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Practical Pearls in AAD Selection
and Management
Kristen Bova Campbell, PharmD
Disclosures
 I have nothing to disclose concerning possible
financial or personal relationships with commercial
entities ...
Objectives
 Discuss the pharmacology of antiarrhythmic drugs
 Highlight clinical pearls to aid in selection of
antiarrhy...
Vaughan Williams Classification
Class Drug Channel Mechanism ECG Effect
I
1a: Quinidine,
Procainamide,
Disopyramide
Sodium...
Class 1a
Quinidine
Procainamide
Disopyramide
Class Ic
Propafenone
(IR, SR)
Flecainide
Class III
Amiodarone
Dofetilide
Dron...
Class Ic Agents
 Suppress both atrial and
ventricular
tachyarrhythmias
 Pronounced effect on
rapid Na+ channels
because ...
Flecainide
 Virtually continuously bound to
Na channel
 Initial: 50-100 mg PO q12h
 Decrease dose:
 Elderly
 Hepatic ...
Propafenone (Rythmol)
 Potent Na+ channel blocker
 Mild beta-blocking and calcium-
blocking properties
 Immediate relea...
Propafenone / Warfarin Interaction
 Significant increase in warfarin levels by
39%
 Increase INR ~ 25%
 Empirically dec...
Class III Antiarrhythmics: Overview
 Block K+ channels that
mediate repolarization
 Increase refractory
periods of cardi...
Class III Antiarrhythmics
 Careful assessment
of risks versus
benefits
 Torsades de Pointes
 Drug-drug
interactions:
 ...
Amiodarone (Cordarone®, Pacerone®)
 Primary mechanism: K+
channel blockade
 Properties of all
antiarrhythmic classes
 B...
 1.2 – 1.8 gm/day,
divided
 Total load: 5 -10 gm PO
 Remember to convert
 1 mg PO = 0.5 mg IV
 Afib: 200mg daily
 VT...
Adverse
Effect
Baseline
Monitoring?
Follow-up Monitoring
Pulmonary  Controversial
Hepatic  Every 3-6 months
Thyroid  Ev...
Amiodarone: Drug Interactions
Warfarin Statins Other
CYP2C9 and 3A4
inhibition
CYP3A4  Digoxin levels
Potentiates warfari...
Dofetilide (Tikosyn®)
 Potassium channel blocker
 Lengthens action
potential
 Prolongs effective
refractory period
 No...
Dofetilide: Dosing
 Cockcroft-Gault Equation
 ACTUAL body weight
CrCl >60 mL/min
CrCl 40-60
mL/min
CrCl 20-39 mL/min
250...
ELIMINATION
 Decreased renal tubular
secretion of cations,
resulting in:
  Dofetilide concentrations
  Risk of arrhyt...
Sotalol (Betapace®)
 Prolongation of action potential
in both atria and ventricles
 Racemic mixture:
 D-sotalol: class ...
 Most drug interactions occur via enhanced pharmacological
and electrophysiologic effects
 Beta blockade
 QT prolongati...
Dronedarone (Multaq®)
 Properties of all four
Vaughan-Williams classes
 Contribution of each to
clinical effect is uncle...
PHARMACOKINETIC
 CYP3A4 and CYP2D6
inhibitor
 Co-administration with
strong CYP3A4
contraindicated
 Azole antifungals
...
Lidocaine
 Inhibits influx of Na
 Increases recovery period after
repolarization
 Suppresses automaticity in His-
Purki...
Mexiletine
 Oral equivalent of lidocaine
 Dosing:
 150 – 300 mg PO q8h
 Titrate every 3 days max or longer
 Peak: 4-6...
Agent Recommendation
Flecainide, dofetilide, propafenone,
and IV ibutilide
Class I, level A
Amiodarone Class IIa, level A
...
Switching Antiarrhythmics
Drug Half-Life Minimum Wash-out
Amiodarone 53+ days Often not possible
Dofetilide 10 hours 36 ho...
Defibrillation Threshold Effects
Increase Decrease
Amiodarone
Flecainide
Propafenone
Lidocaine
Mexiletine
Dofetilide
Sotal...
Conclusions
 Multiple factors must be considered when choosing
an antiarrhythmic drug
 The aggressiveness of therapy sho...
Practical Pearls in AAD Selection
and Management
Kristen Bova Campbell, PharmD
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EP Summit 2015: Practical Pearls in AAD Selection and Management

Kristen Campbell

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EP Summit 2015: Practical Pearls in AAD Selection and Management

  1. 1. Practical Pearls in AAD Selection and Management Kristen Bova Campbell, PharmD
  2. 2. Disclosures  I have nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation
  3. 3. Objectives  Discuss the pharmacology of antiarrhythmic drugs  Highlight clinical pearls to aid in selection of antiarrhythmic drugs
  4. 4. Vaughan Williams Classification Class Drug Channel Mechanism ECG Effect I 1a: Quinidine, Procainamide, Disopyramide Sodium Slow depolarizatio n 1c > 1a > 1b 1a: ↑ QT, QRS, and PR 1b: usually no change 1c: ↑ PR and QRS 1b: Lidocaine, Mexiletine 1c: Propafenone, Flecainide II Beta Blockers AV Nodal Blockade ↓ HR and ↑PR III Amiodarone Ibutilide Dofetilide Dronedarone Sotalol Potassium Slow Repolarizatio n ↑QT IV Calcium Channel Blockers (nondihydropyridine) Calcium AV Nodal Blockade ↓ HR and ↑PR
  5. 5. Class 1a Quinidine Procainamide Disopyramide Class Ic Propafenone (IR, SR) Flecainide Class III Amiodarone Dofetilide Dronedarone Ibutilide Sotalol Atrial Fibrillation Rhythm Control: Contemporary Antiarrhythmic Management Procainamide, disopyramide, and amiodarone are not FDA-approved for treatment of AF. Miller MS, Zipes DP. In: Braunwald et al., eds. Heart Disease. Philadelphia, PA: Elsevier, Inc.; 2001.
  6. 6. Class Ic Agents  Suppress both atrial and ventricular tachyarrhythmias  Pronounced effect on rapid Na+ channels because of slow Na+ channel-binding kinetics  Exhibit use dependence  Negative inotrope  Do not use if structural heart disease  AV Nodal blockers Class 1c Propafenone (IR, SR) Flecainide PACE 1998;21:1999
  7. 7. Flecainide  Virtually continuously bound to Na channel  Initial: 50-100 mg PO q12h  Decrease dose:  Elderly  Hepatic Disease  Severe renal impairment  Smoking  Peak plasma levels: 2-4 hrs  Metabolized by liver (70%)  Primarily CYP2D6  Partially renally eliminated (30%)  Half-life: 12-24 hrs  Visual disturbances  GI upset  Proarrhythmia Class Ia 5 sec Class Ib 0.3 sec Flecainid e 30 sec Mechanism Pharmacokinetics Dosing Adverse Effects
  8. 8. Propafenone (Rythmol)  Potent Na+ channel blocker  Mild beta-blocking and calcium- blocking properties  Immediate release and sustained release formulations are not interchangeable on a dose-dose basis  150 mg q8h IR ~ 325 mg q12h SR  Peak plasma levels: 2-3 hrs  Non-linear kinetics  Extensive vs. Poor metabolizers  Half-life: 12-24 hrs  GI – nausea, constipation  CNS – dizziness, ataxia  Metallic aftertaste  Proarrhythmia Mechanism Pharmacokinetics Dosing Adverse Effects
  9. 9. Propafenone / Warfarin Interaction  Significant increase in warfarin levels by 39%  Increase INR ~ 25%  Empirically decrease warfarin ~ 30% (total weekly dose)
