187-2017

DIGITALIS

Digoxin is indicated in patients with heart failure and atrial fibrillation. It is usually given only when diuretics and ACE inhibitors have failed to control symptoms. Only about 50% of patients with normal sinus rhythm (usually those with documented systolic dysfunction) will have relief of heart failure from digitalis. If the decision is made to use a cardiac glycoside, digoxin is the one chosen in most cases (and the only one available in the USA). When symptoms are mild, slow loading (digitalization) with 0.125–0.25 mg/d is safer and just as effective as the rapid method (0.5–0.75 mg every 8 hours for three doses, followed by 0.125–0.25 mg/d).

Determining the optimal level of digitalis effect may be difficult. Unfortunately, toxic effects may occur before therapeutic effects are detected. Measurement of plasma digoxin levels is useful in patients who appear unusually resistant or sensitive; a level of 1 ng/mL or less is appropriate; higher levels may be required in patients with atrial fibrillation.

Because it has a moderate but persistent positive inotropic effect, digitalis can, in theory, reverse all the signs and symptoms of heart failure. Although the net effect of the drug on mortality is mixed, it reduces hospitalization and deaths from progressive heart failure at the expense of an increase in sudden death. It is important to note that the mortality rate is reduced in patients with serum digoxin concentrations of less than 0.9 ng/mL but increased in those with digoxin levels greater than 1.5 ng/mL.

Other Clinical Uses of Digitalis

Digitalis is useful in the management of atrial arrhythmias because of its cardioselective parasympathomimetic effects. In atrial flutter and fibrillation, the depressant effect of the drug on atrioventricular conduction helps control an excessively high ventricular rate. Digitalis has also been used in the control of paroxysmal atrial and atrioventricular nodal tachycardia. At present, calcium channel blockers and adenosine are preferred for this application. Digoxin is explicitly contraindicated in patients with both Wolff-Parkinson- White syndrome and atrial fibrillation (see Chapter 14).

Toxicity

Despite its limited benefits and recognized hazards, digitalis is still often used inappropriately, and toxicity is common. Therapy for toxicity manifested as visual changes or gastrointestinal disturbances generally requires no more than reducing the dose of the drug. If cardiac arrhythmia is present, more vigorous therapy may be necessary. Serum digitalis level, potassium level, and the electrocardiogram should always be monitored during therapy of significant digitalis toxicity. Electrolytes should be monitored and corrected if abnormal. Digitalis-induced arrhythmias are frequently made worse by cardioversion; this therapy should be reserved for ventricular fibrillation if the arrhythmia is digitalis-induced.

In severe digitalis intoxication, serum potassium will already be elevated at the time of diagnosis (because of potassium loss from the intracellular compartment of skeletal muscle and other tissues). Automaticity is usually depressed, and antiarrhythmic agents may cause cardiac arrest. Treatment should include prompt insertion

of a temporary cardiac pacemaker and administration of digitalis antibodies (digoxin immune fab). These antibodies recognize cardiac glycosides from many plants in addition to digoxin. They are extremely useful in reversing severe intoxication with most glycosides. As noted previously, they may also be useful in eclampsia and preeclampsia.

CARDIAC RESYNCHRONIZATION & CARDIAC CONTRACTILITY MODULATION THERAPY

Patients with normal sinus rhythm and a wide QRS interval, eg, greater than 120 ms, have impaired synchronization of right and left ventricular contraction. Poor synchronization of ventricular contraction results in diminished cardiac output. Resynchronization, with left ventricular or biventricular pacing, has been shown to reduce mortality in patients with chronic heart failure who were already receiving optimal medical therapy. Because the immediate cause of death in severe heart failure is often an arrhythmia, a combined biventricular pacemaker/cardioverter-defibrillator is usually implanted.

Repeated application of a brief electric current through the myocardium during the QRS deflection of the electrocardiogram results in increased contractility, presumably by increasing Ca2+ release, in the intact heart. Preliminary clinical studies of this cardiac contractility modulation therapy are under way.

