DISOPYRAMIDE PHOSPHATE
Chemistry - Structurally dissimilar from other available antiarrhythmic agents, disopyramidephosphate occurs as a white or practically white crystalline powder with a pKa of 10.4. It is freelysoluble in water and slightly soluble in alcohol.
The exact mechanism of action of the drug has not been established. Disopyramide's cardiacelectrophysiologic effects include: 1) shortened sinus node recovery time 2) increased atrial andventricular refractory times 3) decreased conduction velocity through the atria and ventricles 4)decreased automaticity of ectopic atrial or ventricular pacemakers.
Disopyramide has direct negative inotropic effects. It generally has minimal effects on restingheart rates or blood pressure. Systemic peripheral resistance may increase by 20%.
Uses, Indications - Indicated for the oral treatment or prevention of ventricular tachyarrhythmias inthe dog. Because of its negative inotropic effects and short half-life in the dog, disopyramide isgenerally considered to be a 2nd or 3rd line agent for veterinary (canine) use. A controlled releaseproduct is available which may useful, but has not been extensively evaluated in the dog.
Disopyramide is distributed throughout the body in the extracellular water and is not extensivelybound to tissues. Binding to plasma proteins is variable and dependent on the drug's concentration.
At therapeutic levels it is approximately 50-65% plasma protein bound (human data). Disopyramidecrosses the placenta and milk concentrations may exceed those found in the plasma.
Disopyramide is metabolized in the liver, but 40-65% of it is excreted unchanged in the urine.
Patients with renal disease may need dosage adjustments made to prevent drug accumulation. Thehalf-life of the drug is approximately 7 hours in humans with normal renal function, but only 2-3hours in the dog.
Contraindications/Precautions - Disopyramide should usually not be used in patients withglaucoma (closed-angle), urinary retention, or myasthenia gravis because of its anticholinergiceffects.
Disopyramide is contraindicated in 2nd or 3rd degree AV block (unless pacemaker inserted), cardiogenic shock, or if the patient is hypersensitive to the drug.
Disopyramide should not be used in patients with severe uncompensated or poorly compensatedcardiac failure or hypotension because of its negative inotropic effects. Patients with atrial fibrillation or flutter must be digitalized before therapy so as to negate beyond acceptable increased ventricular response after disopyramide therapy. Disopyramide should be used with caution in patients with sick sinus syndrome, bundle branch block, or Wolff-Parkinson-White (WPW) syndrome.
Use of disopyramide with other class 1A antiarrhythmics or propranolol may cause additive negative inotropic effects (see Drug Interactions).
Disopyramide should be used with caution (and possibly at a reduced dosage) in patients with hepatic or renal disease.
Other adverse effects that have been reported in humans include: GI effects (vomiting, diarrhea, etc.), intrahepatic cholestasis, hypoglycemia, fatigue, headache, muscle weakness and pain. Incontrast to the urinary hesitancy effects, disopyramide can also cause urinary frequency andurgency.
Overdosage - Symptoms of overdosage/toxicity include: anticholinergic effects, apnea, loss ofconsciousness, hypotension, cardiac conduction disturbances and arrhythmias, widening of the
QRS complex and QT interval, bradycardia, congestive heart failure, seizures, asystole, and death.
Treatment consists initially of prompt gastric emptying, charcoal, and cathartics. Followed by vigorous symptomatic therapy using, if necessary, cardiac glycosides, vasopressors and sympathomimetics, diuretics, mechanically assisted respiration, and endocardial pacing. Disopyramide can be removed with hemodialysis.
Additive or antagonistic cardiac effects may occur as well as additive toxic effects (e.g negative inotropism) when disopyramide is used with other Class I antiarrhythmic agents (e.g., procainamide, quinidine, lidocaine, phenytoin) or propranolol; use with caution.
Oral anticoagulant (warfarin) doses may need to be adjusted when adding disopyramide.
Disopyramide's metabolism may be increased by drugs that induce microsomal enzymes (e.g., phenobarbital, phenytoin). Serum levels may need to be monitored and dosages adjusted.
Additive anticholinergic effects may be encountered if used concomitantly with other anticholinergics (atropine, glycopyrrolate).
Storage, Stability, Compatibility
Disopyramide capsules should be stored at room temperature(15-30°C) and in well-closed containers. An extemporaneously prepared suspension of 1-10 mg/mlof disopyramide (from capsules) in cherry syrup has been shown to be stable for one month ifstored in amber bottles and refrigerated (2-8°C).Pharmacology - DISOPYRAMIDE PHOSPHATE
Considered to be a class Ia (membrane-stabilizing) antiarrhythmic, with actionssimilar to either quinidine or procainamide, disopyramide reduces myocardial excitability andconduction velocity and also possesses anticholinergic activity (150 mg of disopyramide ยป 0.09 mgof atropine) which may contribute to the effects of the drug.The exact mechanism of action of the drug has not been established. Disopyramide's cardiacelectrophysiologic effects include: 1) shortened sinus node recovery time 2) increased atrial andventricular refractory times 3) decreased conduction velocity through the atria and ventricles 4)decreased automaticity of ectopic atrial or ventricular pacemakers.
