Pharmacological properties of the drug Etatsizin
Etatsizin is a class I antiarrhythmic drug. It has a pronounced and long-lasting antiarrhythmic effect. Inhibits the rate of rise of the front of the action potential, does not change the resting potential. It affects predominantly sodium channels (both on the outer and inner surface of the cell membrane), reduces the amplitude and slows down the processes of inactivation and reactivation of the fast sodium flow. Blocks the entry of calcium ions through slow membrane channels. Extends the duration of the refractory period of the atria and AV node. Slows down the rate of rise of the action potential in atrial and ventricular fibers, Purkinje fibers and additional pathways of excitation through the AV node and the Kent bundle. It inhibits sinoatrial conduction, especially in sick sinus syndrome, and expands the QRS on the ECG (by about 25%), as it slows down conduction through the ventricular myocardium (in the His-Purkinje system). It has a negative inotropic effect, has local anesthetic and antispasmodic activity. Etatsizin does not change heart rate with short-term use and reduces with long-term use. When etacizine is taken orally, it is quickly absorbed in the digestive tract and is detected in the blood within 30–60 minutes. The maximum concentration of etacizin in blood plasma is achieved after 2.5–3 hours; The half-life of etacizine averages 2.5 hours. All of the listed pharmacokinetic parameters are subject to significant individual fluctuations. Ethacizine is extensively metabolized during its initial passage through the liver. Some of the resulting metabolites have antiarrhythmic activity.
Use of the drug Etatsizin
Orally, regardless of food intake, starting with 50 mg 3 times a day. If the effect is insufficient, the dose is increased (under ECG monitoring) to 50 mg 4 times a day (200 mg) or 100 mg 3 times a day (300 mg). The maximum daily dose is 300 mg with mandatory ECG monitoring. When the antiarrhythmic effect is achieved, maintenance therapy is carried out in individually selected doses. The antiarrhythmic effect when taken orally usually develops on the 1st–2nd day; the duration of the course of treatment depends on the form of arrhythmia, the effectiveness and tolerability of the drug.
Special instructions for the use of the drug Etatsizin
Prescribed with extreme caution for sick sinus syndrome, first degree AV block, incomplete bundle branch block, Purkinje fiber conduction disorder, myocardial infarction complicated by cardiac arrhythmias. Just like other antiarrhythmic drugs, etacizin can act arrhythmogenic. Therefore, when prescribing etacizin, contraindications to the use of the drug should be strictly taken into account; identify and eliminate hypokalemia in advance; avoid the use of etacizine in combination with class Ia antiarrhythmic drugs; It is preferable to start course treatment in a hospital (especially in the first 3–5 days of taking the drug and taking into account the dynamics of the ECG after trial and repeated doses of etacizine or ECG monitoring data); immediately stop course treatment if ectopic ventricular complexes become more frequent, blockades or bradycardia appear. Treatment with etacizine should also be stopped immediately if the ventricular complexes expand by more than 25%, their amplitude decreases, or the duration of the P exceeds 0.12 s. During the period of use of the drug, you should not drive vehicles or service potentially dangerous mechanisms.
Etatsizin tablets p/o 50 mg No. 10x5
Name
Etatsizin tablet p/o 50 mg in a contact cell. Pack No. 10x5
Main active ingredient
Diethylaminopropionylethoxycarbonylaminophenothiazine
Release form
Film-coated tablets
Compound
Active ingredient: etacizin (Aethacizinum). Each film-coated tablet contains 50 mg of etacizine. Excipients: Tablet core: potato starch, sugar, methylcellulose, calcium stearate. Tablet shell: sugar, povidone, calcium carbonate, magnesium carbonate basic, silicon dioxide, carnauba wax, dyes: quinoline yellow (E 104), solar yellow (E 110), titanium dioxide (E 171).
Description
Round, biconvex, yellow film-coated tablets.
Dosage
50mg
Pharmacological properties
Pharmacodynamics
Ethacizine is a class 1C antiarrhythmic drug (AAP). It has an intense and long-lasting antiarrhythmic effect. It primarily inhibits the fast incoming sodium current and affects sodium channels on both the outer and inner surfaces of the cell membrane. To a lesser extent, the slow incoming calcium current inhibits. Ethacizine has a negative inotropic effect due to the blockade of slow calcium current. Ethacizine inhibits the rate of rise of the front of the action potential (Umax) and does not change the resting potential. Slows down the conduction of excitation through the myocardial conduction system. On the ECG, under the influence of etacizine, one can observe a widening of the P wave and the QRS complex, as well as a lengthening of the P-Q and PR intervals. Ethacizine does not change heart rate or affect blood pressure. An arrhythmogenic effect rarely develops when using therapeutic doses. Etatsizin increases the threshold of myocardial fibrillation, and also stops cardiac arrhythmias that turn into fibrillation in conditions of acute myocardial ischemia. 1 Etatsizin has anticholinergic and moderate anti-ischemic effects.
