Katzung Chapter 14 Agents Used in Cardiac Arrhythmias PDF

14 C H A P T E R Agents Used in Cardiac Arrhythmias Joseph R. Hume, PhD, & Augustu...

14 C H A P T E R Agents Used in Cardiac Arrhythmias Joseph R. Hume, PhD, & Augustus O. Grant, MD, PhD CASE STUDY A 69-year-old retired teacher presents with a 1-month ensuing month, she continues to have intermittent palpita- history of palpitations, intermittent shortness of breath, tions and fatigue. Continuous ECG recording over a 48-hour and fatigue. She has a history of hypertension. An ECG period documents paroxysms of atrial fibrillation with heart shows atrial fibrillation with a ventricular response of rates of 88–114 bpm. An echocardiogram shows a left ven- 122 bpm and signs of left ventricular hypertrophy. She is tricular ejection fraction of 38% with no localized wall anticoagulated with warfarin and started on sustained- motion abnormality. At this stage, would you initiate treat- release metoprolol 50 mg/d. After 7 days, her rhythm ment with an antiarrhythmic drug to maintain normal sinus reverts to normal sinus spontaneously. However, over the rhythm, and if so, what drug would you choose? Cardiac arrhythmias are a common problem in clinical prac- ELECTROPHYSIOLOGY OF NORMAL tice, occurring in up to 25% of patients treated with digitalis, 50% of anesthetized patients, and over 80% of patients with CARDIAC RHYTHM acute myocardial infarction. Arrhythmias may require treat- The electrical impulse that triggers a normal cardiac contrac- ment because rhythms that are too rapid, too slow, or asyn- tion originates at regular intervals in the sinoatrial (SA) chronous can reduce cardiac output. Some arrhythmias can node ( Figure 14–1), usually at a frequency of 60–100 bpm. precipitate more serious or even lethal rhythm disturbances; This impulse spreads rapidly through the atria and enters the for example, early premature ventricular depolarizations can atrioventricular (AV) node, which is normally the only con- precipitate ventricular fibrillation. In such patients, antiar- duction pathway between the atria and ventricles. Conduction rhythmic drugs may be lifesaving. On the other hand, the through the AV node is slow, requiring about 0.15 seconds. hazards of antiarrhythmic drugs—and in particular the fact (This delay provides time for atrial contraction to propel that they can precipitate lethal arrhythmias in some patients— blood into the ventricles.) The impulse then propagates over has led to a reevaluation of their relative risks and benefits. In the His-Purkinje system and invades all parts of the ventri- general, treatment of asymptomatic or minimally symptom- cles, beginning with the endocardial surface near the apex and atic arrhythmias should be avoided for this reason. ending with the epicardial surface at the base of the heart. Arrhythmias can be treated with the drugs discussed in this Ventricular activation is complete in less than 0.1 seconds; chapter and with nonpharmacologic therapies such as pacemakers, therefore, contraction of all of the ventricular muscle is nor- cardioversion, catheter ablation, and surgery. This chapter describes mally synchronous and hemodynamically effective. the pharmacology of drugs that suppress arrhythmias by a direct Arrhythmias consist of cardiac depolarizations that deviate from the action on the cardiac cell membrane. Other modes of therapy are above description in one or more aspects: there is an abnormality in the discussed briefly (see Box: The Nonpharmacologic Therapy of site of origin of the impulse, its rate or regularity, or its conduction. Cardiac Arrhythmias). 227 228 SECTION III Cardiovascular-Renal Drugs Superior vena cava Phase 0 3 SA node 4 Atrium AV node Overshoot 1 0 2 Phase 0 3 mV Purkinje 4 -100 Resting potential Tricuspid valve Mitral valve Action potential phases 0: Upstroke Ventricle 1: Early-fast repolarization 2: Plateau R 3: Repolarization 4: Diastole T ECG P Q S PR QT 200 ms FIGURE 14–1 Schematic representation of the heart and normal cardiac electrical activity (intracellular recordings from areas indicated and ECG). Sinoatrial (SA) node, atrioventricular (AV) node, and Purkinje cells display pacemaker activity (phase 4 depolarization). The ECG is the body surface manifestation of the depolarization and repolarization waves of the heart. The P wave is generated by atrial depolarization, the QRS by ventricular muscle depolarization, and the T wave by ventricular repolarization. Thus, the PR interval is a measure of conduction time from atrium to ventricle, and the QRS duration indicates the time required for all of the ventricular cells to be activated (ie, the intraventricular conduction time). The QT interval reflects the duration of the ventricular action potential. Ionic Basis of Membrane Electrical Activity peptide chains that make up the channel proteins). Each type of The transmembrane potential of cardiac cells is