Disopyramide (Norpace, Rythmodan) is a class 1A antiarrhythmic medicine like quinidine and procainamide that inhibits the fast sodium channels.

Indications of Disopyramide:

• It is used for the management of life-threatening ventricular arrhythmias (eg, sustained ventricular tachycardia).

• Off Label Use of Disopyramide in Adults:

  • Atrial fibrillation (maintenance of sinus rhythm)
  • Obstructive hypertrophic cardiomyopathy

Disopyramide dose in adults

Disopyramide dose for Ventricular arrhythmias:

Note:

• New agents are preferred over disopyramide due to lesser toxicity.
• When the rapid achievement of disopyramide plasma concentrations is required, the controlled-release formulation should not be used.
• Severe refractory ventricular tachycardia is treated with a maximum dose of up to 400 mg every 6 hours (immediate-release).
• Loading dose should be avoided in patients with cardiomyopathy or possible cardiac decompensation.

• Weight<50 kg:

  • Immediate release:

    • An initial loading dose of 200 mg may be administered if rapid onset is required.
    • Maintenance dose: 100 mg every 6 hours.

  • Controlled release:

    • Maintenance dose: 200 mg every 12 hours.

• Weight≥50 kg:

  • Immediate release:

    • An initial loading dose of 300 mg may be administered if rapid onset is required.
    • Maintenance dose: 150 mg every 6 hours.
    • If rapid control is necessary and no response is seen within 6 hours of loading dose, it may increase maintenance dose to 200 mg every 6 hours.

  • Controlled release:

    • Maintenance dose: 300 mg every 12 hours.

Disopyramide dose in the treatment of Atrial fibrillation for the maintenance of sinus rhythm) (off-label): 

Note:

• In patients with vagally-induced AF or hypertrophic cardiomyopathy associated with dynamic outflow tract obstruction, it is the preferred agent in combination with a beta-blocker or a non-dihydropyridine calcium channel blocker.

• Immediate release:

  • Usual dose: 100 to 200 mg every 6 hours.

• Controlled release:

  • Usual dose: 200 to 400 mg every 12 hours.

Disopyramide dose in the treatment of Hypertrophic cardiomyopathy (obstructive physiology) with or without atrial fibrillation (off-label):

• Initial: Controlled release:
  • 200 to 250 mg b.i.d daily.
  • If symptoms do not improve, increase by 100 mg/day at 2-week intervals to a maximum daily dose of 600 mg.
• Anticholinergic adverse effects (eg, urinary retention, constipation, dry mouth) associated with disopyramide can be controlled by pyridostigmine.

Disopyramide dose in children:

Disopyramide treatment dose for Ventricular arrhythmias:

Note: Initial treatment should be given in the hospital and the lowest effective dose should be started.

• Immediate release: Oral:

  • Infants:
    • 10 to 30 mg/kg/day in divided doses every 6 hours.
  • Children 1 to 4 years:
    • 10 to 20 mg/kg/day in divided doses every 6 hours.
  • Children >4 to 12 years:
    • 10 to 15 mg/kg/day in divided doses every 6 hours.
  • Children >12 and Adolescents ≤18 years:
    • 6 to 15 mg/kg/day in divided doses every 6 hours.
  • Adult maximum daily dose:
    • 1,600 mg/day.

Pregnancy Risk Factor C

• Studies on animal reproduction revealed negative outcomes.
• Disopyramide can stimulate contractions during pregnancy.
• A case report showed that disopyramide was used in the third trimester of the first dose. Hemorrhage occurred after the second dose.
• In some cases, disopyramide has been found in human fetal blood.

Use of disopyramide while breastfeeding

• Breast milk contains disopyramide.
• The manufacturer warns that there are serious adverse reactions possible in nursing infants.
• It recommends that a decision is made about whether to stop nursing or discontinue using the drug.
• This decision will depend on how important the treatment is to the mother.

Disopyramide Dose in Kidney Disease:

• Manufacturer's labeling:

  • Immediate release:

    • CrCl >40 mL/minute:
      • 100 mg every 6 hours.
    • CrCl 30 to 40 mL/minute:
      • 100 mg every 8 hours.
    • CrCl 15 to 30 mL/minute:
      • 100 mg every 12 hours.
    • CrCl <15 mL/minute:
      • 100 mg every 24 hours.

  • Controlled release:

    • CrCl >40 mL/minute:
      • 200 mg every 12 hours.
    • CrCl ≤40 mL/minute:
      • Not recommended for use.

• Alternative recommendations:

  • Immediate release:

    • CrCl >50 mL/minute:
      • 100 to 200 mg every 8 hours.
    • CrCl 10 to 50 mL/minute:
      • 100 to 200 mg every 12 to 24 hours.
    • CrCl <10 mL/minute:
      • 100 to 200 mg every 24 to 48 hours.
    • Dialysis:
      • Not dialyzable (0% to 5%) by hemo- or peritoneal methods; supplemental dose is not necessary.

Disopyramide Dose in Liver disease:

• Manufacturer's labeling:

  • Immediate-release: 100 mg every 6 hours.
  • Controlled-release: 200 mg every 12 hours.

Common Side Effects of Disopyramide:

The most common adverse effects are related to the cholinergic blockade. The most serious adverse effects of disopyramide are hypotension and cardiac failure.

