Antidysrhythmic Toxicity Clinical Presentation

As in the case of any patient with suspected or known acute poisoning, attempt to obtain the original medication containers, pill counts, the quantity that may have been ingested, approximate time of ingestion, and a report of any potential co-ingestants.

In patients with prescribed antidysrhythmic agents, attempt to differentiate primary disease from possible toxic effects of the drug with the following questions:

• What were the indications for starting the drug?
• If the patient does not know, can a call to the prescribing physician or a review of the medical record help?
• How long has the patient taken this agent?
• How do the patient's symptoms correlate with the initiation of drug therapy?
• Is the patient compliant with the drug?
• Has the patient taken any extra doses?
• Has the patient added any new drugs recently?
• Is the patient taking any nonprescription drugs?

Disopyramide - Class IA

• Indications - Treatment of documented ventricular arrhythmias
• Dosages - Must be individualized per patient, usually 400-800 mg/d in divided doses
• Metabolism - Metabolized by the liver, 40-60% excreted by the kidneys
• Therapeutic levels - Dose adjustment is gradual, with close monitoring
• Drug interactions - Phenytoin or hepatic-enzyme inducers lower level
• Cardiac toxicity - Has a greater myocardial depressant effect than other class IA agents; QT and PR prolongation may occur
• Other toxicity - Has greater anticholinergic effects than that of other class IA agents; hypoglycemia has been reported with therapeutic dosing

Procainamide - Class IA

• Indications - Treatment of sustained ventricular arrhythmias
• Dosages - 50 mg/kg/d in 4 divided doses
• Metabolism - Drug elimination follows first order kinetics; is metabolized in the liver by acetylation and excreted by the kidneys
• Therapeutic levels - Dose adjustment individualized per patient
• Drug interactions - Anticholinergic drugs produce additive vagolytic effects; cimetidine increases drug level
• Cardiac toxicity - Prolongation of QT interval and QRS complex
• Other toxicity - Adverse effects include gastrointestinal disturbances, headache, mild hypotension, rash, insomnia, dizziness, ataxia, hallucinations, and weakness

Quinidine - Class IA

• Indications - Suppression of atrial and ventricular dysrhythmias, malaria prophylaxis, and illicit abortifacient
• Dosages - 1200 mg every 12 hours, then cautiously increased based on individual needs
• Metabolism - Hepatic elimination is responsible for 60-80%, whereas kidney elimination is responsible for 20-40%
• Therapeutic levels - 2-6 mg/L or 6.2-18.5 µmol/L by assay
• Drug interactions - Elevation of quinidine serum concentration induced by cimetidine and ketoconazole; verapamil impairs hepatic metabolism, thus reducing oral clearance
• Cardiac toxicity - The D-isomer is a weak base, which is considered a myocardial depressant, decreasing excitability, conduction velocity, and contractility

Lidocaine - Class IB

Lidocaine is an aminoacyl amide synthetic derivative of cocaine. It is an antidysrhythmic and local anesthetic agent.

American Heart Association and American College of Cardiologist 1996 guidelines considered prophylactic lidocaine for the treatment of acute myocardial infarction (AMI) as a class III indication. This recommendation was based upon 4 meta-analyses; however, a 32-year observational study of 4150 patients with AMI showed an incidence of primary ventricular fibrillation of 0.5% (P < 0.0001) in those who received prophylactic lidocaine.

Adverse effects include CNS disturbances (eg, lightheadedness, confusion) and cardiovascular effects (eg, hypotension, atrioventricular block).

It is metabolized through liver dealkalization by 95%. Age, hepatic blood flow, and hepatic function determine the rate of degradation. Lidocaine is metabolized to two active metabolites, monoethylglycinexylidide (MEGX) and glycine xylidide (GX); these metabolites may contribute to toxicity.

Mexiletine and tocainide - Class IB, lidocaine analogs

Mexiletine was developed as anorectic agent but was found to have antidysrhythmic and anticonvulsant properties. Absorption mainly is in the small intestine, with 100% metabolism in liver. The half-life is 12-13 hours. Adverse reactions include nausea, vomiting, tremors, seizures, and ataxia.