determined by the channel has its own type of gate (sodium, calcium, and some potas- + concentrations of several ions—chiefly sodium (Na ), potassium sium channels are each thought to have two types of gates). The + 2+ – (K ), calcium (Ca ), and chloride (Cl )—on either side of the mem- channels primarily responsible for the cardiac action potential brane and the permeability of the membrane to each ion. These (sodium, calcium, and several potassium) are opened and closed water-soluble ions are unable to freely diffuse across the lipid cell (“gated”) by voltage changes across the cell membrane; that is, they membrane in response to their electrical and concentration gradi- are voltage-sensitive. Most are also modulated by ion concentra- ents; they require aqueous channels (specific pore-forming proteins) tions and metabolic conditions, and some potassium channels are for such diffusion. Thus, ions move across cell membranes in primarily ligand- rather than voltage-gated. response to their gradients only at specific times during the cardiac All the ionic currents that are currently thought to contribute to cycle when these ion channels are open. The movements of the ions the cardiac action potential are illustrated in Figure 14–2. At rest, produce currents that form the basis of the cardiac action potential. most cells are not significantly permeable to sodium, but at the start Individual channels are relatively ion-specific, and the flux of ions of each action potential, they become quite permeable (see below). through them is controlled by “gates” (flexible portions of the In electrophysiologic terms, the conductance of the fast sodium  CHAPTER 14 Agents Used in Cardiac Arrhythmias 229 1 2 inward outward 0 3 Phase 4 Gene/protein Na+ current SCN5A/Nav 1.5 L-type CACNA1/Cav 1.2 Ca2+ current T-type CACNA1G,1/Cav 3.1, 3.2 transient lTO1 KCND3/ Kv 4.3 outward lTO2 KCNA4/ Kv 1.4 current lKs KCNA1/ KvLQT 1 delayed rectifiers lKr KCNH2/ hERG (lK) lKur KCNA5/ Kv 1.5 lKP lCl CFTR/CFTR inward rectifier, lK1 KCNJ1/Kir 2.1 pacemaker current, lf HCN2, 4/HCN2, 4 Na+/Ca2+ exchange SLC8A1/NCX 1 Na+/K+-ATPase NKAIN1-4/Na, K-pump FIGURE 14–2 Schematic diagram of the ion permeability changes and transport processes that occur during an action potential and the diastolic period following it. Yellow indicates inward (depolarizing) membrane currents; blue indicates outward (repolarizing) membrane cur- rents. Multiple subtypes of potassium and calcium currents, with different sensitivities to blocking drugs, have been identified. The right side of the figure lists the genes and proteins responsible for each type of channel or transporter. channel suddenly increases in response to a depolarizing stimulus. would drive Na+ into cells. Sodium does not enter the cell at rest Similarly, calcium enters and potassium leaves the cell with each because sodium channels are closed; when sodium channels open, + action potential. Therefore, in addition to ion channels, the cell must the very large influx of Na accounts for phase 0 depolarization of have mechanisms to maintain stable transmembrane ionic condi- the action potential. The situation for K+ in the resting cardiac cell tions by establishing and maintaining ion gradients. The most is quite different. Here, the concentration gradient (140 mmol/L important of these active mechanisms is the sodium pump, Na+/ inside; 4 mmol/L outside) would drive the ion out of the cell, but + K -ATPase, described in Chapter 13. This pump and other active the electrical gradient would drive it in; that is, the inward gradi- ion carriers contribute indirectly to the transmembrane potential by ent is in equilibrium with the outward gradient. In fact, certain maintaining the gradients necessary for diffusion through channels. potassium channels (“inward rectifier” channels) are open in the In addition, some pumps and exchangers produce net current flow resting cell, but little current flows through them because of this (eg, by exchanging three Na+ for two K+ ions) and hence are termed balance. The equilibrium, or reversal potential, for ions is deter- “electrogenic.” mined by the Nernst equation: When the cardiac cell membrane becomes permeable to a spe- cific ion (ie, when the channels selective for that ion are open), Ce Eion = 61 × log movement of that ion across the cell membrane is determined by Ci Ohm’s law: current = voltage ÷ resistance, or current = voltage × conductance. Conductance is determined by the properties of the where Ce and Ci are the extracellular and intracellular concentra- individual ion channel protein. The voltage term is the difference tions, respectively, multiplied by their activity coefficients. Note between the actual membrane potential and the reversal potential that raising extracellular potassium makes EK less negative. When for that ion (the membrane potential at which no current would this occurs, the membrane