Major side effects of class I antiarrhythmic drugs

INTRODUCTION — Quinidine, disopyramide, procainamide, lidocaine, mexiletine, flecainide, and propafenone are all class I antiarrhythmic drugs (table 1) used for the treatment of various atrial and ventricular arrhythmias.

This topic will review the major side effects of the various drugs. Recommendations for the clinical role of these drugs in the treatment of atrial and ventricular arrhythmias are presented separately. (See "Overview of the acute management of tachyarrhythmias".)

WHEN TO MEASURE DRUG CONCENTRATIONS — Monitored drug concentrations are useful for patient care in several situations:

●Acutely, when increasing or decreasing the dose, if there is concern about either an inadequate therapeutic effect or possible toxic effect

●To confirm a stable dose in a medication with narrow therapeutic window and significant potential toxicities

●If you suspect unpredictable metabolism and/or elimination, caused by changes in electrolytes, kidney or liver disease (depending on the major route of elimination of the drug), older age category or congestive heart failure, all of which could result in higher than predicted concentrations resulting in drug toxicity.

More detailed information regarding recommendations for measuring drug concentrations and target drug concentrations for specific medications is available in the drug interactions program.

QUINIDINE — Quinidine is a class Ia antiarrhythmic agent (table 1) that can be used to treat both atrial and ventricular arrhythmias. It is no longer as commonly used as some antiarrhythmic agents, primarily due to concern about side effects (table 2), particularly proarrhythmia and sudden death [1]. Quinidine is rarely used today except to prevent recurrent ventricular tachycardia in Brugada syndrome and short QT syndrome [2,3].

Cardiovascular toxicity — There are a variety of potential cardiac toxicities related to the administration of quinidine, including proarrhythmia, conduction disturbances, hypotension, and congestive heart failure.

Proarrhythmia and ventricular arrhythmias — Ventricular arrhythmias, including isolated ventricular premature beats, couplets, bigeminy, and ventricular tachycardia, can be induced by quinidine [4]. As an example, "quinidine syncope," which is probably due to self-terminating torsades de pointes (a form of polymorphic ventricular tachycardia), has been reported to occur in 1.5 percent of patients per year [5]. Thus, the induction of arrhythmias appears to reflect the proarrhythmic effect of quinidine, rather than true toxicity. Furthermore, there is suggestive evidence that these arrhythmias may be fatal, leading to lower survival rates in patients treated with quinidine. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Class IA antiarrhythmic drugs'.)

Quinidine syncope and torsades de pointes are frequently associated with significant QT prolongation [5,6] precipitated or aggravated by hypokalemia, hypomagnesemia, and bradycardia, and concurrent therapy with digitalis [5-7]. Other antiarrhythmic drugs that prolong the QT interval (such as procainamide, disopyramide, amiodarone, and sotalol) should be avoided.

Electrophysiologically-guided class 1A antiarrhythmic drug treatment with quinidine appears to have a place for patients with Brugada syndrome. The results of small, nonrandomized studies in patients with Brugada syndrome with various clinical presentations and who had inducible VF have shown an excellent protective effect of quinidine during electrophysiological testing and an excellent clinical outcome in drug-treated patients. [8]. (See "Brugada syndrome or pattern: Management and approach to screening of relatives".)

Treatment of torsades de pointes — Treatment of torsades de pointes requires immediate discontinuation of quinidine and any other drug that prolongs the QT interval [9]. Torsades de pointes appears to be induced by triggered activity resulting from early afterdepolarizations associated with QT prolongation [10,11]. The approach to the treatment of torsades de pointes is presented separately. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)

Prevention — Alkalinization with sodium bicarbonate or sodium lactate (lactate is rapidly metabolized to bicarbonate) may diminish the proarrhythmic effect of quinidine [1,12]. At the level of the sodium channel, which is blocked by quinidine in part via a charge effect of this cationic drug, alkalosis will enhance recovery of the sodium channel by at least two mechanisms [13]:

●It will hyperpolarize the cell by decreasing the extracellular potassium concentration. (See "Potassium balance in acid-base disorders".)

●It will drive the reaction

Qud⁺   +   OH^–    <—>    QudOH

to the right, thereby decreasing the availability of the active charged form of the drug. It has also been hypothesized that administration of a sodium containing solution directly reverses the sodium channel blockade.

