Hubbry Logo
DisopyramideDisopyramideMain
Open search
Disopyramide
Community hub
Disopyramide
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Contribute something
Disopyramide
Disopyramide
Disopyramide
View on Wikipedia
from Wikipedia

Disopyramide
Clinical data
Trade namesNorpace
AHFS/Drugs.comMonograph
MedlinePlusa682408
Pregnancy
category
  • AU: B2
Routes of
administration		Oral, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityHigh
Protein binding50% to 65%
(concentration-dependent)
MetabolismHepatic (CYP3A4-mediated)
Elimination half-life6.7 hours (range 4 to 10 hours)
ExcretionRenal (80%)
Identifiers
  • (RS)-4-(Diisopropylamino)-2-phenyl-2-(pyridin-2-yl)butanamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.021.010 Edit this at Wikidata
Chemical and physical data
FormulaC21H29N3O
Molar mass339.483 g·mol−1
3D model (JSmol)
Melting point94.5 to 95 °C (202.1 to 203.0 °F)
  • O=C(N)C(c1ncccc1)(c2ccccc2)CCN(C(C)C)C(C)C
  • InChI=1S/C21H29N3O/c1-16(2)24(17(3)4)15-13-21(20(22)25,18-10-6-5-7-11-18)19-12-8-9-14-23-19/h5-12,14,16-17H,13,15H2,1-4H3,(H2,22,25) checkY
  • Key:UVTNFZQICZKOEM-UHFFFAOYSA-N checkY
  (verify)

Disopyramide (INN, trade names Norpace and Rythmodan) is an antiarrhythmic medication used in the treatment of ventricular tachycardia.[2] It is a sodium channel blocker and is classified as a Class 1a anti-arrhythmic agent.[3][4] Disopyramide has a negative inotropic effect on the ventricular myocardium, significantly decreasing the contractility.[5][6] Disopyramide also has general anticholinergic effects which contribute to unwanted adverse effects. Disopyramide is available in both oral and intravenous forms. In 1972, when it was one of the only alternatives to quinidine, it was praised for being more potent and somewhat less toxic.[6] However, a 2012 review of antiarrhythmic drugs noted that disopyramide is among the most toxic agents, with a high burden of side effects and increased mortality (compared to placebo) when used to treat atrial fibrillation.[7]

Mechanism of action

[edit]

Disopyramide's Class 1a activity is similar to that of quinidine in that it targets sodium channels to inhibit conduction.[4][6] Disopyramide depresses the increase in sodium permeability of the cardiac myocyte during Phase 0 of the cardiac action potential, in turn decreasing the inward sodium current. This results in an increased threshold for excitation and a decreased upstroke velocity.[4] Disopyramide prolongs the PR interval by lengthening both the QRS and P wave duration.[6] This effect is particularly well suited in the treatment of ventricular tachycardia as it slows the action potential propagation through the atria to the ventricles. Disopyramide does not act as a blocking agent for beta or alpha adrenergic receptors, but does have a significant negative inotropic effect on the ventricular myocardium.[8] Anesthetized dogs treated with disopyramide (1 mg/kg) had reduced contractile force of 42%, and the decrease in contractile force from 1 mg/kg of disopyramide was roughly double the decrease seen with quinidine in much higher doses of 5, 10, or 15 mg/kg.[6]

Levites proposed a possible secondary mode of action for disopyramide, against reentrant arrhythmias after an ischemic insult. Disopyramide decreases the inhomogeneity between infarcted and normal myocardium refractory periods; in addition to lengthening the refractory period.[5] This decreases the chance of re-entry depolarization, because signals are more likely to encounter tissue in a refractory state which cannot be excited.[2] This provides a possible treatment for atrial and ventricular fibrillation, as it restores pacemaker control of the tissue to the SA and AV nodes.[9]

Obstructive hypertrophic cardiomyopathy

[edit]

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, occurring in 1:500 individuals in the general population. It is estimated that there are 600,000 individuals in the United States with hypertrophic cardiomyopathy. The most common variant of HCM presents with left ventricular (LV) intracavitary obstruction due to systolic anterior motion of the mitral valve, and mitral-septal contact, diagnosed readily with echocardiography. Pharmacologic treatment with negative inotropic drugs is first-line therapy. Beta-blockers are used first, and while they improve symptoms of shortness of breath, chest pain and exercise intolerance, they do not reduce resting LV intraventricular pressure gradients and often are inadequate to control symptoms. Many investigators and clinicians believe that disopyramide controlled release is the most potent agent available for reducing resting pressure gradients and improving symptoms.[10][11][12][13] Disopyramide has been actively used for more than 30 years.[14] Disopyramide administration for obstructive HCM has a IB recommendation in the 2020 American Heart Association/American College of Cardiology Foundation guidelines for treatment of obstructive HCM.[15] A IB treatment recommendation indicates that a treatment is recommended, and may be useful, and beneficial.

