Pharmacologic Management of Arrhythmias

Understanding the mechanisms by which individual antiarrhythmic agents work requires a detailed understanding of the cardiac action potential (AP). The AP of the ventricular myocyte has 5 phases (0 to 4) and is the standard model of the cardiac AP. At baseline (phase 4, also known as the resting membrane potential), the intracellular environment is negatively charged, compared with that of the extracellular space (−96 mV). This phase is associated with cardiac diastole. The AP is the result of synchronized influx and efflux of multiple cations and anions. Briefly, this gradient is the sum of 3 main factors: 1) an ATPase sodium/potassium (Na/K) pump; 2) the plasma membrane's impermeability to negatively charged intracellular proteins, which prevents their efflux; and 3) chemical properties (best described by the Nernst equation) that are a consequence of various ion channel permeabilities. For simplicity's sake and the purposes of this discussion, we will mention only those ion channel activities that are relevant to the drugs discussed in this review.

During phase 0 (rapid depolarization), fast sodium (Na+) channels open, which results in rapid inward conductance of Na+ and a rapid influx of Na+ ions into the cell, rendering the intracellular space positive relative to the extracellular milieu. Recovery of the resting membrane starts during phase 1 but is most pronounced during phase 3, when positive currents, primarily in the form of K ions, leave the cell through the delayed rectifier K+ channels (rapid repolarization). The most important reminder about antiarrhythmic treatments can be summarized as follows: Activation of the myocardial cells is due to the rapid inward sodium current, while relaxation or repolarization is mainly due to potassium efflux from the cell.

Figures 1 and 2 demonstrate the correlation between these currents and the surface measurements of these activations as shown by the P, QRS, and T waves. The sodium-dependent (inward current) depolarization of ventricular cells can best be thought of as the QRS complex on the surface electrocardiogram. For this reason, any drug that affects this inward sodium current can also affect the QRS. If it delays the influx of Na+, the QRS is widened; conversely, any agent that delays potassium efflux (and a return to the baseline state) delays the recovery phase or repolarization. For ventricular cells, this delay manifests itself electrocardiographically as a longer QT interval.

Fig. 1 The phases of the cardiac action potential.

K = potassium; Na = sodium

Fig. 2 The electrocardiogram and relative ion flow in cardiac cells.

Ca = calcium; K = potassium; Na = sodium

According to the Singh and Vaughan Williams classification of antiarrhythmic agents,¹ there are 5 main classes: class I agents, which are Na+-channel blockers; class II agents, which are antisympathetic nervous system agents, most of which are β-blockers; class III agents, which affect the K+ channels; class IV agents, which affect the calcium (Ca²) current and the atrioventricular (AV) node; and class V agents, which work by other (or unknown) mechanisms of action. Our emphasis will be on the class I and III agents and on some of the class V agents.

Use Dependence and Reverse-Use Dependence

Use dependence and reverse-use dependence are most often associated with Na+ channel-blocking drugs.^2,3 These drugs block open inactivated sodium channels, and they show little affinity for the channels in their resting state. With each AP, they block the channels and, during each diastolic interval, they dissociate from their ligands. When the heart rate increases, the diastolic interval shortens and the dissociation time decreases. Therefore, steady-state Na+ channel blockade increases.²

It makes sense, then, that the electrophysiologic effects and, therefore, the antiarrhythmic activity of any drug with these characteristics would increase as heart rate increases, because they bind more avidly to the active form of the ion channels. In this manner, the higher the proportion of time spent in the open or inactive phase (the period immediately after closing but before resting, during which the channel is refractory), the stronger the effect of these drugs. When the heart beats faster, the ventricular cells spend more time in their open, inactive phase, as the time available for dissociation during diastole decreases.

Reverse-use dependence can be thought of as the opposite, wherein the drug more avidly binds to the ion channel during the resting phase. Most potassium channel-blocking drugs are reverse-use dependent. In general, drugs that prolong repolarization have a decreased effect on depolarizing tissue, because they tend to bind during the resting phases of the ion channel.³ This increases the likelihood that the drug will bind to the channel at times of slower heart rates, during which the ion channel is more often in the resting phase. Reverse-use dependent drugs tend to be effective in the prevention of arrhythmia, presumably because the heart rate is slower.

