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Disopyramide

Disopyramide is a synthetic, oral antiarrhythmic medication classified as a class Ia agent according to the Vaughan Williams system, primarily indicated for the treatment of life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia and ventricular fibrillation.^[1]^[2] It is available in immediate-release capsules containing 100 mg or 150 mg of disopyramide base (as the phosphate salt) and extended-release formulations for once- or twice-daily dosing.^[2] Developed in 1962 from a series of over 500 compounds as a non-quinidine-like alternative to existing antiarrhythmics like quinidine and procainamide, disopyramide has been in clinical use since the 1970s for suppressing abnormal cardiac rhythms that are deemed serious enough to warrant pharmacological intervention.^[1] The drug's mechanism of action involves selective blockade of cardiac sodium channels, which slows conduction velocity, prolongs the action potential duration, and increases the effective refractory period in myocardial tissue, thereby reducing the likelihood of re-entrant arrhythmias.^[1]^[2] Beyond ventricular arrhythmias, disopyramide is also used off-label for vagally mediated atrial fibrillation and as a third-line therapy in hypertrophic obstructive cardiomyopathy (HOCM) to reduce left ventricular outflow tract gradients, with studies showing significant reductions from 75 ± 33 mmHg to 40 ± 32 mmHg (p < 0.0001).^[1] It is not recommended for asymptomatic premature ventricular contractions or prophylactic use after myocardial infarction, as clinical trials like CAST demonstrated no mortality benefit and potential proarrhythmic risks.^[1]^[2] Pharmacologically, disopyramide is a racemic mixture with a molecular formula of C₂₁H₂₉N₃O, achieving peak plasma concentrations within 1 to 2 hours after oral administration and exhibiting a half-life of 4 to 10 hours in patients with normal renal function (prolonged to 8 to 18 hours in renal impairment with creatinine clearance less than 40 mL/min).^[3]^[2] Approximately 50% is excreted unchanged in the urine, with metabolism primarily via CYP3A4, leading to potential drug interactions with inhibitors like erythromycin.^[2] Common adverse effects stem from its potent anticholinergic properties and include dry mouth (up to 32% of patients), urinary hesitancy or retention (14%), and constipation (11%), while serious risks encompass QT prolongation, negative inotropic effects precipitating heart failure, and rare instances of agranulocytosis or hypoglycemia.^[1]^[2] Contraindications include cardiogenic shock, second- or third-degree atrioventricular block without a pacemaker, and congenital long QT syndrome, with initiation typically requiring hospital monitoring due to proarrhythmic potential.^[1]^[2]

Medical uses

Ventricular arrhythmias

Disopyramide is FDA-approved for the treatment of documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia and ventricular fibrillation.^[4]^[1] These conditions involve abnormal electrical activity in the ventricles that can lead to sudden cardiac death if untreated, and disopyramide helps suppress this activity through its class Ia antiarrhythmic properties.^[1] It may be used in select patients with frequent premature ventricular contractions (PVCs) or non-sustained ventricular tachycardia (NSVT) deemed life-threatening despite other therapies, where clinical studies have demonstrated efficacy in reducing ectopy and suppressing repetitive forms.^[5] The drug's sodium channel blocking properties contribute to prolonging the action potential duration, aiding in arrhythmia control.^[1] Evidence from the Cardiac Arrhythmia Suppression Trial (CAST) revealed increased mortality risks with other class I antiarrhythmics like encainide and flecainide in post-myocardial infarction patients with PVCs; disopyramide, as a class Ia agent, was not studied in CAST.^[4] Overall, while no antiarrhythmic has proven to improve survival in benign or asymptomatic ventricular arrhythmias, disopyramide remains a targeted therapy for symptomatic, life-threatening manifestations.^[4] Disopyramide is also used off-label for suppressing vagally mediated atrial fibrillation.^[1] For dosing in ventricular arrhythmias, treatment typically begins with 100 to 200 mg orally every 6 hours for immediate-release formulations, adjusted based on body weight, renal function, and response, with a total daily dose not exceeding 800 mg.^[4] Initiation should occur in a hospital setting for life-threatening cases, with continuous ECG monitoring for QT interval prolongation, as disopyramide can exacerbate this risk and precipitate torsades de pointes.^[4]^[1]