Negative inotropes improve left ventricular (LV) obstruction by decreasing LV ejection acceleration and hydrodynamic forces on the mitral valve. Disopyramide's particular efficacy is due to its potent negative inotropic effects; in head-to-head comparison, it is more effective for gradient reduction than either beta-blocker or verapamil.[16] Disopyramide is most often administered with beta-blockade. When used in patients resistant to beta-blockade, disopyramide is effective in 60% of cases, reducing symptoms and gradient to the extent that invasive procedures such as surgical septal myectomy are not required.[13]

Disopyramide, despite its efficacy, has one main side effect that has limited its use in the US, though it has seen wider application in Canada, UK and Japan. Vagal blockade predictably causes dry mouth, and in men with prostatism, may cause urinary retention. Teichman et al. showed that pyridostigmine used in combination with disopyramide substantially alleviates vagolytic side effects without compromising antiarrhythmic efficacy.[17] This combination has also been shown to be effective and safe in obstructive HCM in a large cohort of patients.[13] Some clinicians prescribe pyridostigmine sustained release (marketed in the US as Mestinon Timespan) to every patient begun on disopyramide.[18] This combination increases acceptance of higher disopyramide dosing, important since there is a dose-response correlation in obstructive HCM, higher doses yielding lower gradients.

Another concern about disopyramide has been the hypothetical potential for inducing sudden death from its type 1 anti-arrhythmic effects. However, a multicenter registry and two recent cohort registries have largely reduced this concern, by showing sudden death rates lower than that observed from the disease itself.[10][11][13]

These concerns about the drug must be viewed from the clinical perspective that disopyramide is generally the last agent that is tried for patients before they are referred for invasive septal reduction with surgical septal myectomy (an open-heart operation) or alcohol septal ablation (a controlled heart attack). Both of these invasive procedures have risk of morbidity and mortality.

For selected patients, a trial of oral disopyramide is a reasonable approach before proceeding to invasive septal reduction. Patients who respond to disopyramide are continued on the drug. Those who continue to have disabling symptoms or who experience side effects are promptly referred for septal reduction. Using such a stepped strategy, investigators have reported that survival does not differ from that observed in the age-matched normal United States population.[13]

Side effects

[edit]

Disopyramide has the following side effects:[19]

Mild side effects
Serious side effects

Adverse effects

[edit]

Cardiac adverse effects

[edit]
  • Acute decompensated heart failure: Disopyramide should not be given to patients with impaired left ventricular (LV) systolic function and low ejection fraction. Heart failure is not seen when disopyramide is used in patients with normal or supernormal LV systolic function.
  • Severe hypotension – Disopyramide should not be given to patients with impaired LV systolic function and low ejection fraction. Hypotension is not seen in patients with normal or supernormal LV systolic function.

Extracardiac adverse effects

[edit]

Disopyramide has atropine-like anticholinergic effects.[20]

Additionally, disopyramide may enhance the hypoglycemic effect of gliclazide, insulin, and metformin.[citation needed]

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Disopyramide

View on Grokipedia
from Grokipedia
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. 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. 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. 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 in myocardial tissue, thereby reducing the likelihood of re-entrant arrhythmias. Beyond ventricular arrhythmias, disopyramide is also used off-label for vagally mediated and as a third-line in hypertrophic obstructive (HOCM) to reduce left gradients, with studies showing significant reductions from 75 ± 33 mmHg to 40 ± 32 mmHg (p < 0.0001). 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. Pharmacologically, disopyramide is a racemic mixture with a molecular formula of C21H29N3O, achieving peak plasma concentrations within 1 to 2 hours after and exhibiting a of 4 to 10 hours in patients with normal renal function (prolonged to 8 to 18 hours in renal impairment with clearance less than 40 mL/min). Approximately 50% is excreted unchanged in the urine, with metabolism primarily via , leading to potential drug interactions with inhibitors like erythromycin. Common adverse effects stem from its potent properties and include dry mouth (up to 32% of patients), urinary hesitancy or retention (14%), and (11%), while serious risks encompass QT prolongation, negative inotropic effects precipitating , and rare instances of or . Contraindications include , second- or without a pacemaker, and congenital , with initiation typically requiring hospital monitoring due to proarrhythmic potential.

