[Figure] "Action Potential Schematic"
[Figure] "SA Node and Perkinje Fiber Action Potentials"
A. Classification of Anti-Arrhythmic Agents [13,24]
- Class I: Fast Sodium Channel Blockers
- IA: Procainamide, Quinidine, Disopyramide - potassium channel blockade also
- IB: Lidocaine, Mexilitine, Tocainide - acts primarily on abnormal, not normal, tissue
- IC: Flecainide, Propafanone, Moricizine - little or no potassium channel blockade
- ß-Adrenergic Blocking Agents
- Agents with Mixed Activity (Atypical Agents)
- Primarily block potassium channels
- Decrease conduction velocities
- Often have ß-adrenergic blocking activity
- Calcium Channel Blockers
B. Class I: Sodium (fast) Channel Blockers
- Inhibit Sodium Channels [37]
- Slow cardiac conduction and increase refractoriness
- Reduce Max Voltage in PHASE 0
- Increase action potential (AP) duration and decrease conduction velocity
- Decrease slope of phase 4 depolarization by inhibiting potassium channels
- Anticholinergic action - blocks vagal stimulation of AV node (variable)
- Alpha-adrenergic blocking activity
- Generally less well tolerated and less effective than sotalol [24]
C. Class IA Agents [12]
- All agents prolong QTc and increase risk of Torsade des Pointes (TDP) and sudden death
- Increase QRS interval also
- Intermediate kinetics potassium channel block with sodium channel block
- Quinidine [23]
- D-isomer of quinine with multiple activities
- May be used for both atrial and ventricular tachyarrhythmias
- Oral agent, minimal anti-inotropic activity, safer than procainamide
- Blocks sodium channels as well as multiple types of potassium channels
- Increased AV nodal refractoriness, precipitate tachycardias in AFib
- Proarrhythmic Effects: syncope, QTc prolongation, TDP, sudden death
- Increased mortality when used for ventricular arrhythmia suppression [25]
- Hematologic Effects: low platelets, hemolysis, lupus-like syndrome
- Other Side Effects: nausea, diarrhea, headache; less common fever, rash
- Inhibits CYP2D6 and is metabolized by CYP3A4
- Multitude of drug interactions: increases digoxin and systemic timolol levels
- Increases warfarin, antipsychotics, tricyclics; amiodarone increases quinidine
- Load quinidine sulfate (600-800mg; 200mg po q2°) then Quinaglute 324mg qid
- Monitor QTc 3-4 days initially (stop if >25% widening or QTc>0.55msec)
- Procainamide (Procan®)
- Load 750mg - 1.5gm (usually 1gm iv over 1 hour) then orally qd
- May be used for both atrial and ventricular tachyarrhythmias
- Hypotension often occurs during loading intravenously
- Monitor QTc 3-4 days initially (stop if >25% widening or QTc > 0.55msc)
- Metabolized to n-acetyl-procainamide (by N-acetyl transferase)
- Side effects: hypotension, QTc prolongation, ANA+ within 1 month
- ~40% of patients who use procainamide develop moderate/severe side effects
- Disopyramide (Norpace®)
- Dose is 100-300mg po q6-8 hours maintenance
- Anti-inotropic, may significantly decrease ejection fraction
- Anti-cholinergic - urinary retention, especially in elderly men, dry mouth and eyes
- Uncommonly used due to side effects and reduction in cardiac contractility
- Sotalol and amiodarone are more effective and better tolerated than these agents
D. Class IB
- These agents are good under ischemic conditions, and act primarily on ischemic tissue
- Reduce QT interval
- Sodium channel blockage with rapid kinetics
- Lidocaine (iv)
- Especially for VT/VF in code setting (effective in ischemic myocardium)
- Dose initial 1mg/kg up to 2mg/kg total; then drip 1-4mg/kg/min
- Side Effects: CNS with drowsiness to stupor and coma; seizures; anti-inotropic
- Mexilitine (po)
- Essentially an oral form of lidocaine
- Generally well tolerated
- Tocainide - rarely used
- Phenytoin (Dilantin®) - may be useful in digoxin toxicity (250mg iv over 5-15 minutes)
E. Class IC [3,12]
- Generally third line therapy due to increased sudden death with several IC agents
- Greatly increase QRS intervals
- Block sodium channels with slow kinetics
- Flecainide (Tambocor®)
- May be useful in patients with SVT, normal EF, unable to have node ablated
