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Pharmacology of antiarrhythmic drugs Dalmo Antonio Ribeiro Moreira MD, PhD

Electrophysiology and Electrocardiography Section Dante Pazzanese Institute of Cardiology, São Paulo Itajubá Medical School, Minas Gerais, Brazil

Introduction Despite the advances of non-pharmacological therapy of cardiac arrhythmias in the last two decades, it is important to note that the initial treatment of rhythm disturbances is still the prerogative of the clinician and for this reason, antiarrhythmic drugs have a role. These agents are used to stop an arrhythmia when administered in the presence of arrhythmia; for preventing recurrence of arrhythmia, for relief of haemodynamic disturbance of an arrhythmia and, finally, to prevent catastrophic effects of a potentially malignant arrhythmias, while other techniques more effective and safe treatment can not be employed, such as the use of automatic cardioverter defibrillator in ventricular arrhythmias with sudden death risk. From the standpoint of electrophysiology, a cardiac arrhythmia can originate by the interaction of three variables (Figure 1): a) the presence of an arrhythmogenic substrate, b) the presence of triggers (represented by extra systoles), c) modulating factors (autonomic sympathetic or parasympathetic neural influence, pH, ischemia, neurohumoral factors, etc.).Only after critical and harmonious interaction of these three factors is that a cardiac arrhythmia can be generated. In practice, antiarrhythmic drugs can act on the substrate, causing changes in tissue refractoriness or so at the speed of propagation of electrical impulse, the most important components of the primary arrhythmogenic mechanism known as re-entry. These effects are based on the actions of different drugs on the electrical properties of cell membranes, particularly ion channels, as will be discussed later.

Figure 1 - Variables involved in the onset of a cardiac arrhythmia. It requires the presence of an arrhythmogenic substrate, triggers and modulating factors that influence both the substrate and the triggers. The drugs generally act in one or more of these variables to normalize heart rhythm.

The drugs may act on the triggers, specifically having an effect on the cellular automatism, depressing the its automatic activity is even blocking its automatic activity, preventing the formation of ectopic action potentials that can act on a reentrant circuit and generate an arrhythmia. Moreover, these agents can block oscillations of phase 3 or 4 of the action potential, responsible for the generation of early or late after-potentials, respectively, collectively known by triggered activity. Finally, the drugs may act on the modulating factors, reducing the effects of autonomic activity in the generation of arrhythmias, improving myocardial blood flow, reducing the effects of hormones or other factors that can destabilize the arrhythmogenic substrate and provide the triggers that generate arrhythmias . Some drugs work in only one or two of these variables that is, on the substrate, triggers or modulating factors. Others considered wide spectrum antiarrhythmic agent work on them

all. Because many variables are involved in the arrhythmia genesis, more than one different type of agent is frequently prescribe to patients in order to obtain the best result in the pharmacological treatment of cardiac arrhythmias.

Classification of antiarrhythmic drugs Although old, the classification of antiarrhythmic drugs recommended by Vaughan-Williams is still the most used nowadays for its simplicity, easy to remember and also consider the specific action of drugs on membrane ion channels, i.e, sodium channels , calcium and potassium channels (Table 1) 1. It is noteworthy that the drugs do not belong to one class only, and may have effects on other classes, such as amiodarone may have multiple actions on various ion channels (potassium, sodium and calcium). Although other drug classifications have been published, these were very complex because they considered the action of the drug on arrhythmogenic mechanisms, ion channels, electrical currents, membrane receptors and other aspects, which would require the clinician a very extensive knowledge of cardiac electrophysiology, making the classification impractical. The classic example of this was the Sicilian gambit2. Depending on their characteristics of action, antiarrhythmic drugs are classified into four classes1. The first is subdivided into three subclasses based on its effects on sodium channels and consequently on the maximum velocity (Vmax) of phase zero of action potential, on cellular refractoriness and its repolarization1: Class IA, reduce Vmax and prolong cellular repolarization and refractoriness: quinidine, procainamide and disopyramide. In practice, these agents act primarily on the arrhythmogenic substrate and little effect on the triggers. Class IB, lower intensity of the sodium channel blockade, causing minor reduction of Vmax and shortening of the cellular repolarization and refractoriness: lidocaine, mexiletine, diphenylhydantoin. These agents act mainly on triggers and little on the arrhythmogenic substrate.

Table 1 - Classification of antiarrhythmic drugs according to Vaughan-second Williams1 Drug Class Action I Sodium Channel Blockers IA - moderate depression of phase 0 Moderate reduction in conduction velocity Prolongation of repolarization Quinidine Procainamide Disopyramide IB - Minimum depression of phase 0 Shortening of repolarization Lidocaine Mexiletine Diphenilhidantoin IC - major depression of phase 0 Significant reduction in conduction velocity Little effect on repolarization Propafenone Flecainide II Beta-blockers Propranolol Atenolol III Prolongation of repolarization Amiodarone Sotalol IV calcium channel blockers Verapamil

The Class IC drugs cause intense block of fast sodium channels, reducing extensively the Vmax of phase zero, but cause less prolongation of cellular repolarization and refractoriness: propafenone and flecainide. The class IC agents act on the arrhythmogenic substrate, triggers, and little on the modulating factors. Group II, beta-blockers. have great effect on the modulating factors and little on the triggers. Group III, causing blockage of potassium channels (and also partial blockade of calcium and sodium channels), amiodarone and sotalol. Particularly amiodarone, has effects on the three components that generate arrhythmias due to its action on multiple ion channels, has anti-adrenergic effects and acts against the other destabilizing factors of the substrate (anti-ischemic and antirenin effects). For this reason this agent is considered the most potent antiarrhythmic drug today. Group IV, calcium channel blockers: verapamil and diltiazem showing more significant actions on the factors that destabilize the substrate and little effect on the triggers.

