Pharmacology - An Illustrated Review

23. Antiarrhythmic Drugs

23.1 Electrophysiology of the Heart

Conduction System of the Heart

The sinoatrial (SA) node is the primary pacemaker of the heart, since it is able to spontaneously generate action potentials (inherent automaticity). These action potentials are conducted rapidly through the right atrial myocardium to the atrioventricular (AV) node, which delays the impulse before conducting it to the ventricles via the bundle of His and Purkinje fibers. This provides an orderly contraction sequence from apex to base for efficient ejection of blood from the ventricles (Fig. 23.1).

– The SA node spontaneously generates action potentials at a rate of ~80 to 100/min.

– The AV node also has inherent automaticity but at a slower rate than the SA node. If the SA node fails, the AV node will take over the pacemaker activity of the heart.

– The delay of the cardiac impulse at the AV node gives the contracting atria adequate time to empty their contents into the ventricles before ventricular contraction is initiated.

Note: The typical resting heart rate is 65 to 75 beats/min. This is due to vagal slowing of the heart below the intrinsic rate set by the SA node.

Fig. 23.1 image Cardiac conduction system.

An impulse initiating cardiac contraction begins in the sinoatrial (SA) node. It travels through the atrial myocardium to the atrioventricular (AV) node. From the AV node, the impulse spreads to the ventricular myocardium via the bundle of His and Purkinje fibers. Contraction of the ventricular myocardium occurs from the inside to the outside from the apex to the base of the heart.


Cardiac Action Potentials

The ionic conductances that are a feature of action potential phases at the SA node, cardiac muscle, and branches of the conduction system are discussed in this section.

Action Potential Phases at the Sinoatrial Node

Refer to the action potential waveforms of slow response tissue in Fig. 23.2.

Phase 0

– This slow upstroke of the action potential shows membrane depolarization (it becomes less negative).

– It results from an increase in Ca2+ conductance, causing inward Ca2+ flow.

Fig. 23.2 image Membrane potential changes in cardiac muscle fibers.

Slow response tissue includes the sinoatrial (SA) node and atrioventricular (AV) node. Fast response tissue includes the atrial and ventricular myocardium, the bundle of His, and Purkinje fibers. Slow and fast response tissues have distinct electrochemical properties. This causes them to react differently to antiarrhythmic drugs.


Phases 1 and 2

– These phases do not occur at the SA node.

Phase 3

– This is the repolarization phase.

– It results from an increase in K+ conductance, which causes outward K+ flow and repolarization of the membrane toward the K+ equilibrium potential (the resting potential).

Phase 4

– The SA node does not have a stable resting membrane potential. During phase 4, it slowly depolarizes (which is responsible for its inherent automaticity).

– It results from an increase in Na+ conductance, causing inward Na+ flow and a decrease in K+ conductance.

Note: The events at the AV node are similar to those at the SA node but slower. As a result, the AV node normally does not generate its own action potentials. This is because action potentials are conducted to the AV node more frequently than its own slow inherent rate of action potential generation.

Action Potential Phases at the Atrial and Ventricular Myocardium, Bundle of His, and Purkinje Fibers

Refer to the action potential waveforms of rapid response tissue in Fig. 23.2.

Phase 0

– This rapid upstroke of the action potential shows membrane depolarization (it becomes less negative).

– It results from an increase in Na+ conductance, causing rapid inward Na+ flow.

– This inward Na+ flow stops after a few milliseconds due to inactivation of Na+ channels.

– The maximum rate of voltage change during phase 0 (dV/dt) determines the conduction velocity.

Phase 1

– This is an early slight membrane repolarization (membrane becomes more negative).

– It results from rapid outward K+ flow (due to a favorable electrochemical gradient) and a decrease in Na+ conductance.

Phase 2

– This is the plateau of depolarization.

– In this phase, there is increased Ca2+ inward flow through L-type Ca2+ channels which approximately balances outward K+ flow.