Tocainide is used for ventricular dysrhythmias. It is 100% bioavailable when taken orally. Metabolism is 60% in the liver and 40% in the kidney. The half-life is 9-20 hours.

Encainide - Class IC

Encainide was withdrawn from US and Canadian markets in Dec of 1991 due to increased mortality in the cardiac dysrhythmia trial

Encainide, analog of lysergic acid, is at least 10 times more potent than procainamide. Its absorption and hepatic metabolism is rapid; these metabolites are as active as the original drug.

Flecainide - Class IC

The Cardiac Arrhythmic Suppression Trial (CAST) was the long-term study that concluded encainide and flecainide substantially increase sudden death and total mortality rates. The Food and Drug Administration (FDA) stated that these drugs should be used only for life-threatening dysrhythmias.

Flecainide is 70% hepatically metabolized and 30% of any single dose is excreted unchanged by the kidneys, with a half-life of 12-27 hours.

Propafenone - Class IC

This drug has a structure similar to beta-blockers; it is approved only for life-threatening arrhythmias based on CAST recommendations. Propafenone has relatively weak beta-blocking and calcium channel blocking activity.

Propafenone is well absorbed with relatively low bioavailability (extensive presystemic clearance). Peak plasma concentration of this drug and metabolites is 1-4 hours and the half-life is 2-32 hours, with extensive first-pass metabolism by the hepatic oxidase pathway.

Adverse effects include GI and neurologic effects, asthma, conduction defect, and myocardial depression.

Ajmaline, cibenzoline, detajmium - Class IC

Most of these drugs are better known and more often used abroad. They have mixed properties; for example, ajmaline has class IA and IC properties, cibenzoline has class IC, III, and IV properties, and detajmium has class IA and IC properties.

Beta-blockers - Class II

These drugs are covered in Toxicity, Beta-blocker. Please refer to this article for toxicity and management.

Bretylium - Class III

Bretylium is a quaternary benzylammonium compound for treating lidocaine-refractory arrhythmias.

Amiodarone - Class III

Amiodarone, an iodinated benzofuran with similar structure to thyroxine, has side effects of photosensitivity, hyperthyroidism (up to 16%), pulmonary fibrosis, skin pigmentation (blue nail coloration), and corneal deposits. It may induce QT prolongation.^[21]

Oral absorption is slow, with a half-life of 31 hours. Amiodarone also has noncompetitive alpha- and beta-sympathetic receptor blocking properties, which can lead to systemic and coronary vasodilatation.

The CASCADE (Cardiac Arrest in Seattle: Conventional versus Amiodarone Drug Evaluation) study demonstrated that, for survivors of cardiac arrests, amiodarone was superior treatment to Class I agents. A meta-analysis of 6553 patients demonstrated that prophylactic amiodarone reduced the rate of arrhythmias/sudden death in high-risk patients with MI or congestive heart failure (CHF), leading to an overall reduction of 13% in total mortality.

A promising new drug, dronedarone, lacks amiodarone's organ toxicity, but its relative safety may be offset by its lower antiarrhythmic efficacy.^{[19, 20]}

N-acetyl procainamide - Class III

This is the N -acetylated derivative of procainamide, which can be used both orally and intravenously.

Adverse effects are GI complaints (eg, nausea, vomiting, diarrhea, anorexia) and CNS complaints.

Bioavailability is favorable (85%) and elimination is chiefly renal as unchanged drug. This drug appears not to induce systemic lupus erythematosus (SLE) or produce antinuclear antibody (ANA).

Sotalol - Class III

This agent is a racemic mixture of d- and l-isomers. It lengthens cardiac repolarization and refractoriness. It also is a beta-adrenergic blocker, thus giving class II bradycardic effect.

Adverse effects include fatigue, dizziness, dyspnea, chest pain, and palpitation.

Sotalol demonstrates good bioavailability with a large volume of distribution. It is predominantly excreted renally.