Sodium Channel Blockade: Flecainide, Propafenone, and Disopyramide

At the onset, it is crucial to note that most antiarrhythmic drugs are extremely promiscuous, binding to multiple channels. For this reason, predicting their effects on the AP or by means of electrocardiography can be confusing without an understanding of each drug's various actions. Furthermore, because sodium channel blockade leads to slowing of myocardial conduction, it can be proarrhythmic in patients who have any type of structural heart disease—in this population, these agents should be used only with great caution.

Flecainide

Flecainide is a class I antiarrhythmic agent with a very potent Na+ channel blockade effect that also blocks the Ca²+ current and the delayed rectifier K+ current. It shortens the AP duration in Purkinje cells, consequent to the blockage of late-opening Na+ channels (blocking this current lessens the influx of positive current during the entire AP, thus truncating its duration); but flecainide prolongs the AP duration in the ventricular cells because of the blockage of the delayed rectifier K+ current. In atrial tissue, flecainide prolongs the AP at fast rates, because of its use-dependent potassium channel blockade.² Elimination of flecainide occurs by both renal excretion and hepatic metabolism. Renal excretion of the unchanged form of the drug is usually adequate in patients who have hepatic dysfunction.

Adverse Effects. In general, there are few subjective complaints. The most common noncardiac adverse effect of flecainide is dose-related blurred vision. In those patients with depressed left ventricular performance, it can exacerbate symptoms of congestive heart failure.² As with all class I antiarrhythmic agents, flecainide increases the capture thresholds of pacemakers—that is, the amount of current required to electrically capture cardiac tissue. Therefore, capture thresholds should be remeasured in individuals with pacemakers after the steady-state flecainide dosage is changed.⁴

There can be central nervous-system-related adverse effects, including hallucination, confusion,⁵ and paresthesia. Toxicity should be suspected when there is a 50% increase in the QRS duration or a 30% increase in prolongation of the PR interval.⁶ In cases of toxicity, sodium bicarbonate use has been shown to be helpful.⁷

Results of the Cardiac Arrhythmia Suppression Trial (CAST)⁸ showed a mortality rate increase in patients using sodium channel blockers when those patients had either structural heart disease (such as a history of myocardial infarction or left ventricular dysfunction) or ventricular arrhythmias. These drugs are therefore contraindicated in such patients.

Rapid Hints

• Typical dose: 50–200 mg, twice a day²

• Half life: 12–18 hr⁹

• It is effective in treating atrial fibrillation (AF), tachycardia, and arrhythmias of the accessory-pathway-dependent type. It is also effective in treating triggered premature ventricular contractions in structurally normal hearts.^9,10 There is minimal risk of proarrhythmia in structurally normal hearts.

• It can be used as 1st-line therapy for paroxysmal supraventricular tachycardia (SVT) in newborns who do not have structural heart disease.¹¹

• QRS prolongation can occur. Some degree of QRS prolongation is to be expected as a consequence of drug initiation. A QRS prolongation of as much as 15% to 20% may be reflective of the pharmacologic effect and does not necessarily augur the need to cut back dosage. However, a greater prolongation would require downward adjustment of the dose.

• A single oral loading dose of 300 mg can be used for pharmacologic cardioversion of AF.¹²

• Because of use dependence, proarrhythmia can occur with exertion (increased effect with increased heart rates).

• Exercise testing is recommended before dismissing patients who are initiated on flecainide.

• The absorption of flecainide can be altered by food digestion, especially when the drug is taken with milk, which blocks its absorption.⁹

Propafenone

Propafenone is a Na+ channel blocker that also blocks K+ channels. It was originally manufactured as a β-blocker, and it maintains significant levels of such activity. It slows conduction in fast-response tissues. Together, these properties lead to prolongation of the PR and QRS durations. Propafenone is used in the treatment of SVT, including AF. It may also be used for ventricular arrhythmias, with modest efficacy.² Propafenone is well absorbed and is eliminated by both the renal and hepatic routes.⁹

Adverse Effects. Adverse effects can include acceleration of the ventricular response in patients with atrial flutter, an increased risk of ventricular tachycardia (VT), exacerbation of heart failure, and the adverse effects of β-adrenergic blockade, such as bradycardia and bronchospasm.² Other adverse effects include hypersensitivity reactions, agranulocytosis, and central nervous system disturbances, such as lightheadedness, blurred vision, and paresthesia.^13–15 Gastrointestinal side effects are frequent but usually transient. On occasion, some patients have noticed a metallic taste when ingesting dairy products.¹⁶

Rapid Hints

• Dosage: 150, 225, or 300 mg, 2 or 3 times a day²

• New sustained-release formulation of 225, 325, or 425 mg, twice a day

• Half life: 2–32 hr²

• A single dose of 600 mg has been used for pharmacologic conversion of AF.¹⁷

• QRS prolongation can occur (as with flecainide), so watch the defibrillation thresholds and look for increased pacing.

