Antiarrhythmic Drugs

Chapter 12 Antiarrhythmic Drugs



I. General Considerations

A. Cardiac contraction (Fig. 12-1): five-step process

1. Spontaneous development of the action potential in the sinoatrial (SA) node

2. Spread of the impulse through the atrium

3. Temporary delay of the impulse at the atrioventricular (AV) node

4. Rapid spread of the impulse along the two branches of the bundle of His and the Purkinje fibers

5. Spread of the impulse along the cardiac muscle fibers of the ventricles

image

12-1 Schematic drawing of the heart.



Know the five steps of the cardiac contraction.


B. Electrophysiology of the heart

1. Action potential (Fig. 12-2)


a. The resting membrane potential of the myocardium (approximately −90 mV).

b. Results from an unequal distribution of ions (high Na+ outside, high K+ inside).

image

12-2 Schematic representation of cardiac electrical activity in the sinoatrial (SA) node and Purkinje fibers as well as ion permeability changes and transport processes that occur during an action potential. AV, atrioventricular.



Resting potential about −90 mV; high extracellular Na+ and high intracellular K+.


2. Five phases of the action potential


a. Rapid depolarization (phase 0)


(1) Rapid inward movement of Na+ due to the opening of voltage-gated sodium channels

(2) Variation in resting membrane potential: −90mV to +15mV

b. Initial rapid repolarization (phase 1)


(1) Inactivation of sodium channels

(2) Influx of Cl−

c. Plateau phase (phase 2)

• Slow but prolonged opening of voltage-gated calcium channels

d. Repolarization (phase 3)


(1) Closure of calcium channels and K+ efflux through potassium channels

(2) Return of inactivated sodium channels to resting phase

e. Diastole (phase 4)


(1) Restoration of ionic concentrations by Na+/K+-activated ATPase (adenosine triphosphatase)

(2) Restoration of resting potential


Na+/K+ activated ATPase (digoxin sensitive) maintains cell membranes resting potential.


3. Important electrocardiographic (ECG) parameters (Fig. 12-3)


a. P wave represents atrial depolarization

b. PR interval equals the delay of conduction through the AV node

image

12-3 Schematic electrocardiogram (ECG) showing depolarization and repolarization of the heart. The P wave is produced by atrial depolarization, the QRS complex by ventricular polarization, and the T wave by ventricular repolarization. The PR interval measures the conduction time from atrium to ventricle, and the QT interval measures the duration of the ventricular action potential. The QRS complex measures the intraventricular conduction time.



Slowed AV node conduction increases PR interval; example vagal slowing of heart.


c. QRS complex represents ventricular depolarization

d. T wave represents ventricular repolarization

e. QT interval equals duration of action potential in the ventricles


Delayed repolarization prolongs QT interval; example Class IA and III antiarrhythmic agents.


II. Arrhythmias and Their Treatment

A. General

1. Arrhythmias are irregularities in heart rhythm

2. They result from disturbances in:


a. Pulse generation

b. Impulse conduction

c. Or both


Disturbances in pulse generation or impulse conduction may result in arrhythmias.


B. Antiarrhythmic drugs produce effects by altering one or more of the following factors:

1. Automaticity

2. Conduction velocity

3. Refractory period

4. Membrane responsiveness


Antiarrhythmic drugs target automaticity, conduction velocity, refractory period or membrane responsiveness.


C. These agents have varying effects on the electrophysiology of the heart (Table 12-1).

III. Antiarrhythmic Drugs According to the Vaughn-Williams Classification (Box 12-1)

A. Class I drugs: Sodium channel blockers


TABLE 12-1 Effects of Antiarrhythmic Drugs on the Electrophysiology of the Heart

image


BOX 12-1 Antiarrhythmic Drugs


ERP, effective refractory period



CLASS IA (Binds to open sodium channels and extends ERP)


Disopyramide


Procainamide


Quinidine



CLASS IB (Binds to inactivated sodium channels and shortens ERP)


Lidocaine


Mexiletine


Tocainide



Class IC (Binds to all sodium channels; minimal effect on ERP)


Flecainide


Propafenone



Class II (Beta blockers)


Esmolol


Metoprolol


Propranolol



Class III (Potassium channel blockers; extend ERP)


Amiodarone


Dofetilide


Ibutilide


Sotalol



Class IV (Calcium channel blockers)


Diltiazem


Verapamil



Miscellaneous Antiarrhythmic Agents


Adenosine


Digoxin


Magnesium


Potassium



Class I drugs: sodium channel blockers


1. General


a. All class I agents (Fig. 12-4)


(1) Are also local anesthetics

(2) Bind to open or inactivate sodium channels—use dependent binding

(3) Inhibit phase 0 depolarization of the action potential

b. Lidocaine is more effective in the treatment of ventricular arrhythmias

c. Quinidine is more effective in the treatment of atrial arrhythmias

2. Class IA drugs

• Block open or activated sodium channels, also block potassium channel; thus prolong action potential and effective refractory period (ERP)

a. Examples


(1) Quinidine

(2) Procainamide

(3) Disopyramide

b. Quinidine


(1) Mechanism of action

(a) Inhibition of sodium channels, extending ERP, thereby decreasing myocardial conduction velocity, excitability, and contractility

image

12-4 Effects of class I antiarrhythmic drugs on the action potential and the electrocardiogram (ECG). ERP, effective refractory period.



Quinidine’s block of α and muscarinic receptors is pro-arrhythmic by increasing heart rate and AV conduction.


(b) Blockade of α-adrenergic receptors, producing vasodilation and leading to a reflex increase in the SA node rate

(c) Blockade of IK channels, prolonging duration of action potential

(d) Blockade of muscarinic receptors, thereby decreasing vagal tone, thus increasing heart rate and enhancing conduction through AV node


Muscarinic receptor blocking activity: Disopyramide > quinidine > procainamide.


(2) Uses

(a) Conversion to or maintenance of sinus rhythm in patients with atrial fibrillation, flutter, or ventricular tachycardia

(b) Treatment of paroxysmal supraventricular tachycardia (PSVT)

(c) Prevention of PSVT in patients with reentrant tachycardias

Including Wolff-Parkinson-White syndrome


Quinidine not used much today clinically but often tested on Board Exams.


(d) Also, has activity against Plasmodium falciparum malaria

(3) Adverse effects

(a) Torsades de pointes

• Rapid, polymorphic ventricular tachycardia with a characteristic twist of the QRS complex


Class IA and III agents most likely to cause torsades de pointes; treat it with magnesium.


(b) ECG changes

Prolonged QRS complex

Giant U wave

• ST-segment depression

• Flattened T wave

(c) Diarrhea

(d) Cinchonism

• Giddiness

• Lightheadedness

• Ringing in the ears

• Impaired hearing

• Blurred vision

(e) Thrombocytopenia


Quinidine may cause cinchonism.


c. Procainamide

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Apr 8, 2017 | Posted by in PHARMACY | Comments Off on Antiarrhythmic Drugs

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