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disopyramide (Norpace)

Tradename: Norpace. Class Ia antiarrhythmic agent. Indications: 1) atrial fibrillation a) chemical cardioversion b) preventing recurrence of atrial fibrillation 2) paroxysmal supraventricular tachycardia (PSVT) 3) ventricular tachycardia - not 1st or 2nd line agent 4) preventing inducible & spontaneous neurally-mediated syncope * useful anti-arrhythmic in hypertrophic cardiomyopathy Contraindications: (cautions) 1) myasthenia gravis - anticholinergic effect may precipitate myasthenic crisis 2) avoid other agents which prolong the QT interval 3) avoid in men with benign prostatic hypertrophy 4) avoid in patients with LV systolic dysfunction Dosage: 100-300 mg PO TID/QID Tabs: 100, 150 mg. Norpace CR: 200-300 mg PO BID. 100, 150 mg Therapeutic range: 2-5 ug/mL. Dose adjustment for renal failure: Creatinine clearance dose (maintenance) in divided doses > 40 mL/min 400-800 mg/day (max 1.6 g/day) 30-40 mL/min 300 mg/day 15-30 mL/min 200 mg/day <15 mL/min 100 mg/day Pharmacokinetics: 1) rapidly & nearly completely absorbed from the GI tract 2) protein binding is concentration-dependent, 50-65% 3) metabolized in the liver by cyt P450 3A4 4) 50% of drug is excreted unchanged in the urine, 30% as metabolites 5) 1/2life is 6.7 hours a) increased with renal insufficiency b) 8-18 hours when creatinine clearance is < 40 mL/min Adverse effects: 1) common (> 10%) - urinary retention/hesitancy (anticholinergic effect) 2) less common (1-10%) - chest pains, congestive heart failure, hypotension, muscle weakness, stomach pain, bloating, blurred vision, dry mouth, hypokalemia 3) uncomon (< 1%) - weight gain, dyspnea, syncope, - conduction disturbances - AV block - widening of QRS - lengthening of QT interval - fatigue, malaise, nervousness, acute psychosis, depression, dizziness, weakness, headache, generalized rash, hypoglycemia, constipation, nausea/vomiting, diarrhea, pain, gas, anorexia, hepatic cholestasis, elevated liver enzymes, increased cholesterol & triglycerides, dry noses, eyes & throat (anticholinergic effects) 4) other - depression of myocardial contractility - may initiate contraction of pregnant uterus - hyperkalemia may enhance toxicity - masking symptoms of hypoglycemia Drug interactions: 1) avoid other agents which prolong the QT interval a) class Ia antiarrhythmics b) class III antiarrhythmics c) phenothiazines d) tricyclic antidepressants e) erythromycin f) terfenadine g) astemizole 2) barbiturates may increase metabolism 3) any drug that inhibits cyt P450 3A4 may increase levels of disopyramide 4) any drug that induces cyt P450 3A4 may diminish levels of disopyramide Laboratory: 1) specimen: serum, plasma (heparin, EDTA) 2) methods: GC-MS, GLC, HPLC, EIA, FPIA 3) labs with Loincs - disopyramide in specimen - disopyramide in body fluid - disopyramide in gastric fluid - disopyramide in serum/plasma - disopyramide in urine Mechanism of action: 1) Class Ia antiarrhythmic agent 2) negative inotrope 3) anticholinergic properties

Interactions

drug interactions drug adverse effects of antiarrhythmic agent, Group IA

Related

cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

General

antiarrhythmic agent, Group IA

Properties

MISC-INFO: elimination route KIDNEY 90% LIVER 10% 1/2life 4.4-8.2 HOURS therapeutic-range 2.8-3.2 UG/ML 3.3-7.5 UG/ML toxic-range >7 UG/ML protein-binding 68% <0.4 ug/mL> 28% <4 ug/mL> elimination by hemodialysis - pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (ed), Companion Handbook, McGraw Hill, NY, 1994
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998 - not on National VA formulary
  5. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
  6. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  7. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com