|Trade names||Norpace, Rythmodan, others|
|Drug class||Class 1a anti-arrhythmic|
|Main uses||Prevention of ventricular tachycardia|
|Side effects||Dry mouth, constipation, blurry vision, urinary retention, nausea, tiredness, dizziness|
|Protein binding||50% to 65%|
|Elimination half-life||6.7 hours (range 4 to 10 hours)|
|Chemical and physical data|
|Molar mass||339.483 g·mol−1|
|3D model (JSmol)|
|Melting point||94.5 to 95 °C (202.1 to 203.0 °F)|
Disopyramide, sold under the brand names Norpace among others, is a medication used to prevent ventricular tachycardia. It is typically only used when other medications are not effective. Use is not recommended for less serious arrhythmias. It is taken by mouth.
Common side effects include dry mouth, constipation, blurry vision, urinary retention, nausea, tiredness, and dizziness. Other side effects may include heart failure, arrhythmias, and low blood sugar. Safety in pregnancy is unclear. It is a class 1a anti-arrhythmic and sodium channel blocker. It has a negative effect on the hearts ability to contract.
Disopyramide was approved for medical use in the United States in 1977. It is available as a generic medication. In the United Kingdom 84 pills of 100 mg costs the NHS about £27 as of 2021. In the United States this amount costs about 55 USD.
Hypertrophic cardiomyopathy (HCM) often presents with left ventricular (LV) intracavitary obstruction due to systolic anterior motion of the mitral valve, and mitral-septal contact, diagnosed readily with echocardiography. Negative inotropic drugs are first-line therapy. Beta-blockers are used first, and while they improve symptoms of shortness of breath, chest pain and exercise intolerance, they do not reduce resting LV intraventricular pressure gradients and often are inadequate to control symptoms. Disopyramide controlled release is the most potent agent available for reducing resting pressure gradients and improving symptoms. Disopyramide has been actively used for more than 30 years. Disopyramide administration for obstructive HCM has a IIa recommendation in the 2011 American Heart Association/American College of Cardiology Foundation guidelines for treatment of obstructive HCM. A IIa treatment recommendation indicates that benefits outweigh risk, and that it is reasonable to administer treatment.
Negative inotropes improve LV obstruction by decreasing LV ejection acceleration and hydrodynamic forces on the mitral valve. Disopyramide's particular efficacy is due to its potent negative inotropic effects; in head-to-head comparison, it is more effective for gradient reduction than either beta-blocker or verapamil. Disopyramide is most often administered with beta-blockade. When used in patients resistant to beta-blockade, disopyramide is effective in 60% of cases, reducing symptoms and gradient to the extent that invasive procedures such as surgical septal myectomy are not required.
Disopyramide, despite its efficacy, has one main side effect that has limited its use in the US, though it has seen wider application in Canada, UK and Japan. Vagal blockade predictably causes dry mouth, and in men with prostatism, may cause urinary retention. Teichman et al. showed that pyridostigmine used in combination with disopyramide substantially alleviates vagolytic side effects without compromising antiarrhythmic efficacy. This combination has also been shown to be effective and safe in obstructive HCM in a large cohort of patients. Some clinicians prescribe pyridostigmine sustained release (marketed in the US as Mestinon Timespan) to every patient begun on disopyramide. This combination increases acceptance of higher disopyramide dosing, important since there is a dose-response correlation in obstructive HCM, higher doses yielding lower gradients.
Another concern about disopyramide has been the hypothetical potential for inducing sudden death from its type 1 anti-arrhythmic effects. However, a multicenter registry and two recent cohort registries have largely reduced this concern, by showing sudden death rates lower than that observed from the disease itself.
These concerns about the drug must be viewed from the clinical perspective that disopyramide is generally the last agent that is tried for patients before they are referred for invasive septal reduction with surgical septal myectomy (an open-heart operation) or alcohol septal ablation (a controlled heart attack). Both of these invasive procedures have risk of morbidity and mortality.
For selected patients, a trial of oral disopyramide is a reasonable approach before proceeding to invasive septal reduction. Patients who respond to disopyramide are continued on the drug. Those who continue to have disabling symptoms or who experience side effects are promptly referred for septal reduction. Using such a stepped strategy, investigators have reported that survival does not differ from that observed in the age-matched normal United States population.
- Acute heart failure – Disopyramide should not be given to patients with impaired LV systolic function and low ejection fraction. Heart failure is not seen when disopyramide is used in patients with normal or supernormal LV systolic function.
- Severe hypotension – Disopyramide should not be given to patients with impaired LV systolic function and low ejection fraction. Hypotension is not seen in patients with normal or supernormal LV systolic function.
- Dry mouth
- Urinary retention – Disopyramide should not be given to patients with symptomatic prostatism.
- Blurred vision
Mechanism of action
Disopyramide's Class 1a activity is similar to that of quinidine in that it targets sodium channels to inhibit conduction. Disopyramide depresses the increase in sodium permeability of the cardiac myocyte during Phase 0 of the cardiac action potential, in turn decreasing the inward sodium current. This results in an increased threshold for excitation and a decreased upstroke velocity. Disopyramide prolongs the PR interval by lengthening both the QRS and P wave duration. This effect is particularly well suited in the treatment of ventricular tachycardia as it slows the action potential propagation through the atria to the ventricles. Disopyramide does not act as a blocking agent for beta or alpha adrenergic receptors, but does have a significant negative inotropic effect on the ventricular myocardium. As a result, the use of disopyramide may reduce contractile force up to 42% at low doses and up to 100% in higher doses leading to heart failure.
Levites proposed a possible secondary mode of action for disopyramide, against reentrant arrhythmias after an ischemic insult. Disopyramide decreases the inhomogeneity between infarcted and normal myocardium refractory periods; in addition to lengthening the refractory period. This decreases the chance of re-entry depolarization, because signals are more likely to encounter tissue in a refractory state which cannot be excited. This provides a possible treatment for atrial and ventricular fibrillation, as it restores pacemaker control of the tissue to the SA and AV nodes.
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