• Gastrointestinal:

  • Xerostomia
  • Constipation

• Genitourinary:

  • Urinary hesitancy

Rare Side Effects of Disopyramide:

• Cardiovascular:

  • Cardiac Conduction Disturbance
  • Cardiac Failure
  • Chest Pain
  • Edema
  • Hypotension
  • Syncope

• Central Nervous System:

  • Dizziness
  • Fatigue
  • Headache
  • Malaise
  • Myasthenia
  • Nervousness

• Dermatologic:

  • Generalized Dermatosis
  • Pruritus
  • Skin Rash

• Endocrine & Metabolic:

  • Hypokalemia
  • Increased Serum Cholesterol
  • Increased Serum Triglycerides
  • Weight Gain

• Gastrointestinal:

  • Abdominal Distention
  • Anorexia
  • Bloating
  • Diarrhea
  • Flatulence
  • Nausea
  • Vomiting

• Genitourinary:

  • Impotence
  • Urinary Frequency
  • Urinary Retention
  • Urinary Urgency

• Neuromuscular & Skeletal:

  • Myalgia

• Ophthalmic:

  • Blurred Vision
  • Xerophthalmia

• Respiratory:

  • Dry Throat
  • Dyspnea

Contraindications to Disopyramide:

• Hypersensitivity to disopyramide and any other component of the formulation
• Congenital Long QT syndrome
• Heart block, 2nd- or 3rd-degree
• Cardiogenic shock
• Canadian labeling: Additional contraindications not in US labeling
• Decompensated heart failure
• Severe sinus node dysfunction
• Severe intraventricular conduction problems (ie, bundle block associated with first degree atrioventricular blocks, double block [left posterior hemiblock or right bundle-branchblock])
• Severe renal failure
• Urinary retention
• Glaucoma
• Combination of antiarrhythmics and drugs that can cause ventricular arrhythmias (especially with torsade-de-pointes).

Warnings and precautions

• Hypotension

  Hypotension can occur during initial therapy, so it is important to monitor closely.

• Proarrhythmic effects

  • This can lead to proarrhythmic effects, including QT prolongation or subsequent torsade-de-pointes.
  • Because of the possibility of QT prolongation or arrhythmias, it is important to start initial therapy in the hospital. 
  • To prevent these events, it is important to monitor closely and adjust the dose.
  • If QT is increasing by >25% from baseline, dosing reduction or discontinuation may be necessary.
  • Disopyramide should not be prescribed to patients with congenital long QT syndrome.
  • Patients with pre-existing heart disease are at greater risk of developing proarrhythmic effects or death from Class Ia antiarrhythmic drugs.

• Atrial fibrillation/flutter:

  • Appropriate Use: Patients with atrial fibrillation and flutter should be treated with AV nodal blocking.

• BPH/urinary retention

  • Patients with BPH or urinary retention should not use it due to its severe anticholinergic side effects.

• Conduction disturbances:

  • Patients with bundle branch block and heart block should be cautious.

• Electrolyte imbalance:

  • Before and during therapy, any electrolyte disorders such as hypokalemia or hypermagnesemia must be corrected.

• Glaucoma:

  • Patients with glaucoma should not use it due to the possibility of serious anticholinergic side effects.

• Heart failure (HF):

  • Disopyramide may cause left ventricular dysfunction and heart failure. It should therefore be used with caution.

• Hepatic impairment

  • Patients with hepatic impairment should be cautious and reduce their doses.

• Myasthenia gravis:

  • Patients with myasthenia gravis should not take this medication as it has severe anticholinergic side effects.

• Renal impairment

  • For renal impairment, dose reduction and caution are necessary.
  • For CrCl >=40mL/minute, the controlled release form should not be used.

• Wolff-Parkinson-White syndrome:

  • Use with caution in patients with Wolff-Parkinson-White syndrome.

Disopyramide: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• BP
• ECG
• urinary retention
• CNS anticholinergic effects (confusion, agitation, hallucinations, etc)
• Disopyramide drug level (if available)
• Signs and symptoms of heart failure

How to administer Disopyramide?

• It should be taken orally on an empty stomach without breaking or chewing.
• For lesser variation in peak and trough serum level,it should be given around-the-clock rather than 4 times/day (ie, 12-6-12-6, not 9-1-5-9).

Mechanism of action of Disopyramide:

• Disopyramide is a class Ia antiarrhythmic. 
• It has anticholinergic, peripheral vasoconstrictive and negative inotropic properties. 
• It reduces myocardial excitability, conduction velocity, and disparity in the refractory between normal myocardium and infarcted.

Onset of action:

• 0.5 to 3.5 hours.

Duration:

• Immediate release: 1.5 to 8.5 hours.

Absorption:

• Rapid and almost complete.

Protein binding (concentration dependent):

• 50% to 65%.

Metabolism:

• Hepatic; N-dealkylation to the active metabolite N-despropyldisopyramide (or monoN-dealkylated [MND] metabolite) and other inactive metabolites.

Half-life elimination:

• Children 5 to 12 years: 3.15 ± 0.64 hours.
• Adults: 4 to 10 hours; prolonged with heart failure and hepatic or renal impairment.

Time to peak serum concentrations:

• Immediate-release: Within 2 hours.
• Controlled-release: 4 to 7 hours.

Excretion:

• Urine (~50% as unchanged drug; ~20% as MND; 10% other metabolites); feces (10% to 15%).

Clearance:

• Children 5 to 12 years: 3.79 ± 0.82 mL/minute/kg (greater than adults).

International Brands of Disopyramide:

• Norpace
• Norpace CR
• Rythmodan
• Biolytan
• Dicorantil-F
• Dicorynan
• Dimodan
• Dirytmin
• Disocor
• Disomet
• Durbis
• Durbis Retard
• Durbis[inj.]
• Harmonix
• Heartoace
• Norbit
• Norpace
• Norpace Retard
• Norpaso
• Palpitin
• Regubeat
• Ritmodan
• Ritmoforine
• Rythmical
• Rythmodan
• Rythmodan Retard
• Rythmodul
• Rythmonal
• Rytmilen

Disopyramide Brands in Pakistan: