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Antidysrhythmic Electrophysiology and Pharmacotherapy


Common Misconceptions

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    Lidocaine is used to prevent ventricular tachycardia following acute myocardial infarction.

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    Only β-blockers with β 2 selectivity precipitate bronchospasm.

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    Amiodarone should be avoided in patients with left ventricular dysfunction.

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    Cardiac arrhythmias are common in critically ill patients.

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    Patients with coronary artery disease (CAD), heart failure (HF), respiratory failure, or renal failure are at risk for different arrhythmias, and antidysrhythmic agents continue to be the mainstay for immediate arrhythmia management in the Cardiac Intensive Care Unit (CICU).

Classification of Antidysrhythmic Medications

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    Two systems are used to classify antidysrhythmic medications.

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    The oldest and most commonly used system remains the Vaughan-Williams system ( Table 19.1 ), which classifies drugs based on mechanism of action.

    Table 19.1
    Modified Vaughan-Williams Classification of Antidysrhythmic Medications
    Drug Effects
    Class I: Na + Channel Blockers
    IA Moderate slowing of conduction with prolonged refractoriness

    • Quinidine

    • Procainamide

    • Disopyramide

    IB Slight slowing of conduction with minimal decrease in refractoriness

    • Lidocaine

    • Mexiletene

    IC Marked slowing of conduction with slight prolongation of refractoriness

    • Flecainide

    • Propafenone

    Class II: β-Blockers β-Adrenergic receptor antagonism

    • Metoprolol

    • Atenolol

    Class III: K + Channel Blockers Prolongation of refractoriness

    • Amiodarone

    • Dronedarone

    • Sotalol

    • Ibutilide

    • Dofetilide

    Class IV: Ca 2+ Channel Blockers Block calcium entry

    • Verapamil

    • Diltiazem

    Class V: Other

    • Adenosine

    • Digoxin

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    However, the Vaughan-Williams classification does not account for drugs having multiple effects, not working through ion channels, or those with different potencies.

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    Because of this, the Sicilian Gambit system was introduced ( Table 19.2 ), which links each medication to the relevant arrhythmia more directly ( Table 19.3 ).

    Table 19.2
    The Modified Sicilian Gambit
    Mechanism Arrhythmia Desired Effect Example Drugs
    Automaticity
    Enhanced Inappropriate sinus tachycardia Decrease phase 4 depolarization β-Blockers
    Idiopathic ventricular tachycardia (some) Decrease phase 4 depolarization Na + channel blockers
    Atrial tachycardia Decrease phase 4 depolarization Muscarinic receptor agonists
    Accelerated idioventricular rhythms Decrease phase 4 depolarization Ca 2+ or Na + channel blockers
    Triggered Activity
    EAD Torsade de pointes Shorten action potential β-Blockers
    EAD suppression

    • Ca 2+ channel blockers

    • Mg 2+

    • β-Blockers

    DAD Digoxin-induced arrhythmias Block calcium entry Ca 2+ channel blockers
    Right ventricular outflow tract tachycardia

    • Block calcium entry

    • DAD suppression

    • Ca 2+ channel blockers

    • β-Blockers

    Na + Channel–Dependent Reentry
    Long excitable gap Typical atrial flutter Depress conduction and excitability Class IA and class IC Na + channel blockers
    Atrioventricular reciprocating tachycardia Depress conduction and excitability Class IA and class IC Na + channel blockers
    Monomorphic ventricular tachycardia Depress conduction and excitability Na + channel blockers
    Short excitable gap Atypical atrial flutter Prolong refractory period K + channel blockers
    Atrial fibrillation Prolong refractory period K + channel blockers
    AV reciprocating tachycardia Prolong refractory period Amiodarone and sotalol
    Polymorphic and uniform ventricular tachycardia Prolong refractory period Class IA Na + channel blockers
    Bundle branch reentry Prolong refractory period Class IA Na + channel blockers and amiodarone
    Na + Channel–Dependent Reentry
    Atrioventricular nodal ­reentrant tachycardia Depress conduction and excitability Ca 2+ channel blockers
    Atrioventricular reciprocating tachycardia Depress conduction and excitability Ca 2+ channel blockers
    Verapamil-sensitive ventricular tachycardia Depress conduction and excitability Ca 2+ channel blockers
    DAD , Delayed afterdepolarization; EAD , early afterdepolarization.

