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Chapter: Basic & Clinical Pharmacology : Agents Used in Cardiac Arrhythmias

Electrophysiology of Normal Cardiac Rhythm

The electrical impulse that triggers a normal cardiac contrac-tion originates at regular inter vals in the sinoatrial (SA) node.


The electrical impulse that triggers a normal cardiac contrac-tion originates at regular inter vals in the sinoatrial (SA) node ( Figure 14–1), usually at a frequency of 60–100 bpm. This impulse spreads rapidly through the atria and enters the atrioventricular (AV) node, which is normally the only con-duction pathway between the atria and ventricles. Conduction through the AV node is slow, requiring about 0.15 seconds. (This delay provides time for atrial contraction to propel blood into the ventricles.) The impulse then propagates over the His-Purkinje system and invades all parts of the ventri-cles, beginning with the endocardial surface near the apex and ending with the epicardial surface at the base of the heart. Ventricular activation is complete in less than 0.1 seconds; therefore, contraction of all of the ventricular muscle is nor-mally synchronous and hemodynamically effective.

Arrhythmias consist of cardiac depolarizations that deviate from the above description in one or more aspects: there is an abnormality in the site of origin of the impulse, its rate or regularity, or its conduction.

Ionic Basis of Membrane Electrical Activity

The transmembrane potential of cardiac cells is determined by the concentrations of several ions—chiefly sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl)—on either side of the mem-brane and the permeability of the membrane to each ion. These water-soluble ions are unable to freely diffuse across the lipid cell membrane in response to their electrical and concentration gradi-ents; they require aqueous channels (specific pore-forming proteins) for such diffusion. Thus, ions move across cell membranes in response to their gradients only at specific times during the cardiac cycle when these ion channels are open. The movements of the ions produce currents that form the basis of the cardiac action potential. Individual channels are relatively ion-specific, and the flux of ions through them is controlled by “gates” (flexible portions of thepeptide chains that make up the channel proteins). Each type of channel has its own type of gate (sodium, calcium, and some potas-sium channels are each thought to have two types of gates). The channels primarily responsible for the cardiac action potential (sodium, calcium, and several potassium) are opened and closed (“gated”) by voltage changes across the cell membrane; that is, they are voltage-sensitive. Most are also modulated by ion concentra-tions and metabolic conditions, and some potassium channels are primarily ligand- rather than voltage-gated.

All the ionic currents that are currently thought to contribute to the cardiac action potential are illustrated in Figure 14–2. At rest, most cells are not significantly permeable to sodium, but at the start of each action potential, they become quite permeable . In electrophysiologic terms, the conductance of the fast sodium channel suddenly increases in response to a depolarizing stimulus. 

Similarly, calcium enters and potassium leaves the cell with each action potential. Therefore, in addition to ion channels, the cell must have mechanisms to maintain stable transmembrane ionic condi-tions by establishing and maintaining ion gradients. The most important of these active mechanisms is the sodium pump, Na+/ K+-ATPase. This pump and other active ion carriers contribute indirectly to the transmembrane potential by maintaining the gradients necessary for diffusion through channels. In addition, some pumps and exchangers produce net current flow (eg, by exchanging three Na+ for two K+ ions) and hence are termed “electrogenic.”

When the cardiac cell membrane becomes permeable to a spe-cific ion (ie, when the channels selective for that ion are open), movement of that ion across the cell membrane is determined by Ohm’s law: current = voltage ÷ resistance, or current = voltage × conductance. Conductance is determined by the properties of the individual ion channel protein. The voltage term is the difference between the actual membrane potential and the reversal potential for that ion (the membrane potential at which no current would flow even if channels were open). For example, in the case of sodium in a cardiac cell at rest, there is a substantial concentration gradient (140 mmol/L Na+ outside; 10–15 mmol/L Na+ inside) and an electrical gradient (0 mV outside; 90 mV inside) thatwould drive Na+ into cells. Sodium does not enter the cell at rest because sodium channels are closed; when sodium channels open, the very large influx of Na+ accounts for phase 0 depolarization of the action potential. The situation for K+ in the resting cardiac cell is quite different. Here, the concentration gradient (140 mmol/L inside; 4 mmol/L outside) would drive the ion out of the cell, but the electrical gradient would drive it in; that is, the inward gradi-ent is in equilibrium with the outward gradient. In fact, certain potassium channels (“inward rectifier” channels) are open in the resting cell, but little current flows through them because of this balance. The equilibrium, or reversal potential, for ions is deter-mined by the Nernst equation:

where Ce and Ci are the extracellular and intracellular concentra-tions, respectively, multiplied by their activity coefficients. Note that raising extracellular potassium makes EK less negative. When this occurs, the membrane depolarizes until the new EK is reached. Thus, extracellular potassium concentration and inward rectifier channel function are the major factors determining the membrane potential of the resting cardiac cell. The conditions required for application of the Nernst equation are approximated at the peak of the overshoot (using sodium concentrations) and during rest (using potassium concentrations) in most nonpacemaker cardiac cells. If the permeability is significant for both potassium and sodium, the Nernst equation is not a good predictor of membrane potential, but the Goldman-Hodgkin-Katz equation may be used:

In pacemaker cells (whether normal or ectopic), spontaneous depolarization (the pacemaker potential) occurs during diastole (phase 4, Figure 14–1). This depolarization results from a gradual increase of depolarizing current through special hyperpolarization-activated ion channels (If, also called Ih) in pacemaker cells. The effect of changing extracellular potassium is more complex in a pacemaker cell than it is in a nonpacemaker cell because the effect on permeability to potassium is much more important in a pace-maker (see Box: Effects of Potassium). In a pacemaker—especially an ectopic one—the end result of an increase in extracellular potassium is usually to slow or stop the pacemaker. Conversely, hypokalemia often facilitates ectopic pacemakers.

The Active Cell Membrane

In normal atrial, Purkinje, and ventricular cells, the action potential upstroke (phase 0) is dependent on sodium current. From a functional point of view, it is convenient to describe the behavior of the sodium current in terms of three channel states (Figure 14–3). The cardiac sodium channel protein has been cloned, and it is now recognized that these channel states actu-ally represent different protein conformations. In addition, regions of the protein that confer specific behaviors, such as volt-age sensing, pore formation, and inactivation, are now being identified. The gates described below and in Figure 14–3 repre-sent such regions.

Effects of Potassium

The effects of changes in serum potassium on cardiac action potential duration, pacemaker rate, and arrhythmias can appear somewhat paradoxical if changes are predicted based solely on a consideration of changes in the potassium electro-chemical gradient. In the heart, however, changes in serumpotassium concentration have the additional effect of alter-ing potassium conductance (increased extracellular potas-sium increases potassium conductance) independent of simple changes in electrochemical driving force, and this effect often predominates. As a result, the actual observed effects of hyperkalemia include reduced action potential duration, slowed conduction, decreased pacemaker rate, and decreased pacemaker arrhythmogenesis. Conversely, the actual observed effects of hypokalemia include prolonged action potential duration, increased pacemaker rate, and increased pacemaker arrhythmogenesis. Furthermore, pace-maker rate and arrhythmias involving ectopic pacemaker cells appear to be more sensitive to changes in serum potas-sium concentration, compared with cells of the sinoatrial node. These effects of serum potassium on the heart probably contribute to the observed increased sensitivity to potassium channel-blocking antiarrhythmic agents (quinidine or sotalol) during hypokalemia, eg, accentuated action potential prolon-gation and tendency to cause torsades de pointes.