Ibutilide and dofetilide - Class III

These drugs were developed to produce a pure class III drug and both are currently under investigation. Ibutilide is available only in intravenous form, but dofetilide is available in oral and intravenous preparations.

They have a profound effect in the plateau phase causing an increased action potential duration and prolongation of the QT interval, leading to torsade de pointes.

Azimilide - Class III

A new class III antiarrhythmic agent that blocks the slow and fast components of cardiac-delayed rectifier potassium currents. This drug is used primarily for atrial fibrillation, atrial flutter, or both. It is available in oral form (tablets).

Using the dosing of 125 mg/day has shown to have the most pronounced antiarrhythmic effect.

The most frequent adverse effects of azimilide were as follows: headache (11%), asthenia (10%), infection (9%), diarrhea (7%), dizziness (6%), increase of the mean percent QTc (up to 7.5%), and torsade de pointes (up to 1.5%). The overall incidence of serious adverse reactions was 8%.

Calcium channel blockers - Class IV

These drugs are covered in Toxicity, Calcium Channel Blocker. Please refer to this article for toxicity and management.

Adenosine

Adenosine is used for terminating and differentiating supraventricular tachydysrhythmias by transiently slowing atrioventricular (AV) node conduction and the sinus rate. It acts upon adenosine receptors.

Ventricular tissue is unaffected. Adverse effects include headache, flushing, and lightheadedness/dizziness. It has an ultrashort half-life of a few seconds and is given as a rapid intravenous bolus. The effects of adenosine are antagonized by methylxanthines (eg, theophylline, caffeine) and potentiated by dipyridamole and carbamazepine.

Based on presentation, toxicity from antidysrhythmic agents can be grouped as follows (for more details on each respective agent refer to each individual section):

• Anticholinergic syndromes - Disopyramide, quinidine (cinchonism), and cibenzoline
• Ventricular and/or supraventricular dysrhythmias - Disopyramide, quinidine, flecainide, amiodarone, N -acetyl procainamide, and ibutilide/dofetilide
• Torsade de pointes - Essentially, can result from all antidysrhythmic agents
• Hypotension and/or shock - Disopyramide, quinidine, mexiletine/tocainide, encainide, flecainide, ajmaline/cibenzoline/detajmium, and bretylium
• CNS symptoms - Procainamide, quinidine, lidocaine, mexiletine/tocainide, encainide, flecainide, propafenone, ajmaline/cibenzoline/detajmium, bretylium, N -acetyl procainamide, and adenosine
• PR and/or QT prolongation - Disopyramide, procainamide, quinidine, encainide, flecainide, ajmaline/cibenzoline/detajmium, and propafenone
• GI symptoms - Procainamide, quinidine, propafenone, ajmaline/cibenzoline/detajmium, and N -acetyl procainamide
• Acute respiratory distress syndrome (ARDS) and/or pulmonary symptoms - Quinidine, amiodarone, lidocaine, and propafenone (asthma, CHF)
• Endocrine - Amiodarone

Disopyramide - Class IA

Minor changes in conduction begin, such as QT and PR prolongation. Minor anticholinergic adverse effects are urinary retention, blurred vision, and dry month.

Cardiovascular collapse and apnea usually appear within a few hours after serious overdose. Theoretically, the collapse can be delayed secondarily to the anticholinergic properties of this drug.

Ventricular and/or supraventricular dysrhythmias and conduction blocks may occur, such as torsade de pointes (see Torsade de pointes treatment in the Emergency Department Care section for more information about this specific arrhythmia). Ventricular fibrillation and stunned or nonresponsive myocardium are the final events.

Procainamide - Class IA

Adverse effects include GI disturbances, headache, mild hypotension, rash, insomnia, dizziness, ataxia, hallucinations, weakness, and prolongation of the QT interval and QRS complex.

In patients with myasthenia gravis, procainamide may cause respiratory weakness, insufficiency, arrest, and myasthenic crisis. In prolonged use of sustained released procainamide, red cell aplasia may occur. In patients with Brugada syndrome, procainamide may induce recurrent VF/VT.

