[Figure] "Action Potential Schematic"
[Figure] "SA Node and Perkinje Fiber Action Potentials"
A. Classification of Anti-Arrhythmic Agents [13,24]

1. Class I: Fast Sodium Channel Blockers
   1. IA: Procainamide, Quinidine, Disopyramide - potassium channel blockade also
   2. IB: Lidocaine, Mexilitine, Tocainide - acts primarily on abnormal, not normal, tissue
   3. IC: Flecainide, Propafanone, Moricizine - little or no potassium channel blockade
2. ß-Adrenergic Blocking Agents
3. Agents with Mixed Activity (Atypical Agents)
   1. Primarily block potassium channels
   2. Decrease conduction velocities
   3. Often have ß-adrenergic blocking activity
4. Calcium Channel Blockers

B. Class I: Sodium (fast) Channel Blockers

1. Inhibit Sodium Channels [37]
   1. Slow cardiac conduction and increase refractoriness
   2. Reduce Max Voltage in PHASE 0
   3. Increase action potential (AP) duration and decrease conduction velocity
   4. Decrease slope of phase 4 depolarization by inhibiting potassium channels
2. Anticholinergic action - blocks vagal stimulation of AV node (variable)
3. Alpha-adrenergic blocking activity
4. Generally less well tolerated and less effective than sotalol [24]

C. Class IA Agents [12]

1. All agents prolong QTc and increase risk of Torsade des Pointes (TDP) and sudden death
   1. Increase QRS interval also
   2. Intermediate kinetics potassium channel block with sodium channel block
2. Quinidine [23]
   1. D-isomer of quinine with multiple activities
   2. May be used for both atrial and ventricular tachyarrhythmias
   3. Oral agent, minimal anti-inotropic activity, safer than procainamide
   4. Blocks sodium channels as well as multiple types of potassium channels
   5. Increased AV nodal refractoriness, precipitate tachycardias in AFib
   6. Proarrhythmic Effects: syncope, QTc prolongation, TDP, sudden death
   7. Increased mortality when used for ventricular arrhythmia suppression [25]
   8. Hematologic Effects: low platelets, hemolysis, lupus-like syndrome
   9. Other Side Effects: nausea, diarrhea, headache; less common fever, rash
   10. Inhibits CYP2D6 and is metabolized by CYP3A4
   11. Multitude of drug interactions: increases digoxin and systemic timolol levels
   12. Increases warfarin, antipsychotics, tricyclics; amiodarone increases quinidine
   13. Load quinidine sulfate (600-800mg; 200mg po q2°) then Quinaglute 324mg qid
   14. Monitor QTc 3-4 days initially (stop if >25% widening or QTc>0.55msec)
3. Procainamide (Procan®)
   1. Load 750mg - 1.5gm (usually 1gm iv over 1 hour) then orally qd
   2. May be used for both atrial and ventricular tachyarrhythmias
   3. Hypotension often occurs during loading intravenously
   4. Monitor QTc 3-4 days initially (stop if >25% widening or QTc > 0.55msc)
   5. Metabolized to n-acetyl-procainamide (by N-acetyl transferase)
   6. Side effects: hypotension, QTc prolongation, ANA+ within 1 month
   7. ~40% of patients who use procainamide develop moderate/severe side effects
4. Disopyramide (Norpace®)
   1. Dose is 100-300mg po q6-8 hours maintenance
   2. Anti-inotropic, may significantly decrease ejection fraction
   3. Anti-cholinergic - urinary retention, especially in elderly men, dry mouth and eyes
   4. Uncommonly used due to side effects and reduction in cardiac contractility
5. Sotalol and amiodarone are more effective and better tolerated than these agents

D. Class IB

1. These agents are good under ischemic conditions, and act primarily on ischemic tissue
   1. Reduce QT interval
   2. Sodium channel blockage with rapid kinetics
2. Lidocaine (iv)
   1. Especially for VT/VF in code setting (effective in ischemic myocardium)
   2. Dose initial 1mg/kg up to 2mg/kg total; then drip 1-4mg/kg/min
   3. Side Effects: CNS with drowsiness to stupor and coma; seizures; anti-inotropic
3. Mexilitine (po)
   1. Essentially an oral form of lidocaine
   2. Generally well tolerated
4. Tocainide - rarely used
5. Phenytoin (Dilantin®) - may be useful in digoxin toxicity (250mg iv over 5-15 minutes)