- Especially useful in atrial fibrillation (AFib) in such patients
- Propafanone (Rhythmol®)
- ß-blocking activity present
- May also be useful for AFib in patients with normal EF
- May be used in patients with coronary artery disease but with caution [20]
- FDA approved for ventricular arrhythmias, 225mg po dose
- Single oral dose converts AFib in ~75% of cases [20]
- Moricizine
- CAST II showed increased mortality associated with this agent [4]
- No longer available
- Indecainide
- Dangerous proarrhythmia in ischemic conitions
- Never used in patients with significant coronary artery disease
- Side Effects of 1C Agents
- Decrease LV function, induce bradyarrhythmias, ventricular pro-arrhythmic
- Encainide and flecainide increase mortality in CAST for VEA suppression [3]
- Flecainide is a safe agent in patients without LV dysfunction or history of MI
F. Class II Anti-Arrhythmics
- ß-Adrenergic Receptor Blocks
- Properties
- Decreases SA Node automaticity
- Increases AV node refractory period
- Decreases AV node conduction velocity
- Utility
- Preferred agents post-myocardial infarction
- Excellent anti-ischemic activity
- Reduces PVC frequency
- Excellent for rapid control of rate in AFib [12]
- Side Effects: generally well tolerated
- Precipitation of bronchospasm (ß2-blocking activity)
- Anti-inotropic, bradycardia
- May cause impotence
- Concern for suppression of symptoms of hypoglycemia in diabetics
- May exacerbate peripheral vascular disease
- No consistent contribution to depression
G. Class III Anti-Arrhythmics
- Atypical (mixed activities); mainly potassium (K+) channel blockers
- Increases AP duration in fast response tissues
- Agents:
- Amiodarone (oral and iv) - agent has properties of all classes of anti-arrhythmics
- Sotalol (oral) - ß-blocker activity and atypical properties
- Bretylium
- Ibutilide (Corvert®)
- Dofetilide
- Bretylium - no longer available
- Ibutilide (Corvert®) [11]
- Inectable agent for conversion in AFib and flutter
- Enhances efficacy of cardioversion, particularly in patients resistant to maintaining NSR, and in patients who fail initial cardioversion [28]
- Prolongs QTc interval in a dose dependent fashion
- Dofetilide (Tikosyn®) [30,33]
- Novel oral Class III agent for conversion of AFib [39]
- Selective inhibitor of the rapid component of the delayed rectifier K+ current (Ko)
- Improves rate of electrical cardioversion, spontaneous conversion, and maintenance of sinus rhythm
- Has no anti-inotropic activities, even in patients with markedly reduced ventricular function
- In AFib, as effective as sotalol without the negative inotropic effects
- Main side effect is increase in QTc interval with increased risk of TDP
- However, overall does not increase rate of arrhythmias in heart failure patients
- Appears to be safe in patients with moderate to severe heart failure (and AFib)
- Routine use after MI with severe LV dysfunction provides no overall benefit [36]
- Dofetilide after MI does reduce risk of atrial flutter and AFib [36]
- Drug should be dose reduced based on renal function (reduces risk of TDP)
H. Amiodarone (Cordarone®) [6,16]
- Mechanism
- Class III agent but has properties of all classes of anti-arrhythmics
- Increases cAMP, blocks potassium channels which prolongs refractory period
- Blocks sodium channels minimally, lowering action potential
- Calcium channel and alpha-adrenergic blocking effects (more with intravenous, IV)
- ß-blocking effects are also present (use only with caution with other ß-blockers)
- ECG Effects
- Reduces heart rate
- Widens QRS
- QTc prolongation but with very low TDP risk
- Prolongs PR interval but low risk of heart block
- Reduces risk of initial and recurrent AFib
- Effects on Cardiac Contractility
- Calcium channel and alpha-adrenergic blocking effects lead to afterload reduction
- Mild anti-inotropic effects with ß-adrenergic and calcium blocking activities
- Mild heart rate reduction is counteracted with afterload reduction (mainly with IV)
- Overall cardiac output is unchanged or slightly increased
