1. Antiarrhythmic Therapy UTHSCSA Pediatric Resident Curriculum for the PICU

2. Antiarrhythmic Therapy Empiric Arrhythmia Diagnosis Interventions Clinical Outcomes Interventions Clinical Outcomes Pathophysiologic Arrhythmia Diagnosis Known or suspected mechanisms Critical components Vulnerable parameters Targeted subcellular units BLACK BOX

3. Antiarrhythmic Therapy Pathophysiologic Arrhythmia Diagnosis Interventions Clinical Outcomes Known or suspected mechanisms Critical components Vulnerable parameters Targeted subcellular units AV node reentrant tachycardia AV node reentry Anatomical fast/slow pathway AV node (slow conduction) AV nodal action potential L-type Ca ++ channel Ca ++ channel blocker  -blocker Sinus rhythm

4. Vaughn-Williams Classification Based on cellular properties of normal His-Purkinje cells Classified on drug’s ability to block specific ionic currents (i.e. Na +, K +, Ca ++ ) and beta-adrenergic receptors Advantages: –Physiologically based –Highlights beneficial/deleterious effects of specific drugs

5. Antiarrhythmic Therapy Empiric Arrhythmia Diagnosis Interventions Clinical Outcomes BLACK BOX Goals Identify the type of dysrhythmia Be familiar with more common antiarrhythmics and their Vaughn-Williams Classification

6. Arrhythmia Types Slow Fast è Fast wide è Fast narrow è Too fast

7. Arrhythmia-focused Therapy Fast Narrow Supraventricular tachycardias –Re-entry type Orthodromic SVT –Automatic A.E.T., Atrial Flutter J.E.T.

8. Arrhythmia-focused Therapy Fast Wide –(rare) Antidromic SVT or SVT with abberancy –Ventricular tachycardia Inappropriate automaticity of ventricular or His-Purkinje tissue

9. Arrhythmia-focused Therapy Select one antiarrhythmic or a limited group of antiarrhythmics to treat the disorder.

10. Antiarrhythmic Agents Vaughn-Williams Classification Class I - Na + - channel blockers (direct membrane action) Class II - Sympatholytic agents Class III - Prolong repolarization Class IV- Ca ++ - channel blockers Purinergic agonists Digitalis glycosides

11. The Action Potential Phase 0 Phase 4 Phase 3 Phase 2 Phase 1 - 90 mV 0 mV 30 mV

12. Class I Na+ Channel Blockers Class I Na+ Channel Blockers IA - Quinidine/Procainamide/Disopyramide IB - Lidocaine/Mexiletine/Phenytoin IC - Flecainide/Propafenone/Ethmozine 1 0 2 3 4 ERPRRP Affects Phase 0

13. Class IA - Na+ Channel Blockers Procainamide/Quinidine/Disopyramide Mode of action – Depress conduction and prolong refractoriness Atrial, His-Purkinje, ventricular tissue – Peripheral alpha block – Vagolytic – Negative inotrope ECG changes – Increase PR, QRS (Diso: PR  > QRS  ) – Toxicity: QTc increases by 30% or QT > 0.5 sec – Ca ++ channel blockade / potent anticholinergic (Diso)

14. Class IA - Na+ Channel Blockers Procainamide Uses – SVT (reentry) or VT – Afib/flutter (on digoxin) Drug interactions- Decrease metabolism of Amiodarone Dose – IV: load 15 mg/kg over 1 hour, then 30-80  g/kg/min – (level 5-10 ng/ml) – PO: 30-70 mg/kg/day Side effects: Lupus- in slow acetylators – ANA  50-90% Symptoms: 20-30 %

15. Arrhythmia-focused Therapy Procainamide has been a long-used intravenous infusion for a wide range of dysrhythmias: – Narrow complex tachycardia: Atrial tachycardia, resistant re-entrant tachycardia – Wide-complex tachycardia: Ventricular tachycardia Downside: Side effects, negative inotrope, pro- arrhythmic

16. Class IB Lidocaine/Mexiletine/Phenytoin Mode of action – Little effect on normal tissues – Decreases Purkinje ERP/ automaticity – Increases Ventricular fibrillation threshold – Depresses conduction, esp. at high rates (Mexiletine) – Suppresses dig-induced delayed afterdepolarizations (Phenytoin) ECG changes – Slight  QTc (Lidocaine/Phenytoin)

17. Class IB Lidocaine Use: VT (acute) – Acts rapidly; no depression of contractility/AV conduction Kinetics – t 1/2 : 5-10 min (1st phase); 80-110 min (2nd phase) Drug interactions – Decreased metabolism w/ CHF/hepatic failure, propranolol, cimetidine – Increased metabolism w/ isuprel, phenobarbital, phenytoin Use: VT (acute) – Acts rapidly; no depression of contractility/AV conduction Kinetics – t 1/2 : 5-10 min (1st phase); 80-110 min (2nd phase) Drug interactions – Decreased metabolism w/ CHF/hepatic failure, propranolol, cimetidine – Increased metabolism w/ isuprel, phenobarbital, phenytoin

18. Class IB Lidocaine Dose – 1 mg/kg, then 20-50  g/kg/min (level: 2-5  g/ml) Side effects – CNS toxicity w/ levels > 5  g/ml Dose – 1 mg/kg, then 20-50  g/kg/min (level: 2-5  g/ml) Side effects – CNS toxicity w/ levels > 5  g/ml

19. Class IB Mexiletine Use: VT (post-op CHD) Kinetics: t 1/2 = 8 - 12 hrs Drug interactions- rare Dose – 3-5 mg/kg/dose (adult 200-300mg/dose) po q 8 hrs Side effects – Nausea (40%) – CNS - dizziness/tremor (25%)

20. Class IB Phenytoin Uses – VT (post-op CHD), digoxin-induced arrhythmias Drug interactions – Coumadin-  PT; Verapamil-  effect (displaces from protein) Dose – PO: 4 mg/kg q 6 hrs x 1 day, then 5-6 mg/kg/day ÷ q 12hr – IV: bolus 15 mg/kg over 1 hr; level 15-20  g/ml Side effects – Hypotension, gingival hyperplasia, rash

21. Arrhythmia-focused Therapy Class IB antiarrhythmics are very effective and very safe. Little or no effect on “normal” tissues First line for ischemic, automatic arrhythmia's (Ventricular tachycardia) Not a lot of effect on normal conduction tissue – not a good medicine for reentry and atrial tachycardias.

22. Class IC Flecainide/Propafenone/Ethmozine Mode of action – Depresses abnormal automaticity (Flec/Ethmozine) – Slows conduction in AV node, AP, ventricle (Flec/Prop) – Shortens repolarization (Ethmozine) – Negative inotrope (Propafenone) – Prolongs atrial/ventricular refractoriness (Propafenone) ECG changes –  PR, QRS –  QTc (Propafenone)

23. Class IC Flecainide Uses: PJRT, AET, CAT, SVT, VT, Afib Kinetics – t 1/2 = 13 hrs (shorter if between 1-15 mos old) Drug interactions – Increases digoxin levels (slight) – Amiodarone: increases flecainide levels

24. Class IC Flecainide Dose – 70-225 mg/m 2 /day ÷ q 8-12 hr – Level: 0.2-1.0  g/ml Side effects – Negative inotrope- use in normal hearts only (NO POST-OPs) – PROARRHYTHMIA - 5-12% (CAST)

25. Arrhythmia –focused Therapy IC’s have a lot of side effects that make them appropriate for use only by experienced providers.

26. Class II Agents Beta-blockers Propranolol Atenolol Metoprolol Nadolol Esmolol d,l-Sotalol

27. Class II Propranolol Uses – SVT (reentry, ectopic) – Sinus tachycardia (thyrotoxicosis) – VT (exercise-induced) Kinetics – t 1/2 = 3 hrs (increased if cyanotic) Drug interactions – Verapamil Hypotension Decreased LV function

28. Class II Propranolol Dose – PO: 2-4 mg/kg/day  q 6 hrs – IV: 0.05-0.15 mg/kg Side effects – Avoid in asthma/diabetes – CNS effects Nonpolar - crosses BBB –  BP Suppresses renin-aldo-angiotensin axis

29. Arrhythmia-focused Therapy Beta-blockers are good for re- entry circuits and automatic dysrhythmias. Their effect of decreasing contractility may be limiting.

30. Class III K + - channel blockers Properties – Prolong repolarization – Prolong action potential duration – Contractility is unchanged or increased Agents – Amiodarone – Sotalol – Bretylium – N-acetyl Procainamide (NAPA)

31. Arrhythmia-focused Therapy  Can be very powerful antiarrhythmics but limited indications for first-line use – beyond the spectrum of primary care providers  Amiodarone: may become a first-line medicine for a broad spectrum of arrhythmias, currently still high-risk

32. Purinergic Agonists Adenosine Mode of action – Vagotonic – Anti-adrenergic – Depresses slow inward Ca ++ current – Increases K + conductance (hyperpolarizes) ECG/EP changes – Slows AV node conduction

33. Purinergic Agonists Adenosine Uses – SVT- termination of reentry – Aflutter- AV block for diagnosis Kinetics – t 1/2 = < 10 secs – Metabolized by RBCs and vascular endothelial cells Dose – IV: 100-300  g/kg IV bolus

34. Purinergic Agonists Adenosine Drug interactions – Methylxanthines (caffeine/theophylline) Side effects – AFib/ sinus arrest/ sinus bradycardia – Bronchospasm – Flushing/headache – Nausea Great medicine: quick onset, quick degradation.

35. Digoxin Mode of action – Na-K ATPase inhibition – Positive inotrope – Vagotonic ECG changes – Increases PR interval – Depresses ST segment – Decreases QT interval

36. Digoxin Use: SVT (not WPW) Kinetics – t 1/2 = preemie (61hrs), neonate (35hrs), infant (18hrs), child (37hrs), adult (35-48hrs ) Interactions  Coumadin-  PT   Digoxin level  Quinidine, amiodarone, verapamil   renal function/renal tubular excretion (Spironolactone)  Worse with  K +,  Ca ++

37. Digoxin Toxicity Nausea/vomiting, lethargy, visual changes Metabolic – Hyper K +, Ca ++ – Hypo K +, Mg ++ – Hypoxemia – Hypothyroidism Proarrhythmia – AV block- decreased conduction – SVT- increased automaticity – VT- delayed afterdepolarizations

38. Digoxin Toxicity Treatment GI decontamination – Ipecac/lavage/charcoal w/ cathartic Arrhythmias – SA node /AV node depression- Atropine; if dig > 6, may need pacing – SVT- Phenytoin or  -blocker – VT- Lidocaine (1 mg/kg) or Phenytoin DC Cardioversion may cause refractory VT/VF!!

39. Proarrhythmia Torsades de Pointes Class IA – Quinidine 2-8% – Procainamide 2-3% – Disopyramide2-3% Class III – d,l-Sotalol 1-5% – d-Sotalol 1-2% – NAPA 3-4% – Amiodarone < 1%

40. Summary SVT: Initial – Adenosine – ?Propranolol – Procainamide SVT: Long Term – Nothing – Propranolol – Digoxin

41. Summary VT : Initial – Lidocaine – Procainamide VT: Long Term – Lidocaine/Procainamide – Beta-blockers – Cardiologist

42. 60 Cycle Interference

43. Atrial Flutter

44. SVT

45. Ventricular Tachycardia

46. Ventricular Fibrillation