Sex differences — Females are more susceptible to QT interval prolongation and torsades de pointes after the administration of quinidine and drugs that delay cardiac repolarization. This effect appears to be independent of serum drug concentrations. In a study of 45 healthy volunteers (21 females) which compared serum quinidine concentrations and changes in QRS and QT intervals between males and females, there were no sex differences in the plasma concentrations or pharmacokinetic variables, but demonstrated a significantly greater increase in QTc and in QRS duration when compared with men [14,15]. Thus, the disparity in prolongation of cardiac repolarization is due to a pharmacodynamic difference, and appears to involve sex-specific effects on both depolarization and repolarization.

Conduction disturbances — The cardiac toxicity associated with quinidine may be initially manifested by slowed sinus or AV nodal conduction, causing sinus node conduction abnormalities or AV block [16,17]. Higher plasma concentrations may lead to marked QRS widening.

Hypotension — Hypotension, requiring either slowing or cessation of intravenous therapy, occurs in approximately 25 percent of patients. Some reports have demonstrated a good response to 500 mL of isotonic saline, a regimen that can be tolerated even in patients with significant HF.

Quinidine can induce hypotension, particularly if large doses are administered rapidly and intravenously. The fall in blood pressure is due both to direct vasodilation and to inhibition of alpha-adrenergic mediated vasoconstriction in arteries and veins [18]. The hemodynamic effects of oral quinidine are similar but less pronounced.

Increased ventricular response during atrial fibrillation or flutter — Quinidine can significantly increase the ventricular rate in patients with uncontrolled atrial fibrillation or flutter [1]. Two factors contribute to this response. By slowing the atrial fibrillation or atrial flutter rate, quinidine increases the likelihood that a given impulse will pass through the AV node. This tendency is enhanced by the direct vagolytic action of quinidine. Thus, conduction through the AV node must be slowed and the ventricular response controlled (using ß-blockers, calcium channel blockers, or digitalis) before therapy with quinidine is initiated in these disorders. (See "Atrial fibrillation: Cardioversion".)

Central nervous system toxicity — Central nervous system toxicity is associated with high-dose therapy and subsequent high plasma quinidine concentrations. The constellation of symptoms that may be seen is called cinchonism and includes tinnitus, hearing loss, confusion, delirium, disturbances in vision, and psychosis. (See 'When to measure drug concentrations' above.)

Gastrointestinal symptoms — The most frequent adverse effects with oral quinidine are gastrointestinal, including nausea, diarrhea, and abdominal bloating and discomfort [1]. These symptoms may be less severe with the gluconate preparation. Gastrointestinal symptoms for quinidine reportedly remain relatively high and are the most common causes for drug discontinuation [19].

Immune-mediated reactions — A number of immune-mediated reactions may be induced by quinidine therapy, such as rash, fever, hemolytic anemia, thrombocytopenia, leukopenia, hepatotoxicity, and anaphylaxis [1]. Thrombocytopenia, for example, results from antibodies to quinidine-platelet complexes, which cause platelets to agglutinate and lyse [20]. A lupus-like syndrome, similar to that induced by procainamide, is a rare problem [21]. (See "Drug-induced lupus".)

Interaction with other drugs and with grapefruit juice — Quinidine is metabolized by the cytochrome P450 system and it is a substrate of the CYP3A4 enzyme. Since CYP3A4 activity can be affected by grapefruit juice and a large number of other medications (table 3), providers must be alert for potential quinidine toxicity when used in combination with CYP3A4 inhibitors and other cardiac drugs after grapefruit juice ingestion. (See "Drugs and the liver: Metabolism and mechanisms of injury", section on 'Phase I reactions'.)

DISOPYRAMIDE — Anticholinergic symptoms are the most common side effect profile of disopyramide, but cardiac toxicity is of greatest concern. In particular, the negative inotropic activity and proarrhythmic potential of disopyramide limits its use in settings in which it might otherwise be effective.

Anticholinergic side effects — The administration of disopyramide is associated with a anticholinergic symptoms including dry mouth (32 percent), urinary hesitancy (14 percent), and constipation (11 percent). As a result, disopyramide should not be used in patients with underlying conditions that may be exacerbated by decreased cholinergic activity including glaucoma, myasthenia gravis, and urinary retention.

The anticholinergic effects can be diminished by the coadministration of drugs that increase cholinergic activity such as physostigmine, pyridostigmine, or bethanechol [22]. These agents selectively reduce anticholinergic symptoms without affecting the electrophysiologic or antiarrhythmic properties of disopyramide [22,23].

