1. 23
Antiarrhythmic Drugs

2. Types of Arrhythmias
Arrhythmias are caused by electrolyte disturbances and overstimulation of the heart and can originate anywhere in the heart.
Most common types are:
Tachycardias
Premature contractions
Flutters
Fibrillations
Learning Outcomes
23.1 Identify the basic terminology and descriptions associated with cardiac arrhythmias.
Arrhythmias are often caused by electrolyte disturbances and overstimulation of the heart. Arrhythmias can originate anywhere in the heart, in the atria, ventricles, or conduction system. The most common types of arrhythmias include tachycardias, premature contractions, flutters, and fibrillations.
Arrhythmias that originate in the atria and atrioventricular (AV) nodal areas are referred to as supraventricular arrhythmias (above the ventricles). Paroxysmal atrial tachycardia, atrial flutter, and atrial fibrillation are common supraventricular arrhythmias. Arrhythmias that originate below the AV node are referred to as ventricular arrhythmias. Ectopic foci, areas of abnormal impulse generation, may appear when electrical impulses traveling through the conduction system are delayed or blocked.
Ectopic foci that originate in the atria are referred to as premature atrial contractions (PACs). A PAC would be classified as a supraventricular arrhythmia. Ectopic foci that originate in the ventricles are referred to as premature ventricular contractions (PVCs).

3. Types of Arrhythmias
Abnormalities in ECG waves indicate conduction malfunction.
Several ions help regulate the heart:
Sodium
Potassium
Calcium
Each one is active during different phases of the cardiac action potential.
Learning Outcomes
23.2 Describe the phases of the cardiac action potential in relationship to the activity of Na, K, and Ca ions.
Abnormalities in the appearance of the ECG waves and measurements of the ECG intervals (PR, QRS, QT) that are not within normal limits indicate abnormalities of conduction.
One of the most important aspects of the heart is the function of several ions that regulate the electrophysiological properties of the heart. The ions are sodium (Na+), potassium (K+), and calcium (Ca2+).
Ventricular muscle does not normally display automaticity. However, it can develop automaticity when there is ischemia, excessive sympathetic stimulation, or other abnormal conditions. When this occurs ventricular muscle can depolarize and generate a premature ventricular contraction (PVC).

4. Types of Arrhythmias Learning Outcomes
23.2 Describe the phases of the cardiac action potential in relationship to the activity of Na, K, and Ca ions.
Antiarrhythmic drugs that slow Phase 0, prolong Phases 1–3, or decrease Phase 4 automaticity produce effective antiarrhythmic actions. Most antiarrhythmic drugs affect the movement of one or more specific ions and exert their major antiarrhythmic action on a specific phase of the action potential.
The therapeutic effects of antiarrhythmic drugs rest in their ability to affect the electrophysiological properties of the cardiac membrane and the movement of ions so that the properties of the heart are restored to normal or are at least improved. One cautionary note should be mentioned: all antiarrhythmic drugs have the potential to make any existing arrhythmia worse.

5. Antiarrhythmic Drugs
Classified according to the Vaughn-Williams classification system.
Organized into four major classes based on major mechanism of action.
Learning Outcomes
23.2 Describe the phases of the cardiac action potential in relationship to the activity of Na, K, and Ca ions.
In addition, antiarrhythmic drugs can cause new arrhythmias. A new or differentarrhythmia caused by administration of an antiarrhythmic drug is referred to as a proarrhythmia. One of the most common proarrhythmias is referred to as torsade de pointes.
Antiarrhythmic drugs are usually classified according to the Vaughn-Williams classification system, which organizes the antiarrhythmic drugs into four major classes based on their major mechanism of action.

6. The following table shows the Vaughan-Williams classification and the basic mechanism of action associated with each class. Note that Class I drugs are further broken down into subclasses because of subtle, yet important differences in their effects on action potentials.

7. Antiarrhythmic Drugs Learning Outcomes
23.2 Describe the phases of the cardiac action potential in relationship to the activity of Na, K, and Ca ions.
In addition, antiarrhythmic drugs can cause new arrhythmias. A new or differentarrhythmia caused by administration of an antiarrhythmic drug is referred to as a proarrhythmia. One of the most common proarrhythmias is referred to as torsade de pointes.
Antiarrhythmic drugs are usually classified according to the Vaughn-Williams classification system, which organizes the antiarrhythmic drugs into four major classes based on their major mechanism of action.