Pharmacokinetics
When taken orally, etacizin is rapidly absorbed from the gastrointestinal tract.' appears in the blood within 30-60 minutes. Eating does not affect the absorption of the drug. The maximum concentration of etacizine in blood plasma is achieved after 2.5-3 hours. Bioavailability of the drug is 40%. 90% of etacizine is bound to plasma proteins. Ethacizin penetrates the placental barrier. Excreted in breast milk. Ethacizine is extensively metabolized during its first passage through the liver. Some of the resulting metabolites have antiarrhythmic activity. The half-life is 2.5 hours. It is excreted from the body in the urine in the form of metabolites.
Indications for use
Supraventricular and ventricular extrasystole, ventricular and supraventricular tachycardia, atrial fibrillation and flutter.
Contraindications
Hypersensitivity to etacizin and/or excipients. Severe dysfunction of the liver and/or kidneys. Children under 18 years of age (efficacy and safety have not been established). - Lactation. — Severe conduction and rhythm disturbances of the heart (including sinoatrial block of the second degree, atrioventricular (AV) block of the second and third degree, intraventricular conduction disturbances, intraventricular disturbances of the heart rhythm (complete block of the bundle branches). — Structural damage to the heart (in including acute coronary syndrome, acute myocardial infarction and for 3 months after acute myocardial infarction, severe left ventricular myocardial hypertrophy, severe dilatation of the heart cavities).—Severe heart failure stage III-IV according to the NYHA classification, decreased left ventricular ejection fraction (echocardiography data), cardiogenic shock, severe arterial hypotension). - Concomitant use of class 1A antiarrhythmic drugs (AAP) with etacizine (quinidine, procainamide, disopyramide, ajmaline). - Simultaneous use of MAO inhibitors.
Use during pregnancy and lactation
Ethacizin penetrates the placental barrier. animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonic and fetal development. There are no clinical trial data on the use of etacizine during pregnancy, as a result of which, when prescribing, the potential benefit to the mother and the possible risk to the fetus should be taken into account, so during pregnancy the drug should be used strictly as prescribed by the doctor. Ethacizine is excreted in breast milk, so use during breastfeeding is contraindicated
Impact on the ability to drive vehicles and maintain machinery.
Due to the risk of dizziness and visual impairment, it is not recommended to drive. vehicles or service complex mechanisms
Directions for use and doses
Etatsizin is prescribed orally regardless of food intake, starting with 50 mg 2-3 times a day. If the clinical effect is insufficient, the dose can be increased to 50 mg 4 times a day. If the antiarrhythmic effect is insufficient, the combined use of etacizin and beta-blockers is possible. Elderly patients should be careful, it is necessary to reduce the initial dose and carefully increase the dose. Use is contraindicated in children and adolescents (under 18 years of age), as there is insufficient data on the safety and effectiveness of the drug. Patients with impaired liver function should be careful during long-term treatment, as hepatotoxic effects are possible (in case of severe impairment of liver function, use is contraindicated). Patients with impaired renal function should be careful (in case of severe impaired renal function, use is contraindicated). Violations of the organ of vision: often - disturbance of accommodation
Side effect
Ethacizine, like other medicines, can cause side effects that may not affect all patients. Frequency of side effects according to the MedDRA classification system (Medical Dictionary of Regulatory Terminology): Very often (? 1/10); Often (?1/100 to
Overdose
Symptoms: increased inhibitory effect on the myocardial conduction system, increased risk of arrhythmogenic effects. Treatment: gastric lavage, symptomatic therapy. Careful monitoring of the patient is necessary, and it is also necessary to monitor blood pressure and ECG (monitoring for at least 6 hours until changes in the ECG disappear). Patients with electromechanical dissociation resulting from the side effects of etacizin (or its relative overdose) must undergo vigorous and prolonged resuscitation measures (external cardiac massage, administration of adrenomimetic drugs, calcium salts, dopamine, rheopolyglucin), treatment of ventricular tachycardia caused by etacizin - electrical pulse therapy (EIT) mu intravenous administration of lidocaine or trimecaine, against the background of which the effectiveness of EIT may increase. The use of class 1A AAPs (procainamide, rhythmylene, ajmaline, etmosin, etc.) is contraindicated for stopping ventricular tachycardia caused by etacizin.
