Image for Cardiovascular Pharmacology Concepts, Richard E Klabunde PhD

Cardiovascular Pharmacology Concepts

Richard E. Klabunde, PhD

Clinical Disorders:

Therapeutic Classes:

Mechanism Classes:


Also Visit
CVphysiology.com


Cardiovascular Physiology Concepts textbook cover

Click here for information on Cardiovascular Physiology Concepts, 2nd edition, a textbook published by Lippincott Williams & Wilkins (2011)

 

Cardiovascular Physiology Concepts textbook cover

Click here for information on Normal and Abnormal Blood Pressure, a textbook published by Richard E. Klabunde (2013)





Sodium-Channel Blockers (Class I Antiarrhythmics)

General Pharmacology

Graph of non-pacemaker action potential

Effects on depolarization

Sodium-channel blockers comprise the Class I antiarrhythmic compounds according to the Vaughan-Williams classification scheme. These drugs bind to and block the fast sodium channels that are responsible for the rapid depolarization (phase 0) of fast-response cardiac action potentials. This type of action potential is found in non-nodal, cardiomyocytes (e.g., atrial and ventricular myocytes; purkinje tissue). Because the slope of phase 0 depends on the activation of fast sodium-channels and the rapid entry of sodium ions into the cell (Figure: Na+ in), blocking these channels decreases the slope of phase 0, which also leads to a decrease in the amplitude of the action potential. In contrast, nodal tissue action potentials (sinoatrial and atrioventricular nodes) do not depend on fast sodium channels for depolarization; instead, phase 0 depolarization is carried by calcium currents. Therefore, sodium-channel blockers have no direct effect on nodal tissue, at least through the blockade of fast sodium-channels.

The principal effect of reducing the rate and magnitude of depolarization by blocking sodium channels is a decrease in conduction velocity in non-nodal tissue (atrial and ventricular muscle, purkinje conducting system). The faster a cell depolarizes, the more rapidly adjacent cells will become depolarized, leading to a more rapid regeneration and transmission of action potentials between cells. Therefore, blocking sodium channels reduces the velocity of action potential transmission within the heart (reduced conduction velocity; negative dromotropy). This can serve as an important mechanism for suppressing tachycardias that are caused by abnormal conduction (e.g., reentry mechanisms). By depressing abnormal conduction, reentry mechanisms can be interrupted.

Effects on repolarization

Besides affecting phase 0 of action potentials, sodium-channel blockers may also alter the action potential duration (APD) and effective refractory period (ERP). Because some sodium-channel blockers increase the ERP (Class IA), while others decrease the ERP (Class IB) or have no effect on ERP (Class IC), the Vaughan-Williams classification recognizes these differences as subclasses of Class I antiarrhythmic drugs. These effects on ERP are not directly related to sodium channel blockade, but instead are related to drug actions on potassium channels involved in phase 3 repolarization of action potentials. These channels regulate potassium efflux from the cell (K+ out), and therefore repolarization. The drugs in these subclasses also differ in their efficacy for reducing the slope of phase 0, with IC drugs having the greatest and IB drugs having the smallest effect on phase 0 (IA drugs are intermediate in their effect on phase 0). The following summarize these differences:

Sodium-channel blockade:
   IC > IA > IB

Increasing the ERP:
   IA > IC > IB (decreases)

Increasing or decreasing the APD and ERP can either increase or decrease arrhythmogenesis, depending on the underlying cause of the arrhythmia. Increasing the ERP, for example, can interrupt tachycardia caused by reentry mechanisms by prolonging the duration that normal tissue is unexcitable (its refractory period). This can prevent reentry currents from re-exciting the tissue. On the other hand, increasing the APD can precipitate torsades de pointes, a type of ventricular tachycardia caused by afterdepolarizations.

Effects on automaticity

By mechanisms not understood and unrelated to blocking fast sodium channels, Class I antiarrhythmics can suppress abnormal automaticity by decreasing the slope of phase 4, which is generated by pacemaker currents.

Indirect vagal effects

The direct effect of Class IA antiarrhythmic drugs on action potentials is significantly modified by their anticholinergic actions. Inhibiting vagal activity can lead to both an increase in sinoatrial rate and atrioventricular conduction, which can offset the direct effects of the drugs on these tissues. Although a IA drug may effectively depress atrial rate during flutter, it can lead to an increase in ventricular rate because of an increase in the number of impulses conducted through the atrioventricular node (anticholinergic effect), thereby requiring concomitant treatment with a beta-blocker or calcium-channel blocker to slow AV nodal conduction. These anticholinergic actions are most prominent at the sinoatrial and atrioventricular nodes because they are extensively innervated by vagal efferent nerves. Different drugs within the IA subclass differ in their anticholinergic actions (see table below).

Specific Drugs and Therapeutic Indications

The following table summarizes Class I compounds in terms of their therapeutic use and some special or distinguishing characteristics. More detailed information on specific drugs can be found at www.rxlist.com.

Class IA:  atrial fibrillation, flutter; supraventricular & ventricular tachyarrhythmias
quinidine* anticholinergic (moderate) cinchonism (blurred vision, tinnitus, headache, psychosis); cramping and nausea; enhances digitalis toxicity
procainamide anticholinergic (weak); relatively short half-life lupus-like syndrome in 25-30% of patients
disopryamide anticholinergic (strong) negative inotropic effect
Class IB:  ventricular tachyarrhythmias (VT)
lidocaine* IV only; VT and PVCs good efficacy in ischemic myocardium
tocainide orally active lidocaine analog can cause pulmonary fibrosis
mexiletine orally active lidocaine analog good efficacy in ischemic myocardium
Class IC:  life-threatening supraventricular tachyarrhythmias (SVT) and ventricular tachyarrhythmias (VT)
flecainide* SVT can induce life-threatening VT
propafenone SVT & VT; β-blocking and Ca++-channel blocking activity can worsen heart failure
moricizine VT; IB activity  

* prototypical drug
Abbreviations: IV, intravenous; PVC, premature ventricular complex.

Side Effects and Contraindications

The anticholinergic effects of IA drugs can produce tachycardia, dry mouth, urinary retention, blurred vision and constipation. Diarrhea, nausea, headache and dizziness are also common side effects of many Class I drugs. Quinidine enhances digitalis toxicity, especially if hypokalemia is present. Quinidine, by delaying repolarization, can precipitate torsades de pointes (especially in patients with long-QT syndrome), a ventricular tachyarrhythmia caused by afterdepolarizations. Disopyramide is contraindicated for patients with uncompensated heart failure because of its negative inotropic actions; propafenone can also depress inotropy. IC compounds can cause increased risk of sudden death in patients with a prior history of myocardial infarction or sustained ventricular arrhythmias.

Revised 12/01/11

DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.