Medical uses

Ventricular arrhythmias

Disopyramide is FDA-approved for the treatment of documented life-threatening ventricular arrhythmias, such as sustained and . 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. It may be used in select patients with frequent premature ventricular contractions () 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. The drug's sodium channel blocking properties contribute to prolonging the action potential duration, aiding in control. Evidence from the Cardiac Arrhythmia Suppression Trial () revealed increased mortality risks with other class I antiarrhythmics like encainide and in post-myocardial patients with ; disopyramide, as a class Ia agent, was not studied in . Overall, while no antiarrhythmic has proven to improve survival in benign or ventricular arrhythmias, disopyramide remains a for symptomatic, life-threatening manifestations. Disopyramide is also used off-label for suppressing vagally mediated . 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. Initiation should occur in a setting for life-threatening cases, with continuous ECG monitoring for prolongation, as disopyramide can exacerbate this risk and precipitate .

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 , with obstructive forms comprising about two-thirds of cases. In oHCM, disopyramide reduces the dynamic LVOT gradient through its potent negative inotropic effects, which decrease and thereby alleviate obstruction without causing significant . It is frequently combined with beta-blockers or other atrioventricular nodal blocking agents to achieve additive negative inotropic benefits and prevent rapid conduction in , enhancing overall gradient reduction in patients who remain symptomatic on monotherapy. According to the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of , 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 . Cardiac inhibitors (e.g., 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. Clinical studies demonstrate that disopyramide improves exercise tolerance and mitigates key symptoms such as dyspnea and , 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. Long-term follow-up confirms sustained benefits, including delayed need for surgery and enhanced , particularly when initiated early in cases. 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 prolongation.

Contraindications and interactions

Contraindications

Disopyramide is contraindicated in patients with cardiogenic shock, as its negative inotropic effects can exacerbate hemodynamic instability. 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. 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. Because of its anticholinergic activity, disopyramide should not be used in patients with narrow-angle glaucoma, (particularly in those with prostatic hypertrophy), or unless adequate overriding measures are taken. Relative contraindications include sick sinus syndrome, in which disopyramide should be used with extreme caution due to uncertain effects on sinus node function. Caution is also warranted in Wolff-Parkinson-White syndrome, particularly with , as the drug may unpredictably influence accessory pathway conduction. constitutes a relative contraindication, given disopyramide's potential to induce or aggravate it. Electrolyte imbalances, such as , are relative contraindications that require correction before therapy to mitigate reduced efficacy and enhanced arrhythmogenic risk. 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. In patients with uncompensated heart failure, the drug is generally contraindicated unless the condition is directly attributable to the arrhythmia under treatment. 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. 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. 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.

Drug interactions

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

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. In addition to sodium channel effects, disopyramide prolongs the action potential duration (APD) and (ERP), preventing re-entrant arrhythmias through enhanced post-repolarization refractoriness. It also moderately blocks s, particularly the rapid delayed rectifier current (IKr), which contributes to prolongation of the by 20-30 ms at therapeutic doses. This interaction underlies both its antiarrhythmic benefits and potential proarrhythmic risks, such as . The negative inotropic properties of disopyramide stem from diminished calcium influx into cardiomyocytes, primarily via inhibition of L-type calcium channels, leading to reduced . This effect decreases the force of ventricular contraction, which is particularly relevant in conditions involving hyperdynamic obstruction. Disopyramide further exhibits activity by antagonizing muscarinic receptors (with greater potency at M1 over M2 subtypes), thereby suppressing on the heart. This results in increased automaticity, elevated , and accelerated atrioventricular nodal conduction, counterbalancing some of its direct depressive effects on cardiac tissue.

Pharmacokinetics

Disopyramide exhibits high oral of 70-90%, with peak plasma concentrations (Cmax) achieved in 1-2 hours (Tmax). Food intake delays the rate of absorption but does not alter the overall extent of . The volume of distribution (Vd) is approximately 0.97 L/kg, indicating moderate tissue penetration. ranges from 50-65%, primarily to alpha-1-acid , which can vary with disease states such as . Disopyramide undergoes hepatic metabolism primarily via the 3A4 enzyme, yielding the mono-N-dealkylated disopyramide (MOND), which accounts for approximately 20% of the administered dose. The elimination ranges from 4-10 hours in healthy adults, with an average of 6.7 hours, influencing the dosing interval to maintain therapeutic levels. 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 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.