Interaction with other drugs
Use is contraindicated in combination with class 1 A AAP. Etatsizin should not be prescribed concomitantly with MAO inhibitors. The combination of beta-blockers with etacizine enhances the antiarrhythmic effect, especially in relation to arrhythmias provoked by exercise or stress. This combination allows the use of small doses of etacizine, which reduces the incidence of side effects. This combination is indicated for the treatment and prevention of paroxysmal tachycardias, including ventricular ones. With the simultaneous use of etatsizin and digoxin, the antiarrhythmic effect of the drugs is enhanced and contractility is improved, increasing the concentration of digoxin in the blood. In these cases, a reduction in the dose of digoxin is required. During treatment with etacizine, you should not drink alcohol.
Precautionary measures
In case of myocardial infarction, the drug is prescribed subject to careful monitoring of the patient's clinical condition. Treatment with etacizine should be started no earlier than 3 months after the development of myocardial infarction. With extreme caution, etatsizin should be prescribed for sick sinus syndrome, bradycardia, first degree atrioventricular (AV) block, severe peripheral circulatory disorders, heart failure (compensated), angle-closure glaucoma, benign prostatic hypertrophy, cardiomegaly (increases the risk of arrhythmogenic effects) , electrolyte imbalance (hypokalemia, hyperkalemia, hypomagnesemia), as well as patients with a pacemaker (risk of arrhythmia), liver and kidney failure. For patients with sinus node syndrome, especially if the drug is prescribed for the first time, monitoring is required; ECG (QRS complex) 2-3 days after prescription. Therefore, when prescribing etacizine, you should:
- strictly take into account contraindications to the use of the drug;
- identify and eliminate hypokalemia in advance;
- avoid the use of etacizine in combination with class 1 A AAP;
- It is preferable to start a course of treatment in a hospital. After a single dose, as well as after taking repeated doses on the 3rd and 5th days, ECG control or ECG monitoring should be performed;
- Stop treatment immediately if ectopic ventricular complexes become more frequent, blockades or bradycardia occur. Treatment with etacizine should also be stopped immediately if the ventricular complexes expand by more than 25%, their amplitude decreases, the duration of the P wave on the ECG increases by more than 0.12 seconds, or the QT interval>500 ms. Caution should be exercised when the QT interval is >400 ms.
The arrhythmogenic effect is not directly related to the dose of the drug. To reduce the likelihood of arrhythmogenic effects, it is recommended to use etacizin simultaneously with small doses of beta blockers. In addition, caution should be exercised in patients with liver disease, since etacizine may be toxic to hepatocytes. During therapy, it is necessary to carefully monitor the patient's condition and the functions of the cardiovascular system (ECG, blood pressure, echocardiography). The drug should not be used in patients with rare congenital fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency. The tablet shell contains solar yellow dye, which can cause allergic reactions.
Storage conditions
In a place protected from moisture and light at a temperature not exceeding 25°C.
Drug interactions Etatsizin
The simultaneous use of class Ic antiarrhythmic drugs - moracizine, encainide, flecainide, propafenone - is contraindicated. The combination of β-adrenergic receptor blockers with class I antiarrhythmic drugs (ethacizine) enhances the antiarrhythmic effect, especially in relation to arrhythmia provoked by exercise or stress. This combination allows the antiarrhythmic drug to be used in low doses, which reduces the incidence of its side effects. This combination is indicated for the treatment and prevention of paroxysmal tachycardias, including ventricular tachycardias. Ethacizine can be combined with amiodarone (class III). In such cases, the doses of both drugs should be reduced. To prevent ventricular fibrillation or ventricular paroxysmal tachycardia, a combination of mexiletine + etacizine + propranolol can be used. With the combined use of etacizin and digoxin, the antiarrhythmic effect of the drugs is enhanced and myocardial contractility is improved. When used together, nausea and anorexia are possible, which is associated with an increase in the concentration of digoxin in the blood serum. In this case, it is necessary to reduce the dose of digoxin. The use of glutamic acid in combination with etacizin neutralizes the cardiodepressive effect of etacizin in patients with initial signs of circulatory disorders. Ethacizine should not be prescribed concomitantly with MAO inhibitors. During treatment with etacizine, you should refrain from drinking alcohol.
The use of class I antiarrhythmic drugs in clinical practice has gone from widespread use in the 80s and early 90s of the 20th century to a sharp narrowing of indications and the disappearance of a number of drugs from the pharmacy network in the next two decades following the publication of the results of the CAST and CAST studies. II [25, 39].