8. Class 1—Sodium Channel Blockers
Class 1 antiarrhythmic drugs:
Possess local anesthetic activity
Block the influx of Na ions during depolarization
Suppress arrhythmias in cardiac cells that are hyperexcitable
Learning Outcomes
23.3 Explain the mechanism of action and main differences between the IA, IB, and IC antiarrhythmic drugs.
One of the common features of the Class 1 antiarrhythmic drugs is that they possess local anesthetic activity. Like local anesthetics, the Class 1 drugs block the influx of Na ions during depolarization of nerves and excitable effect of Class 1 antiarrhythmic drugs is to slow depolarization and conduction during Phase 0 of the action potential.
These actions suppress arrhythmias in cardiac cells that are hyperexcitable and arrhythmogenic (giving rise to arrhythmias). The class I drugs are subdivided into three groups (IA, IB, IC) based on the degree to which they block Na ions during depolarization (Phase 0). IAs produce a moderate block; IBs, a mild block; and ICs, a marked block of Na influx.

9. Class 1—Sodium Channel Blockers
Subdivided into three groups:
IA, IB, IC
IA:
Quinidine
Procainamide
Disopyramide
Learning Outcomes
23.3 Explain the mechanism of action and main differences between the IA, IB, and IC antiarrhythmic drugs.
In the past quinidine has been used to treat supraventricular arrhythmias, such as atrial flutter and fibrillation, and also ventricular arrhythmias. However, quinidine is a cardiac depressant that decreases myocardial contraction. In addition, quinidine produces anticholinergic and alpha-blocking effects. Consequently, quinidine can cause a wide range of adverse effects and potential toxicities and is rarely used.
A synthetic drug related to procaine (a local anesthetic), procainamide produces similar antiarrhythmic actions as quinidine. However, procainamide produces less anticholinergic and alpha-blocking actions than quinidine. Procainamide causes fewer adverse effects and toxicities and is the most frequently used IA antiarrhythmic drug.Procainamide is effective for both supraventricular and ventricular arrhythmias. However, it is primarily indicated for outpatient treatment of ventricular arrhythmias.
The actions of disopyramide (Norpace) on the heart are similar to those of quinidine and procainamide. Disopyramide produces a decrease in conduction and prolongation of the refractory period. This drug is only approved for treating ventricular arrhythmias.

10. Class 1—Sodium Channel Blockers
IB:
Lidocaine
Mexiletine
IC:
Flecanide
Propafenone
Learning Outcomes
23.3 Explain the mechanism of action and main differences between the IA, IB, and IC antiarrhythmic drugs.
A synthetic drug used primarily as a local anesthetic agent, lidocaine (Xylocaine) is widely used for ventricular arrhythmias, especially those resulting from a myocardial infarction or arrhythmias occurring during surgery. As a rule, lidocaine is ineffective in atrial arrhythmias and is therefore not recommended for use in these conditions.The main effect of lidocaine, prevention of ventricular arrhythmias, is attributed to its ability to depress automaticity.
Mexiletine is a derivative of lidocaine that has been structurally modified so that it can be administered orally. Mexiletine produces cardiac effects similar to lidocaine and is used for treatment of outpatient ventricular arrhythmias.
Flecainide (Tambocor) and propafenone (Rythmol) are drugs that are usually reserved for treatment of arrhythmias that are unresponsive to other antiarrhythmic drugs. These drugs markedly depress cardiac conduction.
Flecainide and propafenone are primarily indicated for treatment of supraventricular arrhythmias. Adverse effects include GI disturbances, bradycardia, heart block, and the potential for heart failure.