– Ca2+ entry during phase 2 is necessary for cardiac muscle contraction.

Phase 3

– This is the repolarization phase.

– It results from a decrease in Ca2+ conductance and an increase in K+ conductance. The net effect of this is that there is a rapid outward K+ flow, which repolarizes the membrane toward the K+ equilibrium potential (the resting potential).

Phase 4

– This is the resting membrane potential.

– It is determined by high K+ conductance, and its value is therefore close to the K+ equilibrium potential (−96mV). At this potential, K+ outflow and K+ inflow are equal.

Excitation–contraction coupling in the heart

Contraction of cardiac muscle occurs when the excitation produced by an action potential is transmitted to cardiac myofibrils. Depolarization of the cardiac muscle cell membrane triggers an action potential that passes through T tubules. During phase 2 (plateau) of the action potential, there is increased Ca2+ conductance, causing inward Ca2+ flow. This inward Ca2+ flow initiates the release of Ca2+ from the sarcoplasmic reticulum (Ca2+-induced Ca2+ release) which increases intracellular [Ca2+]. Ca2+ binds to troponin C, and tropomysin moves out of its blocking position, allowing actin and myosin to form cross-bridges. The thick and thin filaments of actin and myosin slide past each other, resulting in cardiac muscle cell contraction.The contraction ends when Ca2+ ATPase facilitates the reuptake of Ca2+ into the sarcoplasmic reticulum, reducing the intracellular [Ca2+]. The force of contraction of cardiac muscle cells is proportional to the amount of Ca2+ release, which varies depending on conditions.


Measuring the Electrical Activity of the Heart: The Electrocardiogram

Recording an ECG

The electrocardiogram (ECG) is an overall representation of the electrical activity in the heart (Fig. 23.3). It is measured by recording voltages through surface electrodes, which “look” at the heart from different positions. A wave of depolarization moving toward a lead causes an upward deflection of the ECG. Analysis of the results of an ECG allows clinicians to diagnose a variety of cardiac disorders, including arrhythmias, ischemia, and the location of myocardial infarction (MI).

Interpretation of ECG Waves, Segments, and Intervals


– The P wave corresponds to atrial depolarization.

– The QRS complex corresponds to ventricular depolarization, which occurs from apex to base.

– The T wave corresponds to ventricular repolarization, which occurs from base to apex.

Note: Repolarization of the atria is masked by the QRS complex.

Fig. 23.3 image Electrocardiogram (ECG) curve.

The ECG depicts electrical activity in the heart. The P wave corresponds to atrial depolarization. The QRS complex represents ventricular depolarization, and the T wave represents ventricular repolarization.



– The PQ segment is an isoelectric period between the P wave and the QRS complex. During this time, the wave of depolarization is traveling through the AV node into the bundle of His.

– The ST segment corresponds to the plateau phase of the cardiac action potential when all ventricular fibers are simultaneously depolarized.


– The PQ interval corresponds to the conduction of the action potential through the AV node.

– The QT interval corresponds to ventricular depolarization and repolarization.

Cardiac axis

The cardiac axis is the mean direction of electrical current flow through the ventricles during depolarization. It is calculated by analysis of the QRS complexes in the ECG leads. Many factors can alter the cardiac axis, including abnormal cardiac anatomy or position, myocardial infarction (MI), ischemia, pulmonary embolism, cardiomyopathy, and conduction abnormalities.


23.2 Arrhythmias

An arrhythmia is a disorder of the heart rate or rhythm. Arrhythmias may occur as a result of abnormal automaticity due to abnormal pacemaker sites within the atria or ventricles, known as ectopic foci. Under normal circumstances, their pacemaker activity is overridden by the pace set by the SA node; however, in cardiac disease states, they can cause additional beats, tachycardia (increased heart rate [>100 beat/min]), or bradycardia (decreased heart rate [< 60 beats/min]), depending on their site and the disease involved. Arrhythmias may also occur due to abnormal (reentry) conduction. This occurs when action potentials travel in a circuit within the heart rather than in one direction causing persistent excitation. Multiple reentry circuits within a chamber of the heart can lead to incoordination of cardiac muscle contraction known as fibrillation.