Obstructive hypertrophic cardiomyopathy

Disopyramide is used off-label but guideline-recommended for managing left ventricular outflow tract (LVOT) obstruction in obstructive hypertrophic cardiomyopathy (oHCM), a condition affecting approximately 1 in 500 individuals overall for hypertrophic cardiomyopathy, with obstructive forms comprising about two-thirds of cases.^[6] In oHCM, disopyramide reduces the dynamic LVOT gradient through its potent negative inotropic effects, which decrease myocardial contractility and thereby alleviate obstruction without causing significant vasodilation.^[7] It is frequently combined with beta-blockers or other atrioventricular nodal blocking agents to achieve additive negative inotropic benefits and prevent rapid conduction in atrial fibrillation, enhancing overall gradient reduction in patients who remain symptomatic on monotherapy.^[7] According to the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy, disopyramide receives a class I recommendation (strong, based on moderate-quality evidence from nonrandomized studies) for symptomatic oHCM patients with resting or provocable LVOT gradients of at least 50 mmHg who have not responded adequately to maximal tolerated doses of beta-blockers or non-dihydropyridine calcium channel blockers.^[7] Cardiac myosin inhibitors (e.g., mavacamten or aficamten, approved for adults) are now an additional option alongside disopyramide or septal reduction therapy. This positioning as second-line therapy underscores its role in preventing progression to invasive interventions like septal reduction therapy in eligible patients.^[7] Clinical studies demonstrate that disopyramide improves exercise tolerance and mitigates key symptoms such as dyspnea and chest pain, with multicenter data showing symptomatic relief in over 80% of treated patients and a significant reduction in LVOT gradients by an average of 40-50 mmHg at rest and during provocation.^[8] Long-term follow-up confirms sustained benefits, including delayed need for surgery and enhanced quality of life, particularly when initiated early in refractory cases.^[9] Typical dosing ranges from 600 to 800 mg per day in divided doses (e.g., 100-200 mg every 6 hours), adjusted based on response and tolerance, with routine ECG monitoring required to detect and prevent excessive QT interval prolongation.^[1]

Contraindications and interactions

Contraindications

Disopyramide is contraindicated in patients with cardiogenic shock, as its negative inotropic effects can exacerbate hemodynamic instability.^[10] It is also contraindicated in those with second- or third-degree atrioventricular block without a functioning pacemaker, due to the risk of further impairing cardiac conduction.^[10] Additional absolute contraindications include congenital QT prolongation, where the drug's propensity to prolong the QT interval heightens the risk of torsades de pointes, and known hypersensitivity to disopyramide or its components.^[10]^[1] Because of its anticholinergic activity, disopyramide should not be used in patients with narrow-angle glaucoma, urinary retention (particularly in those with prostatic hypertrophy), or myasthenia gravis unless adequate overriding measures are taken.^[10]^[11] Relative contraindications include sick sinus syndrome, in which disopyramide should be used with extreme caution due to uncertain effects on sinus node function.^[10] Caution is also warranted in Wolff-Parkinson-White syndrome, particularly with atrial fibrillation, as the drug may unpredictably influence accessory pathway conduction.^[11] Hypotension constitutes a relative contraindication, given disopyramide's potential to induce or aggravate it.^[10] Electrolyte imbalances, such as hypokalemia, are relative contraindications that require correction before therapy to mitigate reduced efficacy and enhanced arrhythmogenic risk.^[10] Pre-existing QT prolongation, whether acquired or not, or concomitant administration of other QT-prolonging agents, warrants avoidance of disopyramide to prevent torsades de pointes.^[1] In patients with uncompensated heart failure, the drug is generally contraindicated unless the condition is directly attributable to the arrhythmia under treatment.^[10] In special populations, safety and effectiveness of disopyramide have not been established in pediatric patients. Use in neonates and infants is not recommended due to potential risks from immature metabolism and excretion pathways.^[10]^[1] Disopyramide is classified as pregnancy category C; it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.^[10] The drug is excreted in human milk, and a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.^[10]