- May be used in patients with very low ejection fraction
- Utility [6]
- Preferred in low EF states with ventricular arrhythmias (also slows arrhythmia rate)
- Prolongs life in high risk patients about 5 years [13,19]
- Post-MI in patients with resistant ventricular arrhythmias (intravenous and po) [9]
- For initial conversion and maintenance of sinus rhythm in AFib [16,35]
- For other patients with AFib with ventricular dysfunction
- Amiodarone 200mg/d superior to quinidine, disopyramide, sotalol, propafenone for AFib [32]
- Amiodarone superior to sotalol (27% versus 24% cardioversion rate) and longer time to recurrence of AFib (569 versus 428 days) [5]
- 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]
- For cardiomyopathy with symptomatic VT, implantable cardioverter (ICD) is generally preferred over amiodarone [41]
- In patients with VTach, ICD and amiodarone had similar efficacy [34]
- Post-MI, amiodarone reduces arrhythmic [17,18] and all-cause [16] mortality
- After open heart surgery, amiodarone reduces risk of first episode of AFib, ventricular tachyarrhthymias, and stroke [38,44]
- Possible benefits (300mg IV push and load) for out-of-hospital cardiac arrest [31]
- IV rapid infusion 5mg/kg for shock resistant VF led to nearly 2X increase in survival to hospital admission compared with lidocaine [40]
- Preoperative amiodarone reduced AFib risk in cardiac bypass surgery by 50% [22]
- IV form has no benefit over standard agents in initial conversion of atrial fibrillation
- ICD but not amiodarone showed mortality benefit in Class II/III CHF with LVEF <35% [43]
- 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]
- 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]
- Drug Disposition
- Wide distribution in fat tissues and eryrthrocyte membranes
- Volume of distribution is extremely large (5000 liters)
- Oral bioavailability is poor, which contributes to need for large loading doses (10-15gm)
- ~37% of the compound is iodine, which can interfere with thyroid function
- Interestingly, thyroid interference is not seen with IV form
- Major metabolite with oral ingestion is N-desethylamiodarone
- Excreted through biliary system; no change in doses for renal or hepatic disease
- Dosing
- Oral: Load 400mg po bid-tid to 10-30gm, then low dose 200mg/d or high dose 400mg/d
- Alternative loading is typically 10mg/kg body weight for 14 days then maintenance
- Poor oral bioavailability makes high dose loading required
- Intravenous (IV): Load 150mg IV over 10 minutes, then 1mg/min x 6 hours [9]
- IV dose of 300-400mg in 20-30mL push has been used for cardiac arrest settings [40]
- IV water soluble formulation has rapid onset of action and effective for VTach [42]
- Overview of Side Effects
- Main problems occur with doses >300mg/day oral (required for VT/VF suppression)
- Side effects are much decreased or even absent with doses <300mg per day
- At 400mg/day, ~70% of patients have side effects, with 20-30% discontinuation
- ~30% of patients have side effects, <10% need to discontinue drug, at <300mg/day
- IV amiodarone is well tolerated, with mild hypotension [16]
- Phlebitis occurs with infusions >2mg/mL concentration (use central venous line)
- Specific Side Effects (usually at >300mg qd)
- Increases digoxin and warfarin (and other P450 metabolite) levels
- Interstitial Pneumonitis: 1-6%
- Hyper- or Hypothyroidism: 1-10%
- Peripheral Neuropathy: 1-2%
- Sinus Bradycardia: 1-2%
- Corneal Deposits: most patients (nearly always asymptomatic)
- Transaminase elevation: 15-20%
- Severe Hepatitis: 1-2%
- Photosensitivity: 10-15%
- QTc prolongation occurs but TDP is very rare (<1%)
- Thyroid Disease [14]
- Amiodarone is composed of 37% iodine by weight
- About 10% of the iodine in an ingested dose is absorbed
- Typically, 7.5-22mg of iodine are absorbed per day in patients on therapy
- Normal dietary iodine requirement is <1mg per day, so patients have very high intake
- Hyperthyroidism and thyrotoxicosis appear in about 15% of patients on amiodarone
- Hypothyroidism occurs in about 10% of patients (range 1-32%)