Table 23.1 provides a classification of arrhythmias.

  Table 23.1 image Classification of Cardiac Arrhythmias




Atrial flutter

The atrial rhythm is both rapid and regular (300−400 beats/min).

One of every two (2:1 block) or three (3:1 block) atrial beats is conducted to the ventricle through the AV node. The ventricular heart rate (133−200 beats/min) is regular but too rapid to allow optimal ventricular filling during diastole.

Atrial fibrillation

The atrial rhythm is rapid (400−600 beats/min) and irregular.

The ventricular rhythm is also rapid and irregular (100−150 beats/min).

The ventricular rate is slower than observed with atrial flutter.

Ventricular premature beats


These beats originate in the ventricles. They usually do not reduce cardiac output. Many patients with frequent premature ventricular beats may be bothered by palpitations.

Ventricular tachycardia

Rapid rhythm (200−400 beats/min) originating in the ventricles

Ventricular tachycardia can be self-terminating or sustained (lasting > 30 s).

Patients with ventricular tachycardia and heart disease have a high probability of developing ventricular fibrillation. Ventricular tachycardia leading to ventricular fibrillation is the leading cause of death in the United States.

Ventricular fibrillation

Rapid rhythm (> 400 beats/min) originating in the ventricles

Ventricular fibrillation is invariably fatal unless electrical defibrillation is performed.

Abbreviation: AV, atrioventricular.

23.3 Antiarrhythmic Drugs

Table 23.2 outlines a classification of antiarrhythmic agents that is based on the ion channel or receptor that they block and the effect they have on the action potential.

  Table 23.2 image Classification of Antiarrhythmic Agents

Drug Class

Mechanism of Action

Effect on Action Potential

Class IA

Na+ channel blockers

Slow phase 0, prolong action potential, slow conduction

Class IB

Na+ channel blockers

Shorten phase 3, slow conduction

Class IC

Na+ channel blockers

Markedly slow phase 0, slow conduction

Class II


Slow phase 4, slow automaticity, slow conduction

Class III

K+ channel blockers

Prolong phase 3, slow conduction

Class IV

Ca2+ channel blockers (verapamil and diltiazem only)

Slow phase 0 to decrease automaticity, decrease amplitude and duration of phase 2

Class I Antiarrhythmic Drugs

All class I antiarrhythmic agents are local anesthetics that act to slow conduction in atrial and ventricular tissue. Their actions on the AV node are different for the individual agents. The effects of class I agents on channel opening, ionic conductances, and cardiac excitability are depicted in Fig. 23.4.

Class IA Agents: Quinidine, Procainamide, and Disopyramide

Mechanism of action. Class IA agents prolong the action potential duration and QT interval, thus slowing conduction. A prolonged QRS interval occurs at moderate and fast heart rates. All class IA drugs have anticholinergic actions. The drugs improve AV nodal conduction by antagonizing the actions of the vagus nerve on the AV node. They also directly depress AV nodal conduction. The net effect on AV nodal conduction is variable.


– Atrial fibrillation

– Atrial flutter

– Ventricular tachycardia

– Ventricular fibrillation

Note: These drugs should not be used alone for the treatment of atrial flutter or atrial fibrillation because the ventricular heart rate may dramatically increase, and the cardiac output may decrease. All three drugs depress myocardial contractility and can worsen existing heart failure.

Side effects

– May cause life-threatening arrhythmias (ventricular tachycardia or ventricular fibrillation) in patients treated for less serious arrhythmias. One life-threatening ventricular arrhythmia produced by both class 1A and class III agents is torsades de pointes.

