AntiarrhythmicsORB311_2024

Lecture Overview

• Lecture Title: Antiarrhythmic Drugs

• Instructor: Dr. Tom Murray, Professor and Provost Emeritus, Department of Pharmacology and Neuroscience, School of Medicine

• Twitter: @tfmurray44

Objectives

• Understand the ionic basis for cardiac action potential and normal cardiac rhythms

• Classification of antiarrhythmic drugs based on their mechanisms of action

  • Class 1: Sodium Channel Blockers

    • Class 1A: Quinidine, Procainamide, Disopyramide

    • Class 1B: Lidocaine, Mexiletine

    • Class 1C: Flecainide

  • Class 2: Beta-adrenoreceptor antagonists (Propranolol, Atenolol)

  • Class 3: Potassium Channel Blockers (Amiodarone, Dofetilide)

  • Class 4: Calcium Channel Blockers (Verapamil, Diltiazem)

• Understand pressor response when epinephrine is used in dental patients treated with propranolol

Electrical and Chemical Gradients

• Potassium (K+) and Sodium (Na+) Gradients:

  • Inside resting cardiac cell: 150 mM K+, 10 mM Na+

  • Outside resting cardiac cell: 4 mM K+, 145 mM Na+

• Resting Membrane Potential: Approximately -90 mV for K+

Timing of Cardiac Events

• Key timing for physiological events:

  • 1 Day: DNA replication and cell division

  • 1 Hour: Gene transcription and protein synthesis

  • 1 Minute: Hormone regulation

  • 0.1 - 1 second: Enzyme activity

  • 1 Millisecond: Electrical signaling

    • Involves vision, hearing, nerve conduction, muscle contraction

Voltage-Gated Sodium Channels

• Functionality:

  • Inactivated state prevents premature action potential firing until channels recover.

  • Essential for coordinated electrical activity in the myocardium

Cardiac Action Potential

• Phases of Action Potential:

  • Phase 0: Rapid depolarization

  • Phase 1: Partial repolarization

  • Phase 2: Plateau

  • Phase 3: Repolarization

  • Phase 4: Pacemaker depolarization

• ECG Reference:

  • SA node, AV node, and Purkinje fibers have varying conduction speeds

Congenital Long-QT Syndrome

• Types of Long-QT Syndrome (LQT1, LQT2, LQT3, LQT4):

  • Characterized by QT interval prolongation

  • Can lead to syncope and torsade de pointes

Mechanisms of Cardiac Arrhythmias

• Causes include:

  • Ectopic Automaticity

  • Afterdepolarizations

  • Reentry circuits (circus movements)

Ectopic Firing Mechanisms

• Includes factors such as Na+ and Ca2+ overload and dysfunction of K+ channels

Afterdepolarizations

• Types:

  • EAD (Early Afterdepolarizations)

  • DAD (Delayed Afterdepolarizations)

• Triggers include hypokalemia, congenital long QT syndrome, myocardial ischemia

Reentry Phenomenon

• Occurs in selective conduction pathways with short refractory periods

Vaughn-Williams Classification

• Classifies antiarrhythmic agents based on their effect on ionic currents:

  • Class I: Na+ channel blockers

  • Class II: Sympatholytic agents

  • Class III: K+ channel blockers

  • Class IV: Ca++ channel blockers

Antiarrhythmic Drug Classification

• Class I:

  • IA: Quinidine (increases refractory period), Procainamide, Disopyramide (ventricular arrhythmias)

  • IB: Lidocaine, Mexiletine (ventricular myocytes interaction)

  • IC: Flecainide (slows conduction globally), Propafenone

• Class II: Beta-adrenergic blockers (Propranolol, Atenolol)

• Class III: K+ channel blockers (Amiodarone, Dofetilide)

• Class IV: Ca2+ channel blockers (Verapamil, Diltiazem)

Specific Pharmacological Effects

• Amiodarone:

  • Most widely used; indications include ventricular and atrial fibrillation

  • Complex pharmacological effects covering multiple classes

Monitoring and Adverse Effects of Amiodarone

• Adverse Effects:

  • Cardiac issues: Bradycardia, prolonged QT interval, Torsades de Pointes

  • Hepatic, thyroid, pulmonary, dermatologic concerns requiring monitoring

Proarrhythmia - Torsades de Pointes

• Highest incidence associated with Class IA and Class III agents

• Amiodarone presents lower risk compared to others.