Class I Drugs Antiarrhythmic agents, according to the classification above, should modify the characteristics of the cellular action potential when acting on ion channels (Figure 2). Thus, the class I drugs, have the property of blocking with variable intensity, the fast sodium channels and, therefore, slow the rise of phase zero of action potential in a more or less intense manner, depending on the type of agent3. Thus, we expect a delay in the propagation speed of electrical impulses within the arrhythmogenic circuit. The class IC drugs (propafenone, flecainide) cause more intense blockade of fast sodium channels, followed by the class IA agents and finally the class IB agents

Figure 2 - Action of antiarrhythmic drugs on the characteristics of cellular action potential (see discussion in the text). The full line corresponds the action potential without drug effect. The class IA agents slow phase zero of action potential and prolong repolarization. The class IB drugs decrease action potential duration without affecting conduction velocity. Class III drugs prolong repolarization by blocking potassium channels. Class IV drugs slow the rise of phase zero of action potential of cells in the sinus node and the atrioventricular node.

Class II Drugs Beta blockers are not considered potent antiarrhythmic agents but play a key role in the treatment of arrhythmias, particularly when associated with true antiarrhythmic drugs such as amiodarone. Beta-blockers act on specific membrane receptors, altering the pattern of cellular response to catecholamines and ion channels sensitive to catecholamines3. Reduce cellular excitability and arrhythmogenic effects caused by catecholamines, particularly for patients with high adrenergic tone, as in heart failure and coronary insufficiency. Studies have shown a significant reduction of sudden death rate caused by ventricular arrhythmias, when a beta-blocker is included in the pharmacologic therapy.

Class III Drugs The class III drugs, especially amiodarone (and other similar drugs like ibutilide, dofetilide and azimilide) exert its main effect on blocking the potassium channels. It may also exert a modest antagonistic effects on sodium channels (and consequently on the phase zero of action potential), and cause discrete block of calcium channels3. The potassium channel blockade is responsible for the prolongation of the action potential and the cell refractory period, and may interrupt arrhythmias in arrhythmogenic circuit by blocking the spread of electrical impulse. Due to its systemic action, and also over other factors that may cooperate to cause arrhythmias, amiodarone is considered a wide spectrum antiarrhythmic drug. Amiodarone has extra-cardiac side effects that may limit its administration in about 20 to 30% of patients . Interstitial pneumonitis and thyroid disorders are the most important. Mentioning is also the peripheral neuritis, liver failure and changes in skin color. To prevent these complications patients should undergo periodic clinical evaluations, including chest X-rays, investigation of thyroid and liver functions4. Sotalol is a beta-blocker but has class III antiarrhythmic properties by increasing the duration of the action potential. Should be administered to patients without ventricular dysfunction, both for the treatment of atrial and ventricular arrhythmias. Along with quinidine, has important proarrhythmic effects (2-3%). Class IV Drugs These agents act by blocking the calcium channels and thus may interfere with the firing frequency of the sinus node and also on the conduction velocity of the atrioventricular node3. Are effective in supraventricular tachyarrhythmias using the atrioventricular node as part of the arrhythmogenic circuit. In atrial fibrillation can be an important tool in reducing the recurrence of arrhythmia when coupled with other antiarrhythmic drugs such as propafenone or amiodarone, because of its effect in reducing the electrical remodeling effects on the atrial tissue5.

Pro-arrhythmic effects of antiarrhythmic drugs One of the factors limiting the prescription of antiarrhythmic drugs is the risk of potentially letal pro-arrhythmic effects6 (figure 3). These are caused by triggering polymorphic ventricular tachycardia called torsades de pointes, which can cause sudden death. Unfortunately, most patients who require antiarrhythmic therapy, like those with ventricular dysfunction and frequent ventricular arrhythmias, are the most vulnerable to these serious complications. The patients at greatest risk are those with complex ventricular arrhythmias, patients with hypokalemia and / or hypomagnesemia (caused by diuretics), heart failure, myocardial ischemia, and female. It should be borne in mind that the antiarrhythmic treatment should always be done very safely to avoid a potentially benign arrhythmia to be transformed into something severe enough that may lead to sudden death. Example in this condition are patients with atrial fibrillation with ventricular dysfunction who are at risk of sudden death when treated with quinidine. Therefore the correct identification of high risk patients can make antiarrhythmic treatment safer and more effective. New antiarrhythmic drugs are currently under clinical evaluation whose mechanism of action is more specific on potassium channels present only in atrial tissue. These agents will be used in the treatment of atrial tachyarrhythmias such as atrial fibrillation7. Vernakalant is now available for intravenous use with this purpose8. The great advantage of these new drugs is the lower risk of pro-arrhythmogenic effects on the ventricles (the risk of torsades de pointes) and of extra-cardiac side effects, the main factors limiting the use of drugs currently available.

Figure 3 - Torsades de pointes polymorphic ventricular tachycardia in a 72 year old female who was taking quinidine for preventing recurrences of atrial fibrillation. See above, ventricular bigeminy and also QT prolongation; below the polymorphic ventricular tachycardia that is manifested as a twist along its axis.

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