E. Class IC [3,12]

1. Generally third line therapy due to increased sudden death with several IC agents
   1. Greatly increase QRS intervals
   2. Block sodium channels with slow kinetics
2. Flecainide (Tambocor®)
   1. May be useful in patients with SVT, normal EF, unable to have node ablated
   2. Especially useful in atrial fibrillation (AFib) in such patients
3. Propafanone (Rhythmol®)
   1. ß-blocking activity present
   2. May also be useful for AFib in patients with normal EF
   3. May be used in patients with coronary artery disease but with caution [20]
   4. FDA approved for ventricular arrhythmias, 225mg po dose
   5. Single oral dose converts AFib in ~75% of cases [20]
4. Moricizine
   1. CAST II showed increased mortality associated with this agent [4]
   2. No longer available
5. Indecainide
   1. Dangerous proarrhythmia in ischemic conitions
   2. Never used in patients with significant coronary artery disease
6. Side Effects of 1C Agents
   1. Decrease LV function, induce bradyarrhythmias, ventricular pro-arrhythmic
   2. Encainide and flecainide increase mortality in CAST for VEA suppression [3]
   3. Flecainide is a safe agent in patients without LV dysfunction or history of MI

F. Class II Anti-Arrhythmics

1. ß-Adrenergic Receptor Blocks
2. Properties
   1. Decreases SA Node automaticity
   2. Increases AV node refractory period
   3. Decreases AV node conduction velocity
3. Utility
   1. Preferred agents post-myocardial infarction
   2. Excellent anti-ischemic activity
   3. Reduces PVC frequency
   4. Excellent for rapid control of rate in AFib [12]
4. Side Effects: generally well tolerated
   1. Precipitation of bronchospasm (ß2-blocking activity)
   2. Anti-inotropic, bradycardia
   3. May cause impotence
   4. Concern for suppression of symptoms of hypoglycemia in diabetics
   5. May exacerbate peripheral vascular disease
   6. No consistent contribution to depression

G. Class III Anti-Arrhythmics

1. Atypical (mixed activities); mainly potassium (K+) channel blockers
2. Increases AP duration in fast response tissues
3. Agents:
   1. Amiodarone (oral and iv) - agent has properties of all classes of anti-arrhythmics
   2. Sotalol (oral) - ß-blocker activity and atypical properties
   3. Bretylium
   4. Ibutilide (Corvert®)
   5. Dofetilide
4. Bretylium - no longer available
5. Ibutilide (Corvert®) [11]
   1. Inectable agent for conversion in AFib and flutter
   2. Enhances efficacy of cardioversion, particularly in patients resistant to maintaining NSR, and in patients who fail initial cardioversion [28]
   3. Prolongs QTc interval in a dose dependent fashion
6. Dofetilide (Tikosyn®) [30,33]
   1. Novel oral Class III agent for conversion of AFib [39]
   2. Selective inhibitor of the rapid component of the delayed rectifier K+ current (Ko)
   3. Improves rate of electrical cardioversion, spontaneous conversion, and maintenance of sinus rhythm
   4. Has no anti-inotropic activities, even in patients with markedly reduced ventricular function
   5. In AFib, as effective as sotalol without the negative inotropic effects
   6. Main side effect is increase in QTc interval with increased risk of TDP
   7. However, overall does not increase rate of arrhythmias in heart failure patients
   8. Appears to be safe in patients with moderate to severe heart failure (and AFib)
   9. Routine use after MI with severe LV dysfunction provides no overall benefit [36]
   10. Dofetilide after MI does reduce risk of atrial flutter and AFib [36]
   11. Drug should be dose reduced based on renal function (reduces risk of TDP)