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 due to prolongation or new . This effect stems from the drug's class Ia blockade, which slows conduction and can facilitate arrhythmogenic triggers in susceptible individuals. Documented cases highlight as a serious complication, particularly when QT prolongation exceeds 25%, necessitating close electrocardiographic monitoring and discontinuation if ectopy persists. The negative inotropic properties of disopyramide can exacerbate , especially in patients with preexisting or left ventricular dysfunction, by reducing and by about 10% during intravenous administration. This hemodynamic depression is more pronounced in those with underlying left ventricular dysfunction, where the drug is contraindicated due to the potential for acute . In clinical studies, intravenous disopyramide has demonstrated potent cardiac 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. 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. Electrophysiologic evaluations confirm significant prolongation of AV nodal and His-Purkinje system refractoriness, heightening this risk in vulnerable patients. Hypotension is another key cardiac , often involving a systolic drop exceeding 20 mm Hg, driven by combined negative inotropic and actions that impair and vascular tone. This is particularly prevalent with rapid intravenous dosing, where decreases in systolic pressure have been reported alongside reductions in , though oral administration rarely causes significant in patients without . In hemodynamic studies, peak effects include approximately a 10% decline in cardiac performance metrics following intravenous boluses, emphasizing the need for gradual infusion and monitoring in acute settings.

Extracardiac adverse effects

Disopyramide's extracardiac adverse effects are primarily attributed to its potent properties, which can manifest in various peripheral systems. Common manifestations include dry mouth, occurring in approximately 32% of patients, as well as and , each reported in 3% to 11% of cases. Urinary hesitancy affects about 14% of users, while , frequency, or urgency occurs in 3% to 9%, with a heightened risk in elderly males due to enlargement exacerbating retention. Central nervous system effects, often linked to activity, include and , each noted in 3% to 9% of patients, alongside in a similar range. These symptoms, including potential , are more prevalent in individuals over 65 years, where reduced reserve amplifies cognitive and sedative impacts. In patients with , particularly those insulin-dependent, disopyramide can induce 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 in this subgroup, often resolving upon discontinuation. Hypersensitivity reactions are infrequent, affecting less than 1% of users, and may include or itching in 1% to 3% of cases, as well as rare instances of , which is reversible upon .

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 beyond 100 ms, which serves as an early indicator of toxicity. This widening is often accompanied by prolongation of the , severe , atrioventricular (AV) block, , and potentially life-threatening ventricular arrhythmias such as . These cardiac effects arise from enhanced blockade and negative inotropic actions at supratherapeutic levels, exacerbating conduction delays and myocardial depression. Disopyramide's potent activity becomes markedly pronounced in overdose, resulting in central and peripheral symptoms such as , , (dilated pupils), (decreased bowel motility), and . In severe cases, these effects can progress to agitation, hallucinations, and seizures, reflecting inhibition of muscarinic receptors in the and autonomic ganglia. Loss of consciousness and respiratory depression may also occur as intensifies. A notable metabolic consequence of disopyramide overdose is profound , particularly in patients with 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. This effect is mediated by the drug's interference with channels in beta cells, leading to hypoglycemic in extreme cases. 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. 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.

Treatment approaches

Management of disopyramide overdose focuses on , reversal of blockade, and treatment of life-threatening arrhythmias such as . Initial supportive care includes airway protection, hemodynamic stabilization, and continuous ECG monitoring. If ingestion occurred within 2 hours, immediate 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. 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. In cases of , 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 and suppress the . Hemodialysis is generally ineffective for disopyramide removal owing to its high protein binding and large , with studies showing minimal extraction (less than 3% of the dose) during sessions. For refractory severe , intravenous lipid emulsion therapy may be considered as a rescue intervention to mitigate toxicity. symptoms, such as dry mouth or , should be monitored supportively without specific antidotal therapy.

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 designed to mimic the pharmacological effects of quinidine while achieving enhanced oral 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 in animal models of induced ventricular arrhythmias, revealing class Ia properties through prolongation of the action potential duration and effective suppression of ectopic rhythms. Further investigations between 1962 and 1970 in various species, including dogs and guinea pigs, confirmed its potency against ventricular tachyarrhythmias while highlighting early-onset effects, such as dry mouth and , as notable tolerability concerns. Initial evaluations, including a reported by Katz and colleagues in 1963, demonstrated disopyramide's ability to suppress ectopic beats in patients with cardiac , supporting its transition to broader phase I testing. These early 1960s trials in volunteers and arrhythmia patients established safety and preliminary efficacy for , culminating in its first marketing approval in 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 , detailing its rapid absorption, , and correlation between serum levels and antiarrhythmic action in both animal and models.