– Heart failure due to negative inotropic effects

– Anticholinergic: dry eyes, dry mouth, and urinary retention

– Skin rash, muscle weakness, and arthralgia (joint pain)

– Cinchonism (ringing in the ears) and diarrhea (quinidine only [quinidine is the d-isomer of quinine])

– Acute lupus erythematosus (procainamide only)

Fig. 23.4 image Effects of antiarrhythmic drugs of the Na+-channel blocking type.

Antiarrhythmics of the Na+ channel blocking type inhibit Na+ channel opening. This can result in a decreased rate of depolarization (phase 0), suppression of action potential (AP) generation, or an increase in the refractory period (phases 1−3).


Torsades de pointes

Torsades de pointes is a rare form of ventricular tachycardia accompanied by distinctive ECG changes. It translates as “twisting of the points,” which refers to the twisting of QRS complexes around the baseline electrical axis of the heart by at least 180 degrees. The QT interval is also prolonged. This arrhythmia can degenerate to ventricular fibrillation causing sudden death if untreated. Causes include therapy with class 1A and III antiarrhythmic agents, hypomagnesemia (low plasma Mg2+), and hypokalemia (low plasma K+).


Class IB Agents: Lidocaine, Mexiletine, and Tocainide

Mechanism of action. Class IB agents shorten the action potential duration and the QT interval. Slow conduction and prolonged QRS interval occur at fast heart rates. Class IB drugs have little effect on AV nodal conduction or myocardial contractility.


– Lidocaine is rapidly metabolized in the liver. It has a short plasma half-life and is used as an intravenous (IV) infusion only in a hospital setting (Fig. 23.5).

– Tocainide and mexiletine are used orally for long-term therapy.


– Ventricular arrhythmias as an alternative to amiodarone (class III antiarrhythmic agent)

Side effects

– Central nervous system: act as local anesthetics in the brain

– Sedation at low doses

– Muscle twitching and vertigo with moderate dosages

– Convulsions at higher doses

– Agranulocytosis (acute low white blood cell count). This is a dangerous but uncommon side effect seen with tocainide.


Cardioversion is a procedure in which an electrical shock is delivered to the heart via paddles or electrodes to convert an arrhythmia to a normal rhythm. It does this by causing all of the cardiac muscle cells to contract simultaneously. This brief interruption to the arrhythmia gives the SA nodes an opportunity to regain control over the pacing of the heart.


Valsalva maneuver

The Valsalva maneuver involves forceful expiration against a closed glottis, resulting in increased intrathoracic pressure that causes a reduction in venous return a reduction in cardiac output due to decreased preload (via the Starling mechanism), reduced heart rate and a fluctuation in aortic pressures (increased initially, then decreased). The Valsalva maneuver can be used to arrest episodes of supraventricular tachycardia and as a diagnostic aid to clinicians for some cardiac diseases (e.g., hypertrophic cardiomyopathy) that are worsened by the Valsalva. The Valsalva is also used by swimmers and people on aircraft to normalize ear pressures. A similar effect to the Valsalva maneuver is seen in people straining during a bowel movement. This is particularly dangerous for patients with pulmonary embolism.


Class IC Agents: Flecainide, Propafenone, and Moricizine

Mechanism of action. Class IC agents slow conduction, and prolonged QRS interval occurs at slow, moderate, and fast heart rates. These agents slow conduction in all cardiac tissues (including the AV node) and also depress cardiac contractility. They have no prominent effect on the duration of the action potential.

Fig. 23.5 image Antiarrhythmic drugs of the Na+-channel blocking type.

Procaine and lidocaine are rapidly degraded in the body by cleavage (at the points indicated by arrows in the chemical structure box). These drugs must be given intravenously or by intravenous infusion. The orally administered drugs procainamide and mexiletine are not subject to such rapid degradation and are thus more likely to cause adverse effects. (CNS, central nervous system)



– Paroxysmal atrial flutter

– Paroxysmal atrial fibrillation

– Life-threatening ventricular arrhythmias

Side effects

– Heart failure (due to negative inotropic effects of all class IC drugs)

– Worsening of cardiac arrhythmias. These drugs may increase mortality when administered to patients surviving myocardial infarction (MI).