  10. 10. Class III Antiarrhythmics: Overview  Block K+ channels that mediate repolarization  Increase refractory periods of cardiac tissue  Reverse use dependence  Risks/benefits Class III Amiodarone Dofetilide Dronedarone Ibutilide Sotalol
  11. 11. Class III Antiarrhythmics  Careful assessment of risks versus benefits  Torsades de Pointes  Drug-drug interactions:  Fluoroquinolones  Macrolide antibiotics  Systemic azole antifungals  Ranolazine  May increase potential for Torsades de Pointes  Electrolyte repletion:  K = 4 mmol/L  Mg = 2 mg/dL  Drug-drug interactions:  Diuretics  Conivaptan  Amphotericin B  Cisplatin QTc Prolonging Drugs Electrolytes
  12. 12. Amiodarone (Cordarone®, Pacerone®)  Primary mechanism: K+ channel blockade  Properties of all antiarrhythmic classes  Beta blockade  Na+ channel blockade  Ca2+ channel blockade  Minimal risk of Torsades de Pointes  Bioavailability: 30-50%  Vd ~ 50 L/kg  Three compartment kinetics (at least)  Half-life ~ 53 days Mechanism Pharmacokinetics
  13. 13.  1.2 – 1.8 gm/day, divided  Total load: 5 -10 gm PO  Remember to convert  1 mg PO = 0.5 mg IV  Afib: 200mg daily  VT: 400 mg daily  Use lowest effective daily dose Amiodarone: Dosing Considerations Load Maintenance
  14. 14. Adverse Effect Baseline Monitoring? Follow-up Monitoring Pulmonary  Controversial Hepatic  Every 3-6 months Thyroid  Every 6 months Ocular  Every 12 months Neuropathy With symptoms Cutaneous Nausea Bradycardia Amiodarone: Adverse Effects & Monitoring Parameters
  15. 15. Amiodarone: Drug Interactions Warfarin Statins Other CYP2C9 and 3A4 inhibition CYP3A4  Digoxin levels Potentiates warfarin anticoagulant effects Increased statin concentrations and increased risk of statin- induced myopathy ↓ lidocaine clearance Increased INR Onset: 4—6 days Peak: 7 weeks Lovastatin: Max 40 mg/day Simvastatin: Max 20 mg/day Potentiate beta blocker and calcium channel blocker effects • Inhibitor of CYP1A2, 2C9, 2D6 and 3A4 • Inhibitor of P-glycoprotein system • Over 200 potential DDI
  16. 16. Dofetilide (Tikosyn®)  Potassium channel blocker  Lengthens action potential  Prolongs effective refractory period  No effect on contractility or BP  Reverse use dependence  Bioavailability: 90%  Peak concentrations: 2- 3 hrs  Elimination: ~80% excreted unchanged in urine  Glomerular filtration and active tubular secretion  Half-life: 10 hours Mechanism Pharmacokinetics
  17. 17. Dofetilide: Dosing  Cockcroft-Gault Equation  ACTUAL body weight CrCl >60 mL/min CrCl 40-60 mL/min CrCl 20-39 mL/min 250 mcg PO q12h500 mcg PO q12h 125 mcg PO q12h
  18. 18. ELIMINATION  Decreased renal tubular secretion of cations, resulting in:   Dofetilide concentrations   Risk of arrhythmias  Associated medications:  Hydrochlorothiazide  Cimetidine  Trimethoprim  Prochlorperazine  Megestrol Dolutegravir METABOLISM  Inhibition of CYP3A4, resulting in  dofetilide concentrations  Associated medications:  Verapamil ( Cmax 42%)  Azole antifungals (ketoconazole  Cmax 50%)  Macrolide antibiotics  Grapefruit juice  Protease inhibitors  Etc. Dofetilide: Drug Interactions
  19. 19. Sotalol (Betapace®)  Prolongation of action potential in both atria and ventricles  Racemic mixture:  D-sotalol: class III effects  L-sotalol: class III and beta- blocking effects  Reverse use dependence  Initial dose: 80 mg PO BID  Usual maintenance dose: 120- 160 mg PO BID  CrCl 40-60 mLmin: daily dosing  CrCl <40 mL/min: avoid use  Bioavailability: 90-100%  Peak concentrations: 2-3 hours  Not metabolized, excreted unchanged by kidneys  Half-life: 8-12 hours  Bradycardia  Hypotension  Torsades de Pointes (dose- related) Mechanism Pharmacokinetics Dosing Adverse Effects