Regulatory approval

Disopyramide was first approved in the 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 . A warning regarding its proarrhythmic potential and increased mortality risk, particularly in post-myocardial patients as evidenced by the CAST trial, was added in the late 1980s. The 2020 AHA/ACC guideline for the diagnosis and treatment of patients with updated recommendations to include disopyramide as a Class 2a (Level of B) option for symptomatic obstructive in patients with persistent symptoms despite beta-blockers or non-dihydropyridine , reflecting its expanded role beyond initial antiarrhythmic indications. Post-market developments include the availability of generic disopyramide since the , broadening access. A 2024 review of antiarrhythmic agents highlighted disopyramide's significant toxicity profile, including effects and negative inotropy, contributing to restricted use in certain regions due to safety concerns and supply limitations.

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK557434/
  2. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=11a68e26-d2e4-48f6-ba0f-9bdd5778f25a
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Disopyramide
  4. https://labeling.pfizer.com/showlabeling.aspx?id=634
  5. https://pubmed.ncbi.nlm.nih.gov/856558/
  6. https://pmc.ncbi.nlm.nih.gov/articles/PMC8770922/
  7. https://www.ahajournals.org/doi/10.1161/CIR.0000000000001250
  8. https://www.jacc.org/doi/10.1016/j.jacc.2005.01.012
  9. https://www.ahajournals.org/doi/10.1161/JAHA.124.037639
  10. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4c02f1b8-4493-429c-b9f7-21f364e330f8
  11. https://www.drugs.com/disease-interactions/disopyramide.html
  12. https://www.drugs.com/pro/disopyramide.html
  13. https://go.drugbank.com/drugs/DB00280
  14. https://reference.medscape.com/drug/norpace-cr-disopyramide-342299
  15. https://www.drugguide.com/ddo/view/Davis-Drug-Guide/51229/all/disopyramide
  16. https://link.springer.com/article/10.1023/A:1011106701063
  17. https://www.researchgate.net/publication/23760778_Mechanism_of_disopyramide-induced_hypoglycaemia_in_a_patient_with_Type_2_diabetes
  18. https://www.ahajournals.org/doi/10.1161/01.RES.68.3.653
  19. https://www.sciencedirect.com/science/article/pii/S0006291X0194269X
  20. https://www.ahajournals.org/doi/10.1161/jaha.116.005152
  21. https://www.jstage.jst.go.jp/article/bpb/46/1/46_b22-00644/_html/-char/en
  22. https://www.ahajournals.org/doi/pdf/10.1161/01.RES.64.2.297
  23. https://pubmed.ncbi.nlm.nih.gov/3524956/
  24. https://labeling.pfizer.com/ShowLabeling.aspx?id=11671
  25. https://pubmed.ncbi.nlm.nih.gov/1721204/
  26. https://pubmed.ncbi.nlm.nih.gov/350555/
  27. https://pubmed.ncbi.nlm.nih.gov/7235820/
  28. https://labeling.pfizer.com/showlabeling.aspx?format=PDF&id=11671
  29. https://pubmed.ncbi.nlm.nih.gov/7226916/
  30. https://pubmed.ncbi.nlm.nih.gov/6829435/
  31. https://www.rxlist.com/norpace-drug.htm
  32. https://www.drugs.com/sfx/disopyramide-side-effects.html
  33. https://www.sciencedirect.com/topics/[neuroscience](/page/Neuroscience)/disopyramide
  34. https://pubmed.ncbi.nlm.nih.gov/2691378/
  35. https://pdf.hres.ca/dpd_pm/00005234.PDF
  36. https://www.ncbi.nlm.nih.gov/books/NBK534798/
  37. https://medlineplus.gov/druginfo/meds/a682408.html
  38. https://pubmed.ncbi.nlm.nih.gov/6635745/
  39. https://emcrit.org/ibcc/nacb/
  40. https://www.merckmanuals.com/professional/cardiovascular-disorders/specific-cardiac-arrhythmias/torsades-de-pointes-ventricular-tachycardia
  41. https://www.ncbi.nlm.nih.gov/books/NBK459388/
  42. https://pubmed.ncbi.nlm.nih.gov/7471602/
  43. https://pubmed.ncbi.nlm.nih.gov/14475124/
  44. https://pubmed.ncbi.nlm.nih.gov/4104224/
  45. https://www.ncbi.nlm.nih.gov/books/NBK548693/
  46. https://www.pfizermedical.com/norpace/warnings
  47. https://www.ahajournals.org/doi/10.1161/CIR.0000000000000937
  48. https://www.drugs.com/availability/generic-norpace.html
  49. https://www.cjcopen.ca/article/S2589-790X%2824%2900138-0/pdf
Add your contribution
Related Hubs
Contribute something
User Avatar
No comments yet.