CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC MEDICATIONS - PowerPoint PPT Presentation

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CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC MEDICATIONS
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CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC MEDICATIONS

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  1. CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC MEDICATIONS Vincent F. Mauro, PharmD, FCCP Professor of Clinical Pharmacy and Adjunct Professor of Medicine The University of Toledo

  2. GOALS To have a better understanding of: • The EPS properties of antiarrhythmics according to their Vaughan-Williams classification • Important pharmacotherapeutic issues related to antiarrhythmic use • The causes & treatment of torsade de pointes

  3. Automaticity

  4. Reentry-induced dysrhythmia

  5. Classification of Antiarrhythmic Agents IAQuinidine ICFlecainide ProcainamidePropafenone DisopyramideEncainide IBLidocaine I?Moricizine Mexiletine Tocainide

  6. Classification of Antiarrhythmic Agents II Beta-adrenergic blockers IIIAmiodarone Ibutilide Dronedarone Dofetilide Sotalol Bretylium IVCalcium channel blockers Diltiazem & Verapamil

  7. Classification of Antiarrhythmic Agents Digoxin Adenosine

  8. Generic Brandname Disopyramide Norpace Mexiletine Mexitil Flecainide Tambocor Propafenone Rythmol Amiodarone Cordarone, Pacerone Dronedarone Multaq Esmolol Brevibloc Sotalol Betapace, Sorine Ibutilide Corvert Dofetilide Tikosyn Digoxin Lanoxin, Digitek Adenosine Adenocard

  9. Type Ix

  10. Type Ia

  11. Type Ib

  12. Type Ic

  13. Ia’s create a double block

  14. Ib’s take away the block

  15. What about Ic’s?- They have no effect on action potential duration

  16. Type II & IV

  17. Type III

  18. CLINICAL INDICATIONS Medication Ventricular Atrial QuinidinePO,SR,IV X X Procainamide IV X X DisopyramidePO,SR X X LidocaineIV X - MexiletinePO X - FlecainidePO X!! X PropafenonePO,SR X X

  19. CLINICAL INDICATIONS Medication Ventricular Atrial Beta-blockersPO,SR,IV E AV AmiodaronePO,IVX X DronedaronePO - X SotalolPO,IV X X/AV DofetilidePO ? X IbutilideIV ? AF/Fl Calcium channel blockersPO,SR,IV E? AV

  20. CLINICAL INDICATIONS Medication Ventricular Atrial DigoxinPO,IV - AV AdenosineIV - PSVT

  21. Quinidine • Type IA antiarrhythmic • Indicated for atrial fibrillation and ventricular tachycardias

  22. Quinidine Adverse Effects • GI irritation • Bitter taste • Hepatitis & other hepatic conditions • Rash & drug fever • Thrombocytopenia • Cinchonism • Tinnitus • Blurred vision • Headaches • Dizziness

  23. Quinidine • Different salts • Sulfate (83%)PO,SR • Gluconate (62%)SR,IV • Hepatically eliminated (t1/2 ~6-8 hr) • Increases digoxin & warfarin levels • IV dosage form – hemodynamic instability • Some concern when IV verapamil or diltiazem is given to a patient on quinidine

  24. Procainamide • Type IA antiarrhythmic • Indicated for acute conversion of ventricular & atrial dysrhythmias

  25. Procainamide • Short half-life (~3 hours) • 6-h & 12-h SR dosage forms once existed • 50% hepatically metabolized, mostly to NAPA (fast/slow acetylators) • NAPA (as w/ 50% of PA) is renally eliminated • Causes drug-induced SLE

  26. Procainamide Adverse Effects • Gastrointestinal • CNS • Fever • Rash • Blood dyscrasias • Some negative inotropic properties • Hypotension w/ rapid IV infusions

  27. Procainamide • Dosing • Acute: 17 mg/kg @ 20 mg/min (50 mg/min, if urgent) • Infusion: 1-4 mg/min (depends on renal fxn) • Metabolism • NAPA produced (a renally eliminated active metabolite of procainamide) • Toxicity if NAPA levels exceed 20 mg/L

