Page 247 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 14 Agents Used in Cardiac Arrhythmias 233

Channels available, percent of maximum 100 Drug Control Recovery time constant (ms) 100,000 Control

Drug

10,000

1000

100

0
–80
–100
–120
Resting membrane potential (mV)
Resting membrane potential (mV) –60 10 0 –120 –100 –80 –60
FIGURE 14–4 Dependence of sodium channel function on the membrane potential preceding the stimulus. Left: The fraction of sodium
channels available for opening in response to a stimulus is determined by the membrane potential immediately preceding the stimulus. The
decrease in the fraction available when the resting potential is depolarized in the absence of a drug (control curve) results from the voltage-
dependent closure of h gates in the channels. The curve labeled Drug illustrates the effect of a typical local anesthetic antiarrhythmic drug. Most
sodium channels are inactivated during the plateau of the action potential. Right: The time constant for recovery from inactivation after repo-
larization also depends on the resting potential. In the absence of drug, recovery occurs in less than 10 ms at normal resting potentials (−85 to
−95 mV). Depolarized cells recover more slowly (note logarithmic scale). In the presence of a sodium channel-blocking drug, the time constant
of recovery is increased, but the increase is far greater at depolarized potentials than at more negative ones.

maximum upstroke velocity of the action potential, which will in phase 3 of the action potential, or delayed afterdepolarizations
turn reduce action potential conduction velocity. (DADs), which occur during phase 4. EADs are usually triggered
In cells like those found in the SA and AV nodes, where excit- by factors that prolong action potential duration. When this pro-
ability is determined by the availability of calcium channels, excit- longation occurs in ventricular cells, there is often a corresponding
ability is most sensitive to drugs that block these channels. As a increase in the QT interval of the electrocardiogram (ECG). Such an
result, calcium channel blockers can decrease pacemaker activity
in the SA node as well as conduction velocity in the AV node.

Early afterdepolarization
MECHANISMS OF ARRHYTHMIAS 0 mV Prolonged (arises from the plateau)
plateau
Many factors can precipitate or exacerbate arrhythmias: ischemia,
hypoxia, acidosis or alkalosis, electrolyte abnormalities, excessive
catecholamine exposure, autonomic influences, drug toxicity (eg,
digitalis or antiarrhythmic drugs), overstretching of cardiac fibers,
and the presence of scarred or otherwise diseased tissue. However, –70
all arrhythmias result from (1) disturbances in impulse formation
and/or (2) disturbances in impulse conduction. 0.5 sec

Disturbances of Impulse Formation 0 mV
Delayed afterdepolarization
Pacemaking activity is regulated by both sympathetic and para- (arises from the resting
sympathetic activity (see above). Therefore, factors that antagonize potential)
or enhance these effects can alter normal impulse formation,
producing either bradycardia or tachycardia. Genetic mutations
have also been found to alter normal pacemaking activity.
Under certain circumstances, abnormal activity can be generated –70
by latent pacemakers, cells that show slow phase 4 depolarization
even under normal conditions (eg, Purkinje cells). Such cells are FIGURE 14–5 Two forms of abnormal activity, early (top) and
particularly prone to accelerated pacemaker activity, especially under delayed afterdepolarizations (bottom). In both cases, abnormal
conditions such as hypokalemia. Abnormalities in impulse formation depolarizations arise during or after a normally evoked action
can also be the result of afterdepolarizations (Figure 14–5). These can potential. They are therefore often referred to as “triggered” automaticity;
be either early afterdepolarizations (EADs), which occur during that is, they require a normal action potential for their initiation.