Overview of New Developments
Antiarrhythmic drugs have not changed substantially over the last several decades. Even when newer agents have been developed, the potential for proarrhythmia and increased mortality continue to plague their broader implementation. Recently, novel ion channel targets have been proposed and newer agents are being researched, but even some experimental agents have halted trials in phase II because of unexpected toxicity. Furthermore, as interventional therapies have progressed, such as implantable defibrillators and ablation, the urgency for new pharmacologic antiarrhythmic therapy has decreased. Most guidelines still advocate for antiarrhythmics remaining first-line therapy for both atrial fibrillation (AF) and ventricular tachycardia (VT). Furthermore, historical antiarrhythmics have now found new purpose for the treatment of various inherited arrhythmia disorders. Therefore, it is still important to understand this eclectic group of pharmacotherapies.
Antiarrhythmic Drugs
Antiarrhythmic drugs are used to suppress arrhythmias with the hopes of alleviating significant symptoms or possibly to affect survival. Prophylactic treatment of arrhythmias has been questioned since the publication of the Cardiac Arrhythmia Suppression Trial and by a meta-analysis of nearly 100,000 patients with acute myocardial infarction (AMI) treated with antiarrhythmic drugs. These studies showed that suppression of ventricular ectopy can actually increase mortality. Therefore, antiarrhythmic drugs should only be used when the suppression of arrhythmia outweighs the adverse effects of the drug. There are very few instances where antiarrhythmic drugs may actually reduce mortality and/or sudden death. β-blockers following myocardial infarction (MI) or in the setting of heart failure reduce mortality. The only antiarrhythmic agent that appears to prevent sudden cardiac death (SCD) is amiodarone, and possibly dofetilide. Amiodarone acts on multiple ionic channels and is therefore effective against a wide spectrum of arrhythmias. However, even amiodarone is inferior to implantable cardioverter defibrillators (ICDs) for sudden-death prevention in the patients at highest risk.
Classification
There are five established classes of antiarrhythmic action ( Table 9.1 ). The original Vaughan Williams classification with four classes now incorporates ionic mechanisms and receptors as the basis of the more complex Sicilian Gambit system for antiarrhythmic drug classification ( Fig. 9.1 ). Recently, a modernized, expanded classification scheme was developed for which the traditional Vaughan Williams classification remains the basis, but the scheme also identifies new potential targets for emerging (or yet to emerge) drugs. A quick reference table is provided summarizing some of the more common antiarrhythmic medications ( Table 9.2 ).
| Class | Channel effects | Repolarization time | Drug examples |
|---|---|---|---|
| IA | Sodium block effect ++ | Prolongs | Quinidine Disopyramide Procainamide Ajmaline |
| IB | Sodium block effect + | Shortens | Lidocaine Phenytoin Mexiletine |
| IC | Sodium block effect +++ | Unchanged | Flecainide Propafenone |
| ID | Sodium block effect + | Prolongs | Ranolazine |
| II | β-Adrenergic block I f , a pacemaker current; indirect Ca ++ channel block; | Unchanged | β-blockers (excluding sotalol that also has class III effects) |
| III | Repolarizing K + currents | Markedly prolongs | Amiodarone Sotalol Ibutilide Dofetilide Vernakalant |
| IV | AV nodal Ca 2 + block | Unchanged | Verapamil Diltiazem |
| V | K + channel opener (hyperpolarization) | Unchanged | Adenosine |
| Unclassified | Ivabradine |
| Agent | Dose | Pharmacokinetics and metabolism | Side effects and contraindications | Interactions and precautions |
|---|---|---|---|---|
| Lidocaine (class IB) | IV 75–200 mg; then 2–4 mg/min for 24–30 h. (No oral use) | Effect of single bolus lasts only few min, then T 1/2 approximately 2 h. Rapid hepatic metabolism. Level 1.4–5 μg/mL; toxic > 9 mcg/mL. | Reduce dose by half if liver blood flow low (shock, β-blockade, cirrhosis, cimetidine, severe heart failure). High-dose CNS effects. | β-blockers decrease hepatic blood flow and increase blood levels. Cimetidine (decreased hepatic metabolism of lidocaine). |
| Mexiletine (class IB) | a IV 100–250 mg at 12.5 mg/min, then 2 mg/kg/h for 3.5 h, then 0.5 mg/kg/h. Oral 100–400 mg 8-hourly; loading dose 400 mg. | T 1/2 10–17 h. Level 1–2 μg/mL. Hepatic metabolism, inactive metabolites. | CNS, GI side effects. Bradycardia, hypotension especially during cotherapy. | Enzyme inducers; disopyramide and β-blockade; increases the theophylline levels. |
| Phenytoin (class IB) | IV 10–15 mg/kg over 1 h. Oral 1 g; 500 mg for 2 days; then 400–600 mg daily. | T 1/2 24 h. Level 10–18 μg/mL. Hepatic metabolism. Hepatic or renal disease requires reduced doses. | Hypotension, vertigo, dysarthria, lethargy, gingivitis, macrocytic anemia, lupus, pulmonary infiltrates. | Hepatic enzyme inducers b . |
| Flecainide (class IC) | a IV 1–2 mg/kg over 10 min, then 0.15–0.25 mg/kg/h. Oral 50–400 mg 2 times daily. Hospitalize. | T 1/2 13–19 h. Hepatic 2/3; 1/3 renal excretion unchanged. Keep trough level below 1 μg/mL. | QRS prolongation. Proarrhythmia. Depressed LV function. CNS side effects. Increased incidence of death postinfarct. | Many, especially added inhibition of conduction and nodal tissue. |