Disopyramide concentration and its metabolite, mono-N-dealkyldisopyramide, concentration should be monitored in patients whose renal function is decreased to prevent anticholinergic side effects associated with disopyramide. When serum mono-N-dealkyldisopyramide concentration is over approximately 1 microg/mL, the dose should be decreased or discontinued [24]. (See 'When to measure drug concentrations' above.)

Cardiac toxicity — Disopyramide has substantial negative inotropic activity in humans, resulting in reductions in cardiac contractility and cardiac output, and a reflex increase in systemic vascular resistance [25].

These changes can lead to overt heart failure (HF). HF usually occurs within the first three weeks of therapy; however, it can be seen as soon as 48 hours after initiation or several months later. This complication is most likely to occur with preexisting HF, affecting 55 percent of such patients versus only 5 percent without a prior history of heart disease. Intravenous disopyramide administration and concurrent renal failure are other risk factors for a significant decline in myocardial function. Patients with known significant chronic kidney disease should have serum drug concentrations measured at steady state in an effort to minimize toxicity. (See 'When to measure drug concentrations' above.)

The decline in contractility generally resolves rapidly after discontinuation of disopyramide. There may, however, be an acute requirement for therapy with diuretics, inotropic agents, or afterload reducing drugs. Other suggestions to enhance the safety of disopyramide in patients with underlying myocardial dysfunction include avoidance of loading doses or intravenous administration, and careful dose titration.

Electrocardiographic and proarrhythmic effects — Significant widening of the QRS interval occurs in a minority of patients treated with disopyramide. This is most likely to occur at high circulating drug concentrations, but may be seen with values in the therapeutic range. Therapy should be discontinued until the plasma disopyramide concentration is determined.

Like other class IA antiarrhythmic drugs, disopyramide can prolong the QT interval, possibly leading to increased ventricular ectopy, torsades de pointes (a form of polymorphic ventricular tachycardia), or syncope [26]. Concurrent use of other class I or class III agents (such as amiodarone or sotalol) can produce an additive increase in both the QRS and QT intervals. A similar effect can be induced by the administration of erythromycin or clarithromycin, drugs that inhibit the metabolism of disopyramide by inhibiting CYP3A4 (table 3) [27-29]. Azithromycin may be safer [30], but potentially fatal ventricular arrhythmias can be induced when used in combination with disopyramide [31].

Disopyramide should be discontinued if the QT interval increases by more than 25 percent or ventricular ectopy is exacerbated. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)

The proarrhythmic potential for disopyramide (6 percent) is less than that for the other class IA drugs, quinidine (15 percent) and procainamide (9 percent) [32]. With each of these drugs, the likelihood of proarrhythmia is increased by hypokalemia, hypomagnesemia, and bradyarrhythmias [33,34]. Intravenous magnesium sulfate has been useful in patients with QT prolongation and torsades de pointes [35,36]. Magnesium may act by suppressing afterdepolarizations.

Increased ventricular response during atrial fibrillation or flutter — Like other class IA antiarrhythmic drugs, disopyramide can increase the ventricular rate in patients with uncontrolled atrial fibrillation or flutter. Two factors contribute to this response: disopyramide slows the fibrillation or flutter rate, thereby making it more likely that a given impulse will pass through the AV node; and the direct anticholinergic effect of disopyramide enhances AV nodal conduction. Thus, the AV node must be slowed and the ventricular rate controlled (with ß-blockers, calcium channel blockers, or digoxin) before therapy with disopyramide is begun. (See "Atrial fibrillation: Cardioversion".)

Safety of disopyramide in obstructive hypertrophic cardiomyopathy — At the typical doses used in modern practice, disopyramide does not appear to induce proarrhythmia in patients with hypertrophic cardiomyopathy (HCM) with symptomatic left ventricular outflow tract obstruction. This is discussed in greater detail separately. (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction", section on 'Disopyramide'.)

The question of outpatient safety for those requiring management with disopyramide has been raised. In a large outpatient clinic focused on HCM, 2015 patients were seen, including 168 who started on disopyramide. No cardiac events were seen within three months of disopyramide initiation. During long-term follow-up (255 patient-years; mean 447 days; interquartile range 201 to 779), two patients developed cardiac events (syncope of unknown cause in both). Thirty-eight (23 percent) developed side effects of disopyramide, and 18 (11 percent) stopped the drug because of these. Disopyramide at a dose of 300 mg prolonged the mean QTc interval by 19±23 msec; however, increasing the dose to 600 mg had no further significant effect [37].