Quinidine - Class IA

An adult who takes a dose of 2.5-4 g will exhibit toxic effects caused by chronic use and overdose. Allergic reactions that are not related to plasma concentration include drug fever, hepatitis, SLE, asthma, anaphylaxis, hemolytic anemia (in G-6-PD deficiency), and bullous lesions.

Diarrhea is the most common complaint with chronic quinidine use. Patients also may present with the cinchonism syndrome, which manifests as headache, fever, mydriasis, visual loss (quinidine amblyopia), hearing changes, delirium, nausea, vomiting, and hot flushed skin.

Massive acute overdose effects often are superimposed with underlying cardiac disease. These include AV block, idioventricular rhythm, asystole, and QT, PR, and QRS widening. Torsade de pointes is another type of dysrhythmia caused by quinidine, as with the other class IA drugs. Patients may develop hypotension and shock due to the myocardial depression and decreased peripheral vascular resistance (secondary to alpha-adrenergic receptor blockade).

Noncardiogenic pulmonary edema and respiratory failure has been reported despite a normal pulmonary capillary wedge pressure (PCWP).

Lidocaine - Class IB

Symptoms may appear with the upper limit of therapeutic levels. Early CNS symptoms include lightheadedness, dizziness, drowsiness, confusion, dysarthria, ataxia, hearing loss, and euphoria.

Late CNS symptoms include visual disturbances, agitation, muscle fasciculation, coma, and seizures.

Cardiovascular (CVS) symptoms include asystole, hypotension, and delayed bundle-branch conduction.

Aspiration pneumonitis can be a presentation because of decreased gag reflex with oral lidocaine.

Mexiletine and tocainide - Class IB, lidocaine analogs

Recent reports describe mexiletine and tocainide overdose (1982, 1985, 1991), which presented with paresthesias of tongue, nausea, seizures, and cardiovascular collapse. Therapeutic levels are 1-2 mg/mL for mexiletine and 5-12 mg/mL for tocainide.

Encainide - Class IC

An overdose may cause CNS symptoms (eg, obtundation, seizures) and CV symptoms, (eg, QT prolongation, bradycardia, hypotension). Encainide's effects are similar to those of class IA agents and tricyclic antidepressants (TCAs); however, encainide does not have the anticholinergic, alpha-adrenergic, or vasodilator capabilities of these drugs. Effective plasma levels vary between 60-300 ng/mL. Classically, all antidysrhythmic literature cites the example in which a 6-month-old child ingested a 25 mg tablet and, within 30 minutes, developed a wide complex tachycardia rapidly leading to ventricular tachycardia (VT). Thus, the lesson is not to delay with an apparently insignificant overdose of this drug.

Flecainide - Class IC

Flecainide toxicity can present as cardiorespiratory failure, ventricular fibrillation, asystole, atrioventricular block (AVB), marked prolongation of QRS and/or QT intervals, and tonic-clonic seizures. Therapeutic levels range 200-1000 ng/mL but reported plasma levels obtained postmortem indicate that toxic levels usually are greater than 1 mg/mL.

Propafenone - Class IC

GI effects - Twenty percent of patients with propafenone toxicity have constipation, nausea, vomiting and bitter taste (5-10%), and neurologic effects. Levels greater than 900 ng/mL can cause visual blurring, dizziness, and paresthesias. Asthma may be exacerbated and, rarely, cholestatic hepatitis may occur. Conduction defects are new left bundle branch block (LBBB), right bundle branch block (RBBB), AVB, or sinus node dysfunction. Myocardial depression worsens CHF. Overdoses cause hypotension, somnolence, and bradycardia worsening to asystole. Prolongation of QRS intervals can occur.

Ajmaline, cibenzoline, detajmium - Class IC

Patients with class IC agent overdose present with AVB, prolongation of the QT interval, shock, and seizures. Mild toxicity may present with GI symptoms such as nausea, vomiting, and diarrhea. Ataxia, loss of consciousness, and apnea may be another clinical presentation. Of unique interest, cibenzoline has anticholinergic effects (dry mouth, urinary retention) and can result in hyperglycemia exacerbation and asymptomatic liver enzyme elevation, in addition to symptoms mentioned above.