| Propafenone (class IC) | IV 2 mg/kg then 2 mg/min. Oral 150–300 mg 3 times daily. | T 1/2 variable 2–10 h, up to 32 h in nonmetabolizers. Level 0.2–3 μg/mL. Variable hepatic metabolism (P-450 deficiency slows). | QRS prolongation. Modest negative inotropic effect. GI side effects. Proarrhythmia. | Digoxin level increased. Hepatic inducers. |
| Ibutilide (class III) | IV infusion: 1 mg over 10 min, (under 60 kg: 0.1 mg/kg). If needed, repeat after 10 min. | Initial distribution T 1/2 is 1.5 minutes. Elimination T 1/2 averages 6 h (range 2–12 h). Efficacy is usually within 40 min. | Nausea, headache, hypotension, bundle branch block, AV nodal block, bradycardia, torsades de pointes, sustained monomorphic VT, tachycardia, ventricular extrasystoles. Avoid concurrent therapy with class I or III agents. Care with amiodarone or sotalol. C/I: previous torsades de pointes, decompensated heart failure. | Interactions with Class IA and other class III antiarrhythmic drugs that prolong the QT interval (e.g. antipsychotics, antidepressants, macrolide antibiotics, and some antihistamines). Check QT (see Fig. 9.4 ). Correct hypokalemia and hypomagnesemia. |
| Dofetilide (class III) | Dose 250 μg twice daily, maximum 500 μg twice daily if normal renal and cardiac function. If LV dysfunction, 250 μg twice daily. Check QT 2–3 h after dose, if QTc is 15% or > 500 ms, reduce dose. If QTc > 500 ms, stop. | Oral peak plasma concentration in 2.5 hours and a steady state within 48 h. 50% excreted by kidneys unchanged. | Torsades de pointes in 3% of patients which can be reduced by ensuring normal serum K, avoiding dofetilide or reducing the dose if abnormal renal function, bradycardia, or base-line QT ↑. Avoid with other drugs increasing QT. C/I: previous torsades, creatinine clearance < 20 mL/min. | Increased blood levels with ketoconazole, verapamil, cimetidine, or inhibitors of cytochrome CYP3 A4, including macrolide antibiotics, protease inhibitors such as ritonavir. Other precautions as previously. |
| Sotalol (class III) | 80–640 mg daily, occasionally higher in two divided doses. | T 1/2 12 h. Not metabolized. Hydrophilic. Renal loss. | Myocardial depression, sinus bradycardia, AV block. Torsades if hypokalemic. | Added risk of torsades with IA agents or diuretics. Decrease dose in renal failure. |
| Amiodarone (class III) | Oral loading dose 600–1200 mg daily; maintenance 50–400 mg daily. IV 150 mg over 10 min, then 360 mg over 6 h, then 540 mg over remaining 24 h, then 0.5 mg/min. | T 1/2 25–110 days. Level 1–2.5 μg/mL. Hepatic metabolism. Lipid soluble with extensive distribution in body. Excretion by skin, biliary tract, lachrymal glands. | Complex dose-dependent side effects including pulmonary fibrosis. QT prolongation. Torsades uncommon. | Class IA agents predispose to torsades. β-blockers predispose to nodal depression, yet give better therapeutic effects. |
a Not licensed for intravenous use in the United States.
b Enzyme hepatic inducers are barbiturates, phenytoin, and rifampin, which induce hepatic enzymes, thereby decreasing blood levels of the drug.
Class IA: Quinidine, Procainamide, Disopyramide, and Ajmaline
The class IA agents inhibit the fast sodium channel with depression of phase 0 of the action potential and have intermediate kinetics, which is to say that they associate and dissociate from the sodium channels at an intermediate rate (between the rapid IB agents and the slow IC agents). These agents also block repolarizing potassium currents (a mild class III effect), which can prolong action potential duration and result in QT prolongation ( Table 9.3 ). Torsades de pointes is therefore the major adverse effect. These agents can be used for treatment of either ventricular or atrial arrhythmias. With atrial flutters, however, they may slow down the atrial rate sufficiently to allow 1:1 conduction to the ventricle thereby accelerating the ventricular rate substantially ( Fig. 9.2 ). There are no large-scale outcome trials to suggest that quinidine or other class I agents decrease mortality; rather there is indirect evidence that suggests increased mortality.
| Agent | Sinus node | Sinus rate | A-His | PR | AV block | H-P | WPW | QRS | QT | Serious hemodynamic effects | Risk of torsades | Risk of monomorphic VT |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Lidocaine | 0 | 0 | 0/↓ | 0 | 0 | 0 | ↓ /0 | 0 | 0 | Toxic doses | 0 | 0 |
| Phenytoin | 0 | 0 | ↑/0 | 0 | Lessens | 0 | ↓ /0 | 0 | ↑ | IV hypotension | 0, + | 0, + |
| Flecainide | 0/↓ | 0 | ↓↓↓ | ↑ | Avoid | ↓↓ | ↓ A/R | ↑ | ↑ (via QRS) | LV ↓↓ | 0 | +++ |
| Propafenone | 0/↓ | 0 | ↓↓ | ↑ | Avoid | ↓↓ | ↓ A/R | ↑ | 0 | LV ↓ | 0 | +++ |
| Sotalol | ↓↓ | ↓↓ | ↓ | ↑ | Avoid | 0 | A/R | 0 | ↑ | IV use | ++ | 0, + |
| Amiodarone | ↓ | ↑↓ | ↓ | 0/↑ | Avoid | 0/↓ | A/R | 0 | ↑↑ | IV use | +/− | 0, + |
Quinidine
Historically, quinidine was the first antiarrhythmic drug used. It has been used for the treatment of both ventricular and atrial arrhythmias. It can also be used in the treatment of Brugada syndrome. Today, because of limited availability in some countries as well as its proarrhythmic potential, quinidine is not used as often, although its application to Brugada syndrome has led to a very small resurgence of interest in the drug.
Pharmacokinetics
Quinidine is a substrate of the cytochrome P450 enzymes and P-glycoprotein. In particular, it is a strong inhibitor of CYP2D6 (strong), and a less strong inhibitor of CYP3A4 and P-glycoprotein. These affects result in the numerous drug interactions of quinidine.