depolarizes until the new EK is reached. flow even if channels were open). For example, in the case of Thus, extracellular potassium concentration and inward rectifier sodium in a cardiac cell at rest, there is a substantial concentration channel function are the major factors determining the membrane + + gradient (140 mmol/L Na outside; 10–15 mmol/L Na inside) potential of the resting cardiac cell. The conditions required for and an electrical gradient (0 mV outside; −90 mV inside) that application of the Nernst equation are approximated at the peak of 230 SECTION III Cardiovascular-Renal Drugs the overshoot (using sodium concentrations) and during rest (using potassium concentrations) in most nonpacemaker cardiac cells. If Effects of Potassium the permeability is significant for both potassium and sodium, the Nernst equation is not a good predictor of membrane potential, The effects of changes in serum potassium on cardiac action but the Goldman-Hodgkin-Katz equation may be used: 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- PK × Ke + PNa × Nae Emem = 61 × log chemical gradient. In the heart, however, changes in serum PK × Ki + PNa × Nai potassium concentration have the additional effect of alter- ing potassium conductance (increased extracellular potas- In pacemaker cells (whether normal or ectopic), spontaneous sium increases potassium conductance) independent of depolarization (the pacemaker potential) occurs during diastole simple changes in electrochemical driving force, and this (phase 4, Figure 14–1). This depolarization results from a gradual effect often predominates. As a result, the actual observed increase of depolarizing current through special hyperpolarization- effects of hyperkalemia include reduced action potential activated ion channels (If, also called Ih) in pacemaker cells. The duration, slowed conduction, decreased pacemaker rate, and effect of changing extracellular potassium is more complex in a decreased pacemaker arrhythmogenesis. Conversely, the pacemaker cell than it is in a nonpacemaker cell because the effect actual observed effects of hypokalemia include prolonged on permeability to potassium is much more important in a pace- action potential duration, increased pacemaker rate, and maker (see Box: Effects of Potassium). In a pacemaker—especially increased pacemaker arrhythmogenesis. Furthermore, pace- an ectopic one—the end result of an increase in extracellular maker rate and arrhythmias involving ectopic pacemaker potassium is usually to slow or stop the pacemaker. Conversely, cells appear to be more sensitive to changes in serum potas- hypokalemia often facilitates ectopic pacemakers. sium concentration, compared with cells of the sinoatrial node. These effects of serum potassium on the heart probably The Active Cell Membrane contribute to the observed increased sensitivity to potassium In normal atrial, Purkinje, and ventricular cells, the action channel-blocking antiarrhythmic agents (quinidine or sotalol) potential upstroke (phase 0) is dependent on sodium current. during hypokalemia, eg, accentuated action potential prolon- From a functional point of view, it is convenient to describe the gation and tendency to cause torsades de pointes. behavior of the sodium current in terms of three channel states (Figure 14–3). The cardiac sodium channel protein has been Resting Activated Inactivated Extracellular Na+ Na+ Na+ + + + m m m m m m + h Intracellular + h h potential (mV) 40 40 40 Membrane 0 0 0 -40 -40 -40 Threshold -60 -60 -60 Recovery + FIGURE 14–3 A schematic representation of Na channels cycling through different conformational states during the cardiac action potential. Transitions between resting, activated, and inactivated states are dependent on membrane potential and time. The activation gate is shown as m and the inactivation gate as h. Potentials typical for each state are shown under each channel schematic as a function of time. The dashed line indicates that part of the action potential during which most Na+ channels are completely or partially inactivated and unavailable for reactivation.  CHAPTER 14 Agents Used in Cardiac Arrhythmias 231. cloned, and it is now recognized that these channel states actu- velocity (called Vmax, for maximum rate of change of membrane ally represent different protein conformations. In addition, voltage), reduced action potential amplitude, reduced excitability, regions of the protein that confer specific behaviors, such as volt- and reduced conduction velocity. age sensing, pore formation, and inactivation, are now being During the plateau of the action potential, most sodium chan- identified. The gates described below and in Figure 14–3 repre- nels are inactivated. Upon repolarization, recovery from inactiva- sent such regions. tion takes place (in the terminology of Figure 14–3, the h gates Depolarization to the threshold voltage results in opening of