11. Class 2—Beta-Blockers
Decrease heart rate, AV conduction, and automaticity of the SA and AV nodes and heart muscle
Most common beta-blockers used for arrhythmias:
Propranolol
Acebutolol
Esmolol
Learning Outcomes
23.4 Describe the antiarrhythmic actions and uses of the beta-blockers.
The beta-adrenergic blockers are classified as Class 2 antiarrhythmic drugs.
By antagonizing the effects of norepinephrine and epinephrine at the beta-1 receptors, beta-blockers decrease heart rate, AV conduction, and automaticity of the SA and AV nodes, and of atrial and ventricular muscle. Beta-blockers are mainly indicated for supraventricular arrhythmias and for prevention of recurrent myocardial infarction. Propranolol, acebutolol, and esmolol are the beta-blockers most frequently used to treat cardiac arrhythmias.
The most common cardiovascular adverse effects are hypotension and bradycardia. In overdosage, propranolol, and other beta-blockers, may cause heart failure and possible cardiac arrest. Skin rashes, mental confusion, and visual disturbances also may occur.
Esmolol is a selective beta-blocker that mainly affects beta-1 receptors in the heart. It is administered by intravenous infusion in emergency situations when rapid betablockade is desired to lower heart rate. Excessive bradycardia, delayed AV conduction, and hypotension are adverse effects associated with overdosage.

12. Class 3—Potassium Channel Blockers
Block potassium during repolarization
Prolong refractory period and decrease frequency of arrhythmias
Common Class 3 antiarrhythmics:
Amiodarone
Sotalol
Dofetilide
Ibutilide
Learning Outcomes
23.5 Explain the mechanism of action of the class III antiarrhythmic drugs and describe the most serious adverse effects of amiodarone.
The main antiarrhythmic action of the Class 3 drugs is to block potassium channels and interfere with the efflux of potassium ions (K+) during repolarization phases 1 through 3. This action prolongs the refractory period of the heart and decreases the frequency of arrhythmias.
Amiodarone is a very potent antiarrhythmic drug that has multiple sites of action. In addition to blocking potassium channels, amiodarone blocks sodium (Class 1) and calcium (Class 4) channels. It also has blocking actions on both beta- (Class 2) and alpha-adrenergic receptors. The result is a drug that can be used for most supraventricular and ventricular arrhythmias.
Sotalol is a nonselective beta-blocker that also has Class 3 antiarrhythmic activity. Sotalol is primarily indicated for treatment of ventricular arrhythmias and atrial fibrillation.
Dofetilide and ibutilide are two Class 3 drugs whose actions are limited to blocking potassium channels. Dofetilide is indicated for the treatment of atrial fibrillation; ibutilide is indicated for the conversion of atrial flutter and atrial fibrillation to normal sinus rhythm.

13. Class 4—Calcium Channel Blockers
Decrease calcium influx into heart cells
Slow depolarization
Decrease heart rate
Slow conduction of AV node
Reduce myocardial contractility
Learning Outcomes
23.6 Describe the antiarrhythmic actions of the calcium channel blockers and their clinical uses.
These drugs decrease the entry of calcium into cells whose electrophysiologic actions depend on the influx of calcium through the slow-type calcium channels.
The effect of calcium channel blockers on the SA node is to slow depolarization and decrease the heart rate. The effect on the AV node is to slow conduction. These actions reduce the ventricular rate during fast supraventricular arrhythmias.
The calcium channel blockers also affect the contraction of cardiac and smooth muscle. Interference with calcium entry into cardiac muscle reduces myocardial contractility. This is usually not a desired therapeutic action and may precipitate heart failure in patients with CHF. While all calcium channel blockers produce vasodilation, only verapamil (Calan) and diltiazem (Cardizem) have direct actions on the heart and are used for their antiarrhythmic actions.

14. Class 4—Calcium Channel Blockers
Common calcium channel blockers:
Verapamil
Diltiazem
Adenosine
Learning Outcomes
23.6 Describe the antiarrhythmic actions of the calcium channel blockers and their clinical uses.
Verapamil decreases SA node activity, resulting in a slight decrease in heart rate. More important, verapamil decreases AV node conduction. This effect makes it very useful in treating various types of rapid AV nodal arrhythmias and other supraventricular tachycardias.
Common adverse effects of verapamil include headache, dizziness, and minor GI disturbances, especially constipation. The vasodilating effect can produce hypotension, especially when patients change position. More serious complications include cardiac depression leading to heart failure and various degrees of heart block.
The cardiac depressant effects of diltiazem are slightly less than those of verapamil, but diltiazem is generally considered to be a more potent vasodilator than verapamil.
Adenosine is considered a miscellaneous antiarrhythmic drug that is only used in emergency and acute situations. Adenosine is the naturally occurring metabolite of adenosine triphosphate (ATP). The drug is administered intravenously to terminate episodes of paroxysmal supraventricular tachycardia. Adverse effects are brief, but include asystole,respiratory difficulties (bronchospasm), and hypotension.

