Disopyramide

Disopyramide
Systematic (IUPAC) name
(RS)-4-(Diisopropylamino)-2-phenyl-2-(pyridin-2-yl)butanamide
Clinical data
Trade names Norpace
AHFS/Drugs.com monograph
MedlinePlus a682408
Pregnancy
category
  • AU: B2
  • US: C (Risk not ruled out)
Routes of
administration		 Oral, intravenous
Legal status
Legal status
Pharmacokinetic data
Bioavailability High
Protein binding 50% to 65%
(concentration-dependent)
Metabolism Hepatic (CYP3A4-mediated)
Biological half-life 6.7 hours (range 4 to 10 hours)
Excretion Renal (80%)
Identifiers
CAS Number 3737-09-5 YesY
ATC code C01BA03 (WHO)
PubChem CID 3114
IUPHAR/BPS 7167
DrugBank DB00280 YesY
ChemSpider 3002 YesY
UNII GFO928U8MQ YesY
KEGG D00303 YesY
ChEBI CHEBI:4657 YesY
ChEMBL CHEMBL517 YesY
Chemical data
Formula C21H29N3O
Molar mass 339.475 g/mol
Physical data
Melting point 94.5 to 95 °C (202.1 to 203.0 °F)
  (verify)

Disopyramide (INN, trade names Norpace and Rythmodan) is an antiarrhythmic medication used in the treatment of ventricular tachycardia.[1] It is a sodium channel blocker and therefore classified as a Class 1a anti-arrhythmic agent.[2][3] Disopyramide has a negative inotropic effect on the ventricular myocardium, significantly decreasing the contractility.[4][5] Disopyramide also has an anticholinergic effect on the heart which accounts for many adverse side effects. Disopyramide is available in both oral and intravenous forms, and has a low degree of toxicity.[5]

Mechanism of action

Disopyramide’s Class 1a activity is similar to that of quinidine in that it targets sodium channels to inhibit conduction.[3][5] 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.[3] Disopyramide prolongs the PR interval by lengthening both the QRS and P wave duration.[5] 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.[6] 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.[5]

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.[4] This decreases the chance of re-entry depolarization, because signals are more likely to encounter tissue in a refractory state which can’t be excited.[7] This provides a possible treatment for atrial and ventricular fibrillation, as it restores pacemaker control of the tissue to the SA and AV nodes.[8]

Obstructive hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease occurring in 1:500 individuals in the general population. It is estimated that there are 600,000 individuals in the United States with hypertrophic cardiomyopathy. The most common variant of HCM presents with left ventricular (LV) intracavitary obstruction due to systolic anterior motion of the mitral valve, and mitral-septal contact, diagnosed readily with echocardiography. Pharmacologic treatment with negative inotropic drugs is 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. Many investigators and clinicians believe that disopyramide controlled release, is the most potent agent available for reducing resting pressure gradients and improving symptoms.[9][10][11][12] Disopyramide has been actively used for nearly 30 years.[13] 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.[14] 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.[15] 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.[12] Effective dosage of disopyramide is 500–600 mg/day given in divided dosage. Lower dosages 400 mg/day in divided dosage may be used in patients with mild renal failure, serum creatinine 1.3-2.0 mg/dl. Disopyramide is most often administered with beta-blockade.

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.[16] This combination has also been shown to be effective and safe in obstructive HCM in a large cohort of patients.[12] Some clinicians prescribe pyridostigmine sustained release (marketed in the US as Mestinon Timespan) to every patient begun on disopyramide, either as twice daily, or as needed.[17] This combinationa 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 2 recent cohort registries have largely reduced this concern, by showing sudden death rates lower than that observed from the disease itself.[9][10][12]

These concerns about the drug must be viewed from the clinical perspective that disopyramide is the last agent that is tried for patients before they are referred for invasive septal reduction with surgical septal myectomy with open heart surgery, or alcohol septal ablation. Ablation is a percutaneous catheter-based technique in which a controlled therapeutic myocardial infarction is produced by instillation of 100% alcohol into a septal perforator artery. Both of these invasive procedures have risk of morbidity and mortality.

For selected patients a trial of oral disopyramide, in adequate dose, 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.[12]

Cardiac adverse effects

Extracardiac effects

Additionally, disopyramide may enhance the hypoglycaemic effect of gliclazide, insulin, and metformin.

