Lecture 1: Class I Anti-Arrhythmics (Sodium Channel Blockers)

Class I Anti-Arrhythmics

A classification of antiarrhythmic medications that primarily block sodium channels and affect Phase 0 in the cardiac action potential.

Class Ia

Includes Disopyramide, Quinidine, and Procainamide.

Class Ib

Includes Lidocaine and Mexiletine.

Class Ic

Includes Flecainide and Propafenone.

Mnemonic for Class 1 Anti-Arrthymics

Double Quarter Pounder Lettuce Mayo Fries Please

Disopyramide, Quinidine, Procainamide, Lidocaine, Mexiletine, Flecainide, Propafenone

Proarrhythmic effects

Potential life-threatening drug-induced arrhythmias caused by Class I antiarrhythmics.

QTc prolongation

measure of delayed ventricular repolarization

must be monitored when using Class I antiarrhythmics

Black Box Warning for Class I antiarrhythmics

mortality → should be reserved for patients with life-threatening ventricular arrhythmias.

Ventricular arrhythmias

Includes vfib, vtach, and PVCs

Bradycardias

Includes sinus bradycardia, sinus pause, sick sinus syndrome, and heart block.

Supraventricular arrhythmias

Includes atrial fibrillation, atrial flutter, atrial tachycardia, and AV nodal reentrant tachycardia.

Cardiac Conduction Pathway

Includes SA Node, Right and Left Atriums, AV Node, Bundle of His, Right and Left Ventricles, and Purkinje Fibers.

Cardiac Action Potential Phase 0

Rapid ventricular depolarization in response to an influx of sodium, leading to ventricular contraction (QRS Complex).

Cardiac Action Potential Phase 1

Sodium channel closes, leading to rapid repolarization.

Cardiac Action Potential Phase 2

Plateau phase in response to an influx of calcium and efflux of potassium.

Cardiac Action Potential Phase 3

Efflux of potassium causing ventricular relaxation and ventricular repolarization (T wave).

Cardiac Action Potential Phase 4

Resting membrane potential and atrial depolarization (P wave).

Disopyramide Brand Name

Norpace, Norpace CR

Disopyramide Mechanism of Action

Decreases myocardial excitability and conduction velocity; reduces disparity in refractory between normal and infarcted myocardium.

Indication for Disopyramide

Ventricular arrhythmias.

Route of Administration for Disopyramide

Oral.

Preparation for Disopyramide

Capsule, Capsule Extend-Release.

Side Effects of Disopyramide

Decreases heart contractility, urinary retention, dry mouth.

Warnings/Precautions for Disopyramide

Dry eye, heart failure, blurred vision, increased IOP, confusion.

Contraindications for Disopyramide

Hypersensitivity, cardiogenic shock, preexisting second- or third-degree heart block (except in patients with a functioning artificial pacemaker), congenital long QT syndrome.

Dosing for Disopyramide

Based on weight, Q6hrs! (not four times daily), renally dosed adjusted.

Monitoring Parameters for Disopyramide

ECG, blood pressure, urinary retention, CNS anticholinergic effects.

Special Populations for Disopyramide

May stimulate contractions in pregnant women.

Quinidine Mechanism of Action

Depresses phase 0 of the action potential

decreases myocardial excitability and conduction velocity, and myocardial contractility by decreasing sodium influx during depolarization and potassium efflux in repolarization.

Quinidine Indications

Atrial fibrillation/flutter, pharmacological conversion; paroxysmal atrial fibrillation/flutter, maintenance of sinus rhythm; ventricular arrhythmias; malaria (children).

Route of Administration for Quinidine

Oral.

Preparation for Quinidine

Tablet, ER Tablet.

Quinidine Contraindications

Hypersensitivity, thrombocytopenia; thrombocytopenic purpura, heart block greater than first degree, idioventricular conduction delays (except in patients with a functioning artificial pacemaker).

Quinidine Warnings

Hemolysis risk - G6PD deficiency, hepatotoxicity.

Quinidine Monitoring Parameters

ECG, CBC, liver function, renal function.

Quinidine Dosing

IR: q6hrs, ER: q8-12hrs, take with food to decrease GI upset.