Clinical use
Quinidine is not often used today but can be used for the treatment of both atrial and ventricular arrhythmias. Quinidine has also been shown to be effective in management of ventricular fibrillation (VF) in the setting of Brugada syndrome. Brugada syndrome results from loss-of-function mutations in the SCN5A gene (and others), which code for the sodium channel. This impairs the inward sodium current and results in an unopposed I to (transient outward potassium current) activity, which can set up reentry in ventricular cells. Quinidine can inhibit I to , thereby reducing the risk of VF in the setting of Brugada.
Dose
For atrial and ventricular arrhythmias, quinidine sulfate intermediate release can be started at 200 mg every 6 hours and cautiously titrated upward. Extended release can be started at 300 mg every 8–12 hours and titrated to effect. The maximum dose is 600 mg every 8–12 hours for the intermediate release formulation. A 267 mg dose of quinidine gluconate is equal to 200 mg of quinidine sulfate. For Brugada, quinidine sulfate can be administered at 500 mg BID or TID. The dose of quinidine should be reduced if the QRS complex widens to 130% of its pretreatment duration, the QTc interval widens to 130% of its pretreatment duration and is > 500 milliseconds, P waves disappear, or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension. Quinidine titration should occur in a monitored setting.
Side effects
The major side effect of quinidine is ventricular proarrhythmia and sudden death, in particular torsades de pointes. This often occurs in association with QT prolongation ( Fig. 9.3 ). In the setting of torsades, intravenous (IV) magnesium and alkalization of urine can help to reduce the effects of the quinidine. Gastrointestinal (GI) intolerance, namely nausea and diarrhea, are also common. At high doses, neurological side effects can occur. Heart block at the level of the sinus or AV node can also occur as can hypotension. Skin rash occurs in 5%–10% of patients and hepatotoxicity can also rarely occur.
Drug interactions and combination
Since quinidine inhibits CYP2D6 (strong), CYP3A4 (weak) and P-glycoprotein, drugs metabolized with these enzymes can be affected. Furthermore, any drug that affects the QT interval can also interact with quinidine. The number of culprit drugs interacting with quinidine is too numerous to list here but should always be checked when a patient is put on this drug.
Procainamide
Like quinidine, procainamide is useful for the treatment of both atrial and ventricular arrhythmias. While IV procainamide can be maintained as an infusion for medium-term arrhythmia management, and oral forms are available for longer-term, outpatient management, most use of procainamide is for the acute conversion of AF, VT, or preexcited AF.
Pharmacokinetics
Procainamide has a very short half-life (2–5.5 hours), which means that oral dosing requires frequent dosing, making long-term compliance challenging. Even sustained-release formulas require dosing every 6–12 hours. For the IV preparation, a single bolus dose can be useful for acute termination of AF, VT, preexcited AF, or flutter. Maintenance infusions can be used, but procainamide is acetylated by the liver to N-acetyl-procainamide (NAPA), which also has active antiarrhythmic properties. Both procainamide and NAPA can accumulate in patients with renal and/or hepatic dysfunction and, therefore, increase the proarrhythmic potential. Both procainamide and NAPA levels may need to be monitored, which has made maintenance infusions of procainamide unpopular.
Clinical use
Procainamide can be used for the treatment of both atrial and ventricular arrhythmias. It is particularly useful for acute medical conversion in the emergency department. In the setting of preexcited atrial fibrillation, procainamide can prolong the refractoriness of both the AV node but also the accessory pathway. This avoids the potential for preferential and more rapid conduction through the pathway alone—possibly inducing VF—which can occur with administration of selective AV nodal blockers alone ( Fig. 9.4 ). In regions where other IV sodium blockers are not available (like IV flecainide or ajmaline), IV procainamide is useful for drug testing to evoke the characteristic electrocardiogram (ECG) findings for Brugada syndrome for patients in whom the diagnosis is being considered but whose baseline ECG findings may be equivocal or absent. IV procainamide is also used in electrophysiology studies to evaluate for the presence of latent AV block by observing for prolongation in the HV interval to > 100 milliseconds.
Dose
For acute conversion of atrial and ventricular arrhythmias, or for Brugada and His-ventricular interval (HV) testing, IV procainamide should be given at a dose of 10–17 mg/kg at a rate of 20–50 mg/minute. For a typical adult, this usually means a dose of about 1 g IV over 20 minutes. Maintenance infusion can be given at 1–6 mg/minute. For oral preparations, the sustained release can be given at 500–750 mg every 6 hours. Renal impairment requires dose reduction of 25%–50% with creatinine clearance < 50 mL/min and 50%–75% with creatinine clearance < 10 mL/minute. Hepatic dysfunction also requires dose reduction of 25%–50%.
Side effects
Like all other antiarrhythmics, procainamide has a risk of proarrhythmia, particularly heart block and QT prolongation. Monitoring for both prolongation in PR interval and QT interval is required. One of the major limitations of procainamide is the development of a drug-induced lupus erythematosus-like syndrome, which occurs in 20%–30% of patients. Patients will develop a positive antinuclear antibody (ANA) titer and/or symptoms of lupus. Development of either rising titers or symptoms should lead to drug discontinuation. Another important side effect is the development of blood dyscrasias. Agranulocytosis, neutropenia, hypoplastic anemia, and thrombocytopenia can all occur in 0.5%–1% of patients and can be fatal. Weekly blood monitoring is required for the first 3 months and then periodically thereafter. Blood counts may return back to normal within 1 month if the drug is discontinued. Finally, if IV procainamide is administered too quickly (faster than recommended rate), hypotension is a significant risk.
Drug interactions and combination
Any drug that affects the QT interval will interact with procainamide and should be avoided ( Fig. 9.5 ).