Drug interactions

Disopyramide is metabolized primarily by the hepatic enzyme CYP3A4, and coadministration with CYP3A4 inhibitors such as ketoconazole or ritonavir can increase disopyramide plasma concentrations by reducing its metabolism, potentially leading to enhanced toxicity including QT prolongation and anticholinergic effects.^[12]^[13] Dose adjustment, such as reduction, is recommended when using strong CYP3A4 inhibitors to maintain therapeutic levels and minimize risks.^[14] Disopyramide exhibits anticholinergic properties, and its concurrent use with other anticholinergic agents like atropine or tricyclic antidepressants can result in additive effects, exacerbating symptoms such as dry mouth, constipation, urinary retention, and blurred vision.^[12]^[15] Close monitoring for these symptoms is advised, with potential need for dose adjustments or alternative therapies in affected patients.^[13] Combination therapy with other antiarrhythmic drugs, particularly class Ia agents like quinidine, can potentiate QT interval prolongation and increase the risk of proarrhythmic events due to additive effects on cardiac conduction and repolarization.^[12] Such combinations should be avoided unless benefits outweigh risks in life-threatening arrhythmias, with continuous ECG monitoring required.^[13] In patients with diabetes, disopyramide can enhance the hypoglycemic effects of insulin or sulfonylureas by stimulating pancreatic beta-cell insulin release, potentially leading to severe hypoglycemia.^[16]^[17] Blood glucose levels should be monitored closely, with antidiabetic doses adjusted as necessary.^[12]

Pharmacology

Mechanism of action

Disopyramide is classified as a class Ia antiarrhythmic drug, primarily acting through blockade of voltage-gated fast sodium channels in cardiac myocytes. This inhibition occurs in a use-dependent fashion, whereby the drug binds more effectively to open or inactivated channels during rapid depolarizations, such as in tachyarrhythmias, thereby accentuating its therapeutic effect at higher heart rates. By reducing sodium influx, disopyramide slows the upstroke velocity (phase 0) of the action potential, which decreases conduction velocity and myocardial excitability.^[1]^[18] In addition to sodium channel effects, disopyramide prolongs the action potential duration (APD) and effective refractory period (ERP), preventing re-entrant arrhythmias through enhanced post-repolarization refractoriness. It also moderately blocks potassium channels, particularly the rapid delayed rectifier current (I_Kr), which contributes to prolongation of the QT interval by 20-30 ms at therapeutic doses. This potassium channel interaction underlies both its antiarrhythmic benefits and potential proarrhythmic risks, such as torsades de pointes.^[1]^[19]^[20] The negative inotropic properties of disopyramide stem from diminished calcium influx into cardiomyocytes, primarily via inhibition of L-type calcium channels, leading to reduced myocardial contractility. This effect decreases the force of ventricular contraction, which is particularly relevant in conditions involving hyperdynamic obstruction.^[21] Disopyramide further exhibits anticholinergic activity by antagonizing muscarinic acetylcholine receptors (with greater potency at M₁ over M₂ subtypes), thereby suppressing vagal tone on the heart. This results in increased sinoatrial node automaticity, elevated heart rate, and accelerated atrioventricular nodal conduction, counterbalancing some of its direct depressive effects on cardiac tissue.^[1]^[22]

Pharmacokinetics

Disopyramide exhibits high oral bioavailability of 70-90%, with peak plasma concentrations (C_max) achieved in 1-2 hours (T_max). Food intake delays the rate of absorption but does not alter the overall extent of bioavailability.^[23]^[13] The volume of distribution (V_d) is approximately 0.97 L/kg, indicating moderate tissue penetration. Plasma protein binding ranges from 50-65%, primarily to alpha-1-acid glycoprotein, which can vary with disease states such as inflammation.^[1]^[24] Disopyramide undergoes hepatic metabolism primarily via the cytochrome P450 3A4 enzyme, yielding the active metabolite mono-N-dealkylated disopyramide (MOND), which accounts for approximately 20% of the administered dose. The elimination half-life ranges from 4-10 hours in healthy adults, with an average of 6.7 hours, influencing the dosing interval to maintain therapeutic levels.^[24]^[13] Approximately 80% of the dose is excreted via the renal route, consisting of 50% as unchanged drug and 30% as metabolites, including MOND. This substantial renal elimination necessitates dose adjustments in patients with impaired kidney function; for instance, the dose should be reduced by 50% when creatinine clearance (CrCl) is less than 40 mL/min to prevent accumulation and toxicity.^[24]^[1]