PROCAINAMIDE — Procainamide is an effective antiarrhythmic drug; however, its use may be limited by a lupus-like syndrome and, an infrequent but potentially severe adverse effect of bone marrow toxicity.

Lupus-like syndrome — Chronic administration of procainamide is associated with a positive antinuclear antibody titer in patients, particularly in those who are slow acetylators. Symptoms similar to those seen in lupus (eg, arthritis, arthralgias, and pleuritis) develop in 15 to 20 percent of patients. The clinical manifestations typically remit when therapy is discontinued or changed to N-acetylprocainamide, the major active metabolite of procainamide [38]. The inability of N-acetylprocainamide to induce the lupus-like syndrome suggests an important pathogenetic role for the aromatic amino group on procainamide [39]. (See "Drug-induced lupus".)

Blood dyscrasia — Pancytopenia or agranulocytosis is a rare but potentially life-threatening complication that may be mediated by allergic, hypersensitivity, or immunologic mechanisms [40,41]. These complications are rare, with an estimated incidence of 0.22 percent, and usually develop within three months after the initiation of therapy [40,41]. Drug withdrawal is indicated in all cases; however, there is a variable degree of recovery of the white blood cell count.

Cardiac toxicity — Although some cardiac side effects of procainamide can be seen at therapeutic concentrations, a variety of more serious and potentially lethal effects are more common at toxic plasma concentrations (above 30 mg/L for procainamide plus its major metabolite N-acetylprocainamide versus a therapeutic range of 4 to 12 mg/L for procainamide alone). Since procainamide is largely metabolized by the liver and eliminated by the kidneys, changes in liver and kidney function could account for changes in the therapeutic concentration in adults. (See 'When to measure drug concentrations' above.)

Among the changes that can occur are:

●Conduction delay, manifested by progressive PR prolongation or widening of the QRS interval

●Prolonged refractoriness, leading to prolongation of the QT interval in proportion to the plasma procainamide concentration

●Arrhythmias, such as ventricular premature contractions and ventricular tachycardia

●Severe left ventricular function depression

Effects on ECG intervals — The electrocardiogram can be used to monitor both the therapeutic and toxic effects of procainamide on the heart. These effects are due to both a direct influence on electrophysiologic properties and the indirect impact of autonomic modulation (vagolytic properties).

PR interval — When atrioventricular (AV) conduction is normal, procainamide has little effect on the PR interval, if however, there is preexisting slowing of AV conduction, then procainamide can depress conduction further, leading to higher degrees of AV block even at therapeutic drug concentrations. The risk of heart block in this setting is heightened since procainamide also reduces ventricular automaticity.

QRS duration — Normal procainamide concentrations widen the QRS complex due to slowing of conduction in the Purkinje system and ventricular muscle. The drug should be discontinued if the QRS duration increases by more than 35 to 50 percent to avoid serious toxicity. Toxic plasma concentrations can cause intraventricular conduction disturbances and reentry, resulting in ventricular arrhythmias.

QT interval — Procainamide prolongs the QT interval, usually in proportion to the plasma procainamide concentration. Marked prolongation occurring in conjunction with hypokalemia can cause early afterdepolarizations and triggered activity leading to ventricular tachycardia.

Other medications that prolong the QT interval, such as fluoroquinolones and certain antihistamines (table 4), should be avoided in patients with known prolongation of the QT interval, and patients receiving procainamide [42]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

Increased ventricular response during atrial fibrillation or flutter — Procainamide, like quinidine and disopyramide, can significantly increase the ventricular rate in patients with uncontrolled atrial fibrillation or flutter. Two factors contribute to this response:

●By slowing the atrial rate of atrial fibrillation or atrial flutter, procainamide increases the likelihood that a given impulse will pass through the AV node, thereby potentially increasing the ventricular rate.

●Procainamide has a direct vagolytic action on the AV node, increasing conduction through the AV node.

Therefore, when administering procainamide for chemical cardioversion of atrial fibrillation, conduction through the AV node must be slowed and the ventricular response controlled (using ß-blockers, calcium channel blockers, or digitalis) before therapy with procainamide is initiated in these disorders [43]. (See "Atrial fibrillation: Cardioversion".)

