Disopyramide

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Disopyramide
Disopyramide.svg
Disopramide.png
Clinical data
Trade names Norpace
AHFS/Drugs.com Monograph
MedlinePlus a682408
Pregnancy
category
  • AU:B2
Routes of
administration 		Oral, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability High
Protein binding 50% to 65%
(concentration-dependent)
Metabolism Hepatic (CYP3A4-mediated)
Elimination half-life 6.7 hours (range 4 to 10 hours)
Excretion Renal (80%)
Identifiers
  • (RS)-4-(Diisopropylamino)-2-phenyl-2-(pyridin-2-yl)butanamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.021.010 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H29N3O
Molar mass 339.483 g·mol−1
3D model (JSmol)
Melting point 94.5 to 95 °C (202.1 to 203.0 °F)
  • O=C(N)C(c1ncccc1)(c2ccccc2)CCN(C(C)C)C(C)C
  • InChI=1S/C21H29N3O/c1-16(2)24(17(3)4)15-13-21(20(22)25,18-10-6-5-7-11-18)19-12-8-9-14-23-19/h5-12,14,16-17H,13,15H2,1-4H3,(H2,22,25) Yes check.svgY
  • Key:UVTNFZQICZKOEM-UHFFFAOYSA-N Yes check.svgY
   (verify)

Disopyramide (INN, trade names Norpace and Rythmodan) is an antiarrhythmic medication used in the treatment of ventricular tachycardia. [2] It is a sodium channel blocker and is classified as a Class 1a anti-arrhythmic agent. [3] [4] Disopyramide has a negative inotropic effect on the ventricular myocardium, significantly decreasing the contractility. [5] [6] 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. In 1972, when it was one of the only alternatives to quinidine, it was praised for being more potent and somewhat less toxic. [6] However, a 2012 review of antiarrhythmic drugs noted that disopyramide is among the most toxic agents, with a high burden of side effects and increased mortality (compared to placebo) when used to treat atrial fibrillation. [7]

Contents

Mechanism of action

Disopyramide's Class 1a activity is similar to that of quinidine in that it targets sodium channels to inhibit conduction. [4] [6] 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. [4] Disopyramide prolongs the PR interval by lengthening both the QRS and P wave duration. [6] 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. [8] Anesthetized dogs treated with disopyramide (1 mg/kg) had reduced contractile force of 42%, and the decrease in contractile force from 1 mg/kg of disopyramide was roughly double the decrease seen with quinidine in much higher doses of 5, 10, or 15 mg/kg. [6]

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. [5] This decreases the chance of re-entry depolarization, because signals are more likely to encounter tissue in a refractory state which cannot be excited. [2] This provides a possible treatment for atrial and ventricular fibrillation, as it restores pacemaker control of the tissue to the SA and AV nodes. [9]

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. [10] [11] [12] [13] Disopyramide has been actively used for more than 30 years. [14] Disopyramide administration for obstructive HCM has a IB recommendation in the 2020 American Heart Association/American College of Cardiology Foundation guidelines for treatment of obstructive HCM. [15] A IB treatment recommendation indicates that a treatment is recommended, and may be useful, and beneficial.

Negative inotropes improve left ventricular (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. [16] 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. [13]

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. [17] This combination has also been shown to be effective and safe in obstructive HCM in a large cohort of patients. [13] Some clinicians prescribe pyridostigmine sustained release (marketed in the US as Mestinon Timespan) to every patient begun on disopyramide. [18] 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. [10] [11] [13]

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. [13]

Side effects

Disopyramide has the following side effects: [19]

Mild side effects
Serious side effects

Adverse effects

Cardiac adverse effects

Extracardiac adverse effects

Disopyramide has atropine-like anticholinergic effects. [20]

Additionally, disopyramide may enhance the hypoglycemic effect of gliclazide, insulin, and metformin.[ citation needed ]

See also

Related Research Articles

Hypertrophic cardiomyopathy is a condition in which muscle tissues of the heart become thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ventricles. This results in the heart being less able to pump blood effectively and also may cause electrical conduction problems. Specifically, within the bundle branches that conduct impulses through the interventricular septum and into the Purkinje fibers, as these are responsible for the depolarization of contractile cells of both ventricles.

