Page 250 - Basic _ Clinical Pharmacology ( PDFDrive )

236 SECTION III Cardiovascular-Renal Drugs

which cause an increase in extracellular potassium that partially abolish reentry may do so by further reducing excitability by
depolarizes the resting membrane potential, slowing sodium blocking sodium (Figure 14–4) or calcium channels, thus convert-
channel recovery from inactivation and prolonging the refractory ing an area of unidirectional block to bidirectional block. Drugs
period in the affected area. (3) Finally, conduction time around that block repolarizing potassium currents may also be effective in
the circuit must be long enough so that by the time the impulse converting a region of unidirectional block to bidirectional block
returns to the site after traveling around the obstacle, the tissue is by prolonging action potential duration, and thereby increasing
no longer refractory. In other words, conduction time around the the refractory period duration.
circuit must exceed the effective refractory period duration in the
area of unidirectional block. Representative ECGs of important
arrhythmias are shown in Figures 14–7 and 14–8. ■ BASIC PHARMACOLOGY OF
Unidirectional block can be caused by prolongation of refrac-
tory period duration due to depression of sodium channel activity THE ANTIARRHYTHMIC AGENTS
in atrial, ventricular, and Purkinje cells. In the AV node, it may
also be a result of depressed calcium channel activity. Drugs that Mechanisms of Action
Arrhythmias are caused by abnormal pacemaker activity or
abnormal impulse propagation. Thus, the aim of therapy of the
PR T arrhythmias is to reduce ectopic pacemaker activity and modify
Panel 1: aVF conduction or refractoriness in reentry circuits to disable circus
Normal movement. The major pharmacologic mechanisms currently
sinus
rhythm available for accomplishing these goals are (1) sodium channel
blockade, (2) blockade of sympathetic autonomic effects in the
heart, (3) prolongation of the effective refractory period, and
P' P' P' R P' P' P'
Panel 2: V 2 (4) calcium channel blockade.
Atrial Antiarrhythmic drugs decrease the automaticity of ectopic pace-
flutter makers more than that of the SA node. They also reduce conduc-
tion and excitability and increase the refractory period to a greater
S extent in depolarized tissue than in normally polarized tissue. This is
T T T
accomplished chiefly by selectively blocking the sodium or calcium
V 1
channels of depolarized cells (Figure 14–9). Therapeutically useful
channel-blocking drugs bind readily to activated channels (ie, dur-
ing phase 0) or inactivated channels (ie, during phase 2) but bind
Panel 3: Before digitalis poorly or not at all to rested channels. Therefore, these drugs block
Atrial S S S electrical activity when there is a fast tachycardia (many channel
fibrillation
V 1
activations and inactivations per unit time) or when there is sig-
nificant loss of resting potential (many inactivated channels during
rest). This type of drug action is often described as use-dependent
After digitalis or state-dependent; that is, channels that are being used frequently,
S S
R R R or are in an inactivated state, are more susceptible to block. Chan-
Panel 4: V 1 nels in normal cells that become blocked by a drug during normal
Ventricular activation-inactivation cycles will rapidly lose the drug from the
tachycardia
(starting at receptors during the resting portion of the cycle (Figure 14–9).
arrow) Channels in myocardium that is chronically depolarized (ie, has a
resting potential more positive than −75 mV) recover from block
very slowly if at all (see also right panel, Figure 14–4).
QS QS T T T In cells with abnormal automaticity, most of these drugs reduce
Panel 5: V 4 the phase 4 slope by blocking either sodium or calcium channels,
Ventricular thereby reducing the ratio of sodium (or calcium) permeability to
fibrillation
potassium permeability. As a result, the membrane potential dur-
ing phase 4 stabilizes closer to the potassium equilibrium poten-
tial. In addition, some agents may increase the threshold (make
FIGURE 14–7 Electrocardiograms of normal sinus rhythm and
some common arrhythmias. Major deflections (P, Q, R, S, and T) are it more positive). Beta-adrenoceptor-blocking drugs indirectly
labeled in each electrocardiographic record except in panel 5, in reduce the phase 4 slope by blocking the positive chronotropic
which electrical activity is completely disorganized and none of action of norepinephrine in the heart.
these deflections is recognizable. (Adapted, with permission, from Goldman In reentry arrhythmias, which depend on critically depressed
MJ: Principles of Clinical Electrocardiography, 11th ed. McGraw-Hill, 1982. Copyright © conduction, most antiarrhythmic agents slow conduction further
The McGraw-Hill Companies, Inc.) by one or both of two mechanisms: (1) steady-state reduction in