MANAGEMENT OF DIASTOLIC HEART FAILURE

Most clinical trials have been carried out in patients with systolic dysfunction, so the evidence regarding the superiority or inferiority of drugs in HFpEF is less extensive. Most authorities support the use of the drug groups described above (Table 13–4), and the SENIORS 2009 study suggests that the β blocker nebivolol is effective in both systolic and diastolic failure. Control of hypertension is particularly important, hyperlipidemia should be treated, and revascularization should be considered if coronary artery disease is present. ACE inhibitors and ARBs are useful. Atrial fibrillation is common in HFpEF, and rhythm control is desirable. Even in sinus rhythm, tachycardia limits filling time. Therefore, bradycardic drugs, eg, ivabradine, may be particularly useful, at least in theory.

MANAGEMENT OF ACUTE HEART FAILURE

Acute heart failure occurs frequently in patients with chronic failure. Such episodes are usually associated with increased exertion, emotion, excess salt intake, nonadherence to medical therapy, or increased metabolic demand occasioned by fever, anemia, etc. A particularly common and important cause of acute failure—with or without chronic failure—is acute myocardial infarction. Measurements of arterial pressure, cardiac output, stroke work index, and

pulmonary capillary wedge pressure are particularly useful in patients with acute myocardial infarction and acute heart failure. Patients with acute myocardial infarction are often treated with emergency revascularization using either coronary angioplasty and a stent, or a thrombolytic agent. Even with revascularization, acute failure may develop in such patients.

Intravenous treatment is the rule in drug therapy of acute heart failure. Among diuretics, furosemide is the most commonly used. Dopamine or dobutamine are positive inotropic drugs with prompt onset and short durations of action; they are most useful in patients with failure complicated by severe hypotension. Levosimendan has been approved for use in acute failure in Europe, and noninferiority has been demonstrated against dobutamine.

Vasodilators in use in patients with acute decompensation include nitroprusside, nitroglycerine, and nesiritide. Reduction in afterload often improves ejection fraction, but improved survival has not been documented. A small subset of patients in acute heart failure will have dilutional hyponatremia, presumably due to increased vasopressin activity. A V1a and V2 receptor antagonist, conivaptan, is approved for parenteral treatment of euvolemic hyponatremia. Some clinical trials have indicated that this drug and related V2 antagonists (tolvaptan) may have a beneficial effect in some patients with acute heart failure and hyponatremia. However, vasopressin antagonists do not seem to reduce mortality. Clinical trials are under way with the myosin activator, omecamtiv mecarbil.

P R E P A R A T I O N S

A V A I L A B L E

DIURETICS

(See Chapter 15)

DIGITALIS

Digoxin Generic, Lanoxin, Lanoxicaps

DIGITALIS ANTIBODY

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Bourge RC et al: Digoxin reduces 30-day all-cause hospital admission in older patients with chronic systolic heart failure. Am J Med 2013;126:701.

Braunwald E: Heart failure. J Am Coll Cardiol HF:Heart Failure 2013;1:1.

Cleland JCF et al: The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539.

Cleland JCF et al: The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: A double blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 2011;378:676.

Colucci WS: Pharmacologic therapy of heart failure with reduced ejection fraction. UpToDate, 2016. http://www.UpToDate.com.

Colucci WS: Treatment of acute decompensated heart failure. Components of therapy. UpToDate, 2016. http://www.UpToDate.com.

Elkayam U et al: Vasodilators in the management of acute heart failure. Crit Care Med 2008;36:S95.

Fitchett DH, Udell JA, Inzucchi SE: Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail 2017;19:43.

George M et al: Novel drug targets in clinical development for heart failure. Eur J Clin Pharmacol 2014;70:765.

Givertz MM et al: Acute decompensated heart failure: Update on new and emerging evidence and directions for future research. J Card Fail 2013;19:371.

Hasenfuss G, Teerlink JR: Cardiac inotropes: Current agents and future directions. Eur Heart J 2011;32:1838.

Lam GK et al: Digoxin antibody fragment, antigen binding (Fab), treatment of preeclampsia in women with endogenous digitalis-like factor: A secondary analysis of the DEEP Trial. Am J Obstet Gynecol 2013;209:119.