• Absorbed best when taken with food.

• β-Blockade may lead to exacerbation of asthma.¹⁸

Disopyramide

The electrophysiologic effects of disopyramide include Na+ channel blockade with minimal prolongation of the AP. It does not have adrenergic antagonistic activity but shows prominent anticholinergic actions, which are responsible for many of its adverse effects.² It is eliminated through both the renal and hepatic pathways. The kidneys excrete an unchanged form of the drug, while the liver excretes a weakly active metabolite.²

Adverse Effects. Adverse effects include precipitation of glaucoma, constipation, dry mouth, urinary retention (especially in men with prostatism), agranulocytosis, rash, and blurred vision.^2,19 It can precipitate heart failure because of its depressive effect on contractility caused by negative inotropic activity.²

Rapid Hints

• Maintenance dosage: 100–200 mg, every 6 hr; or 200–400 mg, every 12 hr²

• Disopyramide is an excellent drug for treatment of vagally induced AF. Vagal excess is a common trigger for lone AF. Vagal tone prolongs refractory periods in ventricular muscle, but the opposite occurs in atrial tissue. In the atrium, adrenergic and vagal stimulation decrease the refractory period and promote the formation of reentrant wavelets, increasing the predisposition to AF. The clinical presentation for this type of AF would be AF during sleep or after digestive precipitants such as cold drinks or spicy foods. Disopyramide has an anticholinergic characteristic in addition to its antiarrhythmic properties (class IA).

• Disopyramide is associated with increased insulin secretion and enhances the hypoglycemic effect of insulin and metformin.^20,21

Potassium Channel Blockade: Amiodarone, Dofetilide, Sotalol, and Dronedarone

Amiodarone

Amiodarone is the most effective drug presently available for sinus-rhythm maintenance in patients with AF.²² It blocks the inactivated Na+ channels, and it decreases the Ca²+ current and outward and the inward rectifier K+ current. It also has a noncompetitive adrenergic blocking effect. During chronic therapy, amiodarone prolongs the PR, QRS, and QT intervals and causes sinus bradycardia.² It prolongs refractoriness in all cardiac tissues. It blocks potassium channels and prolongs myocardial repolarization. It also blocks cardiac sodium channels and decreases conduction velocity. Furthermore, by virtue of its β-adrenergic blockade, amiodarone can cause sinus bradycardia and reduce calcium channel activity (class I, II, and IV characteristics).⁹ However, amiodarone is poorly absorbed, and its oral bioavailability is almost 30%. It is slowly eliminated by the liver and cannot be eliminated by the kidneys.

Adverse Effects. Because of its iodine moiety that binds various tissues, amiodarone has a long list of side effects, including pulmonary fibrosis, corneal microdeposits (asymptomatic), optic neuritis (rare), hepatic dysfunction, peripheral neuropathy, proximal muscle weakness, tremor and ataxia, skin deposits, photosensitivity, and hypo- or hyperthyroidism.^2,9

Rapid Hints

• Dosage: 100–400 mg/day²

• Half life: 60 days (range, 15–142 days)²³

• Most toxicity occurs at doses of 400 mg/day or higher

• Hypotension (with the intravenous form, vasodilation and depression of myocardial performance may be due to the solvent). The intravenous formulation has a higher β-blockade activity.

• Nausea can occur during the loading phase and might necessitate a decrease in the daily dose.

• Despite marked QT prolongation, torsades de pointes is unusual,² because of the blocking of inward currents.⁹

• Dosage adjustment is not needed in patients with hepatic, renal, or cardiac dysfunction.