reopen), making the channels again available for excitation. The the activation (m) gates of sodium channels (Figure 14–3, time between phase 0 and sufficient recovery of sodium channels middle). If the inactivation (h) gates of these channels have in phase 3 to permit a new propagated response to an external not already closed, the channels are now open or activated, stimulus is the refractory period. Changes in refractoriness and sodium permeability is markedly increased, greatly exceed- (determined by either altered recovery from inactivation or altered ing the permeability for any other ion. Extracellular sodium action potential duration) can be important in the genesis or sup- therefore diffuses down its electrochemical gradient into the pression of certain arrhythmias. Another important effect of less cell, and the membrane potential very rapidly approaches negative resting potential is prolongation of this recovery time, as the sodium equilibrium potential, ENa (about +70 mV when shown in Figure 14–4 (right panel). The prolongation of recovery Nae = 140 mmol/L and Nai = 10 mmol/L). This intense time is reflected in an increase in the effective refractory period. sodium current is very brief because opening of the m gates upon A brief, sudden, depolarizing stimulus, whether caused by depolarization is promptly followed by closure of the h gates and a propagating action potential or by an external electrode inactivation of the sodium channels (Figure 14–3, right). arrangement, causes the opening of large numbers of activation Most calcium channels become activated and inactivated in gates before a significant number of inactivation gates can close. what appears to be the same way as sodium channels, but in the In contrast, slow reduction (depolarization) of the resting poten- case of the most common type of cardiac calcium channel (the “L” tial, whether brought about by hyperkalemia, sodium pump type), the transitions occur more slowly and at more positive blockade, or ischemic cell damage, results in depressed sodium potentials. The action potential plateau (phases 1 and 2) reflects currents during the upstrokes of action potentials. Depolarization the turning off of most of the sodium current, the waxing and of the resting potential to levels positive to −55 mV abolishes waning of calcium current, and the slow development of a repolar- sodium currents, since all sodium channels are inactivated. izing potassium current. However, such severely depolarized cells have been found to sup- Final repolarization (phase 3) of the action potential results port special action potentials under circumstances that increase from completion of sodium and calcium channel inactivation and calcium permeability or decrease potassium permeability. These the growth of potassium permeability, so that the membrane “slow responses”—slow upstroke velocity and slow conduction— potential once again approaches the potassium equilibrium poten- depend on a calcium inward current and constitute the normal tial. The major potassium currents involved in phase 3 repolariza- electrical activity in the SA and AV nodes, since these tissues tion include a rapidly activating potassium current (IKr) and a have a normal resting potential in the range of −50 to −70 mV. slowly activating potassium current (IKs). These two potassium cur- Slow responses may also be important for certain arrhythmias. rents are sometimes discussed together as “IK.” It is noteworthy that Modern techniques of molecular biology and electrophysiol- a different potassium current, distinct from IKr and IKs, may control ogy can identify multiple subtypes of calcium and potassium repolarization in SA nodal cells. This explains why some drugs that channels. One way in which such subtypes may differ is in sensi- block either IKr or IKs may prolong repolarization in Purkinje and tivity to drug effects, so drugs targeting specific channel subtypes ventricular cells, but have little effect on SA nodal repolarization may be developed in the future. (see Box: Molecular & Genetic Basis of Cardiac Arrhythmias). MECHANISMS OF ARRHYTHMIAS The Effect of Resting Potential Many factors can precipitate or exacerbate arrhythmias: ischemia, on Action Potentials hypoxia, acidosis or alkalosis, electrolyte abnormalities, excessive catecholamine exposure, autonomic influences, drug toxicity (eg, A key factor in the pathophysiology of arrhythmias and the digitalis or antiarrhythmic drugs), overstretching of cardiac fibers, actions of antiarrhythmic drugs is the relation between the resting and the presence of scarred or otherwise diseased tissue. However, all potential of a cell and the action potentials that can be evoked in arrhythmias result from (1) disturbances in impulse formation, (2) it (Figure 14–4, left panel). Because the inactivation gates of disturbances in impulse conduction, or (3) both. 