LIDOCAINE (INTRAVENOUS) — Lidocaine, administered intravenously in the treatment of ventricular arrhythmias, is generally well tolerated. The major side effects primarily involve the central nervous system, the cardiovascular system, and the gastrointestinal tract.

Neurologic toxicity — The most common adverse effect of intravenous lidocaine is central nervous system (CNS) toxicity [44-47]. The symptoms are usually mild, dose-dependent, and resolve with a decrease in the infusion rate or discontinuation of the drug. These side effects may be particularly frequent in older adults or those with HF, and in patients with significant liver impairment in whom the metabolism of lidocaine is reduced.

Tremor is a useful bedside sign of toxicity. Other neurologic side effects include insomnia or drowsiness, lightheadedness, dysarthria and slurred speech, ataxia, depression, agitation, change in sensorium, a change in personality, nystagmus, hallucinations, memory impairment, and emotional lability.

High plasma concentrations of lidocaine can also provoke seizures that are usually generalized [48]. This can also occur at lower drug concentrations if lidocaine is given to patients congeners of lidocaine, such as oral tocainide or mexiletine. (See 'When to measure drug concentrations' above.)

Cardiovascular toxicity — Cardiac side effects are an infrequent complication of intravenous lidocaine therapy even among patients with significant underlying heart disease. The primary cardiovascular side effects include sinus slowing, asystole, hypotension, and shock. These are most often associated with overdosing or with rapid administration of lidocaine. Individuals who are older than 60 years and those with significant preexisting heart disease are at greatest risk [49,50].

MEXILETINE — The side effects of mexiletine are generally dose- and concentration-dependent. The most common adverse effects are related to the gastrointestinal and central nervous systems [51,52]. Common digestive complaints include nausea, vomiting, or heartburn. These symptoms are reversible and can be reduced by food or antacid administration. The most frequent central nervous system complaints are dizziness, lightheadedness, tremor, nervousness, difficulty with coordination, change in sleep habits, paresthesias, and numbness [51,52]. More serious noncardiac side effects are rare.

Cardiac complications — There are two potential cardiac complications associated with mexiletine: proarrhythmia; and impaired hemodynamics.

Proarrhythmia — Mexiletine has a proarrhythmic effect that is of greatest concern in patients with life-threatening arrhythmias such as sustained ventricular tachycardia [53,54]. Exacerbation of arrhythmia after mexiletine occurs in 10 to 15 percent of patients [32].

Mexiletine also has a depressant effect on sinus node function and can result in sinus bradycardia or prolonged sinus node recovery time in patients with preexisting sinus node dysfunction or following administration of high doses [32,53].

Hemodynamics — Mexiletine is usually well tolerated hemodynamically, lacking the potent negative inotropic effects seen with disopyramide, flecainide, and ß-blockers. Nevertheless, in patients with severe congestive HF, mexiletine should be used with caution because it can aggravate the HF or cause hypotension [55-57]. Cardiodepressant effects may be more evident in patients with severe left ventricular dysfunction. Furthermore, hepatic metabolism may be impaired in HF, resulting in prolongation of the elimination half-life of mexiletine to 25 hours.

Mexiletine-induced hypersensitivity syndrome — Mexiletine-induced hypersensitivity syndrome occurs most frequently in Japanese males and is manifested by fever, rash, peripheral blood eosinophilia, and elevation of liver transaminase enzymes [58,59]. Although the mechanism for the immunogenicity is not clear, a role of reactive drug metabolites in initiating an immune response via hapten formation has been suggested. The involvement of viral infection has been explored suggesting a relationship between human herpes virus 6 and the development of systemic immune responses [60].

Inhibitor of CYP1A2 — Mexiletine is a potent CYP1A2 inhibitor and co-administration of mexiletine increases plasma concentrations of substrates for cytochrome P450 (CYP) 1A2 such as theophylline [61], caffeine [61,62], and tizanidine (a new antispastic agent) [63]. Mexiletine, approved for managing pain, painful neuropathies, and headache when used in conjunction with tizanidine may cause unpredictable changes in plasma concentrations and pharmacodynamic effects and should be used with care as it is with other substrates for CYP1A2 [64].

FLECAINIDE — Flecainide is an effective agent against both ventricular and supraventricular arrhythmias. However, its use is limited by concern about toxicity, particularly its proarrhythmic effects.

