabolism 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 hepatic or renal function (patients with CRF), as well as in patients with heart failure, elderly people, the dose of intravenous drug should be approximately 1/2 of that in healthy individuals. The therapeutic concentration of lidocaine in plasma ranges from 1.5 to 5 μg / ml, the clinical signs of intoxication are manifested when its content in the plasma is above 9 μg / ml.

Propafenone almost completely (85 97%) binds to blood and tissue proteins. The volume of distribution is 3-4 l / kg. Metabolism of drugs is carried out in the liver with the participation of the cytochrome P450 system with the formation of active cleavage products: 5-hydroxypropaphenone, N-depropylpropaphenone. The overwhelming majority of people have a fast type of metabolism (oxidation) of this drug. T1 / 2 for them is 2-10 hours (an average of 5.5 hours). Approximately 7% of patients have oxidation at a slow rate. T1 / 2 in these people is 10-32 hours (an average of 17.2 hours). Therefore, with the introduction of equivalent doses, the concentration of drugs in the plasma in them is higher than that of the rest. 15-35% of metabolites are excreted by the kidneys, most of the drugs are excreted with bile in the form of glucuronides and sulfates.

The peculiarity of pharmacokinetics of amiodarone is a long T1 / 2, ranging from 14 to 107 days. The effective plasma concentration is approximately 1-2 μg / ml, whereas the concentration in the heart is approximately 30 times higher. A large volume of distribution (1.3-70 l / kg) indicates that a small amount of drugs remains in the blood, which necessitates the administration of a loading dose. Due to the high solubility of amido-Daron in fats, its accumulation in fatty and other tissues of the body takes place. Slow achievement of effective therapeutic concentration of drugs in the blood, even with iv introduction (5 mg / kg for 30 minutes) limits its effective use during surgery. Even with large loading doses, it takes 15-30 days to saturate the tissue depots with amiodarone. If side effects occur, they remain long after drug cancellation. Amiodarone is almost completely metabolized in the liver and is excreted from the body with bile and through the intestine.

Brethilia tosylate is administered only IV, since it is poorly absorbed in the intestine. Antiarrhythmic drugs are actively captured by tissues. A few hours after the administration, the concentration of brethil tosylate in the myocardium can be 10 times higher than its serum level. The maximum concentration in the blood is reached 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 brethil tosylate after a single administration ranges from 6 to 24 hours.

T1 / 2 nibentan after IV introduction 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 with the administration of drugs in a dose 0.25 mg / kg is about 2 hours, the clearance is 0.9 l / min, and the volume of distribution is 125 l / kg. Nibentan is metabolized in the liver with the formation of two metabolites, one of which has a significant antiarrhythmic effect, similar to that of nibentane. LS is excreted with bile and through the intestine.

Because of the low absorption of the intake of ibutilide is used exclusively in / in. About 40% of the drugs in the blood plasma bind to plasma proteins. A small volume of distribution (11 l / kg) indicates the primary preservation of it in the vascular bed. T1 / 2 is about 6 hours (from 2 to 12 hours). Plasma clearance of drugs is close to the rate of hepatic blood flow (about 29 ml / min / kg body weight). Metabolisation of drugs is carried out 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-hydroxyl metabolite of ibutilide has antiarrhythmic activity. 82% of metabolic products of drugs are allocated mainly kidneys (7% unchanged) and about 19% with feces.

Adenosine after intravenous administration is captured by erythrocytes and endothelial cells of the vessels, in which it is rapidly metabolized by the action of adenosine-zinedesaminase with the formation of electro-physiologically inactive metabolites of inosine and adenosine monophosphate. Since the metabolism of drugs is not associated with the liver, the presence of liver failure does not affect T1 / 2 adenosine, which is approximately 10 seconds. Adenosine is excreted by the kidneys in the form of inactive compounds.

Contraindications

Common contraindications for almost all antiarrhythmic drugs are the presence of AV blockade of various degrees, bradycardia, weakness of the sinus node, prolongation of the QT interval more than 440 msec, hypokalemia, hypomagnesemia, heart failure and cardiogenic shock.

The use of drugs is contraindicated with increased sensitivity to them. With bronchial asthma and COPD, do not prescribe procainamide, propafenone, amiodarone and adenosine.

Procainamide is contraindicated in patients with impaired liver and kidney function, systemic lupus erythematosus, myasthenia gravis. Lidocaine is not indicated if there is an epileptiform seizure in a patient with an anamnesis. Propaphenone should not be used in patients with myasthenia gravis, marked electrolyte disorders, as well as impaired liver and kidney function.

Brethilia tosylate is contraindicated in patients with fixed CB, pulmonary hypertension, in patients with aortic valve stenosis, acute cerebrovascular accident, severe renal failure.

[24], [25], [26]

Tolerance and side effects

The least amount of adverse reactions is observed with lidocaine. When used in therapeutic doses, antiarrhythmic drugs are usually well tolerated by patients. Lidocaine intoxication (drowsiness and disorientation, followed by development in severe cases of muscle twitching, auditory hallucinations and seizures) practically does not occur in the practice of cardiac anesthesiology and is observed mainly with the use of lidocaine for the purposes of regional anesthesia. Side effects of adenosine are insignificant due to the short duration of its action. Serious side effects are extremely rare.