- Radioactive iodine is not usually effective for treatment of hyperthyroidism
- Thyroidectomy is only consistently effective therapy for hyperthyroidism
- For hypothyroidism, hormone replacement to move serum thyroxine levels to high normal
- TSH, serum thyroxine (and a free-thyroxine index) are recommended monthly monitoring
- Interstitial Pneumonitis [21]
- About ~5% develop interstitial pneumonitis
- Daily dosing >400mg/d nearly always cause some pulmonary toxicity
- Doses of 400mg/d or less are usually well tolerated
- Baseline chest radiograph (CXR) should be done
- If CXR shows abnormalities, careful monitoring of amiodarone therapy is necessary
- Obtain baseline pulmonary function tests (PFTs) with DLCO
- Nodular densities, exudative pleural effusions, subpleural nodules can also occur
- Most characteristic finding in amiodarone lung toxicity is foamy alveolar macrophages
- These may be seen on bronchoalveolar lavage (BAL) specimens
- Pneumonitis nearly always responds to glucocorticoids and drug discontinuation
- Summary of Amiodarone Monitoring Requirements [6]
- Digoxin and warfarin levels must be carefully monitored for initial 2-3 months
- Liver and thyroid function monitored monthly for several months then every 6 months
- Doses >400mg/d can cause pneumonitis; lung function should be monitored
- Baseline CXR and PFTs with DLCO should be obtained
- Eye exam if visual impairment exists at baseline
- Dronedarone [10]
- Related to amiodarone with similar elecrophysiological profile
- Designed to eliminate pulmonary and thyroid toxicity of amiodarone
- Elimination half-life 1-2 days versus 30-55 for amiodarone
- Superior to placebo for maintaining NSR after conversion of AFib for 1 year
- Reduces ventricular response rate in patients who relapse into AFib
- Dronedarone 400mg bid given to hospitalized patients with severe CHF increased mortality, mainly with worsening CHF [45]
- Dose is 400mg bid
- After 1 year, no increase in thyroid, liver, or pulmonary toxicity versus placebo
I. Sotalol (Sotacor®, Betapace®)
- ß1,2-blocker, increased AP duration, slows HR, prolonged QTc
- Excellent agent, well tolerated, for control of ventricular arrhythmias [24]
- Reduces inappropriate and appropriate shocks due to implantable defibrillators [29]
- Reduces risk of death in patients implantable defibrillators with normal and reduced left ventricular fraction [29]
- Increased mortality post-MI in patients with reduced LV EF [15]
- 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]
- Side Effects
- ß-blocking activity causes anti-inotropic acitivity and bradycardia
- Congestive Failure in ~3% of patients
- Dose (and age) dependent QTc prolongation leads to small risk TDP (~4%)
- Generally well tolerated
- No known idiopathic drug interactions
J. Class IV Anti-Arrhythmics
- Calcium channel blockers (act primarily on SA node)
- Reduce conduction velocity, increases refractoriness in slow response tissues
- Agents: verapamil, diltiazem (other agents are primarily vasodilators)
- Side Effects: bradycardia, conduction block, anti-inotropic
- Agents are poor anti-arrhythmics but good anti-ischemics, anti-hypertensives, etc.
- These are first choice for most patients with atrial fibrillation [12]
K. Radiofrequency Ablation [27]
- Electrophysiology studies detect specific abnormal conduction tracts
- Radiofrequency (RF) waves are used to induce tissue destruction
- RF waves at tip of catheter induce tissue necrosis with thermal injury
- Accessory tracts, part of the AV node, or other areas are selectively ablated
- Mild scarring occurs, but these techniques tend to be very successful
- Additional drug therapy may be needed in certain conditions
- However, techniques are often curative for SVT, WPW and other arrhythmias (as above)
- Complications
- Death ~0.08%
- Cardiac Tamponade 0.5%
- Unintended AV Block 0.5%
- Coronary artery spasm 0.2%
- Mild mitral regurgitation 0.2%
- Femoral artery complications (hematoma, thrombosis, fistula) ~0.5%
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