However, the lack of new antiarrhythmic drugs, the unavailability of a number of class III drugs in the Russian Federation, the insufficient antiarrhythmic activity of the β-blockers and d,l-sotalol available to the cardiologist, the extracardiac side effects of amiodarone, the presence of resistant forms of arrhythmias - all this contributed to the fact that in Over the past 5-7 years, after an almost twenty-year break, the attention of researchers has again been attracted to class IC antiarrhythmic drugs, including those synthesized in the USSR.
Most studies [4, 8, 9, 16] have attempted to expand the indications for the use of these drugs by using them in patients with “moderate organic changes in the heart.” This concept itself is interpreted by authors differently, but among other nosologies, as a rule, it includes stable forms of coronary heart disease (CHD). Moreover, modern studies focus on the safety of antiarrhythmic therapy, since the frequency of proarrhythmic effects is the main factor currently limiting the use of any antiarrhythmic drug. This problem seems to be very closely related to the problem of life-threatening ventricular tachyarrhythmias and sudden cardiac death (SCD) in general.
In recent years, a number of new non-invasive electrophysiological (electrocardiographic) indicators have been added to the predictors of the risk of death from ventricular arrhythmias. Among them, the most interesting are heart rate turbulence (HRT) and microvoltage T wave alternans (mAZT). Despite a fairly large number of scientific studies demonstrating the feasibility of using these predictors in SCD risk stratification, many aspects of their practical application remain poorly understood. These aspects include the effect of antiarrhythmic drugs on TRS and mAZT. While the dynamics of these indicators with the use of β-blockers and amiodarone were examined in a number of studies [12, 24, 26-28, 30, 31, 33, 37, 42], the effect of class I antiarrhythmics on new predictors of SCD has not been studied.
The purpose of this study was to study the effect of the IC class antiarrhythmic drug etacizine (diethylaminopropionylethoxycarbonylaminophenothiazine) on non-invasive electrophysiological predictors of SCD - TRS, heart rate variability (HRV) and mAZT.
Material and methods
The study included 33 patients (9 men and 24 women) over the age of 18 years (mean age 49.2±17.9 years) without structural heart pathology.
The indication for the use of etatsizin was poor tolerance of rhythm disturbances: frequent ventricular extrasystoles (VC) - in 20, the average number of extrasystoles per day was 11,647 (6586; 19,569); paroxysms of atrial fibrillation (AF) - in 10, frequent supraventricular extrasystoles (SVC) - in 3 patients who had from 8,000 to 15,000 extrasystoles per day.
Exclusion criteria from the study were coronary artery disease, heart defects, cardiomyopathies, chronic heart failure of functional class II-IV, left ventricular hypertrophy ≥14 mm, the presence of an implanted pacemaker, Wolff-Parkinson-White syndrome (due to the impossibility of adequate assessment of mAZT for this pathology) , conduction disorders, sick sinus syndrome, concomitant cancer, thyrotoxicosis, severe anemia (hemoglobin <90 g/l).
All patients initially underwent a standard clinical examination, recording of an electrocardiogram (ECG) in 12 leads (QRS 88±5 ms, PQ 162±31 ms), echocardiography (left ventricular ejection fraction 60.2±5.8%, interventricular septal thickness 0. 96±0.13 cm, thickness of the posterior wall of the left ventricle 1.0±0.12 cm, end-diastolic size of the left ventricle 4.8±0.6 cm, end-diastolic volume of the left ventricle 84.9±25.1 ml).
In case of complaints of pain in the heart area, as well as in men over 50 years of age and in women over 60 years of age, regardless of the presence of cardialgia, stress tests were performed to exclude stress-induced myocardial ischemia: in 11 patients, treadmill test or bicycle ergometry, in 5 - myocardial scintigraphy. In one case, direct coronary angiography was performed, in another 6 cases, multislice computed tomography-coronary angiography was performed. In 7 patients with frequent PVCs, magnetic resonance imaging of the heart was performed to exclude arrhythmogenic dysplasia.
In 12 (36%) patients, hypertension was diagnosed, in 8 (24%) myocarditis was assumed to be the cause of arrhythmias, in the remaining 13 (40%) rhythm disturbances were regarded as idiopathic. Drug therapy, if indicated, included antihypertensive drugs (in 5 patients - angiotensin-converting enzyme inhibitors, in 5 - thiazide or thiazide-like diuretics, in 3 - angiotensin II receptor blockers, in 2 - dihydropyridine calcium antagonists), as well as anticoagulants according to current recommendations (in 5 patients with AF).