Lingrel JB: The physiological significance of the cardiotonic steroid/ouabainbinding site of the Na, K-ATPase. Annu Rev Physiol 2010;72:395.

Lother A, Hein L: Pharmacology of heart failure: From basic science to novel therapies. Pharmacol Ther 2016;166:136.

Malik FI et al: Cardiac myosin activation: A potential therapeutic approach for systolic heart failure. Science 2011;331:1439.

Marso SP et al: Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311.

Papi L et al: Unexpected double lethal oleander poisoning. Am J Forensic Med Pathol 2012;33:93.

Parry TJ et al: Effects of neuregulin GGF2 (cimaglermin alfa) dose and treatment frequency on left ventricular function in rats following myocardial infarction. Eur J Pharmacol 2017;796:76.

Ponikowski P et al: 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016;18:2129.

Pöss J, Link M, Böhm M: Pharmacological treatment of acute heart failure: Current treatment and new targets. Clin Pharmacol Ther 2013;94:499.

Redfield MM: Heart failure with preserved ejection fraction. N Engl J Med 2016;375:1868.

Seed A et al: Neurohumoral effects of the new orally active renin inhibitor, aliskiren, in chronic heart failure. Eur J Heart Fail 2007;9:1120.

Taur Y, Frishman WH: The cardiac ryanodine receptor (RyR2) and its role in heart disease. Cardiol Rev 2005;13:142.

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C A S E S T U D Y A N S W E R

The patient has a low ejection fraction with systolic heart failure, probably secondary to hypertension. His heart failure must be treated first, followed by careful control of the hypertension. He was initially treated with a diuretic (furosemide, 40 mg twice daily). On this therapy, he was less short of breath on exertion and could also lie flat without dyspnea. An angiotensin-converting enzyme (ACE) inhibitor was added (enalapril, 20 mg twice daily), and over the next few weeks, he continued to feel better. Because of

continued shortness of breath on exercise, digoxin at 0.25 mg/d was added with a further modest improvement in exercise tolerance. The blood pressure stabilized at 150/90 mm Hg, and the patient will be educated regarding the relation between his hypertension and heart failure and the need for better blood pressure control. Cautious addition of a β blocker (metoprolol) will be considered. Blood lipids, which are currently in the normal range, will be monitored.

C A S E S T U D Y

A 69-year-old retired teacher presents with a 1-month history of palpitations, intermittent shortness of breath, and fatigue. She has a history of hypertension. An electrocardiogram (ECG) shows atrial fibrillation with a ventricular response of 122 beats/min (bpm) and signs of left ventricular hypertrophy. She is anticoagulated with warfarin and started on sustainedrelease metoprolol, 50 mg/d. After 7 days, her rhythm reverts to normal sinus rhythm spontaneously. However, over the

Cardiac arrhythmias are a common problem in clinical practice, occurring in up to 25% of patients treated with digitalis, 50% of anesthetized patients, and over 80% of patients with acute myocardial infarction. Arrhythmias may require treatment because rhythms that are too rapid, too slow, or asynchronous can reduce cardiac output. Some arrhythmias can precipitate more serious or even lethal rhythm disturbances; for example, early premature ventricular depolarizations can precipitate ventricular fibrillation. In such patients, antiarrhythmic drugs may be lifesaving. On the other hand, the hazards of antiarrhythmic drugs—and in particular the fact that they can precipitate lethal arrhythmias in some patients—have led to a reevaluation of their relative risks and benefits. In general, treatment of asymptomatic or minimally symptomatic arrhythmias should be avoided for this reason.

Arrhythmias can be treated with the drugs discussed in this chapter and with nonpharmacologic therapies such as pacemakers, cardioversion, catheter ablation, and surgery. This chapter

The authors thank Joseph R. Hume, PhD, for his contributions to previous editions.

ensuing month, she continues to have intermittent palpitations and fatigue. Continuous ECG recording over a 48-hour period documents paroxysms of atrial fibrillation with heart rates of 88–114 bpm. An echocardiogram shows a left ventricular ejection fraction of 38% (normal ≥ 60%) with no localized wall motion abnormality. At this stage, would you initiate treatment with an antiarrhythmic drug to maintain normal sinus rhythm, and if so, what drug would you choose?

describes the pharmacology of drugs that suppress arrhythmias by a direct action on the cardiac cell membrane. Other modes of therapy are discussed briefly (see Box: The Nonpharmacologic Therapy of Cardiac Arrhythmias, later in the chapter).