Disopyramide
Disopyramide is a class IA drug and was approved for treatment of ventricular and atrial arrhythmias. However, it is not a very potent antiarrhythmic for either the ventricle or atrium. Its main therapeutic property is its profound negative inotropic effect. It can inhibit ventricular contraction by 40%–90% in low to high doses respectively and should therefore be completely avoided in patients with heart failure. The negative inotropy can be useful for patients with hypertrophic obstructive cardiomyopathy, particularly for reduction in outflow gradients. Disopyramide is more effective than both β-blockers and verapamil for outflow tract gradient reduction and is often used prior to consideration of invasive therapy such as septal myectomy or alcohol ablation. Disopyramide may also be helpful for treatment of AF in patients with hypertrophic obstructive cardiomyopathy and does not seem to increase the risk of sudden death. The main side effects are anticholinergic including dry mouth, prostatism, constipation, and urinary retention. Coadministration with pyridostigmine can alleviate the anticholinergic effects without impairing the antiarrhythmic effect. Hypoglycemia can rarely occur. QT prolongation and widening of the QRS can occur.
Ajmaline
Ajmaline is another class IA antiarrhythmic that is not available in all jurisdictions worldwide (used predominantly in Europe). It has a very short half-life and is only used for IV administration. It blocks both sodium ion channels but also the hERG potassium channel. While it can be used for acute treatment of preexcited AF and some ventricular arrhythmias, it is predominantly used for electrophysiology testing. It is particularly useful for test for Brugada syndrome. In individuals where Brugada is suspected but the baseline ECG is either normal or equivocal, an IV ajmaline challenge may bring out the typical Brugada ECG pattern with ST segment elevation in V1–V3. It can be given as 1 mg/kg administered at 1 mg/sec or over 10 minutes. It can also be used to provoke HV lengthening (> 100 milliseconds) to look for latent AV block.
Class IB: Lidocaine and Mexilitine
As a group, class IB agents inhibit the fast sodium current (typical class I effect; see Fig. 9.1 ) while shortening the action potential duration (APD) in nondiseased tissue. They also have rapid kinetics, which means they associate and dissociate from the sodium channels rapidly. The former is the more powerful effect, whereas the latter mitigates any QT prolongation. Class IB agents act selectively on diseased or ischemic tissue, where they are thought to promote conduction block, thereby interrupting reentry circuits. They have a particular affinity for binding with inactivated sodium channels with rapid onset-offset kinetics, which may be why such drugs are more selective for sodium channels in ventricular tissue versus atrial tissue. There are also differences in the β subunit of the rapid sodium channels in atrial versus ventricular tissue, which may affect binding of the class IB agents.
Lidocaine
Lidocaine (Xylocaine, Xylocard) has become a standard IV agent for suppression of serious ventricular arrhythmias associated with AMI, cardiac surgery, or other ventricular storm. Lidocaine acts preferentially on the ischemic myocardium and is more effective in the presence of a high external potassium concentration. Therefore, hypokalemia must be corrected for maximum efficacy (also for other class I agents). This is an IV drug and therefore has no role in the control of chronic recurrent ventricular arrhythmias. The concept of prophylactic lidocaine to prevent VT and VF in AMI has long been outdated and is therefore no longer done. Lidocaine has no value in treating supraventricular tachyarrhythmias.
Pharmacokinetics
The bulk of an IV dose of lidocaine is rapidly deethylated by liver microsomes (see Table 9.2 ). The two critical factors governing lidocaine metabolism and hence its efficacy are liver blood flow (decreased in old age and by heart failure, β-blockade, and cimetidine) and liver microsomal activity (enzyme inducers). Because lidocaine is so rapidly distributed within minutes after an initial IV loading dose, a second loading dose is often required followed by a continuous infusion ( Fig. 9.6 ). Lidocaine metabolites circulate in high concentrations and may contribute to toxic and therapeutic actions. After prolonged infusions, the half-life may be longer (up to 24 hours) because of redistribution from poorly perfused tissues.
Clinical use
Lidocaine should not be used for prophylactic treatment of ventricular arrhythmias post-MI. Evidence from more than 20 randomized trials and 4 meta-analyses have shown that lidocaine reduces VF but adversely affects mortality rates, presumably because of bradyarrhythmias and asystole. Lidocaine can be used when tachyarrhythmias or very frequent premature ventricular contractions seriously interfere with hemodynamic status in patients with AMI (especially when already β-blocked). It can also be used to treat sustained ventricular arrhythmias and/or ventricular storm in patients presenting with refractory VT/VF (causing repeated implantable cardioverter defibrillator [ICD] shocks), especially during or after cardiac surgery or in the setting of ischemic cardiomyopathy. However, the efficacy of lidocaine alone is relatively low (15%–20%), but it can also be easily combined with other antiarrhythmic therapy, namely IV amiodarone and β-blockade.
Dose
A constant infusion would take 5–9 hours to achieve therapeutic levels (1.4–5 μg/mL), so standard therapy includes a loading dose of 75–100 mg intravenously, followed after 30 minutes by a second loading dose, or 400 mg intramuscularly. Thereafter lidocaine is infused at 2–4 mg/minute for 24–30 hours, aiming at 3 mg/minute, which prevents VF but may cause serious side effects in approximately 15% of patients, in half of whom the lidocaine dose may have to be reduced. Poor liver blood flow (low cardiac output or β-blockade), liver disease, or cimetidine or halothane therapy calls for halved dosage. The dose should also be decreased for older adult patients in whom toxicity develops more frequently and after 12–24 hours of infusion.
Side effects
Lidocaine is generally free of hemodynamic side effects, even in patients with congestive heart failure (CHF), and it seldom impairs nodal function or conduction ( Table 9.3 ). The higher infusion rate of 3–4 mg/minute may result in neurologic toxicity such as drowsiness, numbness, speech disturbances, and dizziness, especially in patients older than 60 years of age. Minor adverse neural reactions can occur in approximately half the patients, even with 2–3 mg/minute of lidocaine. Occasionally there is sinoatrial (SA) arrest, but usually with coadministration of other drugs that potentially depress nodal function.