An inotrope or inotropic is a drug or any substance that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.

<span class="mw-page-title-main">Diltiazem</span> Calcium channel blocker medication

Diltiazem, sold under the brand name Cardizem among others, is a nondihydropyridine calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used. It is taken by mouth or injection into a vein. When given by injection, effects typically begin within a few minutes and last a few hours.

<span class="mw-page-title-main">Flecainide</span> Antiarrhythmic medication

Flecainide is a medication used to prevent and treat abnormally fast heart rates. This includes ventricular and supraventricular tachycardias. Its use is only recommended in those with dangerous arrhythmias or when significant symptoms cannot be managed with other treatments. Its use does not decrease a person's risk of death. It is taken by mouth or injection into a vein.

Pulsus paradoxus, also paradoxic pulse or paradoxical pulse, is an abnormally large decrease in stroke volume, systolic blood pressure and pulse wave amplitude during inspiration. Pulsus paradoxus is not related to pulse rate or heart rate, and it is not a paradoxical rise in systolic pressure. Normally, blood pressure drops less precipitously than 10 mmHg during inhalation. Pulsus paradoxus is a sign that is indicative of several conditions, most commonly pericardial effusion.

Tachycardia-induced cardiomyopathy (TIC) is a disease where prolonged tachycardia or arrhythmia causes an impairment of the myocardium, which can result in heart failure. People with TIC may have symptoms associated with heart failure and/or symptoms related to the tachycardia or arrhythmia. Though atrial fibrillation is the most common cause of TIC, several tachycardias and arrhythmias have been associated with the disease.

<span class="mw-page-title-main">Restrictive cardiomyopathy</span> Medical condition

Restrictive cardiomyopathy (RCM) is a form of cardiomyopathy in which the walls of the heart are rigid. Thus the heart is restricted from stretching and filling with blood properly. It is the least common of the three original subtypes of cardiomyopathy: hypertrophic, dilated, and restrictive.

<span class="mw-page-title-main">Acecainide</span> Antiarrythmic drug

Acecainide is an antiarrhythmic drug. Chemically, it is the N-acetylated metabolite of procainamide. It is a Class III antiarrhythmic agent, whereas procainamide is a Class Ia antiarrhythmic drug. It is only partially as active as procainamide; when checking levels, both must be included in the final calculation.

<span class="mw-page-title-main">Amrinone</span> Chemical compound

Amrinone, also known as inamrinone, and sold as Inocor, is a pyridine phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initiated in the heart by high-gain calcium induced calcium release (CICR). The positive inotropic effect of amrinone is mediated by the selective enhancement of high-gain CICR, which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca2+ calmodulin kinase pathways.

<span class="mw-page-title-main">Prajmaline</span> Chemical compound

Prajmaline (Neo-gilurythmal) is a class Ia antiarrhythmic agent which has been available since the 1970s. Class Ia drugs increase the time one action potential lasts in the heart. Prajmaline is a semi-synthetic propyl derivative of ajmaline, with a higher bioavailability than its predecessor. It acts to stop arrhythmias of the heart through a frequency-dependent block of cardiac sodium channels.

<span class="mw-page-title-main">Takotsubo cardiomyopathy</span> Sudden temporary weakening of the heart muscle

Takotsubo cardiomyopathy or takotsubo syndrome (TTS), also known as stress cardiomyopathy, is a type of non-ischemic cardiomyopathy in which there is a sudden temporary weakening of the muscular portion of the heart. It usually appears after a significant stressor, either physical or emotional; when caused by the latter, the condition is sometimes called broken heart syndrome.

