Disopyramide toxicity

DISOPYRAMIDE ANTIVIRALS Disopyramide levels may be t by protease inhibitors Inhibition of CYP3A4-mediated metabolism of disopyramide Watch closely for disopyramide toxicity... 

Stapleton JT, Gillman MW. Hypoglycemic coma due to disopyramide toxicity. Sou MedJ (1983) 76, 1453. 

All antiarrhythmic dra are used cautiously in patients with renal or hepatic disease. When renal or hepatic dysfunction is present, a dosage reduction may be necessary. All patients should be observed for renal and hepatic dysfunction. Quinidine and procainamide are used cautiously in patients with CHF. Disopyramide is used cautiously in patients with CHF, myasthenia gravis, or glaucoma, and in men with prostate enlargement. Bretylium is used cautiously in patients with digitalis toxicity because the initial release of norepinephrine with digitalis toxicity may exacerbate arrhythmias and symptoms of toxicity. Verapamil is used cautiously in patients with a history of serious ventricular arrhythmias or CHF. Electrolyte disturbances such as hypokalemia, hyperkalemia, or hypomagnesemia may alter the effects of the antiarrhythmic dru . Electrolytes are monitored frequently and imbalances corrected as soon as possible... 

When two antiarrhythmic dragp are administered concurrently the patient may experience additive effects and is at increased risk for drug toxicity. When quinidine and procainamide are administered with digitalis, tiie risk of digitalis toxicity is increased. Hiarmacologic effects of procainamide may be increased when procainamide is administered with quinidine When quinidine is administered with the barbiturates or cimetidine, quinidine serum levels may be increased. When quinidine is administered with verapamil, there is an increased risk of hypotensive effects. When quinidine is administered with disopyramide, there is an increased risk of increased disopyramide blood levels and/or decreased serum quinidine levels. 

Potassium imbalance Disopyramide may be ineffective in f7ypokalemia and its toxic effects may be enhanced in /lyperkalemia. Correct any potassium deficit before instituting therapy. 

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. 

Toxic concentrations of disopyramide can precipitate all of the electrophysiologic disturbances described under quinidine. As a result of its negative inotropic effect, disopyramide may precipitate heart failure de novo or in patients with preexisting depression of left ventricular function. Because of this effect, disopyramide is not used as a first-line antiarrhythmic agent in the USA. It should not be used in patients with heart failure. 

DISOPYRAMIDE DIURETICS-CARBONIC ANHYDRASE INHIBITORS, LOOP DIURETICS, THIAZIDES Risk oft myocardial depression Cardiac toxicity directly related to hypokalaemia Monitor potassium levels closely... 

GRAPEFRUIT JUICE DISOPYRAMIDE Likely interaction with possibility of t plasma concentrations and toxic effects of disopyramide. Flowever, the clinical significance is not yet known as the interaction has not been scientifically tested Unclear Monitor ECG and side-effects more closely... 

Interestingly, the secondary effects of enantiomers may be masked by the presence of their antipodes and only surface after the therapeutic and toxicity properties of the enantiomers are compared with their respective racemate. For example, enantiomers of disopyramide illicit equal antiarrhythmic effects, but the S enantiomer possesses a greater extent of anticholinergic side-effects (12). Intuitively, a formulation composed of the R enantiomer would seem to be a safer alternative. However, it appears that the single enantiomer of disopyramide possesses additional side-effects that are minimal after administration of the racemic drug. 

Handa SP. Disopyramide-induced toxic cutaneous bhsters and coagulopathy. Dialysis Transplant 1982 ll 706-7. 

Ellrodt G, Singh BN. Adverse effects of disopyramide (Norpace) toxic interactions with other antiarrhythmic agents. Heart Lung 1980 9(3) 469-74. 

Maddux BD, Whiting RB. Toxic synergism of disopyramide and hyperkalemia. Chest 1980 78(4) 654-6. 

Additional investigations in the second case suggested enhanced insulin secretion induced by toxic disopyramide concentrations as the probable mechanism. 

Elecainide, proprietary name Tambocor, is a sodium channel blocker with cardiac activity like disopyramide. The drug has significant toxicity in patients with myocardial infarction and has therefore fallen out of favor. For those patients who fail to respond to other sodium channel blockers, it might be a drug of last resort. 

A series of dibenzazepines (18a, 18b) were compared to disopyramide (.1) The compounds suppressed ventricular arrhythmias in dogs but may have been more toxic than the latter. Preliminary reports on a series of 3-amino-3-methyloxindoles indicate that one member (19) is as effective as lidocaine in the mouse chloroform test and possesses a higher LD50 59... 

The metabolism of the antidepressant drug mianserin (41) (Fig. 13.35) revealed analogies and differences with disopyramide. Indeed, aromatic oxidation in human liver microsomes occurred more readily for the (S)-enantiomer, whereas N-demethylation was the major route for the (/ )-enantiomer. At low drug concentrations, cytotoxicity toward human mononuclear leucocytes was caused by (J2)-miansejrin more than by (S)-mianserin and showed a significant correlation with N-demethylation (176). Thus, the toxicity of mianserin seemed associated with N-demethylation rather than with aromatic oxidation, in contrast to disopyramide. The chemical nature of the toxic intermediates was not established, but a comparison between disopyramide and mianserin emphasizes that no a priori expectation should influence toxicometabolic studies. 

V 1 1 IV. 6 hr half-life, partially metabolized in liver, low plasma protein binding. Hypersensitivity to amrinone. Amrinone increases diuresis in patients on diuretics. Digitalis inotropy and risk of toxicity increased (amrinone causes hypokalemia). Excessive hypotension with disopyramide. If cellular supplies of cAMP are depleted, amrinone will not be effective. Capable of increasing myocardial contraction even in the presence of p-adrenergic antagonists. 

D. Important drug interactions may result in toxicity. Hypotension is more likely to occur in patients taking beta blockers, nitrates, or both, especially if they are hypovolemic after diuretic therapy. Patients taking disopyramide or other... 

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