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 .