All patients were prescribed etacizine at an initial dose of 75 mg/day. The dose was increased after 1-2 days to 100 mg, then after the same time interval to 150 mg/day. In 9 (27%) patients, a good effect was observed when taking 100 mg/day, so there was no further increase in the dose.
Holter monitoring (HM) ECG was performed at baseline and on the 2nd day of achieving the target dose (100 or 150 mg/day) of etacizine. Cardioday Getemed software (General Electric, USA) was used to analyze the 24-hour ECG recording. The minimum, maximum and average heart rate (HR) day and night, the type and number of rhythm and conduction disturbances, and the dynamics of the ST segment were determined.
To assess HRV, SDNN (standard deviation of all NN intervals) and pNN50 (percentage of pairs of consecutive NN intervals differing by more than 50 ms) were determined using the time analysis method built into the program. TRS was calculated using an automatic software method based on determining differences in the duration of RR intervals after PVCs. The indicators were determined: turbulence onset (TO; onset of turbulence - the magnitude of the increase in sinus rhythm after a PVC) and turbulence slope (TS; turbulence slope - the intensity of the deceleration of the sinus rhythm after its increase in the post-extrasystolic period). TO ≥0, TS ≤2.5 ms/RR were taken as pathological values. In the absence of PVCs suitable for analysis during the recording, TRS was considered normal [21, 22]. mAZT was calculated using the modified moving average method [34] in 2 Holter leads. We used an updating factor (FA) of 1/8 and 1/32, reflecting the number of QRS complexes for which averaging was performed. According to the method previously described by us [13], the following mAZT values were assessed: the maximum value during the day (mAZTmax), the value at a heart rate of 100 beats/min (mAZT100) and at 05:00 hours (mAZT5:00). A total of 12 mAZT parameters were determined for each patient.
The effectiveness of etacizin in patients with extrasystole was assessed based on the results of chemometry. The effect was considered good when the daily number of extrasystoles was reduced by 75% or more, and doubtful when the daily number of extrasystoles was reduced by 50-74%. If the number of extrasystoles per day decreased by less than 50%, the drug was considered ineffective and was replaced with another antiarrhythmic drug. In patients with AF attacks, in addition to the immediate result (absence of AF episodes, reduction in the number of NVEs and PVCs during control CM), the clinical effect was taken into account for a period at least twice as long as the initial rate of recurrence of paroxysms, and ranging from 2 months to 1 year. The effect was regarded as good in the absence of relapse of AF during this period, as partial - with a significant decrease in the frequency and duration of paroxysms.
Statistical analysis.
The obtained data were processed using SPSS software version 17.0.
For a normal distribution, data are presented as the mean ± standard deviation; otherwise, the median (25th percentile; 75th percentile) or percentage of the total number of patients is indicated. The significance of differences in the case of normal distribution was assessed using a two-sided t-test, in other cases - using non-parametric methods (Mann-Whitney, Wilcoxon, &khgr;2 tests). Correlation relationships were studied using regression analysis and Spearman's rank correlation coefficient. The probability of p
<0.05 was considered sufficient to conclude that the differences between the variation series were significant;
if p
>0.05 but less than 0.1, the difference between the values was regarded as having a tendency to differ.
results
A good antiarrhythmic effect of therapy was observed in 13 (65%) patients with PVCs, a questionable effect in 3 (15%), and the drug was ineffective in 4 (20%). In this subgroup, the average number of PVCs decreased from 11,647 (6586; 19,569) to 742 (6; 4738) per day ( p
<0.05), and paired PVCs (initially detected in 9 (27%) patients) - from 5 (1; 20) to 0 (0; 1) per day (
p
<0.02). In 3 patients with initially registered unstable ventricular tachycardia (in 1 patient - in the form of continuously recurrent attacks with a heart rate of 100-120 beats/min), a complete elimination of this type of arrhythmia was noted during control CM.
The drug turned out to be effective in 2 cases of frequent VE: during the control CM, extrasystole was practically not recorded. In another patient, the decrease in the number of NVEs per day was 69% (the effect is questionable).
In AF, the drug was less effective - the effect was assessed as good in 5 out of 10 patients, partial in 2, and ethacizin was ineffective in another 3.