Drug interactions and combination
In patients receiving cimetidine, propranolol, or halothane, the hepatic clearance of lidocaine is reduced, and toxicity may occur more readily, so that the dose should be reduced. With hepatic enzyme inducers (barbiturates, phenytoin, and rifampin), the dose needs to be increased. Combination of lidocaine with early β-blockade is generally acceptable, because β-blockade can reduce liver blood flow and can rarely potentiate lidocaine-associated side effects ( Tables 9.2, 9.4 ). Often, however, lidocaine IV is coadministered with IV amiodarone and β-blockade for the treatment of refractory ventricular arrhythmias/ventricular storm.
| Drug | Interaction with | Result |
|---|---|---|
| Lidocaine | β-blockers, cimetidine, halothane, enzyme inducers a | Reduced liver blood flow (increased blood levels) Decreased blood levels |
| Flecainide | Major kinetic interaction with amiodarone Added negative inotropic effects (β-blockers, quinidine, disopyramide) Added AV conduction depression (quinidine, procainamide) | Increase of blood F levels; half-dose As previously Conduction block |
| Propafenone | As for flecainide (but amiodarone interaction not reported); digoxin; warfarin | Enhanced SA, AV, and myocardial depression; digoxin level increased; anticoagulant effect enhanced |
| Sotalol | Diuretics, Class IA agents, amiodarone, tricyclics, phenothiazines (see Fig. 9.4 ) | Risk of torsades; avoid hypokalemia |
| Amiodarone | As for sotalol digoxin phenytoin flecainide warfarin | Risk of torsades Increased digoxin levels Double interaction, see text Increased flecainide levels Increased warfarin effect |
| Ibutilide | All agents increasing QT | Risk of torsades |
| Dofetilide | All agents increasing QT Liver interactions with verapamil, cimetidine, ketoconazole, trimethoprim | Risk of torsades Increased dofetilide blood level, more risk of torsades |
| Verapamil Diltiazem | β-blockers, excess digoxin, myocardial depressants, quinidine | Increased myocardial or nodal depression |
| Adenosine | Dipyridamole Methylxanthines (caffeine, theophylline) | Adenosine catabolism inhibited; much increased half-life; reduce A dose Inhibit receptor; decreased drug effects |
a Enzyme inducers = hepatic enzyme inducers (i.e., barbiturates, phenytoin, rifampin).
Lidocaine failure for VT and VF
If lidocaine apparently fails, consider other problems, especially concomitant hypokalemia, hypomagnesemia, severe ongoing ischemia, or other reversible underlying factors. There may have been a technical error in dosing—often people forget to bolus twice before starting the infusion. Lidocaine can also be used in combination with IV amiodarone and β-blockade for refractory ventricular arrhythmias. There is very little data comparing lidocaine with amiodarone IV. In a retrospective analysis of AMI patients, 6% developed sustained VT and VF, and of those who survived 3 hours, amiodarone, but not lidocaine, was associated with an increased risk of death. However, the worse outcome of amiodarone-treated patients was likely due to selection of sicker patients as opposed to an effect of the drug itself.
Mexiletine (Mexetil)
Often considered an “oral form” of lidocaine, mexiletine can be useful for chronic management of ventricular arrhythmias ( Table 9.2 ). It is typically not effective for treatment of acute ventricular arrhythmias (for which IV lidocaine is preferred), but patients on lidocaine can be transferred to oral mexiletine by giving the first dose as soon as the lidocaine infusion is stopped. Mexiletine is not useful for treatment of any atrial arrhythmias. Like lidocaine, the utility of mexiletine is reduced in the setting of hypokalemia and hypomagnesemia, therefore these electrolyte disorders should be corrected while on mexiletine.
Pharmacokinetics
Mexiletine is predominantly metabolized by CYP1A2 and CYP2D6. Therefore, medications that either inhibit or induce these enzymes can significantly alter the effects of mexiletine (see the “Drug interactions and combinations” section).
Clinical use
Mexiletine is most commonly used for chronic management of ventricular arrhythmias, especially in patients with cardiomyopathy and recurrent VT/VF. As monotherapy, mexiletine is often not very effective, so it is most commonly combined with oral amiodarone when amiodarone monotherapy has failed. It may be used as an alternative to amiodarone in those patients who have developed amiodarone toxicity. In long QT syndrome type III (LQTS 3), there is a mutation in the SCN5A subunit of the sodium channel that causes a gain in function and delays repolarization, therefore prolonging action potential duration and QT interval. Mexiletine has been used in patients with this subtype of LQTS to block the sodium current and regularize the QT interval and prevent torsades de pointes.
Dose
The drug may be started at 100–200 mg PO every 8 hours and can be titrated up in 50–100 mg intervals to a maximum dose of 300 mg every 8 hours. For LQTS 3, for pediatric patients, it is recommended to use 6–8 mg/kg/day in two or three divided doses for 2–3 days, then increase to 2–5 mg/kg/dose every 8–12 hours; continue to increase by 1–2 mg/kg/dose every 2–3 days until desired effect. The maximum daily dose is 15 mg/kg/day or 1200 mg/day whichever is less.
Side effects
The major dose-limiting side effect of mexiletine is GI intolerance—namely nausea, vomiting, and diarrhea, which can occur in about 30%–40% of patients. Many of these GI intolerances can be mitigated by taking the medication with food or by administering a concomitant proton pump inhibitor antacid. Neurological side effects include dizziness, tremor, ataxia, paresthesia, and blurred vision. These symptoms can occur in 10%–20% of patients. Rare but important side effects include blood dyscrasias such as marked leukopenia or thrombocytopenia. Truncal erythema, facial swelling, and pustules can develop rarely. Particularly in the Japanese, a marked hypersensitivity can occur with fever, rash, eosinophilia, and elevated liver enzymes.