Septal myectomy is a cardiac surgery treatment for hypertrophic cardiomyopathy (HCM). The open-heart surgery entails removing a portion of the septum that is obstructing the flow of blood from the left ventricle to the aorta.

Alcohol septal ablation (ASA) is a minimally invasive heart procedure to treat hypertrophic cardiomyopathy (HCM).

<span class="mw-page-title-main">Noncompaction cardiomyopathy</span> Congenital disease of heart muscle

Noncompaction cardiomyopathy (NCC) is a rare congenital disease of heart muscle that affects both children and adults. It results from abnormal prenatal development of heart muscle.

The following outline is provided as an overview of and topical guide to cardiology, the branch of medicine dealing with disorders of the human heart. The field includes medical diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular heart disease and electrophysiology. Physicians who specialize in cardiology are called cardiologists.

<span class="mw-page-title-main">Hypertrophic cardiomyopathy screening</span> Procedure for detecting a form of heart disease

Hypertrophic cardiomyopathy screening is an assessment and testing to detect hypertrophic cardiomyopathy (HCM).

<span class="mw-page-title-main">AH-1058</span> Chemical compound

AH-1058 is a lipophilic antiarrhythmic calcium channel blocker synthesized by the Pharmaceutical Research Laboratories of Ajinomoto Co., Inc in Kawasaki, Japan. It is derived from cyproheptadine, a compound with known antiserotonic, antihistaminic and calcium channel blocking properties. The IUPAC name of AH-1058 is: 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[E-3-(3-methoxy-2-nitro) phenyl-2-propenyl]piperidine hydrochloride.

<span class="mw-page-title-main">Heart failure with preserved ejection fraction</span> Medical condition

Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the left ventricle is maximally filled – is normal, defined as greater than 50%; this may be measured by echocardiography or cardiac catheterization. Approximately half of people with heart failure have preserved ejection fraction, while the other half have a reduction in ejection fraction, called heart failure with reduced ejection fraction (HFrEF).

<span class="mw-page-title-main">Istaroxime</span> Chemical compound

Istaroxime is an investigational drug under development for treatment of acute decompensated heart failure

Tissue Doppler echocardiography (TDE) is a medical ultrasound technology, specifically a form of echocardiography that measures the velocity of the heart muscle (myocardium) through the phases of one or more heartbeats by the Doppler effect of the reflected ultrasound. The technique is the same as for flow Doppler echocardiography measuring flow velocities. Tissue signals, however, have higher amplitude and lower velocities, and the signals are extracted by using different filter and gain settings. The terms tissue Doppler imaging (TDI) and tissue velocity imaging (TVI) are usually synonymous with TDE because echocardiography is the main use of tissue Doppler.