Beta-blockers - Class II

These drugs are covered in Toxicity, Beta-blocker. Please refer to this article for toxicity and management.

Amiodarone - Class III

Serious adverse reactions can lead to VT and torsade de pointes. In addition, ARDS and pulmonary fibrosis may occur because of a hypersensitivity reaction. Amiodarone-pulmonary toxicity, manifested by acute pulmonitis and chronic fibrosis, and amiodarone-associated hemoptysis can also occur. Symptoms may develop acutely or gradually, despite drug withdrawal. (Remember that this drug has a long half-life.) Endocrine effects include development of hypothyroidism (up 30% of patients), hyperthyroidism (5-16%), and thyrotoxicosis without the characteristic eye findings.

Photosensitivity and blue nail coloration are rare. Hepatic effects range from elevation of liver function tests to acute hepatic failure. Most extracardiac effects are related to dosage and tissue concentration and are reversible. Therapeutic plasma concentration is 1-2.5 mg/L.

Bretylium - Class III

Although reports are limited, most effects are neurologic, such as nonreactive pupils, depressed gag reflex, and neurologic depression; these effects are temporary. Hypotension is common and due to adrenergic blockade. Dramatic presentations include anuria, asystole, and fatality.

N-acetyl procainamide - Class III

Adverse reactions include GI (eg, nausea, vomiting, diarrhea, anorexia) and CNS (eg, fatigue, somnolence, lightheadedness, blurry vision, mild paresthesias). Effects can be present within therapeutic ranges and resolve rapidly upon discontinuation of drug. Sudden fatality was reported in 24% of patients. Also, torsade de pointes, VT, and ventricular fibrillation have been reported. Therapeutic levels are 10-37 mg/mL.

Sotalol - Class III

Whereas prolongation of action potential is responsible for most of the extracardiac adverse effects observed, the beta-adrenergic antagonism is responsible for the proarrhythmic potential of sotalol. The overall incidence of torsade de pointes, sotalol's most common arrhythmia, is 4.1-5.9%.

Several clinical measures that correlate with increased risk of torsade de pointes have been identified, such as history of CHF, drug dose, baseline serum creatinine, and female sex.

Survival with oral d-sotalol trial (SWORD), the largest placebo-controlled trial, determined that the greatest risk for arrhythmic fatality appeared to be in individuals with remote myocardial infarction (MI) and left ventricular ejection fraction (LVEF) of 31-40%. Patients with better LVEF had a lower risk of fatality. CNS adverse effects are less common because of the hydrophilic nature of sotalol.

Ibutilide and dofetilide - Class III

The risk of a ventricular arrhythmic event is greater within the first hour of the initial drug infusion. The incidence of torsade de pointes in early clinical trials (still ongoing) is 4-5%, and may be lower in patients who have good left ventricular function and higher heart rates.

Azimilide - Class III

The most frequent adverse effects of azimilide were as follows: headache (11%), asthenia (10%), infection (9%), diarrhea (7%), dizziness (6%), increase of the mean percent QTc (up to 7.5%), and torsade de pointes (up to 1.5%). The overall incidence of serious adverse reactions was 8%.

Calcium channel blockers - Class IV

These drugs are covered in Toxicity, Calcium Channel Blocker. Please refer to this article for toxicity and management.

Adenosine

Dose-related toxic symptoms include cutaneous flushing, dyspnea, chest pain, nausea, lightheadedness, and dizziness (20%).

Patients also may develop transient bradycardia, atrial flutter, atrial fibrillation, or AVB. No overdoses have been published.

Disopyramide - Class IA

Erythromycin interferes with the hepatic dealkylation of disopyramide, increasing serum levels and resulting in prolongation of the QTc interval. Rifampin decreases levels of disopyramide. Arrhythmias may be enhanced by hypokalemia.