Cardiac toxicity

Proarrhythmia — Flecainide was one of two class IC antiarrhythmic medications included in the CAST trial, which evaluated patients with asymptomatic, non-life-threatening ventricular arrhythmias who were six days to two years after an acute myocardial infarction (MI) [65]. Flecainide had an apparent proarrhythmic effect with a significantly increased incidence of mortality plus nonfatal cardiac arrest (6.1 percent versus 2.3 percent in the placebo group).

It has been proposed that the increase in malignant arrhythmias was due to the use of flecainide in the setting of ischemia and/or cardiac structural abnormalities (eg scar from the prior infarction). This hypothesis is supported by the following observations:

●All patients in the CAST trial had prior MI.

●A case series of three patients without CHD who developed ventricular arrhythmias after flecainide use for atrial fibrillation included one patient with a prosthetic mitral valve, one patient with hypertrophic cardiomyopathy, and one patient without known cardiac structural abnormalities [66].

●Flecainide did not increase mortality when used for the treatment of supraventricular arrhythmias in structurally normal hearts [67].

Conduction abnormalities — Due to its significant effect on sodium channels, flecainide prolongs depolarization and can slow conduction in the AV node, the His-Purkinje system, and below. These changes can lead to prolongation of the PR interval, increased QRS duration, and first- and second-degree heart block. In addition, profound sinus bradycardia can be induced in patients with preexisting sinus node disease [68]. In contrast, flecainide does not affect repolarization and therefore has little effect on the QT interval [69].

The cardiac safety profile of flecainide was assessed in 227 outpatients with paroxysmal atrial fibrillation (PAF) [70]. Patients were treated with 200 mg daily for 24 weeks. The following results were reported:

●Mean QRS duration increase was 11.4 percent, and 19 percent of patients had ≥25 percent increase in QRS duration.

●Significant left ventricular ejection fraction (LVEF) reduction occurred in 1.4 percent of patients.

●Bradycardia (13.2 percent) and ventricular extrasystoles (10.6 percent) were the most frequently identified proarrhythmic effects.

●Other adverse cardiac events included atrioventricular block (4.0 percent), supraventricular tachycardia (2.2 percent), bundle branch block (1.8 percent) and atrial fibrillation (1.3 percent).

Extracardiac effects — Flecainide can induce a variety of noncardiac side effects, including dizziness, blurred vision or difficulty in focusing, headache, and nausea, each of which occurs in 10 to 20 percent of patients [71].

Renal dysfunction — Flecainide accumulates in patients with renal failure; close monitoring of concentrations is needed. Although the absorption and volume of distribution of flecainide are unaffected by renal failure, the plasma elimination half-life is prolonged in mild to moderate renal impairment (10 to 30 h) compared with normal renal function (6 to 15 h). Moreover, the half-life increases further in patients with stage 5 chronic kidney disease (up to 40 h) [72]. Since flecainide is not removed efficiently by dialysis there is a potential for toxicity in patients undergoing dialysis. (See 'When to measure drug concentrations' above.)

Renal failure may predispose to toxicity at lower serum flecainide concentrations and cause severe neurotoxicity [73-75]. While dizziness and visual disturbances, including diplopia, are not unusual, severe neurologic complications are rare. However, they include paranoid psychosis, dysarthria, visual hallucinations, generalized seizures and cerebello-myoclonic syndrome.

CYP2D6 inhibitors — Flecainide is a substrate of the hepatic enzyme system CYP2D6, which is inhibited by the selective serotonin-reuptake inhibitors (SSRIs), fluoxetine and paroxetine. Thus, these CYP2D6 inhibitors also have the potential to cause central nervous system toxicity with flecainide (table 5) [76,77].

PROPAFENONE — Patients with known structural heart disease should not receive propafenone. Propafenone should be discontinued in patients who develop sustained VT.

Approximately 15 to 20 percent of patients taking propafenone will have side effects that require drug discontinuation [78-80]. The most common adverse reactions involve the gastrointestinal, central nervous, and cardiovascular systems. Most of these complications are dose-dependent, particularly central nervous system side effects such as dizziness, nausea, unusual taste, and blurred vision, which are often ameliorated if the propafenone dose is reduced [78]. Potential side effects involving the cardiovascular system are most concerning, as the cardiac side effects are the most life-threatening. The risk of cardiovascular toxicity is greater in patients with structural heart disease and in those treated for ventricular rather than supraventricular arrhythmias [78,79].

