A. There are five phases in the cardiac action potential:
1. Phase 0—upstroke due to the sodium current
2. Phase 1—peak due to inactivation of sodium channels and activation of potassium channels
3. Phase 2—plateau due to the inward calcium current balancing the outward potas-sium current
4. Phase 3—repolarization due to the potassium current after calcium channels close 5. Phase 4—diastolic depolarization due to gradual increase in sodium permeability B. BRADYARRHYTHMIAS can be treated with atropine or ββ-agonists.
C. TACHYARRHYTHMIAS can be treated with the antiarrhythmics, which depress the electrical activity of the myocardial cells. The antiarrhythmics reduce tach-yarrhythmias by
1. Decreasing ectopic automaticity
2. Enhancing or depressing conduction to reduce reentry
D. There are four primary mechanisms of antiarrhythmic action, which correspond to four major classes of antiarrhythmics. (See Table 5-1.)
1. Sodium channel blockade (Classes IA, IB, and IC) 2. ββ-blockade (Class II)
3. Increased refractoriness due to potassium channel blockade (Class III) 4. Calcium channel blockade (Class IV)
E. CLASS IA antiarrhythmics are sodium channel blockers (direct action) with anti-cholinergic activity (indirect action).
1. Effects of the two actions are listed in Table 5-2.
2. Changes of the myocardial action potential are illustrated in Figure 5-5.
a. Slowing of the diastolic depolarization (Phase 4) leads to the reduced auto-maticity.
b. Slowing of the rate of rise of the action potential (Phase 0) leads to the reduced excitability and reduced conduction velocity.
VI
Weiss_Ch05_062-079.qxd 8/28/08 2:11 PM Page 74
Class Category Mechanism AP/ERP Length Uses
IA Na⫹channel blocker Slows phase 0 Longer SV, ventricular
depolarization tachycardia
IB Na⫹channel blocker Shortens phase 3 Shorter Ventricular
repolarization tachycardia
IC Na⫹channel blocker Slows phase 0 No change Refractory ventricular
depolarization arrhythmias
II Beta blocker Suppresses phase 4 Longer Atrial arrhythmias,
depolarization SV tachycardia
III K⫹channel blocker Prolongs phase 3 Longer Atrial arrhythmias,
repolarization ventricular tachycardia
IV Ca2⫹channel blocker Shortens action Longer Atrial arrhythmias,
potential SV tachycardia
AP ⫽ action potential. ERP ⫽ effective refractory period. SV ⫽ supraventricular
SUMMARY OF ANTIARRHYTHMIC DRUGS TABLE5-1
Sodium Channel Block Vagal Block (SA and AV nodes)
↓ automaticity ↑ automaticity
↓ excitability ↑ excitability
↑ effective refractory period ↓ effective refractory period Sum total of effects of IA antiarrhythmics:
SA and AV nodes—variable effects atrial and ventricular muscle—direct effects predominate
AV ⫽ atrioventricular; SA ⫽ sinoatrial; ↑ ⫽ increased; ↓ ⫽ decreased
CHANGES IN MYOCARDIAL CELL PROPERTIES DUE TO THE DIRECT (SODIUM CHANNEL BLOCK) AND INDIRECT (VAGAL BLOCK)
ACTIONS OF GROUP IA ANTIARRHYTHMICS TABLE5-2
Co ntrol
Qu inid
in e
Time
Voltage
Figure 5-5 Changes in the myocardial action potential induced by Class IA antiarrhythmics (e.g., quinidine). There is a decrease in the slope of phases 4 and 0, as well as prolongation of the action potential and the effective refractory period.
75 CARDIOVASCULAR PHARMACOLOGY
Weiss_Ch05_062-079.qxd 8/28/08 2:11 PM Page 75
76 CHAPTER 5
c. Prolongation of the action potential leads to the increased effective refractory period.
3. Indirect actions from the anticholinergic activity only occur at the SA and AV nodes because these are the primary sites of parasympathetic innervation.
a. The net effect of the IA antiarrhythmics on the SA and AV nodes is variable, depending upon whether the direct or indirect effects predominate.
b. At atrial and ventricular muscle, the direct effects predominate, because there is little parasympathetic innervation.