Drug interactions and combination
Drugs that inhibit or induce CYP1A2 and CYP2D6 can significantly alter the effects of mexiletine. In particular, there are several protease inhibitors (used in the treatment of human immunodeficiency viruses [HIV]), which may interact with mexiletine. Interestingly, tobacco, heroin, and cannabis can all lower the levels of mexiletine. Selective serotonin reuptake inhibitors (SSRIs) can decrease metabolism of mexiletine (increasing drug levels) except for sertraline.
Phenytoin (Diphenylhydantoin)
Phenytoin (Dilantin, Epanutin) is now much less used. It may be effective against the ventricular arrhythmias occurring after congenital heart surgery. Occasionally in patients with epilepsy and arrhythmias a dual antiarrhythmic and antiepileptic action is useful. See Table 9.3 for effects.
Class IC: Flecainide and Propafenone
Class IC agents have acquired a particularly bad reputation as a result of the proarrhythmic effects seen in the Cardiac Arrhythmia Suppression Trial (CAST) (flecainide) and the Cardiac Arrest Study Hamburg (CASH) study (propafenone). As such, these drugs should absolutely be avoided in patients with coronary ischemia or structural heart disease ( Fig. 9.3 ). Nonetheless, when carefully chosen, they fulfill a niche not provided by other drugs. As a group they have three major electrophysiologic (EP) effects ( Table 9.3 ). First, they are powerful inhibitors of the fast sodium channel, causing a marked depression of the upstroke of the cardiac action potential, which may also explain their marked inhibitory effect on His-Purkinje conduction with QRS widening. In addition, they may variably prolong the APD by delaying inactivation of the slow sodium channel and inhibition of the rapid repolarizing current ( I Kr ). In contrast to other class I agents, the IC’s have very slow kinetics and dissociate slowly from the sodium channels during diastole, resulting in increased effect at a more rapid rate—so-called “use-dependence.” This characteristic may explain their excellent antiarrhythmic efficacy, especially against supraventricular arrhythmias. However, use-dependence may also contribute to the proarrhythmic activity of these drugs, especially in the diseased myocardium, resulting in incessant VT ( Fig. 9.3 ). Some advocate performing exercise stress testing upon initiation of the drug to look for QRS widening that may not present at rest. If the QRS widens by 25% or more, the drug dose may need to be reduced or discontinued. However, absence of demonstrating use-dependence on exercise stress testing does not preclude the possibility of proarrhythmia from the drug. This class of drugs can also have significant negative chronotropic activity and should be avoided in patients with severe sinus node dysfunction or AV block. However, the drugs do not significantly prolong the QT interval ( Table 9.3 ). Class IC agents are all potent antiarrhythmics used largely in the control of paroxysmal supraventricular tachyarrhythmias, especially AF, and ventricular arrhythmias resistant to other drugs. By inhibiting the ryanodine receptor open state and minimizing prolonged outward calcium movement, they are also effective in the unusual condition of catecholaminergic polymorphic VT. Flecainide may also be useful in LQTS 3 characterized by the SCN5A:DeltaKPQ mutation in which the sodium channel repetitively opens prolonging the APD.
Flecainide
Pharmacokinetics
Flecainide is metabolized by CYP2D6, which is inhibited by the SSRIs, therefore causing a significant interaction. Metabolites of flecainide are excreted mostly in the urine, so patients with impaired renal function need very close monitoring. For pharmacokinetics, side effects, and drug interactions, see Tables 9.2 to 9.4 .
Clinical use
Indications are (1) paroxysmal supraventricular tachycardia (PSVT) including paroxysmal atrial flutter or fibrillation and Wolff-Parkinson-White (WPW) arrhythmias, and always only in patients without structural heart disease; (2) life-threatening sustained VT in which benefit outweighs proarrhythmic risks; (3) catecholaminergic polymorphic VT, by blocking open RyR2 channels; and (4) LQTS 3 with the SCN5A:DeltaKPQ mutation. Flecainide is especially useful for maintenance of sinus rhythm after cardioversion of AF ( Fig. 9.7 ) and for control of premature ventricular beats in patients with structurally normal hearts. Finally, IV flecainide is used in some jurisdictions (mainly Europe) for drug testing to evoke the typical Brugada ECG changes in patients with normal or equivocal resting ECGs; it can also be used to induce HV prolongation, which could be an indicator of latent AV block. Flecainide is contraindicated in patients with coronary ischemia, structural heart disease, and in patients with right bundle branch block and left anterior hemiblock unless a pacemaker is implanted. It is also contraindicated in the sick sinus syndrome and when the left ventricle is depressed and in the postinfarct state. Specifically, for AF, flecainide IV is superior to IV amiodarone for acute conversion at 8 hours (but not at 24 hours). Oral flecainide is superior to placebo but similar to sotalol and propafenone for maintenance of sinus rhythm with 65% of patients responding in the short term and 49% in the long term. It is better tolerated than both quinidine and propafenone. The PITAGORA trial demonstrated that flecainide was noninferior to oral amiodarone for maintenance of sinus rhythm in AF patients over 21 months. Amiodarone was better for prevention of longer AF episodes. Propafenone was slightly inferior to both amiodarone and flecainide. Flecainide has also been used orally as pill-in-pocket therapy for acute onset AF. This is particularly useful in patients with rare episodes of paroxysmal AF. The strategy is successful in 84%–94% of episodes and the mean conversion time is 2 hours, although up to 8 hours may be required. Occasionally, atrial flutter with rapid ventricular rate can occur, and therefore it is recommended that the first trial of such therapy be performed in a medically supervised environment (such as an emergency room). There is a boxed warning in the package insert against use of flecainide in chronic sustained AF.