    Table 19.3
    Actions of Antiarrhythmic Drugs Used in Critical Care
    Drug CHANNELS RECEPTORS PUMPS CLINICAL EFFECTS ECG INTERVAL EFFECT
    Na + Fast Na + Medium Na + Slow Ca 2+ Ca 2+ γ α β M2 A1 Na + /K + -ATPase LV Function Sinus Rate Extracardiac PR QRS QT
    Lidocaine Low → → Med ↓
    Procainamide ASB Med ↓ → High ↑ ↑ ↑
    Verapamil Low High Med ↓ ↓ Low ↑
    Diltiazem Med ↓ ↓ Low ↑
    Sotalol High High ↓ ↓ Low ↑ ↑
    Amiodarone Low Low High Med Med → ↓ High ↑ ↑
    Propanolol Low High ↓ ↓ Low ↑
    Adenosine Agonist ? ↓ Low ↑
    Digoxin Agonist High ↑ ↓ High ↑ ↓
    Potency of blockade: Low , low potency; Med , medium potency; High , high potency. ASB , Activated state blocker.

Antidysrhythmic Medications of Clinical Relevance in the CICU

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    Table 19.4 lists the dosing and administration of the antidysrhythmic medications most commonly used in the CICU.

    Table 19.4
    Usual Dosing of Antidysrhythmic Drugs Used in Critical Care
    Drug INTRAVENOUS ORAL (mg) Peak Plasma Concentration (Oral Dosing in Hours)
    Loading Maintenance Loading Maintenance
    Procainamide 6–15 mg/kg at 0.2–0.5 mg/kg/min 2–6 mg/min 500–1000

    • 350–1000

    • q3–q6h

    		1
    Lidocaine 1–3 mg/kg over 15–45 min 1 mg/kg/h
    Propanolol 1–3 mg at 1 mg/min 10–200 q6–8 h 4
    Ibutilide 1–2 mg
    Amiodarone 5 mg/kg over 10–30 min 720–1000 mg q24h

    • For VT: 1200–1600 qd for 1–2 wk then 600–800 qd for 2–4 wk

    • For SVT: 600–800 qd for 2 wk

    • For VT: 200–400 qd

    • For SVT: 200 qd

    Verapamil 10 mg over 1–2 min 80 mg q12h up to 320 mg/d 1–2
    Adenosine 6–12 mg
    Digoxin 1 mg over 24 h in divided doses 0.125–0.25 mg q24h 1 mg over 24 h in divided doses 0.125–0.25 mg q24h 1–3
    SVT , Supraventricular tachycardia; VT , ventricular tachycardia.

Class IA

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    Procainamide is the only class IA agent that is commonly used in the CICU.

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    It is metabolized via acetylation from a sodium channel blocker to N-acetylprocainamide (NAPA) that has potassium channel blocking properties, decreases conduction velocity, and prolongs the His-Purkinje action potential (AP) and the effective refractory period.

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    It can also suppress automaticity in the sinoatrial node (SAN) and the atrioventricular node (AVN) and triggered activity in normal Purkinje fibers.

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    Procainamide can prolong the QT interval.

Indications

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    Historically, procainamide has been utilized as first-line therapy for management of stable ventricular tachycardia (VT).

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    Procainamide also remains the treatment of choice for treating preexcited atrial fibrillation (AF) in the setting of Wolff-Parkinson-White syndrome.

Electrocardiographic Effects

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    Patients demonstrate use-dependent widening of the QRS at faster heart rates or with high plasma concentrations.

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    The PR interval and QT intervals can also lengthen.

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    QRS widening by greater than 25% may suggest toxicity and be an indication to monitor therapy.

Side Effects

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    In addition to QT prolongation, procainamide can be negatively inotropic and cause hypotension.

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    Noncardiac effects, such as pancytopenia and agranulocytosis, can be life threatening.

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    Headaches, gastrointestinal effects, and mental disturbances can also occur.

Administration

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    Procainamide is used in the intravenous (IV) form in the CICU and is often initiated with a loading dose.

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    One gram administered over 20 to 30 minutes is often used to convert preexcited AF.

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    Procainamide can also be given as 6 to 15 mg/kg at 0.2 to 0.5 mg/kg/min.

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    Care should be taken to reduce the dose in the setting of renal or cardiac impairment.

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    Following the loading dose, maintenance should be administered at 1 mg/kg/h.

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    The metabolism of this drug is widely variable, including the acetylation to NAPA; thus, levels of both procainamide and NAPA should be monitored with prolonged usage and should be less than 30 µg/mL combined.