Quinidine Side Effects

QT prolongation, thrombocytopenia, diarrhea, stomach cramping, gastrointestinal distress including esophagitis, heartburn, dizziness, drug-induced lupus, cinchonism (tinnitus, hearing loss, blurred vision, headache, delirium).

Procainamide Mechanism of Action

Decreases myocardial excitability and conduction velocity and may depress myocardial contractility, by increasing the electrical stimulation threshold of ventricle, His-Purkinje system and through direct cardiac effects.

Procainamide Indications

Ventricular tachycardia, atrioventricular reentrant tachycardia (off-label), atrial fibrillation with preexcitation (off-label).

Route of Administration for Procainamide

Injection.

Preparation for Procainamide

Continuous infusion, IV, IM.

Procainamide Contraindications

Hypersensitivity to procainamide, procaine, other ester-type local anesthetics, or any component of the formulation; complete heart block; second-degree AV block or various types of hemiblock (without a functional artificial pacemaker); systemic lupus erythematosus; torsade de pointes.

Black Box Warning for Procainamide

Drug-induced lupus erythematosus-like syndrome. Positive ANA Tests.

Blood Dyscrasias

Agranulocytosis, bone marrow depression, neutropenia, hypoplastic anemia and thrombocytopenia.

Procainamide Dosing

Renal adjustment for CrCl <50.

Procainamide Therapeutic Range

4-10 mcg/mL.

N-Acetyl Procainamide (NAPA) Therapeutic Range

15-25 mcg/mL

Procainamide Monitoring Parameters

ECG, Blood Pressure, Kidney function, Liver Function, CBC with differential, Blood concentration (in kidney/liver impairment or continuous infusion >12 hrs).

Procainamide Side Effects

Agranulocytosis, Hypotension, Bradycardia, Rash, Lupus like-syndrome (joint/muscle pain, flu-like syndrome, butterfly-like rash) (reversible), Diarrhea.

Procainamide Onset

10 -30 mins (IM).

Procainamide Metabolism

hepatic via acetylation to active metabolite

procainamide half-life in children

1.7 hrs

procainamide half-life in adults

2.5-4.7

NAPA half-life in children

6 hours

NAPA half-life in adults

6-8 hours

procainamide time to peak

15 to 60 mins (IM)

Procainamide Excretion

>50% renally cleared.

urine > feces

NAPA Excretion

>80% Renally cleared.

Lidocaine brand name

Xylocaine

Lidocaine Mechanism of Action

Suppresses automaticity of conduction tissue, by increasing electrical stimulation threshold of ventricle, His-Purkinje system, and spontaneous depolarization of the ventricles during diastole by a direct action on the tissues.

Blocks the initiation and conduction of nerve impulses by decreasing the neuronal membrane permeability to sodium ions, which results in inhibition of depolarization with resultant blockade of conduction

Lidocaine Indication

Ventricular arrhythmia - especially in refractory cases (Vfib, Pulse-less VT).

Lidocaine Route of Administration

Injection (IV)

Lidocaine Contraindications

Hypersensitivity to lidocaine or another local anesthetic of the amide type, Adam-Stokes syndrome, Wolff-Parkinson-White syndrome, Severe degrees of SA, AV, or intraventricular heart block (except in patients with a functioning artificial pacemaker), Corn-derived dextrose (premixed injections).

Lidocaine metabolism

via CYP1A2 and CYP3A4

Lidocaine IV onset and duration

IV bolus onset: 45-90 secs

Duration: 10-20 mins

Lidocaine Monitoring Parameters

LFTs, ECG, Neurologic signs.

Lidocaine Side Effects

Bradycardia, Hypotension, Vomiting, Tinnitus, Blurred vision, CNS toxicity with accumulation of metabolites.

Mexiletine Mechanism of Action

Decreases rate of rise of phase 0, increases effective refractory period/action potential duration ratio.

Mexiletine Indication

Ventricular arrhythmias.

Mexiletine Route of Administration

Oral.

Mexiletine Black Box Warning

Acute Liver Injury. abnormal liver function tests especially in the setting of congestive heart failure or ischemia.