Disopyramide has direct negative inotropic effects. It generally has minimal effects on restingheart rates or blood pressure. Systemic peripheral resistance may increase by 20%.
Uses, Indications - Indicated for the oral treatment or prevention of ventricular tachyarrhythmias inthe dog. Because of its negative inotropic effects and short half-life in the dog, disopyramide isgenerally considered to be a 2nd or 3rd line agent for veterinary (canine) use. A controlled releaseproduct is available which may useful, but has not been extensively evaluated in the dog.
Pharmacokinetics - DISOPYRAMIDE PHOSPHATE
In humans, disopyramide is rapidly absorbed following oral administrationwith peak levels occurring within 2-3 hours after the conventional capsules are administered. Peaklevels occur at about 6 hours post dose with the controlled-release capsules.Disopyramide is distributed throughout the body in the extracellular water and is not extensivelybound to tissues. Binding to plasma proteins is variable and dependent on the drug's concentration.
At therapeutic levels it is approximately 50-65% plasma protein bound (human data). Disopyramidecrosses the placenta and milk concentrations may exceed those found in the plasma.
Disopyramide is metabolized in the liver, but 40-65% of it is excreted unchanged in the urine.
Patients with renal disease may need dosage adjustments made to prevent drug accumulation. Thehalf-life of the drug is approximately 7 hours in humans with normal renal function, but only 2-3hours in the dog.
Contraindications/Precautions - Disopyramide should usually not be used in patients withglaucoma (closed-angle), urinary retention, or myasthenia gravis because of its anticholinergiceffects.
Disopyramide is contraindicated in 2nd or 3rd degree AV block (unless pacemaker inserted), cardiogenic shock, or if the patient is hypersensitive to the drug.
Disopyramide should not be used in patients with severe uncompensated or poorly compensatedcardiac failure or hypotension because of its negative inotropic effects. Patients with atrial fibrillation or flutter must be digitalized before therapy so as to negate beyond acceptable increased ventricular response after disopyramide therapy. Disopyramide should be used with caution in patients with sick sinus syndrome, bundle branch block, or Wolff-Parkinson-White (WPW) syndrome.
Use of disopyramide with other class 1A antiarrhythmics or propranolol may cause additive negative inotropic effects (see Drug Interactions).
Disopyramide should be used with caution (and possibly at a reduced dosage) in patients with hepatic or renal disease.
Adverse Effects, Warnings
Most common adverse reactions are secondary to disopyramide'santicholinergic effects (dry mouth, eyes, nose; constipation; urinary hesitancy or retention) andcardiovascular effects (edema, hypotension, dyspnea, syncope, conduction disturbances (AV block).Other adverse effects that have been reported in humans include: GI effects (vomiting, diarrhea, etc.), intrahepatic cholestasis, hypoglycemia, fatigue, headache, muscle weakness and pain. Incontrast to the urinary hesitancy effects, disopyramide can also cause urinary frequency andurgency.
Overdosage - Symptoms of overdosage/toxicity include: anticholinergic effects, apnea, loss ofconsciousness, hypotension, cardiac conduction disturbances and arrhythmias, widening of the
QRS complex and QT interval, bradycardia, congestive heart failure, seizures, asystole, and death.
Treatment consists initially of prompt gastric emptying, charcoal, and cathartics. Followed by vigorous symptomatic therapy using, if necessary, cardiac glycosides, vasopressors and sympathomimetics, diuretics, mechanically assisted respiration, and endocardial pacing. Disopyramide can be removed with hemodialysis.
Drug Interactions
Do not use disopyramide within 48 hours of using verapamil.Additive or antagonistic cardiac effects may occur as well as additive toxic effects (e.g negative inotropism) when disopyramide is used with other Class I antiarrhythmic agents (e.g., procainamide, quinidine, lidocaine, phenytoin) or propranolol; use with caution.
Oral anticoagulant (warfarin) doses may need to be adjusted when adding disopyramide.
Disopyramide's metabolism may be increased by drugs that induce microsomal enzymes (e.g., phenobarbital, phenytoin). Serum levels may need to be monitored and dosages adjusted.
Additive anticholinergic effects may be encountered if used concomitantly with other anticholinergics (atropine, glycopyrrolate).