Among patients to whom etacizine was prescribed as the first antiarrhythmic ( n
=13), the drug was effective in 12 (92%). A good effect of etacizine was also observed in 9 patients who had previously unsuccessfully taken other antiarrhythmic drugs: lappaconitine hydrobromide (6 patients), d,l-sotalol (5 patients), amiodarone (4 patients), propafenone (2 patients). Among 11 patients in whom etacizin was ineffective or only a partial treatment result was observed, there was a history of initial or subsequent insensitivity to lappaconitine hydrobromide and propafenone (6 patients each), d,l-sotalol and amiodarone (4 each), quinidine (1).
All assessed heart rate indicators did not change significantly while taking etacizine, with the exception of the maximum heart rate in the daytime, which decreased statistically significantly (Table 1)
.
When taking etacizine, a significant decrease in the average values of SDNN and pNN50 was noted (Table 2)
, which indicates a relative increase in sympathetic activity and a decrease in vagal influences.
A decrease in SDNN was detected in 25 (74%) patients, pNN50 in 23 (70%), and for SDNN the magnitude of the decrease by an average of 27 (13-47) ms correlated with the initial value of the indicator (rs = 0.589; p
= 0.002).
It was possible to evaluate TRS initially in 31 patients, and while taking etacizin, PVCs suitable for TRS analysis were recorded in only 26 patients. Initially, TRS disorders were detected in 28% of patients, and all of them had type 1 disorders, when either TO or TS are in the zone of pathological values. There was no significant change in the frequency of TRS disorders while taking the drug: the number of patients with a type 1 disorder did not change, but one patient had a TRS disorder of the second type (pathological values of both TO and TS). The average values of TRS indicators also changed unreliably (see Table 2)
.
In the general group, while taking etacizin, mAZT did not change significantly. Only for mAZT measured in the early morning hours (first and second leads at FA 1/8), as well as for mAZT100 (first lead, FA 1/8) a downward trend was detected (Table 3)
.
However, it was mAZT5:00, measured in the first monitor lead at FA 1/8, that initially demonstrated a direct correlation with the number of PVCs per day (rs = 0.428; p
= 0.016)
(Fig. 1)
.
Figure 1. Relationship between the daily number of PVCs and mAZT at 5:00 in patients without structural heart pathology.
An analysis conducted in a subgroup of patients with PVCs showed that while taking etacizin, mAZT5:00, measured at PA 1/8, significantly decreased in the first (from 18 [10; 45] μV to 10 [7; 16] μV; p
=0.004) and second (from 12 [8; 23] to 9 [5; 16];
p
=0.049) monitor leads
(Fig. 2)
.
Figure 2. Dynamics of mAZT5:00 (FA 1/8) in patients with frequent PVCs during therapy with etacizin.
Discussion
In this study, we for the first time undertook an assessment of the effect of the drug etacizin, long used in practical cardiology, on new non-invasive predictors of the risk of SCD. In our opinion, studying this issue may be of interest from several points of view.
1. Clarification of methodological aspects of the use of new predictors of SCD. When applying any medical indicator in practice, we must clearly understand the factors that influence its formation. Regarding the issue under consideration, this provision can be formulated as follows: “can we obtain true values of TRS, mAZT while taking antiarrhythmics, or is drug withdrawal required for an adequate assessment?”
Data on the effect of antiarrhythmics on TRS and mAZT in the literature are scarce and contradictory. β-Blockers, according to the results of some studies, do not affect TPC [12, 32] and mAZT [12, 42]; according to other reports, they reduce mAZT [24, 30], TS, but do not affect TO values [33, 37]. Amiodarone, according to W. Grimm et al., in patients with dilated cardiomyopathy [26, 27] and according to the results of our study [12] in patients with post-infarction cardiosclerosis, did not demonstrate a significant effect on TRS. Regarding changes in mAZT while taking amiodarone, the data are contradictory: both a decrease [28] and an increase [12, 30] of this indicator was noted.
There is virtually no information in the literature on the dynamics of TRS and mAZT when using class IC antiarrhythmics. We can only note the experimental work of H. Tachibana et al. [38], who, during intracoronary administration of antiarrhythmic drugs to anesthetized dogs, revealed the appearance of ST segment alternans, which was more pronounced during the administration of large doses of flecainide compared to disopyramide and lidocaine. Moreover, following the appearance of alternans, flecainide provoked spontaneous ventricular fibrillation [38]. In our study, etacizine, used in moderate therapeutic doses in patients with ventricular arrhythmias in the absence of structural heart pathology, caused a significant decrease in mAZT assessed in the early morning hours. The definition of this indicator was previously proposed by us [13], firstly, in order to standardize the conditions for measuring mAZT (same measurement time and physiological state), and secondly, based on data on an increase in the frequency of SCD in the morning [34]. From this point of view, the identified positive correlation of mAZT with the number of PVCs per day seems very symbolic. Previously, we found a correlation between mAZT and the severity of arrhythmic syndrome (with mAZTmax) in patients with coronary artery disease [11] and hypertrophic cardiomyopathy [18]. Discussing the question of the mechanisms of action of etacizin on the level of mAZT, it should be noted that currently the main hypothesis of the origin of mAZT is the assumption of the relationship between changes in the morphology of the T wave with fluctuations in the level of calcium in cardiomyocytes (primarily with its exchange between the cytosol and the sarcoplasmic reticulum), leading to changes in the duration of the action potential (AP) of the long-short-long type and (according to the so-called phenomenon of AP restitution) the appearance of repolarization dispersion [1, 40]. To trigger ventricular tachyarrhythmias by the re-entry mechanism, the appearance of so-called discordant alternation is also necessary: the appearance of long and short APs in adjacent areas of the myocardium, which leads to fragmentation of the depolarization wave front, the appearance of spatial dispersion of repolarization and conditions for the formation of a unidirectional conduction block. Thus, although the exact mechanisms of this phenomenon continue to be debated, it is currently accepted that mAZT is a reflection of electrical instability of the myocardium.
As is known, etacizine blocks sodium channels and partially blocks the slow incoming calcium current, and also slows down the conduction velocity in various parts of the myocardium [3, 15]. The ability of sodium channel blockers to reduce mAZT and improve patient survival has been demonstrated for ranolazine. However, in this case we are talking about blockade of the late sodium current [35, 36]. N. Kavesh et al. [29] indicate a decrease in the frequency of a positive test for mAZT during intravenous infusion of procainamide. At the same time, class IA antiarrhythmics are characterized by a more pronounced effect on the duration of AP compared to that of class IC [7]. Thus, the role of blockade of fast sodium channels by etacizine in reducing mAZT is unclear. It seems more logical to explain the identified patterns by blockade of calcium channels. A number of experiments performed 20-25 years ago showed that calcium antagonists can reduce the level of T wave macroalternation, but so far clinical confirmation of these experimental data has been obtained only for patients with Prinzmetal’s angina [40]. The third hypothesis that can be proposed in this situation: a decrease in mAZT occurs due to a uniform decrease in the conduction velocity in the ventricular fibers, slowing down the restitution of AP and preventing the development of discordant alternation. However, if this assumption is correct, then the most important condition for such an effect is the homogeneity of the myocardium itself. Otherwise (for example, in conditions of ischemia, reperfusion, with severe myocardial hypertrophy, the presence of post-infarction scars), this effect may have the opposite meaning and lead to increased spatial heterogeneity with a proarrhythmogenic effect.
TRS, like HRV, belongs to the group of SCD predictors that characterize the state of the autonomic nervous system. The effect of class I antiarrhythmics on TRS has not been previously studied, but a number of scientific studies have assessed the dynamics of HRV indicators while taking etacizine [5, 6, 10, 14]. More often, the authors [6, 10] note a relative decrease in parasympathetic activity, which coincides with our data on a significant decrease in SDNN and pNN50 and is explained by the anticholinergic properties of the drug [15]. Moreover, according to E.G. Pavlova [14], similar dynamics of time parameters of HRV were noted with the combination of etacizine with β-blockers. Two conclusions arise regarding the indications for the use of etacizin: 1) it is most appropriate to use it in persons with initial vagotonia (the maximum effectiveness of the antiarrhythmic precisely with such a vegetative balance is noted in most studies [5, 16, 19]), which is more often characteristic of persons without organic heart diseases (for example, isolated AF) [6]; 2) on the contrary, for patients with sympathicotonia, which is characteristic of a number of organic heart diseases (especially in the presence of chronic heart failure), an additional decrease in “parasympathetic protection” can have adverse consequences. Taking into account the data of E.G. Pavlova [14], even the combination of etacizine with β-blockers in such a situation does not completely avoid this undesirable effect.
We did not detect any significant dynamics of TRS when using etacizine. Currently, the baroreflex is of great importance in the genesis of the TRS phenomenon. The origin of TO is explained by an increase in heart rate in response to a decrease in blood pressure caused by PVCs, and TS is explained by post-extrasystolic potentiation, accompanied by an increase in blood pressure and a decrease in heart rate [22, 41]. Thus, the regulatory mechanisms of TPC and HRV coincide only partially. It is no coincidence that the correlations between the indicators of these two phenomena in most studies (including our own) were very weak [11, 18, 23]. Nevertheless, the question of the effect of etacizine on TPC needs further clarification. It is possible that in our study, a limited number of patients did not allow us to identify significant dynamics in indicators: it was possible to evaluate TRS while taking the drug only in 79% of patients due to the high effectiveness of the antiarrhythmic and the almost complete elimination of PVCs necessary to determine TRS.