Class IB

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    Lidocaine is the only medication in this class useful in the CICU to treat ventricular arrhythmias.

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    More recently, it has fallen out of favor compared with other agents, particularly amiodarone.

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    Lidocaine exerts most of its actions on the Purkinje fibers and has little effect on the SAN or AVN.

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    Lidocaine is a sodium channel blocker that decreases conduction velocity.

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    Compared with other sodium channel blockers, it shortens the AP and decreases automaticity by decreasing the slow or phase 4 diastolic depolarization.

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    It can be helpful in both reentrant and automatic arrhythmia suppression.

Indications

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    Lidocaine is most commonly used for ventricular arrhythmias refractory to β-blockers and amiodarone.

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    Prophylactic lidocaine was previously thought to be beneficial for patients with myocardial infarctions to prevent ventricular arrhythmias, but more recent studies demonstrated no benefit.

Electrocardiographic Effects

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    Generally, no changes are seen on the ECG in patients receiving therapeutic doses of lidocaine.

Side Effects

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    The most common toxicities of lidocaine are central nervous system (CNS) effects, particularly mental status changes.

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      In most cases, these are mild and resolve with cessation or dose reduction.

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      Elderly patients and those with HF are at higher risk of CNS toxicity.

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      In addition, because lidocaine is mostly cleared hepatically, liver failure predisposes to toxicity.

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      Tremors are the first CNS symptom observed with early toxicity; seizures occur at extremely high plasma concentrations.

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    Bradyarrhythmia and hypotension only occur at very high plasma levels.

Administration

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    The first-pass clearance of lidocaine is so high that it is administered only in IV form.

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    It has a very short half-life of fewer than 3 hours.

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    The metabolites have only weak antidysrhythmic properties.

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    It is highly bound to α-acid glycoproteins, which are increased in patients with HF.

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    Finally, the reduced volume of distribution in HF leads to higher concentrations of the drug.

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    In general, a loading dose of 1 to 3 mg/kg is administered over several minutes followed by maintenance infusions of 1 to 4 mg/min.

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    For acute arrhythmia treatment, patients can receive a bolus several times, if needed, until the steady state is reached by the maintenance infusion, which can take 3 to 4 hours.

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    Therapeutic levels of lidocaine are between 1.5 to 5 µg/mL.

Class IC

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    Flecainide and propafenone are the only two medications in this class left on the market, used in the outpatient setting, for atrial arrhythmias.

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    They cannot be used in patients with structural heart disease or significant renal dysfunction and are available only in oral formulations.

Class II

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    β-blockers have been shown to reduce mortality in a variety of situations, including HF, acute myocardial infarction, and CAD.

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    They also decrease the rate of shocks for patients with implantable cardioverter-defibrillators and prevent degeneration of VT to ventricular fibrillation.

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    β-Blockers may bind to β 1 receptors, β 2 receptors, or both.

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    Some β-blockers also block α1 receptors.

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    β 1 Receptors are found in the cardiovascular system.

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    β 2 Receptors are noncardiac and lead to side effects, such as pulmonary bronchospasm.

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    α 1 Receptor antagonism causes additional arteriolar vasodilation; drugs with α 1 receptor blockade tend to be used more commonly for hypertension or HF ( Table 19.5 ).

    Table 19.5
    Dosing and Metabolism of Commonly Used β-Blockers
    Drug β1 Selective IV Dosage Half-Life Elimination Other Properties
    Atenolol Yes 5 mg q 10 min up to 10 mg 6–9 h Renal None
    Esmolol Yes 500 µg/kg loading; 50–300 µg/kg/min maintenance 9 min Blood esterase None
    Labetalol No 20 mg IV push; 2 mg/min infusion up to 300 mg 3–4 h Hepatic α-Blockade
    Metoprolol Yes 5 mg q 2–5 min up to 15 mg 3–4 h Hepatic None
    Propanolol No 1 mg/min up to 5 mg 3–4 h Hepatic Membrane stabilization

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    The myriad benefits of β-blocker therapy are mostly a result of blocking the effects of adrenergic stimulation, which can cause a variety of undesirable electrophysiologic changes, including increased automaticity, triggered activity, reentrant excitation, and delayed afterdepolarizations.

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    Carvedilol, bisoprolol, and long-acting metoprolol, are indicated for long-term treatment of patients with HF in the setting of left ventricular (LV) dysfunction.

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