Depolarization to the threshold voltage results in opening of the activation (m) gates of sodium channels (Figure 14–3, middle). If the inactivation (h) gates of these channels have not already closed, the channels are now open or activated, and sodium permeability is markedly increased, greatly exceed-ing the permeability for any other ion. Extracellular sodium therefore diffuses down its electrochemical gradient into the cell, and the membrane potential very rapidly approaches the sodium equilibrium potential, ENa (about +70 mV when Nae= 140 mmol/L and Nai= 10 mmol/L). This intense sodium current is very brief because opening of the m gates upon depolarization is promptly followed by closure of the h gates and inactivation of the sodium channels (Figure 14–3, right).

Most calcium channels become activated and inactivated in what appears to be the same way as sodium channels, but in the case of the most common type of cardiac calcium channel (the “L” type), the transitions occur more slowly and at more positive potentials. The action potential plateau (phases 1 and 2) reflects the turning off of most of the sodium current, the waxing and waning of calcium current, and the slow development of a repolar-izing potassium current.

Final repolarization (phase 3) of the action potential results from completion of sodium and calcium channel inactivation and the growth of potassium permeability, so that the membrane potential once again approaches the potassium equilibrium poten-tial. The major potassium currents involved in phase 3 repolariza-tion include a rapidly activating potassium current (IKr) and a slowly activating potassium current (IKs). These two potassium cur-rents are sometimes discussed together as “IK.” It is noteworthy that a different potassium current, distinct from IKr and IKs, may control repolarization in SA nodal cells. This explains why some drugs that block either IKr or IKs may prolong repolarization in Purkinje and ventricular cells, but have little effect on SA nodal repolarization (see Box: Molecular & Genetic Basis of Cardiac Arrhythmias).

The Effect of Resting Potential on Action Potentials

A key factor in the pathophysiology of arrhythmias and the actions of antiarrhythmic drugs is the relation between the resting potential of a cell and the action potentials that can be evoked in it (Figure 14–4, left panel). Because the inactivation gates of sodium channels in the resting membrane close over the potential range −75 to −55 mV, fewer sodium channels are “available” for diffusion of sodium ions when an action potential is evoked from a resting potential of −60 mV than when it is evoked from a resting potential of −80 mV. Important consequences of the reduction in peak sodium permeability include reduced maximum upstroke velocity (called Vmax, for maximum rate of change of membrane voltage), reduced action potential amplitude, reduced excitability, and reduced conduction velocity.

During the plateau of the action potential, most sodium chan-nels are inactivated. Upon repolarization, recovery from inactiva-tion takes place (in the terminology of Figure 14–3, the h gates reopen), making the channels again available for excitation. The time between phase 0 and sufficient recovery of sodium channels in phase 3 to permit a new propagated response to an external stimulus is the refractory period. Changes in refractoriness (determined by either altered recovery from inactivation or altered action potential duration) can be important in the genesis or sup-pression of certain arrhythmias. Another important effect of less negative resting potential is prolongation of this recovery time, as shown in Figure 14–4 (right panel). The prolongation of recovery time is reflected in an increase in the effective refractory period.

A brief, sudden, depolarizing stimulus, whether caused by a propagating action potential or by an external electrode arrangement, causes the opening of large numbers of activation gates before a significant number of inactivation gates can close. In contrast, slow reduction (depolarization) of the resting poten-tial, whether brought about by hyperkalemia, sodium pump blockade, or ischemic cell damage, results in depressed sodium currents during the upstrokes of action potentials. Depolarization of the resting potential to levels positive to −55 mV abolishes sodium currents, since all sodium channels are inactivated. However, such severely depolarized cells have been found to sup-port special action potentials under circumstances that increase calcium permeability or decrease potassium permeability. These “slow responses”—slow upstroke velocity and slow conduction— depend on a calcium inward current and constitute the normal electrical activity in the SA and AV nodes, since these tissues have a normal resting potential in the range of −50 to −70 mV. Slow responses may also be important for certain arrhythmias.

Modern techniques of molecular biology and electrophysiol-ogy can identify multiple subtypes of calcium and potassium channels. One way in which such subtypes may differ is in sensi-tivity to drug effects, so drugs targeting specific channel subtypes may be developed in the future.

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