Mexiletine Preparation

Capsule.

Mexiletine Dosing

Administer with food or antacid (needs alkaline environment), Can use loading dose, Maximum: 1.2g/day.

Mexiletine

A medication contraindicated in cardiogenic shock and second- or third-degree AV block (except in patients with a functioning artificial pacemaker).

Contraindications of Mexiletine

Cardiogenic shock; Second- or third-degree AV block (except in patients with a functioning artificial pacemaker).

Side Effects of Mexiletine

Blood dyscrasis; Drug reactions with eosinophilia and systemic symptoms (DRESS); Arrhythmia exacerbations; Dizziness.

Monitoring Parameters for Mexiletine

Ataxia; Liver function tests; ECG; Nervousness; GI distress; Nausea and vomiting; Tremor.

Mexiletine onset

30-120 mins

Mexiletine half-life

10-12 hrs

- CrCl<10: 15 hrs

- Hepatic impairment: 25 hrs

Mexiletine metabolism

via CYP2D6

Mexiletine Excretion

urine

Mexiletine time to peak

2-3 hrs

Flecainide Mechanism of Action

Slows conduction in cardiac tissue by altering transport of ions across cell membranes

Causes slight prolongation of refractory periods

↓ rate of rise of the action potential without affecting its duration;

↑ electrical stimulation threshold of ventricle, His-Purkinje system;

Possesses local anesthetic and moderate negative inotropic effects.

Indications for Flecainide

Ventricular arrhythmias (prevention); Atrial fibrillation/flutter or supraventricular tachycardias in patients with no structural heart disease.

Flecainide Route of Administration

Oral.

Flecainide Preparation

Tablet.

Flecainide Dosing

Renal adjustment CrCl <35

avoid in severe hepatic and renal impairment.

Flecainide Contraindications

Hypersensitivity; Pre-existing second- or third-degree AV block or with right bundle branch block when associated with a left hemiblock (bifascicular block) (except in patients with a functioning artificial pacemaker); Cardiogenic shock; Concurrent use of ritonavir.

Flecainide Monitoring Parameters

ECG; Heart Rate; Blood Pressure; Serum concentrations.

Flecainide Side Effects

Proarrhythmic effects (ventricular arrhythmia); 1:1 AV conduction; Fatal complications with structural heart disease (heart failure, MI); Dizziness; Visual disturbances (blurred vision, seeing spots).

Propafenone Mechanism of Action

Possesses local anesthetic properties; Blocks the fast inward sodium current and slows the rate of increase of the action potential; Prolongs conduction and refractoriness in all areas of the myocardium; Reduces spontaneous automaticity and exhibits some beta-blockade activity.

Indications for Propafenone

Ventricular arrhythmias; Atrial fibrillation/flutter and Supraventricular tachycardia, maintenance of sinus rhythm in patients without structural heart disease.

Propafenone Route of Administration

Oral.

Propafenone Preparation

IR tablet, ER capsule.

Propafenone Contraindications

Hypersensitivity; Sinoatrial, atrioventricular, and intraventricular disorders of impulse generation or conduction (except in patients with a functioning artificial pacemaker); Known Brugada syndrome; Bradycardia; Cardiogenic shock; Heart failure; Marked hypotension; Bronchospastic disorders or severe obstructive pulmonary disease; Marked electrolyte imbalance.

Propafenone Drug Interactions

Increase digoxin concentrations

Increase warfarin concentrations.

Propafenone Monitoring Parameters

ECG; Blood pressure; Pulse.

Propafenone Side Effects

Nausea and vomiting; Metallic taste; Dizziness; Visual disturbances.

Flecainide Pharmacokinetics

Half-life: Extensive metabolizer: 2-10 hrs; Poor metabolizers: 10-32 hrs; Time to peak: Children: 8 hrs; Adolescents: 11-12 hrs; >12: 12-27 hrs; Kidney impairment: 58 hrs; Time to peak: 1-6 hrs; Excretion: Urine > feces.

Propafenone Pharmacokinetics

Half-life: IR: 3.5 hrs; ER: 3-8 hrs; Excretion: Urine and feces.