• Amiodarone inhibits the hepatic metabolism or elimination of many drugs. Therefore, if patients are also taking warfarin, other antiarrhythmic agents such as flecainide and procainide, or digoxin, they will need to have their dosages of these drugs adjusted during concurrent administration of amiodarone.

• Amiodarone is not dialyzable. The intravenous formulation, with its strong β-blocker activity, is approved by the U.S. Food and Drug Administration (FDA) for the treatment of VF and unstable VT.⁹

• Screening tests, such as chest radiographs and tests for pulmonary function, thyroid-stimulating hormone, and liver function, are recommended. Other than the pulmonary function tests, these studies should be repeated at 3, 6, and 12 months, and annually thereafter. Despite these recommendations, there are no other established guidelines.

Dofetilide

Dofetilide is a potent, pure K+ blocker with no extracardiac pharmacologic effect. It is safe in patients with structural heart diseases.^2,9 Its potassium blockade is reverse-use dependent and the risk of torsades de pointes is therefore greatest during bradycardia. It is excreted unchanged by the kidneys and undergoes minor hepatic metabolism. Dosage adjustments should be made in patients with mild-to-moderate impairments in renal function. Certain drugs inhibit its elimination and are contraindicated in patients who are taking dofetilide. These include cimetidine, verapamil, ketoconazole, trimetoprim-sulfamethoxazole, prochloroperazine, and hydrochlorthiazide.⁹

Adverse Effects. Its only significant toxicity relates to QT prolongation and torsades de pointes.⁹ There is a risk of torsades de pointes in 1% to 3% of patients taking dofetilide. It has relative selectivity for the atrium.

Rapid Hint

• By FDA mandate, dofetilide must be initiated in the hospital, and the starting dose of 0.5 mg twice daily is the highest acceptable dose. It is contraindicated in patients with advanced renal failure (creatinine clearance rate, <20 mL/min).

Sotalol

Sotalol is a nonselective β-blocker that inhibits the delayed rectifier and other K+ currents and prolongs the cardiac AP (class III antiarrhythmic agent and class II effect).² It does not affect other ion channels at most clinical dosage ranges.⁹ It prolongs the QT interval (with a dose-dependent effect). It decreases automaticity, slows AV nodal conduction, and prolongs AV refractoriness. It displays reverse-use dependence, increases the AP duration at slower heart rates, and is less effective at faster heart rates.⁹ It has 100% bioavailability and is eliminated by renal excretion of the unchanged drug.^2,9

Adverse Effects. Adverse effects of sotalol include QT prolongation and the risk of torsades de pointes. There are also the effects of β-adrenergic receptor blockade.²

Rapid Hints

• Typical oral dosage: 80–160 mg, twice daily⁹

• Half life: 6–12 hr^2,9

• It should be avoided in patients with a creatinine clearance rate <40 mL/min.⁹

• Doses <120 mg twice daily have a higher proportion of β-blocking effect, with little class III action.⁹

Dronedarone

Dronedarone is a modified analogue of amiodarone and has the pharmacologic ability to block multiple ion channels, including the L-type calcium current, the inward sodium current, and multiple potassium currents. It also has sympatholytic effects. Dronedarone prolongs the time to recurrence of AF and slows the ventricular rate in AF by an average of 11 to 13 beats/min.^24,25

Dronedarone is generally less efficacious than amiodarone,²⁶ and its half life of 1 to 2 days is shorter than that of amiodarone. It has no risk of thyroid or pulmonary toxicity.⁹

Patients with lone AF have a high risk of cardiovascular hospitalization within 1 year, but when dronedarone is added to the regimen, the risk of cardiovascular hospitalizations is reduced in this population.²⁷ However, this compound is less effective than its mother compound amiodarone in maintaining sinus rhythm.²⁷

Adverse Effects. The FDA released a warning about a number of reports of hepatic toxicity related to dronedarone administration. The agency notified healthcare providers and patients about rare but severe cases of liver damage, including 2 cases of acute liver failure that led to liver transplantation. As a result, the FDA has added a new warning and adverse-effect section to dronedarone labeling.

Rapid Hint

• Dronaderone should not be used in patients with unstable or decompensated heart failure, because it has been shown to increase adverse events and outcomes in this population. It also causes a nontoxic but bothersome gastrointestinal effect, which can be minimized by taking the drug with meals. This also acts to increase its bioavailability.