The relation between propafenone dose, concentration, clinical response, and toxicity is complex. The main metabolic route of propafenone is via the cytochrome P450 2D6 isoenzyme. This metabolic pathway, known to have genetic polymorphisms, is functionally absent in approximately 7 percent of White and African Americans. In these "slow metabolizers," the extent of first-pass hepatic metabolism is much less than in "extensive metabolizers," and increased plasma concentration may be more likely to cause side effects. Moreover, because the oxidative elimination of propafenone is saturable, small dose increases may cause a rapid and disproportionate increase in plasma concentrations, thus augmenting its potential for causing toxicity. (See 'When to measure drug concentrations' above.)

Cardiovascular effects

Inotropic effects — In patients with a normal or minimally decreased LVEF (≥40 percent), oral propafenone can decrease the ejection fraction without causing symptoms of HF [81]. However, overt HF may be induced in patients with preexisting ventricular systolic dysfunction [82]. The negative inotropic effect of propafenone is associated with significant increases in pulmonary capillary wedge pressure and in systemic and pulmonary vascular resistance and a decline in cardiac output. Propafenone should therefore be avoided in patients with overt HF. However, propafenone can be administered cautiously to patients with mildly reduced LVEF who have no clinical signs or symptoms of HF, with close monitoring over one to two weeks for the development of HF symptoms following the initiation of therapy.

Chronotropic effects — Propafenone has a variety of effects that can lead to bradycardia including its Class IC activity and its beta-blocker and calcium channel blocker properties. As a result, patients with known sinus node dysfunction, including the sinus node dysfunction, should not receive propafenone in the absence of a permanent pacemaker [83]. Alternatively, because potential variations in propafenone metabolism may exist and remain undetected in everyday practice, some authors have suggested a heart rate challenge, such as exercise testing, for patients using chronic propafenone [84].

Conduction disturbances — Propafenone slows atrioventricular conduction and causes prolongation of the PR and QRS intervals. Prolongation of the PR interval ranges from 15 to 25 percent; it is a common finding and is not necessarily regarded as a sign of toxicity. However, on rare occasions propafenone has been associated with the development of atrioventricular block. Patients on propafenone who develop second or third degree AV block should have their dose of propafenone reduced or discontinued.

Propafenone has been associated with QRS prolongation, new left bundle branch block, and new right bundle branch block [85,86]. These conduction disturbances usually occur in patients with underlying heart disease and appear to be dose-dependent. No specific dose adjustments are required in this setting.

Proarrhythmia — Like other antiarrhythmic agents, propafenone has a proarrhythmic effect that can trigger sustained ventricular tachycardia (VT) [32]. The proarrhythmic effect of propafenone may be somewhat reduced by its beta-blocking activity.

The potential for proarrhythmia is greater with the class IC agents, such as flecainide or propafenone, compared with the IA or IB drugs (table 1) [87]. The two most powerful predictors of proarrhythmia are previous VT and decreased LVEF.

CNS side effects — A variety of adverse central nervous system (CNS) effects have been reported in association with propafenone, with dizziness being the most common along with nausea, unusual taste, and blurred vision. Ataxia caused by propafenone has also been reported [88].

Although the side effects of the drug are usually dose-related, the precise mechanism is not fully understood. Blockade of beta-adrenergic receptors may be partly responsible, because this action can in itself cause CNS symptoms including sleep disturbance, depression, drowsiness, fatigue, lethargy, hallucination, delirium, paranoia, and amnesia.

In patients who develop CNS effects from propafenone, it is reasonable to consider lowering the dose in an effort to reduce side effects. If CNS side effects persist, propafenone should be discontinued.

Gastrointestinal side effects — Gastrointestinal side effects from propafenone, usually mild in nature, are among the most commonly reported adverse effects. Up to 20 percent of patients receiving propafenone report an unusual taste , and up to 10 percent develop nausea. The frequency of side effects may be reduced when medication is taken with food.

Propafenone intoxication — HF, conduction disturbances, and seizures are major clinical signs of intoxication. While adverse reactions to propafenone are relatively common, reports of death secondary to propafenone intoxication are comparatively rare [89].

Propafenone intoxication is associated with ingested doses from 1800 to 9000 mg and serum concentrations as high as 12,000 ng/mL have been reported (normal therapeutic and toxic ranges for propafenone are 400 to 1100 ng/mL and 1100 to 2000 ng/mL, respectively) [89,90].