ELECTROPHYSIOLOGY OF NORMAL CARDIAC RHYTHM

The electrical impulse that triggers a normal cardiac contraction originates at regular intervals 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 conduction 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 down the His-Purkinje system and invades all parts of the ventricles, beginning with the endocardial surface near the apex and ending with the epicardial surface at the base of the heart. Activation of the entire ventricular myocardium is complete

valve

Action potential phases

0:Upstroke

1:Early-fast repolarization

2:Plateau

3:Repolarization

4:Diastole

Phase 0

node

Atrium

node

0

mV

Purkinje

–100

Ventricle

ECG

200 ms

3

4

Overshoot

1

2

Phase

03

4

Resting potential

R

T

P

Q S

PR QT

in less than 0.1 second. As a result, ventricular contraction is synchronous and hemodynamically effective. Arrhythmias represent electrical activity that deviates from the above description as a result of an abnormality in impulse initiation and/or impulse propagation.

Ionic Basis of Membrane Electrical Activity

The electrical excitability of cardiac cells is a function of the unequal distribution of ions across the plasma membrane—chiefly sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl−)—and the relative permeability of the membrane to each ion. The gradients are generated by transport mechanisms that move these ions across the membrane against their concentration gradients. The most important of these transport mechanisms is the Na+/K+-ATPase, or sodium pump, described in Chapter 13. It is responsible for keeping the intracellular sodium concentration

low and the intracellular potassium concentration high relative to their respective extracellular concentrations. Other transport mechanisms maintain the gradients for calcium and chloride.

As a result of the unequal distribution, when the membrane becomes permeable to a given ion, that ion tends to move down its concentration gradient. However, because of its charged nature, ion movement is also affected by differences in the electrical charge across the membrane, or the transmembrane potential. The potential difference that is sufficient to offset or balance the concentration gradient of an ion is referred to the equilibrium potential (Eion) for that ion, and for a monovalent cation at physiologic temperature, it can be calculated by a modified version of the Nernst equation:

Eion = 61 × log Ce Ci

where Ce and Ci are the extracellular and intracellular ion concentrations, respectively. Thus, the movement of an ion across the membrane of a cell is a function of the difference between the transmembrane potential and the equilibrium potential. This is also known as the “electrochemical gradient” or “driving force.”

The relative permeability of the membrane to different ions determines the transmembrane potential. However, ions contributing to this potential difference are unable to freely diffuse across the lipid membrane of a cell. Their permeability relies on aqueous channels (specific pore-forming proteins). The ion channels that are thought to contribute to cardiac action potentials are illustrated in Figure 14–2. Most channels are relatively ion-specific, and the current generated by the flux of ions through them is controlled by “gates” (flexible portions of the peptide chains that make up the channel proteins). Sodium, calcium, and some potassium channels are thought to have two types of gates—one that opens or activates the channel and another that closes or inactivates the channel. For the majority of the channels responsible for the cardiac action potential, the movement of these gates is controlled by voltage changes across the cell membrane; that is, they are voltage-sensitive. However, certain channels are primarily ligandrather than voltage-gated. Furthermore, the activity of many voltage-gated ion channels can be modulated by a variety

of other factors, including permeant ion concentrations, tissue metabolic activity, and second messenger signaling pathways.

Pumps and exchangers that contribute indirectly to the membrane potential by creating ion gradients (as discussed above) can also contribute directly because of the current they generate through the unequal exchange of charged ions across the membrane. Such transporters are referred to as being “electrogenic.” An important example is the sodium-calcium exchanger (NCX). Throughout most of the cardiac action potential, this exchanger couples the movement of one calcium ion out of the cell for every three sodium ions that move in, thus generating a net inward or depolarizing current. Although this current is typically small during diastole, when intracellular calcium levels are low, spontaneous release of calcium from intracellular storage sites can generate a depolarizing current that contributes to pacemaker activity as well as arrhythmogenic events called delayed afterdepolarizations (see below).

