A key factor in the pathophysiology of arrhythmias and the actions of antiarrhythmic agents is the relationship between the membrane potential and the effect it has on the ion channels responsible for excitability of the cell. During the plateau of atrial, ventricular, or Purkinje cell action potentials, most sodium channels are inactivated, rendering the cell refractory or inexcitable. Upon repolarization, recovery from inactivation takes place (in the terminology of Figure 14–3, the h gates reopen), making the channels available again for excitation. This is a timeand voltage-dependent process. The actual time required for enough sodium channels to recover from inactivation in order that a new propagated response can be generated is called the refractory period. Full recovery of excitability typically does not occur until action potential repolarization is complete. Thus, refractoriness or excitability can be affected by factors that alter either action potential duration or the resting membrane potential. This relationship can also be significantly impacted by certain classes of antiarrhythmic agents. One example is drugs that block sodium channels. They can reduce the extent and rate of recovery from inactivation (Figure 14–4). Changes in refractoriness caused by either altered recovery from inactivation or altered action potential duration can be important in the genesis or suppression of certain arrhythmias. A reduction in the number of available sodium channels can reduce excitability. In some cases, it may result in the cell being totally refractory or inexcitable. In other cases, there may be a reduction in peak sodium permeability. This can reduce the
Drug Control Drug Control Channels available, percent of maximumRecovery time constant (ms) 100 0 100,000 10,000 1000 100 10 0
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 repolarization 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.
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, all arrhythmias result from (1) disturbances in impulse formation and/or (2) disturbances in impulse conduction.
Disturbances of Impulse Formation