Treatment for propafenone intoxication centers on hemodynamic support and includes intravenous glucagon (to reverse any toxicity due to the beta blocker effects), hypertonic sodium bicarbonate, hypertonic saline, and inotropic agents [90]. A temporary pacemaker may be required for patients with high-degree AV block related to the overdose. Routine blood testing for propafenone concentrations should be performed in patients following resuscitation, particularly in patients undergoing treatment for arrhythmias. (See "General approach to drug poisoning in adults", section on 'Poisoning management'.)

SUMMARY AND RECOMMENDATIONS

●Quinidine side effects

•Gastrointestinal – These are the most frequent adverse effects with oral quinidine. Nausea, diarrhea, and abdominal bloating and discomfort can occur.

•Central nervous system toxicity – This is associated with high-dose therapy and subsequent high plasma quinidine concentrations. The constellation of symptoms is called cinchonism and includes tinnitus, hearing loss, confusion, delirium, disturbances in vision, and psychosis.

•Cardiac toxicities – These include proarrhythmia with lengthening of the QT interval (potentially resulting in polymorphic ventricular tachycardia), slowed atrioventricular (AV) nodal conduction (potentially leading to heart block), and hypotension. (See 'Quinidine' above.)

●Disopyramide side effects

•Anticholinergic symptoms – These include dry mouth, urinary hesitancy, and constipation.

•Cardiac effects – These include negative inotropic activity (potentially resulting in heart failure) and proarrhythmia with lengthening of the QT interval (potentially resulting in polymorphic ventricular tachycardia). (See 'Disopyramide' above.)

●Procainamide side effects

•Gastrointestinal disturbances.

•Central nervous system dysfunction.

•Fever, rash, and myalgias.

•Positive antinuclear antibody titer – This is seen in almost all patients with chronic administration of procainamide. This is particularly seen in slow acetylators, with symptoms similar to those in systemic lupus erythematosus (eg, arthritis, arthralgias, and pleuritis) in 15 to 20 percent of patients.

•Serious and potentially lethal cardiac effects – These are more common at toxic plasma concentrations (above 30 mg/L for procainamide plus its major metabolite N-acetylprocainamide versus a therapeutic range of 4 to 12 mg/L for procainamide alone), including conduction delay (with PR prolongation or QRS widening), QT prolongation, ventricular tachyarrhythmias, increased AV nodal conduction, and depressed left ventricular function. (See 'Procainamide' above.)

●Lidocaine side effects – When administered intravenously in the treatment of ventricular arrhythmias, lidocaine is generally well tolerated.

•Central nervous system – These include tremor, insomnia or drowsiness, lightheadedness, ataxia, and agitation.

•Gastrointestinal – These include nausea, vomiting, and anorexia.

•Cardiovascular system – These include sinus node slowing, asystole, hypotension, and shock. (See 'Lidocaine (intravenous)' above.)

●Mexiletine side effects – The side effects of mexiletine are generally dose and concentration dependent.

•Gastrointestinal tract – These are the most common adverse effects and include nausea, vomiting, or heartburn.

•Central nervous system – These include dizziness, lightheadedness, tremor, nervousness, difficulty with coordination, change in sleep habits, paresthesias, and numbness.

•Cardiac – A proarrhythmic effect can contribute to ventricular tachyarrhythmias. (See 'Mexiletine' above.)

●Flecainide side effects – This is generally well tolerated, though it can induce a variety of generally mild and tolerable side effects.

•Noncardiac – These include dizziness, blurred vision or difficulty in focusing, headache, and nausea, each of which occurs in 10 to 20 percent of patients.

•Cardiac – Proarrhythmia and the potential for fatal ventricular arrhythmias can occur in persons with structural heart disease. Conversely, flecainide does not appear to increase mortality when used for the treatment of supraventricular arrhythmias in persons with structurally normal hearts. (See 'Flecainide' above.)

●Propafenone side effects – Approximately 15 to 20 percent of patients taking propafenone will have side effects that require drug discontinuation.

•Gastrointestinal – These are the most common and include nausea and an unusual taste sensation.

•Central nervous system – Most commonly, dizziness occurs.

•Cardiovascular – These include negative inotropic effects, bradycardia and AV block, and proarrhythmia.

•Overdose – Propafenone intoxication, often due to overdose, is a life-threatening condition marked by heart failure, hemodynamically-unstable ventricular tachyarrhythmias and/or bradyarrhythmias, and seizures. (See 'Propafenone' above.)