Dose
For atrial arrhythmias, flecainide is usually started at 50 mg orally BID and increased in 50-mg increments until therapeutic effect or when limited by side effects. The maximum daily dose is 300–400 mg. For ventricular arrhythmias, the dose may be started at 100 mg BID. For the pill in pocket approach, a single dose of 200–300 mg may be given, usually in conjunction with a fast-acting, low-dose β-blocker (like metoprolol 12.5–25 mg). ECG should be monitored once flecainide is initiated for any QRS prolongation—if the QRS is prolonged > 25%, then the dose should be reduced/discontinued. Performance of exercise stress testing prior to drug initiation to rule out coronary disease is reasonable. Stress testing on drug to look for use-dependent QRS prolongation may also be useful but does not preclude proarrhythmic risk. Flecainide should almost always be coadministered with a concomitant AV nodal blocker (β-blocker, nondihydropyridine calcium channel blocker) to avoid increased ventricular conduction as atrial arrhythmias slow ( Fig. 9.2 ). For creatinine clearance < 35 mL/min, the dose should be reduced to once daily. IV flecainide is not approved in many jurisdictions but can be dosed as 2 mg/kg (maximum 150 mg) administered over 10 minutes.
Side effects
The major side effect of flecainide is ventricular proarrhythmia and sudden death. The cardiac proarrhythmic effects of flecainide include aggravation of ventricular arrhythmias and threat of sudden death as in the CAST study ( Fig. 9.3 ). The proarrhythmic effect is related to nonuniform slowing of conduction, and the risk is greatest in patients with prior MI, especially those with significant ventricular ectopy. Patients at risk of AMI are probably also at increased risk. Monitoring the QRS interval is logical but “safe limits” are not established. Furthermore, as shown in the CAST study, late proarrhythmic effects can occur. In patients with preexisting sinus node or atrioventricular (AV) conduction problems, there may be worsening of arrhythmia. Flecainide increases the endocardial pacing threshold and should therefore be used with some caution in pacemaker-dependent patients—particularly if the thresholds are elevated at baseline. Pacing thresholds should be checked at baseline and after 1 week. Atrial proarrhythmia occurs when the drug decreases the atrial rate, which can allow for increased AV nodal conduction and a paradoxical increase in the ventricular rate ( Fig. 9.2 ). This can precipitate VT or VF and could be fatal. This is why class IC agents are always coadministered with an AV blocking drug such as a β-blocker or nondihydropyridine calcium channel blocker (like diltiazem). Digoxin is generally not used, since it is less effective for AV blockade in high catecholamine states. Central nervous system reactions (visual disturbance, dizziness, paresthesias, headache) occur in 1%–3% of patients. Rash can occur in 1% and nausea in 6% of patients.
Drug interactions and combination
Neurological toxicity is increased when other CYP2D6 inhibitors are used (like older SSRIs paroxetine and sertraline). QT-prolonging drugs should also be avoided ( Fig. 9.5 ). Kinase inhibitors, which can increase the risk of AF, can be used in combination with flecainide but with careful monitoring. See Table 9.4 .
Propafenone
Pharmacokinetics
In keeping with its class IC effects, propafenone blocks the fast-inward sodium channel, has a potent membrane stabilizing activity, and increases PR and QRS intervals without effect on the QT interval ( Table 9.3 ). It also has mild β-blocking and calcium (L-type channel) antagonist properties, especially at higher doses. It is estimated that the β-blockade effect is approximately 1/40th that of propranolol, so the effect is quite weak and does not preclude the possibility of causing increased ventricular rates as the atrial rates are slowed for atrial flutter or AF. Because of its short half-life, the drug requires two to three times daily dosing. Propafenone is primarily metabolized by the liver. Note that in 7% of white patients, the hepatic cytochrome isoenzyme CYP2D6 is genetically absent, so that propafenone breakdown is much slower. Propafenone is also metabolized partially via the p-glycoprotein mechanism. For further pharmacokinetics, drug interactions, and combinations, see Tables 9.2 to 9.4 .
Clinical use
Indications are very similar to flecainide: (1) PSVT including paroxysmal atrial flutter or fibrillation and WPW arrhythmias, and always only in patients without structural heart disease; and (2) life-threatening sustained VT in which benefit outweighs proarrhythmic risks. Like flecainide, propafenone is primarily used for maintenance of sinus rhythm after cardioversion of AF and less commonly for control of premature ventricular beats in patients with structurally normal hearts. Propafenone is contraindicated in patients with coronary ischemia, structural heart disease, and in patients with right bundle branch block and left anterior hemiblock unless a pacemaker is implanted. It is also contraindicated in the sick sinus syndrome and when the left ventricle is depressed and in the postinfarct state. Oral propafenone may be the same as (or slightly inferior to) flecainide in terms of efficacy for maintenance of sinus rhythm in AF patients, but may be less well tolerated. Propafenone has also been used orally as pill-in-pocket therapy for acute-onset AF. This is particularly useful in patients with rare episodes, of paroxysmal AF. The strategy is successful in 94% of episodes and the mean conversion time is 113 minutes, although up to 8 hours may be required. Occasionally, atrial flutter with rapid ventricular rate can occur, and therefore it is recommended that the first trial of such therapy be performed in a medically supervised environment (such as an emergency room).
Dose
For atrial and ventricular arrhythmias, propafenone is usually started at 150 mg orally BID and increased to 300 mg TID until therapeutic effect or when limited by side effects. The maximum daily dose is 900 mg. Where available, the sustained-release formula can be dosed 225–425 mg BID. For the pill-in-pocket approach, a single dose of 450–600 mg may be given, usually in conjunction with a fast-acting, low-dose β-blocker (like metoprolol 12.5–25 mg). Renal adjustment is not required, but hepatic dysfunction may require decreasing to once or twice daily. ECG should be monitored once propafenone is initiated for any QRS prolongation—if the QRS is prolonged > 25%, then the dose should be reduced/discontinued. Performance of exercise stress testing prior to drug initiation to rule out coronary disease is reasonable. Stress testing on drug to look for use-dependent QRS prolongation may also be useful but does not preclude proarrhythmic risk. Propafenone should almost always be coadministered with a concomitant AV nodal blocker (β-blocker, nondihydropyridine calcium channel blocker) to avoid increased ventricular conduction as atrial arrhythmias slow ( Fig. 9.2 ). For creatinine clearance < 35 mL/min, the dose should be reduced to once daily.