2. It can be assumed that the improvement of certain indicators used in SCD risk stratification is a reflection of a decrease in the degree of risk: for example, with normalization of TRS - due to an increase in vagal influences, and with a decrease in mAZT - due to a decrease in the electrical instability of the myocardium [40] . Oddly enough, this seemingly obvious position currently does not have solid scientific confirmation. There have been no studies demonstrating that antiarrhythmic drug treatment improves TRS and mAZT levels along with a significant reduction in the incidence of SCD. Previously, we noted a seemingly paradoxical increase in mAZT in patients with coronary artery disease while taking amiodarone [12], as well as the drug ?3-polyunsaturated fatty acids Omacor [2] - drugs that have proven effective in the prevention of SCD in patients who have had myocardial infarction [20]. Moreover, in both cases the antiarrhythmic effect was completely clear. When using etacizin, the situation turned out to be more “logical”: an initial correlation between the number of PVCs and mAZT was revealed; while taking the drug, mAZT decreased significantly, which was combined with a good antiarrhythmic effect. Of course, the identified differences in the effects of drugs require further clarification, but we would like to emphasize first of all the different populations of patients who participated in these studies. In this study, we principally included only patients without structural heart pathology. Oddly enough, the effectiveness of etacizin in this essentially target category of patients has been poorly studied. In the “pre-caste era,” no importance was attached to the division of patients with arrhythmias according to the etiology of the disease [3], and in recent years, most studies have been aimed at expanding the indications for the use of the drug, and patients with coronary artery disease were included in them for fundamental reasons [6, 9, 14 , 16, 17]. An exception may be the work of E.V. Shlyakhto et al. [19], which analyzes the effectiveness of etacizine in the treatment of ventricular arrhythmias in patients without structural heart pathology. A good result was obtained in 77% of cases. Comparable effectiveness of the drug was found in most studies for rhythm disturbances of various etiologies. As a rule, there is a better effect of etacizin in ventricular (54-88%, on average about 80%) than in supraventricular arrhythmias (with AF 60-68%, with VVC 63-67%). Our data are generally comparable with the results of most studies. The somewhat lower effectiveness of etacizin in our work can be explained by lower doses of the drug, not exceeding 150 mg/day, more stringent evaluation criteria compared to some of the studies performed earlier (summing up good and incomplete results, we obtained comparable effectiveness), as well as the characteristics of the population patients - the drug did not have the desired effect mainly in patients refractory to most antiarrhythmic drugs.
3. Taking into account the information obtained about a significant decrease in mAZT when prescribing etacizine, one can try to trace the relationship of the initial level and/or degree of decrease in mAZT with the degree of effectiveness of the antiarrhythmic and use such data to predict the effect of the drug. Of course, the present work is limited in this regard due to the small number of patients included in the study. Its continuation will allow us to test the stated hypothesis.
The second important aspect of this problem is an attempt to predict proarrhythmia based on the dynamics of non-invasive predictors of SCD. Similar thoughts were previously expressed by T. Klingenheben [30], who, describing the appearance of previously non-existent mAZT while taking amiodarone, pointed out the possible value of this indicator in predicting the proarrhythmic effect of the drug. From this point of view, in individuals without structural heart pathology, etacizin generally demonstrated favorable trends - no effect on TRS, improvement in mAZT. It is difficult to consider a significant decrease in HRV in this category of patients as something unacceptable. On the contrary, such a result may have a positive meaning in patients with initial vagotonia [19]. In any case, not a single case of ventricular proarrhythmia was noted in our patients.
conclusions
In patients without structural heart pathology, etacizin effectively eliminates PVCs (in 65% of cases) and NVCs (67%), and prevents relapses of AF paroxysms in 50% of patients. The exclusion of organic heart diseases contributes to the safe use of the drug. The values of mAZT measured in the early morning hours (mAZT5:00) in individuals without structural heart pathology correlate with the number of PVCs per day. In patients with frequent PVCs, etacizine significantly reduces mAZT5:00. The meaning of these changes, as well as their mechanisms, need clarification. There was no significant effect of the drug on TRS. The decrease in temporary HRV indicators while taking etacizine is explained by the anticholinergic effect and confirms the advisability of using the drug in patients with initial vagotonia.