  20. 20.  Most drug interactions occur via enhanced pharmacological and electrophysiologic effects  Beta blockade  QT prolongation  AV blockade  No DDI associated with hepatic metabolism  Eliminated as unchanged drug Sotalol: Drug Interactions
  21. 21. Dronedarone (Multaq®)  Properties of all four Vaughan-Williams classes  Contribution of each to clinical effect is unclear  *Does NOT cardiovert  400mg PO BID  High fat meal ↑ 15%  Bioavailability: 4%  Extensive first-pass metabolism  Peak concentrations: 3-6 hours  Steady state: 4-8 days  Half-life: 13-19 hours  GI effects  Bradycardia  Serum creatinine increases  Rash  Cautions: heart failure and liver failure Mechanism Pharmacokinetics Dosing Adverse Effects
  22. 22. PHARMACOKINETIC  CYP3A4 and CYP2D6 inhibitor  Co-administration with strong CYP3A4 contraindicated  Azole antifungals  Clarithromycin  Cyclosporine  Etc. PHARMACODYNAMIC  Beta-blockers  Bradycardia  Calcium channel blockers  Conduction  Digoxin Potentiates electrophysiology effects  Potassium-sparing diuretics Electroyte abnormalities Dronedarone: Drug Interactions
  23. 23. Lidocaine  Inhibits influx of Na  Increases recovery period after repolarization  Suppresses automaticity in His- Purkinje system  Not enough to suppress SA node  Appears to act preferentially on ischemic tissue  Cardiac Arrest:  Bolus: 1 – 1.5 mg/kg  Repeat: 0.5 – 0.75 mg/kg to total of 3 mg/kg  Continuous Infusion  1 – 4 mg/min  Lidocaine levels  Onset: immediate  Duration: 15-20 minutes  Half-life: 1.5 – 2 h  CNS (occur first)  Dizziness  Drowsiness  Vision changes  Cardiac  Bradycardia  Hypotension Mechanism Pharmacokinetics Dosing Adverse Effects
  24. 24. Mexiletine  Oral equivalent of lidocaine  Dosing:  150 – 300 mg PO q8h  Titrate every 3 days max or longer  Peak: 4-6h  Half-life: 8-16h  Same indications  Same adverse effects  Ataxia, blurred vision, tremor
  25. 25. Agent Recommendation Flecainide, dofetilide, propafenone, and IV ibutilide Class I, level A Amiodarone Class IIa, level A Propafenone or flecainide “pill-in- the-pocket” Class IIa, level B Pharmacological Cardioversion J Am Coll Cardiol. 2014 Sotalol and dronedarone do not cardiovert
  26. 26. Switching Antiarrhythmics Drug Half-Life Minimum Wash-out Amiodarone 53+ days Often not possible Dofetilide 10 hours 36 hours Dronedarone 13-19 hours 48 hours Flecainide 12-24 hours 36 hours Propafenone Extensive metabolizers: 2-10 hrs Poor metabolizers: 10-32 hrs 72 hours Sotalol 8-12 hours 36 hours
  27. 27. Defibrillation Threshold Effects Increase Decrease Amiodarone Flecainide Propafenone Lidocaine Mexiletine Dofetilide Sotalol  Controversial  Weigh risks and benefits Fogoros RN. Antiarrhythmic Drugs, 2nd edition. 2007
  28. 28. Conclusions  Multiple factors must be considered when choosing an antiarrhythmic drug  The aggressiveness of therapy should be tailored to the individual patient’s goals  Knowledge of pharmacokinetic and pharmacodynamic properties can aid in choosing the safest option
  29. 29. Practical Pearls in AAD Selection and Management Kristen Bova Campbell, PharmD

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