Side effects
The major side effect of propafenone is ventricular proarrhythmia and sudden death. The cardiac proarrhythmic effects of flecainide include aggravation of ventricular arrhythmias and threat of sudden death as in the CAST study. In patients with preexisting sinus node or AV conduction problems, there may be worsening of arrhythmia. Atrial proarrhythmia occurs when the drug decreases the atrial rate, which can allow for increased AV nodal conduction and a paradoxical increase in the ventricular rate ( Fig. 9.2 ). This can precipitate VT or VF and could be fatal. This is why class IC agents are always coadministered with an AV-blocking drug such as a β-blocker or nondihydropyridine calcium channel blocker (like diltiazem). Digoxin is generally not used, since it is less effective for AV blockade in high catecholamine states. Propafenone often causes a change in taste (bitter or metallic). Central nervous system reactions (fatigue, headache, insomnia, and abnormal dreams) occur in 1%–3% of patients. Rarely, drug-induced lupus erythematosus and agranulocytosis have also occurred (see Procainamide for details). Hepatotoxicity has also been reported. Like flecainide, propafenone can also alter pacing thresholds, although usually not as profoundly.
Drug interactions and combination
CYP2D6 inhibitors can profoundly increase propafenone levels. Propafenone can also increase colchicine levels. Because of its mild β-blockade effects, propafenone can potentiate the bradycardia caused by concomitant β-blockers. Propafenone is also metabolized partially via the p-glycoprotein mechanism so it can increase serum levels of edoxaban and dabigatran. These oral anticoagulants should be avoided. QT-prolonging drugs should also be avoided ( Fig. 9.5 ). See Table 9.4 .
Class ID: Ranolazine
While there is officially no “class ID” in the Vauhgan Williams classification, ranolazine does not fit into one of the other three class I categories. It inhibits the late inward sodium current (I Na ) but also inhibits I Kr, which can cause some QT prolongation. By inhibiting the late sodium current, it inhibits intracellular calcium levels and leads to reduced wall tension and decreased oxygen requirements. It may also stimulate myogenesis. Therefore, this drug has predominantly been used as an antianginal medication. However, ranolazine does have some antiarrhythmic effects. It may promote conversion of AF to sinus, especially during acute coronary syndromes, and may also inhibit ventricular arrhythmias in patients with or without implantable defibrillators. It can be used in patients with heart failure. It is metabolized by CYP3A and inhibits CYP2D6. It should be avoided in patients with severe liver disease.
Class II Agents: β -Adrenoceptor Antagonists
Whereas class I agents are increasingly suspect from the long-term point of view, β-blockers have an excellent track record. The general arguments for β-blockade include (1) the role of tachycardia in precipitating some arrhythmias, especially those based on triggered activity; (2) the increased sympathetic activity in patients with sustained VT and in patients with AMI; (3) the fundamental role of the second messenger of β-adrenergic activity, cyclic AMP, in the causation of ischemia-related VF; and (4) the associated antihypertensive and antiischemic effects of these drugs. As a result, these drugs have demonstrated clear mortality benefits in patients post-MI and in patients with heart failure with left ventricular dysfunction.
Pharmacokinetics
These agents act on the β receptors. β-1 are found primarily in heart muscle, so inhibition causes decreased heart rate, contractility, and AV node conduction. β-2 are mostly in bronchial and peripheral vascular tissue, so inhibition of these can cause bronchospasm and vasoconstriction. β-3 are found in adipose tissue and the heart and can reduce thermogenesis. Typically, the more β-1 selective agents are better antiarrhythmics with fewer side effects. β-blockers may also inhibit both the α-1 and α-2 receptors, which can inhibit smooth muscle contraction in the GI tract and bladder and cause vasodilation (α-1) but also inhibit platelet activation and cause impotence (α-2). β-blockers also inhibit the current I f , now recognized as an important pacemaker current ( Fig. 9.8 ) that also promotes proarrhythmic depolarization in damaged heart tissue. β-blockers can also inhibit the inward calcium current, I Ca-L , which is indirectly inhibited as the level of tissue cyclic adenosine monophosphate (cAMP) falls. Metoprolol and propranolol are predominantly eliminated by the liver, while atenolol and sotalol are mostly eliminated by the kidneys. Bisoprolol is metabolized by a mixture of both kidney and liver and carvedilol is metabolized by liver and excreted in the bile. Cardio-selectivity refers to agents that more selectively inhibit β-1 receptors in the heart. Bisoprolol is the most cardioselective followed by metoprolol and atenolol and nadolol. Propranolol is not as selective. Labetolol and carvediolol have both α and β blockade properties and therefore may cause some associated vasodilation in addition to the typical β-1 effects. Acebutolol and pindolol have intrinsic sympathomimetic activity (ISA) that can produce some mild β-1 agonism at rest while antagonizing more with activity. Such activity may reduce profound bradycardia at rest, although at higher doses the ISA effect may be lost. Details on cardioselectivity and ISA are provided. Esmolol is a selective β 1 antagonist but has a very short half-life (9 minutes) with full recovery from its β-blockade properties at 18 to 30 minutes. Esmolol is quickly metabolized in red blood cells, independently of renal and hepatic function. Because of its short half-life, esmolol can be useful in situations in which there are relative contraindications or concerns about the use of a β-blocker: e.g., patient with arrhythmia and associated chronic obstructive airway disease or decompensated LV dysfunction.