– Headache

Class II Antiarrhythmic Drugs

Beta-Adrenergic Receptor Antagonists: Propranolol and Esmolol

Mechanism of action. Class II β–adrenergic receptor antagonists slow phase 4 depolarization thus slowing automaticity, AV nodal conduction, and decreasing heart rate and contractility.

Uses. Class II agents are used to depress AV nodal conduction with atrial flutter-fibrillation and to prevent ventricular fibrillation during the first 2 years following myocardial infarction (MI).

Class III Antiarrhythmic Drugs

Amiodarone and Sotalol

Mechanism of action. The class III antiarrhythmic drugs prolong action potential duration without slowing conduction velocity.


– The half-life of amiodarone is ~30 days. There is a prolonged time to achieve efficacy with oral administration, and effects are prolonged after drug withdrawal.


– Treatment of recurrent ventricular tachycardia-fibrillation.

Note: Due to the high incidence of serious side effects, the class III drugs are restricted for life-threatening arrhythmias.

Side effects

– Amiodarone: corneal opacities, photosensitivity that produces a gray-blue skin rash, thyroid dysfunction (drug contains iodine atoms), peripheral neuropathy, and life-threatening pulmonary toxicity (pulmonary fibrosis and interstitial pneumonitis) that may not remit with drug withdrawal.

– Sotalol: all adverse effects seen with β-blockers and torsades de pointes

Class IV Antiarrhythmic Agents

Calcium Channel Blockers: Verapamil and Diltiazem

Mechanism of action. Class IV drugs inhibit calcium entry through L-type calcium channels in the myocardium and depress AV nodal transmission.

Note: Nifedipine and nicardipine, although excellent vasodilators and antianginal drugs, are poor inhibitors of AV nodal transmission and are ineffective as antiarrhythmic drugs.


– Treatment of atrial flutter-fibrillation

– Acute termination of AV nodal reentry

Side effects

– Sinus arrest or complete AV nodal blockade in the presence of β-adrenergic receptor blockade (verapamil)

Miscellaneous Antiarrhythmic Agents


Mechanism of action. Adenosine increases the vagal tone of the AV node and may directly depress AV nodal conduction.

Pharmacokinetics. Adenosine is administered as an IV bolus and has a plasma half-life of a few seconds (it is taken up by red blood cells). A repeat bolus can be given again within minutes if the first dose is ineffective.


– Acute termination of AV node reentry

Side effects

– Transient dyspnea

– Flushing

Nondrug therapies for arrhythmias

Surgical interventions have an important role in addition to or in place of drug therapy for arrhythmias. Catheter ablation of the source or conduction path of the arrhythmia by application of radiofrequency current applied through a large-tip electrode on a steerable catheter may be useful for supraventricular tachycardias, atrial arrhythmias, atrial fibrillation, and ventricular tachycardia. In patients with sinus node dysfunction or AV nodal block, or if heart block persists following an ablative procedure, implantation of a permanent pacemaker may be indicated. In ventricular fibrillation or ventricular tachycardia, implantation of a cardioverter defibrillator is superior to drug therapy in certain patient populations.

  Table 22.2 image Summary of Mechanisms of Antianginal Drugs

Drug Class

Parameter Affected



↓ preload and afterload

↓ myocardial O2 consumption

↓ coronary artery spasm

↑ blood flow to ischemic areas of the heart

Activates guanylate cyclase to ↑ cGMP


↓ heart rate and contractility

↓ myocardial O2 consumption

Blocks sympathetic activation

Calcium channel blockers

↑ coronary blood flow

↓ myocardial O2 consumption

Blocks L-type Ca2+ channels to dilate blood vessels and decrease contractility of cardiac muscles

Abbreviation: cGMP, cyclic guanosine monophosphate.