Adverse effects

Cardiac adverse effects

Disopyramide carries a risk of proarrhythmia, occurring in approximately 8% of patients treated with class I antiarrhythmic agents including this drug, often manifesting as torsades de pointes due to QT interval prolongation or new ventricular tachycardia.^[25] This effect stems from the drug's class Ia sodium channel blockade, which slows conduction and can facilitate arrhythmogenic triggers in susceptible individuals.^[26] Documented cases highlight torsades de pointes as a serious complication, particularly when QT prolongation exceeds 25%, necessitating close electrocardiographic monitoring and discontinuation if ectopy persists.^[27]^[28] The negative inotropic properties of disopyramide can exacerbate heart failure, especially in patients with preexisting heart failure or left ventricular dysfunction, by reducing myocardial contractility and cardiac output by about 10% during intravenous administration.^[28] This hemodynamic depression is more pronounced in those with underlying left ventricular dysfunction, where the drug is contraindicated due to the potential for acute decompensation.^[1] In clinical studies, intravenous disopyramide has demonstrated potent cardiac depressant effects in such patients, underscoring the need for cautious use or avoidance in this population. Patients with pre-existing conduction abnormalities face a risk of atrioventricular (AV) block progression with disopyramide, which may advance from first-degree to second- or third-degree block, sometimes requiring pacemaker implantation for management.^[28] The drug is contraindicated in second- or third-degree AV block without a pacemaker, as it prolongs infranodal conduction time and can precipitate complete heart block in those with bifascicular block patterns.^[29] Electrophysiologic evaluations confirm significant prolongation of AV nodal and His-Purkinje system refractoriness, heightening this risk in vulnerable patients.^[30] Hypotension is another key cardiac adverse effect, often involving a systolic blood pressure drop exceeding 20 mm Hg, driven by combined negative inotropic and chronotropic actions that impair cardiac output and vascular tone. This is particularly prevalent with rapid intravenous dosing, where decreases in systolic pressure have been reported alongside reductions in cardiac index, though oral administration rarely causes significant hypotension in patients without heart failure.^[28] In hemodynamic studies, peak effects include approximately a 10% decline in cardiac performance metrics following intravenous boluses, emphasizing the need for gradual infusion and blood pressure monitoring in acute settings.

Extracardiac adverse effects

Disopyramide's extracardiac adverse effects are primarily attributed to its potent anticholinergic properties, which can manifest in various peripheral systems. Common manifestations include dry mouth, occurring in approximately 32% of patients, as well as blurred vision and constipation, each reported in 3% to 11% of cases. Urinary hesitancy affects about 14% of users, while urinary retention, frequency, or urgency occurs in 3% to 9%, with a heightened risk in elderly males due to prostate enlargement exacerbating retention.^[31]^[32] Central nervous system effects, often linked to anticholinergic activity, include dizziness and fatigue, each noted in 3% to 9% of patients, alongside headache in a similar range. These symptoms, including potential confusion, are more prevalent in individuals over 65 years, where reduced cholinergic reserve amplifies cognitive and sedative impacts.^[31]^[32] In patients with diabetes, particularly those insulin-dependent, disopyramide can induce hypoglycemia by stimulating insulin secretion through blockade of pancreatic ATP-sensitive potassium channels, with cases reported even at therapeutic doses. Although the overall incidence is low based on literature reviews documenting around 14 cases up to the late 1980s, it poses a notable risk in this subgroup, often resolving upon discontinuation.^[32]^[34] Hypersensitivity reactions are infrequent, affecting less than 1% of users, and may include rash or itching in 1% to 3% of cases, as well as rare instances of agranulocytosis, which is reversible upon drug withdrawal.^[31]^[1]

Overdose and management

Symptoms of overdose

Overdose of disopyramide can lead to severe cardiac manifestations due to its class Ia antiarrhythmic properties, including excessive widening of the QRS complex beyond 100 ms, which serves as an early indicator of toxicity.^[31] This widening is often accompanied by prolongation of the QT interval, severe bradycardia, atrioventricular (AV) block, hypotension, and potentially life-threatening ventricular arrhythmias such as torsades de pointes.^[35] These cardiac effects arise from enhanced sodium channel blockade and negative inotropic actions at supratherapeutic levels, exacerbating conduction delays and myocardial depression.^[1] Disopyramide's potent anticholinergic activity becomes markedly pronounced in overdose, resulting in central and peripheral symptoms such as delirium, hyperthermia, mydriasis (dilated pupils), ileus (decreased bowel motility), and urinary retention.^[32] In severe cases, these effects can progress to agitation, hallucinations, and seizures, reflecting inhibition of muscarinic receptors in the central nervous system and autonomic ganglia.^[36] Loss of consciousness and respiratory depression may also occur as toxicity intensifies.^[37] A notable metabolic consequence of disopyramide overdose is profound hypoglycemia, particularly in patients with diabetes or those with predisposing factors like renal impairment, where blood glucose levels can drop below 50 mg/dL due to stimulation of insulin secretion from pancreatic beta cells.^[38] This effect is mediated by the drug's interference with potassium channels in beta cells, leading to hypoglycemic coma in extreme cases.^[34] Therapeutic plasma concentrations of disopyramide typically range from 2 to 5 mcg/mL, while levels exceeding 7 mcg/mL are associated with increased risk of toxicity, including QRS widening and AV block.^[1] Monitoring plasma levels is crucial, as toxicity thresholds may vary with individual factors such as renal function, and concentrations above 9-10 mcg/mL often correlate with severe manifestations.^[14]