  28. Disopyramide • Type IA antiarrhythmic • Indicated in atrial and ventricular arrhythmias

  29. Disopyramide • Concentration-dependent plasma protein binding • An increase in dosage rate results in an increase in the percentage of disopyramide that is unbound • Increased unbound drug allows for enhanced clearance • As a result, increasing the dosage rate results in a less than proportional increase in total drug concentration

  30. Concentration at Steady State Dosage Rate

  31. Disopyramide • Therefore, total drug concentrations have a limited role in assisting on how much to adjust the dosage of disopyramide due to its concentration-dependent plasma protein binding • Total drug concentrations can be used to document a patient’s “effective” drug concentration once efficacy has been demonstrated

  32. Disopyramide Adverse Effects • Gastrointestinal • Negative inotrope • Anticholinergic adverse effects • Dry mouth • Blurred vision • Constipation • Urinary hesitation

  33. Disopyramide • Elimination • ~50% hepatic • ~50% renal • Half-life • ~7 hours

  34. Disopyramide • Used in neurocardiogenic syncope & hypertrophic hearts • Anticholinergic properties • Negative inotropic properties

  35. Lidocaine • Type IB antiarrhythmic • Indicated in acute treatment and prevention of ventricular dysrhythmias

  36. Lidocaine • Half Life • Initially, 1.5hours; but increases to 3.0 hours 2-3 days into therapy • Lidocaine reduces its own rate of metabolism

  37. Lidocaine • Toxicity most often manifested by: Nausea Dizziness Drowsiness Confusion Tremors Facial numbness Paresthesias Peripheral numbness Altered speech Seizures

  38. Lidocaine • Dosing • 1.0-1.5 mg/kg IVP over 1-2 min; repeat every 5-10 min with 0.5-0.75 mg/kg, as needed, until 3 mg/kg total dose • Typical maintenance dose: 1.0-4.0 mg/min • Use lower rate with CHF

  39. Mexiletine • Type IB antiarrhythmic • Only indicated to prevent ventricular arrhythmias

  40. Mexiletine Adverse Effects • ExtremelyGI irritating • Altered CNS functioning • Hepatically metabolized • Half-life: 6-12 hours

  41. Flecainide • Type IC antiarrhythmic • Since it is very proarrhythmic: • Generally used only for atrial dysrhythmias

  42. Flecainide • Very proarrhythmic in patients with: • CAD • CHF • Ventricular dysrhythmias • Used primarily in atrial fibrillation when concerns for proarrhythmias are not present

  43. Flecainide Adverse Effects • Gastrointestinal • CNS • Negative inotrope Pharmacokinetics • Mostly hepatic clearance (60%); some renal (30%) • Half-life: ~20 hours

  44. Propafenone • Type IC with some beta-blocking properties • Primarily used for atrial dysrhythmias • Rarely, ventricular

  45. Propafenone Adverse Effects • Gastrointestinal • CNS • Negative inotrope • Metallic taste

  46. Propafenone • Non-linear absorption & elimination • Bioavailability increases w/ higher doses • IR and SR dosages are NOT bioequivalent • SR has reduced bioavailability • Clearance decreases w/ higher doses • Hepatic elimination • Active metabolites • Extensive (90%) & Slow (10%) metabolizers • Increases digoxin levels

  47. Sotalol • Non-selective beta-blocker with type III antiarrhythmic activity • Used to acutely treat and prevent atrial & ventricular dysrhythmias

  48. Sotalol • Renally eliminated • Negative inotrope • Beta-blocker concerns • Torsade de pointes

  49. Sotalol • Renally eliminated • Negative inotrope • Beta-blocker concerns • Torsade de pointes • Do not initiate if QT > 450 msec • Desire QT < 500 msec for first 3 days • Desire QT < 520 msec thereafter