Procainamide - Class IA

IV dosing is potentially dangerous if administered quickly (>50 mg/min) because the smaller initial volume of distribution, which is the heart in this case, leads to cardiac dysrhythmias. Drug interactions (eg, cimetidine, amiodarone, trimethoprim) may increase serum levels.

Quinidine - Class IA

This drug has a high bioavailability, with peak GI absorption of 3-4 hours. Hepatic elimination is responsible for 60-80% and the kidneys eliminate 20-40%. Cimetidine, verapamil, and ketoconazole increase the serum concentration.

Lidocaine - Class IB

Toxic reactions are likely to occur in CHF, shock, and liver disease because of decreased hepatic blood flow. Cimetidine and propranolol are associated with toxic reactions. After an IV bolus, lidocaine rapidly is distributed to highly perfused tissues (eg, brain, heart, lung, liver). Therefore, the total lidocaine dose (3 mg/kg) should not exceed 4 mg/min.

Mexiletine and tocainide - Class IB, lidocaine analogs

CHF, renal disease, and cirrhosis decrease clearance of these drugs. Cimetidine and digoxin have no significant concomitant effect with mexiletine.

Encainide - Class IC

The population is stratified in two types of metabolizers of this drug, extensive and nonextensive. This may contribute to different toxicity; for example, nonextensive metabolizers have plasma levels of encainide and its metabolites that are 20 times higher than extensive metabolizers do.

Flecainide - Class IC

Individuals who smoke have greater clearance and distribution of flecainide than nonsmokers. Combined use with amiodarone increases flecainide levels. Alkalization of urine increases elimination. Renal insufficiency and CHF decrease flecainide clearance.

Propafenone - Class IC

Multiple drug interactions may affect clearance of this drug, and use of other antidysrhythmic agents increases cardiac effects. Propafenone decreases the clearance with quinidine, and rifampin lowers plasma concentration, reducing propafenone's cardiac effect. Warfarin, metoprolol, and digoxin plasma concentration is increased by propafenone, thus increasing their activity and toxicity. Although no good correlation of plasma concentration and suppression of arrhythmias exists, therapeutic levels are thought to be 200-500 ng/mL.

Ajmaline, cibenzoline, detajmium - Class IC

For ajmaline, no correlation exists between ingested drug and fatal outcome. Phenobarbital may increase activity of the hepatic microsomal enzyme system, accelerating the metabolism of ajmaline. Cibenzoline concentrations correlate very well with antiarrhythmic effect and, possibly, with toxicity. Cimetidine decreases total body clearance.

Amiodarone - Class III

Renal elimination is responsible for only 1%. Amiodarone levels increase with the digoxin, diltiazem, quinidine, procainamide, oral anticoagulants, and phenytoin.

Bretylium - Class III

Hypotension is caused by adrenergic blockade.

N-acetyl procainamide - Class III

Bioavailability is 85% and renal elimination is performed by the kidneys, unchanged in the urine. This drug does not appear to induce systemic lupus erythematosus (SLE) or produce antinuclear antibodies (ANA).

Sotalol - Class III

Extent of absorption is excellent (90-100%) with 100% bioavailability. The half-life is 12-16 hours. Elimination is almost exclusively renal; therefore, decrease doses in patients with altered renal function. Sotalol does not interact with other drugs. Therapeutic serum level is 1-4 mg/mL.

Ibutilide and dofetilide - Class III

Despite extensive hepatic metabolism and essentially unchanged excretion in urine, these drugs do not interact with other drugs. The half-life is 4-8 hours for ibutilide and 7-13 hours for dofetilide.

Azimilide - Class III

A significant interaction was found between the efficacy of azimilide against the recurrence of arrhythmia when a baseline history of ischemic heart disease or CHF is present.

Adenosine

Several contraindications and cautions are associated with adenosine (eg, sick sinus syndrome, second degree AVB, third degree AVB).

Be cautious of asthmatics or history of wheezing and/or bronchoconstriction (inhaled adenosine caused bronchospasm)

Reduce dose if using central venous line to 3 mg instead of 6 (may produce a profound effect on atrioventricular conduction).