See also

References

  1. ↑ Guyton, Arthur C., Hall, John E. (2006). Textbook of Medical Physiology (11th ed.). Philadelphia: Elsevier Saunders.
  2. ↑ Rizos, I; Brachmann, J; Lengfelder, W; Schmitt, C; von Olshausen, K; Kübler, W; Senges, J (1987). "Effects of intravenous disopyramide and quinidine on normal myocardium and on the characteristics of arrhythmias: Intraindividual comparison in patients with sustained ventricular tachycardia". European heart journal 8 (2): 154–63. PMID 3569310.
  3. 1 2 3 Kim, S. Y.; Benowitz, N. L. (1990). "Poisoning due to class IA antiarrhythmic drugs. Quinidine, procainamide and disopyramide". Drug safety 5 (6): 393–420. PMID 2285495.
  4. 1 2 Levites, R; Anderson, G. J. (1979). "Electrophysiological effects of disopyramide phosphate during experimental myocardial ischemia". American Heart Journal 98 (3): 339–44. PMID 474380.
  5. 1 2 3 4 5 Mathur, P. P. (1972). "Cardiovascular effects of a newer antiarrhythmic agent, disopyramide phosphate". American Heart Journal 84 (6): 764–70. PMID 4150336.
  6. ↑ Hulting J, Rosenhamer G: Hemodynamic and electrocardiographic effects of disopyramide in patients with ventricular arrhythmia. Acta Med Scand 199:41-51, 1976.
  7. ↑ Guyton, Arthur C., Hall, John E. (2006). Textbook of Medical Physiology (11th ed.). Philadelphia: Elsevier Saunders.
  8. ↑ Katzung, Bertram G., Masters, Susan B., Trevor, Anthony J. (2009). Basic and Clinical Pharmacology (11th ed.). New York: McGraw Hill
  9. 1 2 Ball W, Ivanov J, Rakowski H, Wigle ED, Linghorne M, Ralph-Edwards A, Williams WG, Schwartz L, Guttman A, Woo A. Long-term survival in patients with resting obstructive hypertrophic cardiomyopathy comparison of conservative versus invasive treatment. J Am Coll Cardiol. 2011;58:2313-2321
  10. 1 2 Sherrid MV, Barac I, McKenna WJ, Elliott PM, Dickie S, Chojnowska L, Casey S, Maron BJ. Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005;45:1251-1258
  11. ↑ Elliott PM, Gimeno JR, Thaman R, Shah J, Ward D, Dickie S, Tome Esteban MT, McKenna WJ. Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy. Heart. 2006;92:785-791
  12. 1 2 3 4 5 Sherrid, M. V.; Shetty, A; Winson, G; Kim, B; Musat, D; Alviar, C. L.; Homel, P; Balaram, S. K.; Swistel, D. G. (2013). "Treatment of obstructive hypertrophic cardiomyopathy symptoms and gradient resistant to first-line therapy with β-blockade or verapamil". Circulation: Heart Failure 6 (4): 694–702. doi:10.1161/CIRCHEARTFAILURE.112.000122. PMID 23704138.
  13. ↑ Pollick C. Muscular subaortic stenosis: Hemodynamic and clinical improvement after disopyramide. N Engl J Med. 1982;307:997-999
  14. ↑ Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;58:e212-260
  15. ↑ Kajimoto K, Imai T, Minami Y, Kasanuki H. Comparison of acute reduction in left ventricular outflow tract pressure gradient in obstructive hypertrophic cardiomyopathy by disopyramide versus pilsicainide versus cibenzoline. Am J Cardiol. 2010;106:1307-1312
  16. ↑ Teichman SL, Ferrick A, Kim SG, Matos JA, Waspe LE, Fisher JD. Disopyramide-pyridostigmine interaction: Selective reversal of anticholinergic symptoms with preservation of antiarrhythmic effect. J Am Coll Cardiol. 1987;10:633-641
  17. ↑ Sherrid MV, Arabadjian M. A primer of disopyramide treatment of obstructive hypertrophic cardiomyopathy. Prog Cardiovasc Dis. 2012;54:483-492
  18. ↑

External links

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