DISOPYRAMIDE Chemical Properties

Melting point:

94.5-950C

Boiling point:

475.43°C (rough estimate)

Density 

1.0779 (rough estimate)

refractive index 

1.6300 (estimate)

storage temp. 

Inert atmosphere,Room Temperature

solubility 

Soluble in DMSO (25 mg/ml) and Ethanol (>35 mg/mL)

form 

solid

pka

10.2; also reported as 10.45(at 25℃)

color 

White

Water Solubility 

6.17mg/L(22.5 ºC)

Merck 

14,3360

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 1 month.

CAS DataBase Reference

3737-09-5(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xn,Xi,T,F

Risk Statements 

22-36/37/38-39/23/24/25-23/24/25-11

Safety Statements 

36-26-45-36/37-16-7

WGK Germany 

3

RTECS 

UR8432000

HS Code 

2933.39.4100

Toxicity

LD50 i.p. in mice: 517 mmol/kg (Ruenitz, Mokler)

MSDS

• Language:English Provider:SigmaAldrich

DISOPYRAMIDE Usage And Synthesis

Description

Structurally, disopyramide does not belong to any of the known classes of antiarrhythmics; however, being a drug of the class IA sodium channel blockers, it exhibits membranestabilizing action and increases the effective refractory period and duration of an action potential in the atrium and ventricles. It causes a decrease in contractability and excitability of the myocardium, slowing of conductivity, and suppression of sinoatride automatism.

Chemical Properties

Crystalline Solid

Originator

Rythmodan,Cassenne,France,1969

Uses

Disopyramide is used for preventing and restoring atrial and ventricular extrasystole and tachycardia in order to prevent atrial flutter and arrhythmia.

Uses

Antiarrhythmic (class IA). Sodium channel blocker

Uses

Antiarrhythmic;Na+ channel blocker

Definition

ChEBI: A monocarboxylic acid amide that is butanamide substituted by a diisopropylamino group at position 4, a phenyl group at position 2 and a pyridin-2-yl group at position 2. It is used as a anti-arrhythmia drug.

Manufacturing Process

To a solution of 35.3 parts of phenylacetonitrile and 47.6 parts of 2- bromopyridine in 175 parts of dry toluene is added 53.4 parts of sodamide slowly with stirring over a period of 45 minutes. The resultant mixture is stirred at 100°C for 2 hours before it is cooled and the excess sodamide is decomposed by the addition of water. The toluene layer is separated and washed with water to remove excess alkali. The toluene solution is extracted with 6 N hydrochloric acid and the acid extract is made alkaline and then extracted with toluene. The toluene solution is dried over sodium sulfate and the solvent is evaporated. Recrystallization of the residue from alcohol-hexane gives α-phenyl-2-pyridineacetonitrile melting at about 87-88°C.
To a solution of 41 parts of α-phenyl-2-pyridineacetonitrile in 350 parts of dry toluene is added 9.2 parts of sodamide and the mixture is stirred and heated at 90°C for 30 minutes. Heating is stopped and a solution of 38.5 parts of 2- diisopropylaminoethyl chloride in 110 parts of dry toluene is added slowly over a period of 30 minutes. The mixture is stirred and refluxed for 6 hours before it is cooled and decomposed by the addition of water. The toluene layer is separated and washed with water and extracted with 6 N hydrochloric acid. The acid extract is made alkaline and extracted with toluene. The toluene solution is washed with water and dried and the solvent is evaporated. Distillation of the residue gives 4-diisopropylamino-2-phenyl-2-(2-pyridyl)- butyronitrile boiling at about 145°-160°C at 0.3 mm pressure.
A solution of 27.2 parts of 4-diisopropylamino-2-phenyl-2-(2- pyridyl)butyronitrile in 200 parts of concentrated sulfuric acid is heated on a steam bath for 4 hours and then poured onto ice. The resultant mixture is alkalized with 10 N sodium hydroxide, and the pH is adjusted to 6 by the addition of acetic acid. The solution is washed once with benzene before it is alkalized again with 10 N sodium hydroxide solution. The resultant mixture is extracted with benzene, and the solvent is evaporated from the benzene extract. The resultant residue is dissolved in ethanol and the alcohol solution is treated with charcoal and filtered. Evaporation of the solvent leaves a residue which is recrystallized from hexane to give 4-diisopropylamino-2- phenyl-2-(2-pyridyl)butyramide melting at about 94.5-95°C. It may be converted to the phosphate with phosphoric acid.

brand name

Norpace (Searle).

Therapeutic Function

Antiarrhythmic

Mechanism of action

Disopyramide has a pharmacological profile similar to that of quinidine and procainamide . Clinically, it is active against most forms of arrhythmias (supraventricular and ventricular).