15. The drugs that make up the different classes differ in their efficacy (and sometimes safety) for different types of arrhythmias. The following table provides an overview of drug classes and associated arrhythmias. Antiarrhythmic agents that are not included in the Vaughan-Williams scheme are also shown in the table.

16. Sinus tachycardia
Class II, IV
Other underlying causes may need treatment
Atrial fibrillation/flutter
Class IA, IC, II, III, IV digitalis
Ventricular rate control is important goal; anticoagulation is required
Paroxysmal supraventricular tachycardia
Class IA, IC, II, III, IV adenosine
AV block
atropine
Acute reversal
Ventricular tachycardia
Class I, II, III
Premature ventricular complexes
Class II, IV magnesium sulfate
PVCs are often benign and do not require treatment
Digitalis toxicity
Class IB magnesium sulfate

17. Special Considerations
The control of arrhythmias can be difficult.
Antiarrhythmic drugs are frequently administered by IV infusion.
Many anthiarrhythmic drugs are cardiac depressants:
Can produce heart failure
Can produce new cardiac arrhythmias
Learning Outcomes
23.7 Recognize the special precautions required with the use of antiarrhythmic drugs.
Antiarrhythmic drugs are frequently administered in the hospital by IV infusion. Dosages (drips per minute) are carefully adjusted to deliver the proper amount of drug.
It is important to be aware of the adverse effects of the various antiarrhythmic drugs and to be alert for their appearance. Many of the antiarrhythmic drugs are cardiac depressants and can produce heart failure or any variety of cardiac arrhythmias themselves.
Sinus bradycardia is defined as a heart rate below 60 beats per minute. The most effective drug for this condition is the anticholinergic drug atropine.

18. Preferred Therapy To stabilize and protect ventricles:
Beta-blockers
Calcium channel blockers
Digoxin
For chronic therapy of arrhythmias:
Learning Outcomes
23.7 Recognize the special precautions required with the use of antiarrhythmic drugs.
Sinus bradycardia is defined as a heart rate below 60 beats per minute. The most effective drug for this condition is the anticholinergic drug atropine.
Beta-blockers, calcium channel blockers, and digoxin, which slow AV conduction, are the preferred drugs to stabilize and protect the ventricles. The second concern is to prevent formation of blood clots in the atria (thromboembolism), which involves the use of anticoagulants.
In the acute setting, adenosine (Adenocard) is the preferred drug. It provides the fastest onset and shortest duration of action. Electrical cardioversion and vagal maneuvers are alternate therapies in acute situations. For chronic therapy of this arrhythmia, there are several choices depending on the patient and other existing conditions. Drugs that slow AV conduction, beta-blockers, calcium channel blockers (verapamil or diltiazem), and digoxin are the preferred drugs.

19. Preferred Therapy If there is increased sympathetic tone:
Beta-blockers
For ventricular tachycardia:
Amiodarone
Lidocaine
Ventricular arrhythmias & tachycardia:
Learning Outcomes
23.7 Recognize the special precautions required with the use of antiarrhythmic drugs.
If there is increased sympathetic tone, beta-blockers such as propranolol (Inderal) or metoprolol (Lopressor) are generally preferred. The calcium channel blockers verapamil (Calan) and diltiazem (Cardizem) are also very effective and may be preferred depending on the patient and clinical situation.
Ventricular tachycardia is defined as three or more consecutive PVCs. Since this is a serious condition that can lead to ventricular fibrillation, immediate treatment is required. In the acute setting, the preferred drug is IV administration of amiodarone (Cordarone); IV administration of lidocaine (Xylocaine) is an alternate choice. For the chronic control of ventricular arrhythmias and ventricular tachycardia, amiodarone is usually the preferred drug. Sotalol (Betapace) and beta-blockers are alternate choices.