Most side effects of antiarrhythmic drugs are associated with their basic electrophysiological actions. Due to the prolongation of AV conduction, many antiarrhythmic drugs can cause bradycardia. The likelihood of its development increases with increasing doses. Thus, adenosine may cause a pronounced bradycardia when the dose is increased, which quickly passes after stopping the infusion of the drug or in / in the administration of atropine. Bradycardia rarely occurs with the appointment of nibentane. Lidocaine and brethilium tosylate do not cause bradycardia, since they do not prolong AV conduction.

Many antiarrhythmic drugs are more or less characterized by an arrhythmogenic effect, which can be manifested by the development of dangerous ventricular arrhythmias, for example, ventricular pirouette tachycardia. This arrhythmia often develops with the appointment of funds that extend the interval Q-T: LS classes IA and III. Although amiodarone, as well as other drugs of class III, causes blockade of potassium channels and, accordingly, prolongs the Q-T interval, with its iv introduction rarely develops VT. Therefore, a small elongation of Q-T is not an indication to stop its administration. Lidocaine, like other antiarrhythmic drugs that cause blockade of sodium channels, slows the excitation of the ventricles, and therefore, in patients with AV blockade, depending only on idioventricular rhythm, the use of lidocaine may develop asystole. This situation can be observed with the preventive use of lidocaine after removing the clamp from the aorta in order to achieve recovery of the sinus rhythm after a single defibrillation. Propaphenone 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 oppression of the activity of the sinus node and automatism of the ventricles, which can lead to a transient loss of cardiac cycles.

All antiarrhythmic drugs are more or less able to lower the level of blood pressure. To the greatest extent this effect is expressed in the brethil tosylate, which, by its mechanism of action, is a sympatholytic agent. Brethilia tosylate accumulates in the peripheral adrenergic nerve endings. At the beginning, the sympathomimetic effect predominates due to the release of norepinephrine. Later, brethilia tosylate blocks the release of noradrenaline, which is associated with the adrenergic blockade of the neuron. This can be manifested by the development of pronounced hypotension.

Class I antiarrhythmics 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. In lidocaine, a pronounced negative inotropic effect is observed only at a high concentration of drugs 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. The anticholinergic effect is less pronounced with the administration of procainamide.

Propafenone, amiodarone and adenosine can cause bronchospasm. However, this mechanism is based on different mechanisms. The bronchospastic effect of propafenone and amiodarone is due to their ability to block beta-adrenergic receptors of the bronchi. Adenosine can provoke (quite rarely) the development of bronchospasm mainly in persons 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 spasm of the bronchi via stimulation of the H1 receptors.

Among the other side effects of adenosine is the ability to reduce pulmonary vascular resistance, increase intrapulmonary bypass and reduce arterial oxygen saturation (SaO2) by suppressing pulmonary hypoxic vasoconstriction like NG and NNT, albeit to a much lesser extent. Adenosine can cause narrowing of the kidney vessels, 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, possessing the properties of local anesthetics, can cause side effects from the side of the central nervous system (convulsions, fainting, stopping breathing) only with the introduction of toxic doses.

Classification of antiarrhythmic agents

• class I - blockers of fast sodium channels:
  • 1a (quinidine, procainamide, disopyramide, primalium butartrate);
  • 1c (lidocaine, bumecaine, mexiletine, phenytoin);
  • 1c (propafenone, ethacyzine, lappaconitin, moricisin);
• class II - beta-adrenoreceptor blockers (propranolol, esmolol, etc.);
• class III - potassium channel blockers (amiodarone, brethil tosylate, sotalol, ibutilide, nibentane);
• class IV - calcium channel blockers (verapamil, diltiazem).

As anti-arrhythmic agents, other drugs are used in practice, which can not be classified in any of Vaughan Williams's classification groups by their electrophysiological properties. These include cardiac glycosides, magnesium and potassium salts, adenosine and some others.

[27], [28], [29], [30], [31], [32], [33], [34], [35], [36]

Interaction

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

Procainamide potentiates the effect of antiarrhythmic, anticholinergic and cytostatic agents, as well as muscle relaxants. LS reduces the activity of antimiasthenic drugs. Interactions procainamide with warfarin and digoxin was not observed.

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

Cimetidine inhibits the P450 system and can slow the metabolism of propafenone. Propaphenone causes an increase in the concentration of digoxin and warfarin and enhances their effect, which should be borne in mind in patients receiving long-term glycosides. Propaphenone reduces the excretion of metoprolol and propranolol, so their dose should be reduced when using propafenone. Co-administration with local anesthetics increases the likelihood of CNS damage.

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

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

Dipyridamole enhances the action of adenosine, blocking its capture by cells and slowing the metabolism. The action of adenosine is also enhanced by carbamazepine. On the contrary, methylxanthines (caffeine, euphyllin) are antagonists and weaken its effect.

Caveats

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

To correct possible hypotension at hand, the anesthetist should always have vasopressors. At the end of the infusion of ibutilide, ECG monitoring should be performed for at least 4 hours until the normal Q-T interval is restored. In the case of the development of the arrhythmogenic effect of AAS, a patient with IV injections of potassium and magnesium preparations; carry out cardioversion or defibrillation, with slowing of the rhythm appoint atropine and beta-adrenostimulyatory.

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 (a danger of pronounced hypotension), as well as to patients with severe heart failure with a decrease in myocardial contractility. Before using propafenone, the patient must determine the state of electrolyte balance (especially the level of potassium in the blood). In the case of an expansion of the complex by more than 50%, the introduction of drugs should be discontinued.

Antiarrhythmic drugs of Class I with caution are used in patients with liver and kidney damage, which often develop side effects and toxic effects.

[37], [38], [39], [40], [41]