4. Class IA antiarrhythmics are often combined with cardiac glycosides.
a. The indirect effects (anticholinergic) of the antiarrhythmic oppose the indirect effects (vagomimetic) of the cardiac glycoside.
b. The combination results in little indirect activity, and leads to sodium channel blockade with increased myocardial contractility.
5. Several Class IA antiarrhythmics are commonly used.
a. Quinidine (Quinidex, Cardioquin) is only used orally, as parenteral administra-tion has marked hypotensive effects.
i. The side effects include cinchonism, which is characterized by ringing in the ears, blurred vision, nausea, and vomiting.
ii. Thrombocytopenia can also be induced.
iii. Quinidine reduces the renal elimination of digoxin, which can lead to an increase in the toxicity from digoxin.
b. Procainamide (Pronestyl) can be used orally or intravenously.
i. N-Acetylprocainamide is an active metabolite that behaves like a class III drug.
ii. A lupus-like syndrome can be induced, especially in patients who have a slow acetylator phenotype.
c. Disopyramide (Norpace) is an oral antiarrhythmic that is also the most potent antimuscarinic.
6. Some side effects are common to all Class IA antiarrhythmics.
a. Ventricular arrhythmias induced by Class IA antiarrhythmics can lead to syncope.
b. AV block induced by the Class IA antiarrhythmics can lead to an increased PR interval.
c. There may also be increased QRS and QT intervals. The polymorphic ventricu-lar arrhythmia, torsades de pointes, can be induced by the prolonged QT interval.
d. Decreased contractility can aggravate heart failure, especially with disopyramide.
e. Direct vasodilation can lower blood pressure.
7. Uses for Class IA antiarrhythmic drugs are:
a. Treatment and prophylactic control of symptomatic ventricular tach-yarrhythmias
b. Prophylactic control of supraventricular arrhythmias
F. CLASS IB antiarrhythmic drugs are sodium channel blockers without anticholinergic activity.
1. Lidocaine (Xylocaine) is a very effective parenteral antiarrhythmic.
a. It is rapidly metabolized in the liver (high extraction ratio) and has a low bioavailability (0.3); thus it is not used orally.
i. Heart failure will decrease the liver blood flow and thereby slow the metabolism of lidocaine.
ii. The maintenance dose of lidocaine should be reduced in patients with heart failure or liver disease.
Weiss_Ch05_062-079.qxd 8/28/08 2:11 PM Page 76
b. The elimination of lidocaine follows two-compartment kinetics (Figure 5-6);
thus, repeated dosing will increase the duration of the therapeutic effect.
c. The effects of lidocaine on the myocardial action potential are illustrated in Figure 5-7.
i. Automaticity is decreased.
ii. Excitability is decreased.
iii. The effective refractory period is decreased.
d. The actions of lidocaine on myocardial muscle are frequency-dependent, with the highest activity at the higher frequencies. Thus it acts preferentially on arrhythmic muscle.
e. There are few side effects; however, at large dosages it can
i. Produce local anesthetic side effects, such as tremors and convulsions Initia
l p ha
se
Terminal phase
Time
Log [lidocaine]
Con tr
ol Lid
oca ine
Time
Voltage
Figure 5-6 Lidocaine concentration versus time relationship, which displays two phases (two compartments).
Figure 5-7 Changes in the myocardial action potential induced by Class IB antiarrhythmics (e.g., lidocaine). Phase 3 repolarization is shortened, which decreases the duration of the action potential. In addition, lidocaine decreases the slope of phase 0, thereby decreasing the effective refractory period.
77 CARDIOVASCULAR PHARMACOLOGY
Weiss_Ch05_062-079.qxd 8/28/08 2:11 PM Page 77
78 CHAPTER 5
ii. Reduce myocardial contractility iii. Slow AV conduction
f. The indications for lidocaine are limited to ventricular tachyarrhythmias, including:
i. Ventricular tachycardia
ii. Premature ventricular complexes iii. Ventricular fibrillation
iv. Digitalis-induced ventricular arrhythmias
2. Mexiletine (Mexitil) has effects that are similar to lidocaine. However:
a. It is effective when given orally, as there is no first-pass metabolism.
b. Its half-life is much longer.