Treatment approaches

Management of disopyramide overdose focuses on decontamination, reversal of sodium channel blockade, and treatment of life-threatening arrhythmias such as torsades de pointes. Initial supportive care includes airway protection, hemodynamic stabilization, and continuous ECG monitoring.^[1] If ingestion occurred within 2 hours, immediate gastric lavage or administration of activated charcoal is recommended to prevent absorption. Multiple-dose activated charcoal should be considered subsequently due to the potential for delayed absorption and enterohepatic recirculation, enhancing elimination even hours after ingestion.^[1] For QRS widening resulting from sodium channel blockade, intravenous sodium bicarbonate at 1-2 mEq/kg should be administered rapidly, with repeat doses as needed to target a serum pH of 7.45-7.55, thereby improving conduction and hemodynamic stability.^[39] In cases of torsades de pointes, magnesium sulfate 2 g should be given intravenously over 10 minutes, even if serum magnesium levels are normal; this may be followed by overdrive pacing or isoproterenol infusion to increase heart rate and suppress the arrhythmia.^[40]^[41] Hemodialysis is generally ineffective for disopyramide removal owing to its high protein binding and large volume of distribution, with studies showing minimal extraction (less than 3% of the dose) during sessions.^[42] For refractory severe cardiotoxicity, intravenous lipid emulsion therapy may be considered as a rescue intervention to mitigate toxicity.^[39] Anticholinergic symptoms, such as dry mouth or urinary retention, should be monitored supportively without specific antidotal therapy.^[1]

History

Development

Disopyramide was developed in 1962 from a series of over 500 compounds and synthesized in the early 1960s by G.D. Searle & Company as an antiarrhythmic agent designed to mimic the pharmacological effects of quinidine while achieving enhanced oral bioavailability and reducing the cinchonism side effects commonly associated with quinidine. Preclinical studies, beginning with the work of Mokler and Van Arman in 1962, evaluated its antiarrhythmic activity in animal models of induced ventricular arrhythmias, revealing class Ia properties through prolongation of the action potential duration and effective suppression of ectopic rhythms.^[43] Further investigations between 1962 and 1970 in various species, including dogs and guinea pigs, confirmed its potency against ventricular tachyarrhythmias while highlighting early-onset anticholinergic effects, such as dry mouth and urinary retention, as notable tolerability concerns.^[44] Initial human evaluations, including a clinical trial reported by Katz and colleagues in 1963, demonstrated disopyramide's ability to suppress ectopic beats in patients with cardiac arrhythmias, supporting its transition to broader phase I testing. These early 1960s trials in volunteers and arrhythmia patients established safety and preliminary efficacy for oral administration, culminating in its first marketing approval in Europe in 1970. A seminal 1971 study published in the Archives of International Pharmacodynamics and Therapeutics by Ranney et al. elucidated the pharmacokinetic-pharmacologic correlations of disopyramide phosphate, detailing its rapid absorption, plasma protein binding, and correlation between serum levels and antiarrhythmic action in both animal and human models.^[44]

Regulatory approval

Disopyramide was first approved in the United Kingdom in 1971 under the brand name Rythmodan for the treatment of ventricular arrhythmias. In the United States, the FDA approved disopyramide in 1977 as Norpace for the treatment of life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia.^[45] A black box warning regarding its proarrhythmic potential and increased mortality risk, particularly in post-myocardial infarction patients as evidenced by the CAST trial, was added in the late 1980s.^[46] The 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy updated recommendations to include disopyramide as a Class 2a (Level of Evidence B) option for symptomatic obstructive hypertrophic cardiomyopathy in patients with persistent symptoms despite beta-blockers or non-dihydropyridine calcium channel blockers, reflecting its expanded role beyond initial antiarrhythmic indications.^[47] Post-market developments include the availability of generic disopyramide since the 1990s, broadening access.^[48] A 2024 review of antiarrhythmic agents highlighted disopyramide's significant toxicity profile, including anticholinergic effects and negative inotropy, contributing to restricted use in certain regions due to safety concerns and supply limitations.^[49]

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