The Active Cell Membrane

In atrial and ventricular cells, the diastolic membrane potential (phase 4) is typically very stable. This is because it is dominated by a potassium permeability or conductance that is due to the activity of channels that generate an inward-rectifying potassium current (IK1). This keeps the membrane potential near the potassium

Phase 4

Na+ current Ca2+ L-type current T-type

transient lto,f outward

current lto,s

delayed lKs rectifiers lKr (lK) lKur

lK,ACh lCl inward rectifier, lK1

pacemaker current, lf

Na+/Ca2+ exchange

Na+/K+-ATPase

Gene/protein

SCN5A/Nav 1.5

CACNA1/Cav 1.2

CACNA1G, H/Cav 3.1, 3.2

KCND3/Kv 4.3

KCNA4/Kv 1.4

KCNQ1/KvLQT 1

KCNH2/hERG

KCNA5/Kv 1.5

KCNJ3,5/Kir 3.1, 3.4

CFTR/CFTR

KCNJ2/Kir 2.1

HCN2,4/HCN2, 4

SLC8A1/NCX 1

NKAIN1-4/Na, K-pump

equilibrium potential, EK (about –90 mV when Ke = 5 mmol/L and Ki = 150 mmol/L). It also explains why small changes in extracellular potassium concentration have significant effects on the resting membrane potential of these cells. For example, increasing extracellular potassium shifts the equilibrium potential in a positive direction, causing depolarization of the resting membrane potential. It is important to note, however, that potassium is unique in that changes in the extracellular concentration can also affect the permeability of potassium channels, which can produce some nonintuitive effects (see Box: Effects of Potassium).

The upstroke (phase 0) of the action potential is due to the inward sodium current (INa). From a functional point of view, the behavior of the channels responsible for this current can be described in terms of three states (Figure 14–3). It is now recognized that these states actually represent different conformations of the channel protein. Depolarization of the membrane by an impulse propagating from adjacent cells results in opening of the activation (m) gates of sodium channels (Figure 14–3, middle), and sodium permeability is markedly increased. Extracellular sodium is then able to diffuse down its electrochemical gradient into the cell, causing the membrane potential to move very rapidly toward the sodium equilibrium potential, ENa (about +70 mV when Nae = 140 mmol/L and Nai = 10 mmol/L). As a result, the maximum upstroke velocity of the action potential is very fast. This intense influx of sodium is very brief because opening of the m gates upon depolarization is promptly followed by closure of the h gates and inactivation of these channels (Figure 14–3, right). This inactivation contributes to the early repolarization phase of the action potential (phase 1). In some cardiac myocytes, phase 1 is also due to a brief increase in

Effects of Potassium

Changes in serum potassium can have profound effects on electrical activity of the heart. An increase in serum potassium, or hyperkalemia, can depolarize the resting membrane potential due to changes in EK. If the depolarization is great enough, it can inactivate sodium channels, resulting in increased refractory period duration and slowed impulse propagation. Conversely, a decrease in serum potassium, or hypokalemia, can hyperpolarize the resting membrane potential. This can lead to an increase in pacemaker activity due to greater activation of pacemaker channels, especially in latent pacemakers (eg, Purkinje cells), which are more sensitive to changes in serum potassium than normal pacemaker cells.

If one only considers what happens to the potassium electrochemical gradient, changes in serum potassium can also produce effects that appear somewhat paradoxical, especially as they relate to action potential duration. This is because changes in serum potassium also affect the potassium conductance (increased potassium increases the conductance, decreased potassium decreases the conductance), and this effect often predominates. As a result, hyperkalemia can reduce action potential duration, and hypokalemia can prolong action potential duration. This effect of potassium probably contributes to the observed increase in sensitivity to potassium channel-blocking antiarrhythmic agents (quinidine or sotalol) during hypokalemia, resulting in accentuated action potential prolongation and a tendency to cause torsades de pointes arrhythmia.

potassium permeability due to the activity of channels generating transient outward currents.