H. Amiodarone (Cordarone®) [6,16]

1. Mechanism
   1. Class III agent but has properties of all classes of anti-arrhythmics
   2. Increases cAMP, blocks potassium channels which prolongs refractory period
   3. Blocks sodium channels minimally, lowering action potential
   4. Calcium channel and alpha-adrenergic blocking effects (more with intravenous, IV)
   5. ß-blocking effects are also present (use only with caution with other ß-blockers)
2. ECG Effects
   1. Reduces heart rate
   2. Widens QRS
   3. QTc prolongation but with very low TDP risk
   4. Prolongs PR interval but low risk of heart block
   5. Reduces risk of initial and recurrent AFib
3. Effects on Cardiac Contractility
   1. Calcium channel and alpha-adrenergic blocking effects lead to afterload reduction
   2. Mild anti-inotropic effects with ß-adrenergic and calcium blocking activities
   3. Mild heart rate reduction is counteracted with afterload reduction (mainly with IV)
   4. Overall cardiac output is unchanged or slightly increased
   5. May be used in patients with very low ejection fraction
4. Utility [6]
   1. Preferred in low EF states with ventricular arrhythmias (also slows arrhythmia rate)
   2. Prolongs life in high risk patients about 5 years [13,19]
   3. Post-MI in patients with resistant ventricular arrhythmias (intravenous and po) [9]
   4. For initial conversion and maintenance of sinus rhythm in AFib [16,35]
   5. For other patients with AFib with ventricular dysfunction
   6. Amiodarone 200mg/d superior to quinidine, disopyramide, sotalol, propafenone for AFib [32]
   7. Amiodarone superior to sotalol (27% versus 24% cardioversion rate) and longer time to recurrence of AFib (569 versus 428 days) [5]
   8. Oral amiodarone 10mg/kg 6 days prior to through 6 days after open-heart surgery reduced risk of AFib ~50% and sustained VTach >50% regardless of ß-blocker use [7]
   9. For cardiomyopathy with symptomatic VT, implantable cardioverter (ICD) is generally preferred over amiodarone [41]
   10. In patients with VTach, ICD and amiodarone had similar efficacy [34]
   11. Post-MI, amiodarone reduces arrhythmic [17,18] and all-cause [16] mortality
   12. After open heart surgery, amiodarone reduces risk of first episode of AFib, ventricular tachyarrhthymias, and stroke [38,44]
   13. Possible benefits (300mg IV push and load) for out-of-hospital cardiac arrest [31]
   14. IV rapid infusion 5mg/kg for shock resistant VF led to nearly 2X increase in survival to hospital admission compared with lidocaine [40]
   15. Preoperative amiodarone reduced AFib risk in cardiac bypass surgery by 50% [22]
   16. IV form has no benefit over standard agents in initial conversion of atrial fibrillation
   17. ICD but not amiodarone showed mortality benefit in Class II/III CHF with LVEF <35% [43]
   18. Sporadic shocks from ICDs can be reduced with sotalol (57% reduction) or amiodarone (73% reduction) when added to ß-blockers compared with ß-blockers alone [8]
   19. Amiodarone is associated with increased risk of pulmonary and hypothyroid disease compared with sotalol but is more effective at reducing sporadic ICD shocks [6,8]
5. Drug Disposition
   1. Wide distribution in fat tissues and eryrthrocyte membranes
   2. Volume of distribution is extremely large (5000 liters)
   3. Oral bioavailability is poor, which contributes to need for large loading doses (10-15gm)
   4. ~37% of the compound is iodine, which can interfere with thyroid function
   5. Interestingly, thyroid interference is not seen with IV form
   6. Major metabolite with oral ingestion is N-desethylamiodarone
   7. Excreted through biliary system; no change in doses for renal or hepatic disease
6. Dosing
   1. Oral: Load 400mg po bid-tid to 10-30gm, then low dose 200mg/d or high dose 400mg/d
   2. Alternative loading is typically 10mg/kg body weight for 14 days then maintenance
   3. Poor oral bioavailability makes high dose loading required
   4. Intravenous (IV): Load 150mg IV over 10 minutes, then 1mg/min x 6 hours [9]
   5. IV dose of 300-400mg in 20-30mL push has been used for cardiac arrest settings [40]
   6. IV water soluble formulation has rapid onset of action and effective for VTach [42]
7. Overview of Side Effects
   1. Main problems occur with doses >300mg/day oral (required for VT/VF suppression)
   2. Side effects are much decreased or even absent with doses <300mg per day
   3. At 400mg/day, ~70% of patients have side effects, with 20-30% discontinuation
   4. ~30% of patients have side effects, <10% need to discontinue drug, at <300mg/day
   5. IV amiodarone is well tolerated, with mild hypotension [16]
   6. Phlebitis occurs with infusions >2mg/mL concentration (use central venous line)
8. Specific Side Effects (usually at >300mg qd)
   1. Increases digoxin and warfarin (and other P450 metabolite) levels
   2. Interstitial Pneumonitis: 1-6%
   3. Hyper- or Hypothyroidism: 1-10%
   4. Peripheral Neuropathy: 1-2%
   5. Sinus Bradycardia: 1-2%
   6. Corneal Deposits: most patients (nearly always asymptomatic)
   7. Transaminase elevation: 15-20%
   8. Severe Hepatitis: 1-2%
   9. Photosensitivity: 10-15%
   10. QTc prolongation occurs but TDP is very rare (<1%)
9. Thyroid Disease [14]
   1. Amiodarone is composed of 37% iodine by weight
   2. About 10% of the iodine in an ingested dose is absorbed
   3. Typically, 7.5-22mg of iodine are absorbed per day in patients on therapy
   4. Normal dietary iodine requirement is <1mg per day, so patients have very high intake
   5. Hyperthyroidism and thyrotoxicosis appear in about 15% of patients on amiodarone
   6. Hypothyroidism occurs in about 10% of patients (range 1-32%)
   7. Radioactive iodine is not usually effective for treatment of hyperthyroidism
   8. Thyroidectomy is only consistently effective therapy for hyperthyroidism
   9. For hypothyroidism, hormone replacement to move serum thyroxine levels to high normal
   10. TSH, serum thyroxine (and a free-thyroxine index) are recommended monthly monitoring
10. Interstitial Pneumonitis [21]
    1. About ~5% develop interstitial pneumonitis
    2. Daily dosing >400mg/d nearly always cause some pulmonary toxicity
    3. Doses of 400mg/d or less are usually well tolerated
    4. Baseline chest radiograph (CXR) should be done
    5. If CXR shows abnormalities, careful monitoring of amiodarone therapy is necessary
    6. Obtain baseline pulmonary function tests (PFTs) with DLCO
    7. Nodular densities, exudative pleural effusions, subpleural nodules can also occur
    8. Most characteristic finding in amiodarone lung toxicity is foamy alveolar macrophages
    9. These may be seen on bronchoalveolar lavage (BAL) specimens
    10. Pneumonitis nearly always responds to glucocorticoids and drug discontinuation
11. Summary of Amiodarone Monitoring Requirements [6]
    1. Digoxin and warfarin levels must be carefully monitored for initial 2-3 months
    2. Liver and thyroid function monitored monthly for several months then every 6 months
    3. Doses >400mg/d can cause pneumonitis; lung function should be monitored
    4. Baseline CXR and PFTs with DLCO should be obtained
    5. Eye exam if visual impairment exists at baseline
12. Dronedarone [10]
    1. Related to amiodarone with similar elecrophysiological profile
    2. Designed to eliminate pulmonary and thyroid toxicity of amiodarone
    3. Elimination half-life 1-2 days versus 30-55 for amiodarone
    4. Superior to placebo for maintaining NSR after conversion of AFib for 1 year
    5. Reduces ventricular response rate in patients who relapse into AFib
    6. Dronedarone 400mg bid given to hospitalized patients with severe CHF increased mortality, mainly with worsening CHF [45]
    7. Dose is 400mg bid
    8. After 1 year, no increase in thyroid, liver, or pulmonary toxicity versus placebo

