Disopyramide

Observational studies

Because of its negative inotropic effect, disopyramide reduces the left ventricular outflow gradient and improves symptoms in patients with hypertrophic obstructive cardiomyopathy. However, its long-term effects have not been well studied. In 118 patients who took disopyramide (mean dose 432 mg/day for a mean of 3.1 years) and 373 who did not, all-cause annual cardiac death rates (1.4% versus 2.6% per year) and sudden death rates (1.0% versus 1.8% per year) did not differ significantly, although there was a tendency for disopyramide to reduce mortality [ ]. The authors concluded that disopyramide is not prodysrhythmic in hypertrophic obstructive cardiomyopathy. The main adverse effects of disopyramide were attributable to its anticholinergic effects—dry mouth and prostatism, which required drug withdrawal in 7% of the patients.

Comparative studies

Disopyramide (by intravenous infusion of 2 mg/kg/minute up to a maximum total dose of 100 mg) has been compared with pilsicainide (in a single oral dose of 100–150 mg) in the treatment of paroxysmal atrial fibrillation in 72 patients [ ]. Conversion to sinus rhythm occurred in 29 of the 40 patients given pilsicainide and 18 of 32 patients given disopyramide, a non-significant difference. However, the mean time to conversion was faster with disopyramide (23 versus 60 minutes). No adverse effects were observed with either drug.

General adverse effects and adverse reactions

The adverse effects of disopyramide are mostly mediated by its effects on the cardiovascular system and by its anticholinergic effects. Disopyramide has a strong negative inotropic effect on the myocardium and can cause heart failure and hypotension. It prolongs the QT interval and can cause serious ventricular tachydysrhythmias. Anticholinergic effects can cause dry mouth, blurred vision, urinary retention, glaucoma, and erectile impotence. Hypoglycemia can also occur. Disopyramide can cause uterine contractions and should not be used during pregnancy. Angioedema has been reported rarely. Tumor-inducing effects have not been reported.

Cardiovascular

Disopyramide has three effects that can lead to cardiovascular complications [ ].

• 1.

  Anticholinergic . The anticholinergic effects of disopyramide on the vagus have been reported to cause tachycardia with bundle branch block or conversion to 1:1 conduction of a supraventricular tachycardia with block.

• 2.

  QT interval prolongation . There have been several reports of ventricular dysrhythmias (for example polymorphous ventricular tachycardia, ventricular fibrillation, ventricular tachycardia) in association with a prolonged QT interval [ ].

• 3.

  Negative inotropic effect . Disopyramide can worsen cardiac failure and occasionally causes hypotension.

The risk of adverse cardiac effects of disopyramide during intravenous administration relates to the speed of its administration rather than to the total dose given [ ].

Torsade de pointes due to disopyramide is well described [ ]. This effect is associated with prolongation of the QT interval. There has been a study of the effects of disopyramide on the QT interval in patients with pre-existing QT interval prolongation [ ]. In eight patients with QT interval prolongation during bradycardia and five patients without QT interval prolongation, disopyramide significantly prolonged the QT interval; however, the change was more pronounced in those with pre-existing bradycardia (78 versus 35 ms). The authors proposed that this difference might be due to an underlying abnormality of potassium channels in those with pre-existing bradycardia. Thus, those who are genetically predisposed to cardiac dysrhythmias may be at greater risk of the prodysrhythmic effects of antidysrhythmic drugs.

The risk of myocardial depression with consequent hypotension is greatest when disopyramide is infused rapidly intravenously [ ]. Loading doses of disopyramide should therefore be infused slowly (over 30–60 minutes).

Respiratory

• Pneumonitis has been attributed to disopyramide in a 72-year-old man; the symptoms began soon after the first dose [ ]. Bronchoalveolar lavage fluid contained a high percentage of lymphocytes (65%) and a high CD4:CD8 ratio (69:1).

The results of a lymphocyte stimulation test suggested that disopyramide had been responsible.

Nervous system

Through its anticholinergic effects disopyramide causes dry mouth and blurred vision and can occasionally cause serious adverse effects, including glaucoma and acute urinary retention [ ].

Neuropathy has rarely been attributed to disopyramide [ ].

• A 71-year-old woman, who had taken disopyramide 500 mg/day for 4 years, developed fatigue, paresthesia, pain, and cramps in her legs [ ]. She had proximal weakness in all four limbs and an unsteady gait. Electrophysiology showed a sensorimotor polyneuropathy, with reduced motor conduction velocity and muscle denervation. All antibodies were negative. The symptoms did not respond to prednisone but improved in the months after disopyramide withdrawal.

Neuromuscular function

Worsening of pre-existing myasthenia gravis has been attributed to disopyramide [ ].

• A 63-year-old woman with ocular myasthenia gravis and an anti-acetylcholine receptor antibody concentration of 16 nmol/l responded to a cholinesterase inhibitor and prednisolone 10 mg/day. When she developed atrial fibrillation and heart failure she was given disopyramide 300 mg/day and furosemide 20 mg/day. Within 6 weeks she developed an aspiration pneumonia secondary to dysphagia with bulbar paralysis-like symptoms. A myasthenic crisis was excluded, since the antiacetylcholine receptor antibody concentration was 0.3 nmol/l. The electrocardiogram showed QT _c interval prolongation (549 msec) and she developed torsade de pointes. Despite correction of hypokalemia, administration of magnesium, and a continuous intravenous infusion of lidocaine, the tachydysrhythmia did not improve, but it was resolved by intravenous verapamil. All medications were withheld and after 4 days her spontaneous respiration and muscle weakness improved. She eventually died with sepsis and disseminated intravascular coagulation from acute enteritis.

Psychiatric

Acute psychosis has been attributed to disopyramide [ , ].

Metabolism

Disopyramide can cause hypoglycemia [ ], perhaps due to increased secretion of insulin, and can also potentiate the effects of conventional hypoglycemic drugs [ ]. This effect may be due to its chief metabolite mono- N -dealkyldisopyramide, since many of the reported cases of hypoglycemia have been in patients with renal impairment, in which the metabolite accumulates. In six subjects who were being considered for treatment with disopyramide, serum glucose concentrations were measured at 13, 15, 17, and 19 hours after supper, with no further food, with and without the added administration of two modified-released tablets of disopyramide 150 mg with supper and 12 hours later [ ]. Disopyramide significantly reduced the serum glucose concentration at all measurement times by an average of 0.54 mmol/l. The fall in serum glucose concentration was not related to the serum concentration of disopyramide or the serum creatinine concentration; it was greater in older patients and in underweight patients.

• Hypoglycemia has also been reported in a 70-year-old woman with type 2 diabetes mellitus taking disopyramide [ ].