Although a small fraction of the sodium channels activated during the upstroke may actually remain open well into the later phases of the action potential, sustained depolarization during the plateau (phase 2) is due primarily to the activity of calcium channels. Because the equilibrium potential for calcium, like sodium, is very positive, these channels generate a depolarizing inward current. Cardiac calcium channels activate and inactivate in what appears to be a manner similar to sodium channels, but in the case of the most common type of calcium channel (the “L” type), the transitions occur more slowly and at more positive potentials. After activation, these channels eventually inactivate and the permeability to potassium begins to increase, leading to final repolarization (phase 3) of the action potential. Two types of potassium channels are particularly important in phase 3 repolarization. They generate what are referred to as the rapidly activating (IKr) and slowly activating (IKs) delayed rectifier potassium currents. Repolarization, especially late in phase 3, is also aided by the inward rectifying potassium channels that are responsible for the resting membrane potential.

It is noteworthy that other delayed rectifier-type potassium currents also play important roles in repolarization of certain cardiac cell types. For example, the ultra-rapidly activating delayed rectifier potassium current (IKur) is particularly important in repolarizing the atrial action potential. The resting membrane potential and repolarization of atrial myocytes are also affected by potassium channels that are gated by the parasympathetic neurotransmitter acetylcholine.

Purkinje cells are similar to atrial and ventricular cells in that they generate an action potential with a fast upstroke due to the activity of sodium channels. However, unlike atrial and ventricular cells, the membrane potential during phase 4 exhibits spontaneous depolarization. This is due to the presence of pacemaker channels that generate an inward depolarizing pacemaker current. This is sometimes referred to as the “funny” current (If), because the channels involved have the unusual property of being activated by membrane hyperpolarization. Under some circumstances, Purkinje cells can act as pacemakers for the heart by spontaneously depolarizing and initiating an action potential that is then propagated throughout the ventricular myocardium. However, under normal conditions, the action potential in Purkinje cells is triggered by impulses that originate in the SA node and are conducted to these cells through the AV node.

Pacemaking activity in the SA node is due to spontaneous depolarization during phase 4 of the action potential as well (Figure 14–1). This diastolic depolarization is mediated in part by the activity of pacemaker channels. It is also thought to be due to the net inward current generated by the sodium-calcium exchanger, which is activated by the spontaneous release of calcium from intracellular storage sites. Unlike the action potential in Purkinje cells, spontaneous depolarization in the SA node triggers the upstroke of an action potential that is primarily due to an increase in permeability to calcium, not sodium. Because the calcium channels involved open or activate slowly, the maximum upstroke velocity of the action potential in SA node cells is

relatively slow. Repolarization occurs when the calcium channels subsequently close due to inactivation and delayed rectifier-type potassium channels open.

A similar process is involved in generating action potentials in the AV node. Although the intrinsic rate of spontaneous diastolic depolarization in the AV node is typically faster than that of Purkinje cells, it is still slower than the rate of depolarization in the SA node. Therefore, action potentials in the AV node are normally triggered by impulses that originate in the SA node and are conducted to the AV node through the atria. It is important to recognize that action potential upstroke velocity is a key determinant of impulse conduction velocity. Because the action potential upstroke in AV node cells is mediated by calcium channels, which open or activate relatively slowly, impulse conduction through the AV node is slow. This contributes to the delay between atrial and ventricular contraction.

Electrical activity in the SA node and AV node is significantly influenced by the autonomic nervous system (see Chapter 6). Sympathetic activation of β adrenoceptors speeds pacemaker activity in the SA node and impulse propagation through the AV node by enhancing pacemaker and calcium channel activity, respectively. Conversely, parasympathetic activation of muscarinic receptors slows pacemaker activity and conduction velocity by inhibiting the activity of these channels, as well as by increasing the potassium conductance by turning on acetylcholine-activated potassium channels.

The Effect of Membrane Potential on Excitability

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