References

  1. ↑ "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control]. Diário Oficial da União [Official Diary of the Union] (in Brazilian Portuguese). Brazilian Health Regulatory Agency (Anvisa) (published 2023-04-04). 2023-03-31. Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. 1 2 Hall JE, Guyton AC (2006). Pocket Companion to Guyton & Hall Textbook of Medical Physiology. Elsevier. ISBN   9788480862325. OCLC   1027935564.
  3. ↑ Rizos I, Brachmann J, Lengfelder W, Schmitt C, von Olshausen K, Kübler W, et al. (February 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): 154–163. doi:10.1093/oxfordjournals.eurheartj.a062243. PMID   3569310.
  4. 1 2 3 Kim SY, Benowitz NL (1990). "Poisoning due to class IA antiarrhythmic drugs. Quinidine, procainamide and disopyramide". Drug Safety. 5 (6): 393–420. doi:10.2165/00002018-199005060-00002. PMID   2285495. S2CID   71415838.
  5. 1 2 Levites R, Anderson GJ (September 1979). "Electrophysiological effects of disopyramide phosphate during experimental myocardial ischemia". American Heart Journal. 98 (3): 339–344. doi:10.1016/0002-8703(79)90046-2. PMID   474380.
  6. 1 2 3 4 5 Mathur PP (December 1972). "Cardiovascular effects of a newer antiarrhythmic agent, disopyramide phosphate". American Heart Journal. 84 (6): 764–770. doi:10.1016/0002-8703(72)90069-5. PMID   4150336.
  7. ↑ Camm J (2012-03-22). "Antiarrhythmic drugs for the maintenance of sinus rhythm: risks and benefits". Int. J. Cardiol. 155 (3): 362–371. doi:10.1016/j.ijcard.2011.06.012. PMID   21708411 . Retrieved 1 May 2024. Compared with controls, patients treated with disopyramide had a significantly higher mortality, with a Peto odds ratio (i.e., pooled odds ratio) of 7.56.
  8. ↑ Hulting J, Rosenhamer G: Hemodynamic and electrocardiographic effects of disopyramide in patients with ventricular arrhythmia. Acta Med Scand 199:41-51, 1976.
  9. ↑ Katzung BG, Masters SB, Trevor AJ (2009). Basic and Clinical Pharmacology (11th ed.). New York: McGraw Hill.
  10. 1 2 Ball W, Ivanov J, Rakowski H, Wigle ED, Linghorne M, Ralph-Edwards A, et al. (November 2011). "Long-term survival in patients with resting obstructive hypertrophic cardiomyopathy comparison of conservative versus invasive treatment". Journal of the American College of Cardiology. 58 (22): 2313–2321. doi: 10.1016/j.jacc.2011.08.040 . PMID   22093509.
  11. 1 2 Sherrid MV, Barac I, McKenna WJ, Elliott PM, Dickie S, Chojnowska L, et al. (April 2005). "Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy". Journal of the American College of Cardiology. 45 (8): 1251–1258. doi: 10.1016/j.jacc.2005.01.012 . PMID   15837258.
  12. ↑ Elliott PM, Gimeno JR, Thaman R, Shah J, Ward D, Dickie S, et al. (June 2006). "Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy". Heart. 92 (6): 785–791. doi:10.1136/hrt.2005.068577. PMC   1860645 . PMID   16216855.
  13. 1 2 3 4 5 Sherrid MV, Shetty A, Winson G, Kim B, Musat D, Alviar CL, et al. (July 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.
  14. ↑ Pollick C (October 1982). "Muscular subaortic stenosis: hemodynamic and clinical improvement after disopyramide". The New England Journal of Medicine. 307 (16): 997–999. doi:10.1056/nejm198210143071607. PMID   7202121.
  15. ↑ Ommen SR, Mital S, Burke MA, Day SM, Deswal A, Elliott P, et al. (December 2020). "2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines". Journal of the American College of Cardiology. 76 (25): e159–e240. doi: 10.1016/j.jacc.2020.08.045 . PMID   33229116.
  16. ↑ 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
  17. ↑ Teichman SL, Ferrick A, Kim SG, Matos JA, Waspe LE, Fisher JD (September 1987). "Disopyramide-pyridostigmine interaction: selective reversal of anticholinergic symptoms with preservation of antiarrhythmic effect". Journal of the American College of Cardiology. 10 (3): 633–641. doi: 10.1016/s0735-1097(87)80207-3 . PMID   3624669.
  18. ↑ Sherrid MV, Arabadjian M. A primer of disopyramide treatment of obstructive hypertrophic cardiomyopathy. Prog Cardiovasc Dis. 2012;54:483-492
  19. ↑ "Disopyramide - Drug Information | MedlinePlus". medlineplus.gov. Retrieved 2023-12-12.
  20. ↑ Ritter JM, Flower R, Henderson G, Loke YK, MacEwan D, Robinson E, et al. (2023-05-24). Rang and Dale's Pharmacology. Elsevier. ISBN   9780323873956. OCLC   1362865747.
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