I. Sotalol (Sotacor®, Betapace®)

1. ß1,2-blocker, increased AP duration, slows HR, prolonged QTc
2. Excellent agent, well tolerated, for control of ventricular arrhythmias [24]
3. Reduces inappropriate and appropriate shocks due to implantable defibrillators [29]
4. Reduces risk of death in patients implantable defibrillators with normal and reduced left ventricular fraction [29]
5. Increased mortality post-MI in patients with reduced LV EF [15]
6. Sporadic shocks from ICDs can be reduced with sotalol (57% reduction) or amiodarone (73% reduction) when added to ß-blockers compared with ß-blockers alone [8]
7. Side Effects
   1. ß-blocking activity causes anti-inotropic acitivity and bradycardia
   2. Congestive Failure in ~3% of patients
   3. Dose (and age) dependent QTc prolongation leads to small risk TDP (~4%)
   4. Generally well tolerated
   5. No known idiopathic drug interactions

J. Class IV Anti-Arrhythmics

1. Calcium channel blockers (act primarily on SA node)
2. Reduce conduction velocity, increases refractoriness in slow response tissues
3. Agents: verapamil, diltiazem (other agents are primarily vasodilators)
4. Side Effects: bradycardia, conduction block, anti-inotropic
5. Agents are poor anti-arrhythmics but good anti-ischemics, anti-hypertensives, etc.
6. These are first choice for most patients with atrial fibrillation [12]

K. Radiofrequency Ablation [27]

1. Electrophysiology studies detect specific abnormal conduction tracts
2. Radiofrequency (RF) waves are used to induce tissue destruction
3. RF waves at tip of catheter induce tissue necrosis with thermal injury
4. Accessory tracts, part of the AV node, or other areas are selectively ablated
5. Mild scarring occurs, but these techniques tend to be very successful
6. Additional drug therapy may be needed in certain conditions
7. However, techniques are often curative for SVT, WPW and other arrhythmias (as above)
8. Complications
   1. Death ~0.08%
   2. Cardiac Tamponade 0.5%
   3. Unintended AV Block 0.5%
   4. Coronary artery spasm 0.2%
   5. Mild mitral regurgitation 0.2%
   6. Femoral artery complications (hematoma, thrombosis, fistula) ~0.5%

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