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 Disturbances of Impulse Formation a resting potential of −60 mV than when it is evoked from a resting The interval between depolarizations of a pacemaker cell is the potential of −80 mV. Important consequences of the reduction in sum of the duration of the action potential and the duration of the peak sodium permeability include reduced maximum upstroke diastolic interval. Shortening of either duration results in an 232 SECTION III Cardiovascular-Renal Drugs Molecular & Genetic Basis of Cardiac Arrhythmias It is now possible to define the molecular basis of several congenital the LQT syndromes now raises the possibility that specific therapies and acquired cardiac arrhythmias. The best example is the polymor- may be developed for individuals with defined molecular abnor- phic ventricular tachycardia known as torsades de pointes (shown in malities. Indeed, preliminary reports suggest that the sodium chan- Figure 14–8), which is associated with prolongation of the QT interval nel blocker mexiletine can correct the clinical manifestations of (especially at the onset of the tachycardia), syncope, and sudden congenital LQT subtype 3 syndrome. It is likely that torsades de death. This must represent prolongation of the action potential of at pointes originates from triggered upstrokes arising from early after- least some ventricular cells (Figure 14–1). The effect can, in theory, be depolarizations (Figure 14–5). Thus, therapy is directed at correcting attributed to either increased inward current (gain of function) or hypokalemia, eliminating triggered upstrokes (eg, by using β block- decreased outward current (loss of function) during the plateau of ers or magnesium), or shortening the action potential (eg, by the action potential. In fact, recent molecular genetic studies have increasing heart rate with isoproterenol or pacing)—or all of these. identified up to 300 different mutations in at least eight ion channel The molecular basis of several other congenital cardiac arrhyth- genes that produce the congenital long QT (LQT) syndrome mias associated with sudden death has also recently been identi- ( Table 14–1), and different mutations may have different clinical fied. Three forms of short QT syndrome have been identified that implications. Loss-of-function mutations in potassium channel genes are linked to gain-of-function mutations in three different potas- produce decreases in outward repolarizing current and are respon- sium channel genes (KCNH2, KCNQ1, and KCNJ2). Catecholaminergic sible for LQT subtypes 1, 2, 5, 6, and 7. HERG and KCNE2 (MiRP1) genes polymorphic ventricular tachycardia, a disease that is characterized encode subunits of the rapid delayed rectifier potassium current (IKr), by stress- or emotion-induced syncope, can be caused by genetic whereas KCNQ1 and KCNE1 (minK) encode subunits of the slow mutations in two different proteins in the sarcoplasmic reticulum delayed rectifier potassium current (IKs). KCNJ2 encodes an inwardly that control intracellular calcium homeostasis. Mutations in two rectifying potassium current (IKir). In contrast, gain-of-function muta- different ion channel genes (HCN4 and SCN5A) have been linked to tions in the sodium channel gene (SCN5A) or calcium channel gene congenital forms of sick sinus syndrome. The Brugada syndrome, (CACNA1c) cause increases in inward plateau current and are respon- which is characterized by ventricular fibrillation associated with sible for LQT subtypes 3 and 8, respectively. persistent ST-segment elevation, and progressive cardiac conduc- Molecular genetic studies have identified the reason why con- tion disorder (PCCD), characterized by impaired conduction in the genital and acquired cases of torsades de pointes can be so strik- His-Purkinje system and right or left bundle block leading to com- ingly similar. The potassium channel IKr (encoded by HERG) is plete atrioventricular block, have both been linked to several loss- blocked or modified by many drugs (eg, quinidine, sotalol) or elec- of-function mutations in the sodium channel gene, SCN5A. At least trolyte abnormalities (hypokalemia, hypomagnesemia, hypocalce- one form of familial atrial fibrillation is caused by a gain-of-function mia) that also produce torsades de pointes. Thus, the identification mutation in the potassium channel gene, KCNQ1. of the precise molecular mechanisms underlying various forms of Channels available, percent of maximum Recovery time constant (ms) 100,000 Drug 100 10,000 Control 1000 100 Drug Control 10 0 0 –120 –100 –80 –60 –120 –100 –80 –60 Resting membrane potential (mV) Resting membrane potential (mV) 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 poten- tials (−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.  