Pharmacokinetics

Disopyramide phosphate is used orally for the treatment of certain ventricular and atrial arrhythmias. Despite its structural dissimilarity to procainamide, its cardiac effects are very similar. Disopyramide is rapidly and completely absorbed from the gastrointestinal tract. Peak plasma level is usually reached within 1 to 3 hours, and a plasma half-life of 5 to 7 hours is common. Approximately half of an oral dose is excreted unchanged in the urine. The remaining drug undergoes hepatic metabolism, principally to the corresponding N-dealkylated form. This metabolite retains approximately half the antiarrhythmic activity of disopyramide and also is subject to renal excretion.

Clinical Use

Disopyramide (Norpace) can suppress atrial and ventricular arrhythmias and is longer acting than other drugs in its class.
The indications for use of disopyramide are similar to those for quinidine, except that it is not approved for use in the prophylaxis of atrial flutter or atrial fibrillation after DC conversion.The indications are as follows: unifocal premature (ectopic) ventricular contractions, premature (ectopic) ventricular contractions of multifocal origin, paired premature ventricular contractions (couplets), and episodes of ventricular tachycardia. Persistent ventricular tachycardia is usually treated with DC conversion.

Side effects

The major toxic reactions to disopyramide administration include hypotension, congestive heart failure, and conduction disturbances. These effects are the result of disopyramide’s ability to depress myocardial contractility and myocardial conduction. Although disopyramide initially may produce ventricular tachyarrhythmias or ventricular fibrillation in some patients, the incidence of disopyramide-induced syncope in long-term therapy is not known. Most other toxic reactions (e.g., dry mouth, blurred vision, constipation) can be attributed to the anticholinergic properties of the drug.
CNS stimulation and hallucinations are rare.The incidence of severe adverse effects in long-term therapy may be lower than those observed with quinidine or procainamide.

Synthesis

Disopyramide, |á-(2-diisopropylaminoethyl)-|á-phenyl-2-pyridineacetamide (18.1.6), is synthesized by arylating benzylcyanide with 2-chloropiridine in the presence of sodium amide and subsequent alkylation of the resulting |á-phenyl-|á-(2-pyridyl) acetonitrile (18.1.4) with 2-diisopropylaminoethylchloride using sodium amide. Sulfuric acid hydrolysis of the resulting nitrile (18.1.5) leads to the formation of |á-(2-diisopropylaminoethyl)- |á-phenyl-2-pyridineacetamide, disopyramide.

Drug interactions

In the presence of phenytoin, the metabolism of disopyramide is increased (reducing its effective concentration) and the accumulation of its metabolites is also increased, thereby increasing the probability of anticholinergic adverse effects. Rifampin also stimulates the hepatic metabolism of disopyramide, reducing its plasma concentration.
Unlike quinidine, disopyramide does not increase the plasma concentration of digoxin in patients receiving a maintenance dose of the cardiac glycoside. Hypoglycemia has been reported with the use of disopyramide, particularly in conjunction with moderate or excessive alcohol intake.

Precautions

Disopyramide should not be administered in cardiogenic shock, preexisting second- or third-degree A-V block, or known hypersensitivity to the drug. Neither should it be given to patients who are poorly compensated or those with uncompensated heart failure or severe hypotension. Because of its ability to slow cardiac conduction, disopyramide is not indicated for the treatment of digitalis-induced ventricular arrhythmias.
Patients with congenital prolongation of the QT interval should not receive quinidine, procainamide, or disopyramide because further prolongation of the QT interval may increase the incidence of ventricular fibrillation. Because of its anticholinergic properties, disopyramide should not be used in patients with glaucoma. Urinary retention and benign prostatic hypertrophy are also relative contraindications to disopyramide therapy. Patients with myasthenia gravis may have a myasthenic crisis after disopyramide administration as a result of the drug’s local anesthetic action at the neuromuscular junction.The elderly patient may exhibit increased sensitivity to the anticholinergic actions of disopyramide. Caution is advised when disopyramide is used in conjunction with other cardiac depressant drugs, such as verapamil, which may adversely affect atrioventricular conduction.

References

1) Hell?et al.?(1978),?Disopyramide: a review of its pharmacological properties and therapeutic use in treating cardiac arrhythmias; Drugs?115?331 2) Verlinden?et al.?(2015),?Disopyramide for Hypertrophic Cardiomyopathy: A Pragmatic Reappraisal of an Old Drug; Pharmacotherapy,?35?1164 3) Nakajima?et al.?(1989),?Anti-Cholinergic Effects of Quinidine, Disopyramide, and Procainamide in Isolated Atrial Myocytes: Mediation by Different Molecular Mechanisms; Circ. Res.,?64?297

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