3. Phenytoin (Dilantin), an anticonvulsant, also has antiarrhythmic effects.
G. CLASS IC antiarrhythmic drugs (e.g., flecainide [Tambocor], propafenone [Rythmol]) induce marked reductions of the sodium permeability changes.
1. They cause marked slowing of conduction in all cardiac tissue, with minor effect on duration of action potential and effective refractory period.
2. Class IC drugs are used to treat refractory ventricular arrhythmias, but they can cause ventricular tachycardia as a side effect.
H. CLASS II antiarrhythmics are ββ-blockers (e.g., propranolol [Inderal], metoprolol [Toprol]) 1. They act primarily by reducing the effects of the sympathetic nervous system
on the myocardium.
a. Phase 4 depolarization is reduced, leading to a reduction of automaticity and conduction velocity in the SA node, the AV node, and the Purkinje fibers.
b. Excitability is reduced.
c. The effective refractory period of the AV node is increased.
2. High doses may induce sodium channel blockade.
3. Indications for β-blockers include:
a. Sympathetic-induced tachyarrhythmias.
b. Paroxysmal supraventricular tachycardia (PSVT), because β-blockers reduce reentry at the AV node.
c. Atrial flutter and fibrillation, because β-blockers slow AV conduction, thereby reducing the ventricular rate.
d. Prophylaxis after an acute MI;β-blockers reduce sudden death.
I. CLASS III antiarrhythmics prolong the action potential and effective refractory period by blocking potassium channels and prolonging phase 3 repolarization.
1. Amiodarone (Cordarone) has effects of all four major classes, but its predominant effect is to increase the refractory period.
a. It acts at all sites in the myocardium, which is unusual for an antiarrhythmic, and it effectively reduces almost any arrhythmia.
b. The half-life is very long, approximately 30 days.
c. Toxicity is very high, including:
i. Pneumonitis and pulmonary fibrosis. Pulmonary toxicity is fatal in 10%
of patients affected.
ii. Change of thyroid function.
iii. Blue skin discoloration due to its iodine content.
iv. Hepatotoxicity.
2. Bretylium (Bretylol) decreases catecholamine release, prolongs the action potential, and increases the effective refractory period in the myocardium. It is rarely used.
Weiss_Ch05_062-079.qxd 8/28/08 2:11 PM Page 78
3. Sotalol (Betapace) is a nonselective β-blocker with Class III activity.
4. Ibutilide (Corvert) given IV prolongs the action potential and can be used to con-vert atrial flutter or fibrillation to normal sinus rhythm.
J. CLASS IV antiarrhythmics are calcium channel blockers (e.g., verapamil [Calan, Isoptin]).
1. Calcium channels are particularly important for action potential generation in the SA and AV nodes.
2. Blockade of the L-type calcium channels decreases heart rate, slows AV conduc-tion, and increases the effective refractory period.
3. Verapamil has a low bioavailability due to first-pass metabolism, and 80%–90% of verapamil in the serum is bound to plasma proteins.
4. Indications for the calcium channel blockers include supraventricular arrhyth-mias, such as:
a. PSVT b. Atrial flutter c. Atrial fibrillation
5. Side effects of verapamil include:
a. Bradycardia b. AV block
c. Excessive ventricular rate in patients with Wolff–Parkinson–White syndrome who are being treated for atrial fibrillation
d. Heart failure, due to reduced myocardial contractility e. Constipation
6. The effects of calcium channel blockers on the myocardium can be antagonized by catecholamines, digoxin, or calcium.
K. MISCELLANEOUS antiarrhythmics are also useful.
1. Adenosine (Adenocard) hyperpolarizes supraventricular muscle membranes and is used to terminate PSVT. The duration of action is very brief.
2. Digoxin (Lanoxin) has antiarrhythmic effects due to depression of AV nodal conduction.
a. Increased myocardial contractility and the long duration of action of digoxin are unusual for antiarrhythmics.
b. Uses include:
i. Atrial flutter and fibrillation ii. PSVT
iii. Arrhythmias in patients with congestive heart failure
3. Phenylephrine increases blood pressure, which reflexly reduces heart rate and reduces PSVT.
4. Potassium and magnesium can be useful to decrease digoxin toxicity.
79 CARDIOVASCULAR PHARMACOLOGY
Weiss_Ch05_062-079.qxd 8/28/08 2:11 PM Page 79
80