CHAPTER 14 Agents Used in Cardiac Arrhythmias 233 TABLE 14–1 Molecular and genetic basis of some cardiac arrhythmias. Chromosome Ion Channel or Type Involved Defective Gene Proteins Affected Result LQT-1 11 KCNQ1 IKs LF LQT-2 7 KCNH2 (HERG) IKr LF LQT-3 3 SCN5A INa GF 1 LQT-4 4 Ankyrin-B LF LQT-5 21 KCNE1 (minK) IKs LF LQT-6 21 KCNE2 (MiRP1) IKr LF 2 LQT-7 17 KCNJ2 IKir LF 3 LQT-8 12 CACNA1c ICa GF SQT-1 7 KCNH2 IKr GF SQT-2 11 KCNQ1 IKs GF SQT-3 17 KCNJ2 IKir GF 4 CPVT-1 1 hRyR2 Ryanodine receptor GF CPVT-2 1 CASQ2 Calsequestrin LF 5 Sick sinus syndrome 15 or 3 HCN4 or SCN5A LF Brugada syndrome 3 SCN5A INa LF PCCD 3 SCN5A INa LF Familial atrial fibrillation 11 KCNQ1 IKs GF 1 + + + + Ankyrins are intracellular proteins that associate with a variety of transport proteins including Na channels, Na /K -ATPase, Na , Ca exchange, and Ca2+ release channels. 2+ 2 Also known as Andersen syndrome. 3 Also known as Timothy syndrome; multiple organ dysfunction, including autism. 4 2+ 2+ CPVT, catecholaminergic polymorphic ventricular tachycardia; mutations in intracellular ryanodine Ca release channel or the Ca buffer protein, calsequestrin, may result in 2+ 2+ enhanced sarcoplasmic reticulum Ca leakage or enhanced Ca release during adrenergic stimulation, causing triggered arrhythmogenesis. 5 HCN4 encodes a pacemaker current in sinoatrial nodal cells; mutations in sodium channel gene (SCN5A) cause conduction defects. GF, gain of function; LF, loss of function; LQT, long QT syndrome; PCCD, progressive cardiac conduction disorder; SQT, short QT syndrome. increase in pacemaker rate. The more important of the two, dia- Molecular & Genetic Basis of Cardiac Arrhythmias). DADs, on stolic interval, is determined primarily by the slope of phase the other hand, often occur when intracellular calcium is increased 4 depolarization (pacemaker potential). Vagal discharge and (see Chapter 13). They are exacerbated by fast heart rates and are β-receptor–blocking drugs slow normal pacemaker rate by reduc- thought to be responsible for some arrhythmias related to digitalis ing the phase 4 slope (acetylcholine also makes the maximum excess, to catecholamines, and to myocardial ischemia. diastolic potential more negative). Acceleration of pacemaker dis- charge is often brought about by increased phase 4 depolarization slope, which can be caused by hypokalemia, β-adrenoceptor Disturbances of Impulse Conduction stimulation, positive chronotropic drugs, fiber stretch, acidosis, Severely depressed conduction may result in simple block, eg, AV and partial depolarization by currents of injury. nodal block or bundle branch block. Because parasympathetic con- Latent pacemakers (cells that show slow phase 4 depolarization trol of AV conduction is significant, partial AV block is sometimes even under normal conditions, eg, some Purkinje fibers) are par- relieved by atropine. Another common abnormality of conduction ticularly prone to acceleration by the above mechanisms. However, is reentry (also known as “circus movement”), in which one all cardiac cells, including normally quiescent atrial and ventricu- impulse reenters and excites areas of the heart more than once lar cells, may show repetitive pacemaker activity when depolarized (Figure 14–6). under appropriate conditions, especially if hypokalemia is also The path of the reentering impulse may be confined to very small present. areas, eg, within or near the AV node, or it may involve large portions Afterdepolarizations (Figure 14–5) are transient depolariza- of the atrial or ventricular walls. Some forms of reentry are strictly tions that interrupt phase 3 (early afterdepolarizations, EADs) anatomically determined; for example, in Wolff-Parkinson-White or phase 4 (delayed afterdepolarizations, DADs). EADs are usu- syndrome, the reentry circuit consists of atrial tissue, the AV node, ally exacerbated at slow heart rates and are thought to contribute ventricular tissue, and an accessory AV connection (bundle of Kent, to the development of long QT-related arrhythmias (see Box: a bypass tract). In other cases (eg, atrial or ventricular fibrillation), 234 SECTION III Cardiovascular-Renal Drugs round trips through the pathway the reentrant impulse makes before Early afterdepolarization dying out, the arrhythmia may be manifest as one or a few extra beats Prolonged (arises from the plateau) 0 mV plateau or as a sustained tachycardia. For reentry to occur, three conditions must coexist, as indi- cated in Figure 14–6. (1) There must be an obstacle (anatomic or physiologic) to homogeneous conduction, thus establishing a circuit around which the reentrant wavefront can propagate. (2) There must be unidirectional block at some point in the –70 circuit; that is, conduction must die out in one direction but continue in the opposite direction (as shown in Figure 14–6, the 0.5 sec impulse can gradually decrease as it invades progressively more depolarized tissue until it finally blocks—a process known as dec- 0 mV remental conduction). (3) Conduction time around the circuit Delayed afterdepolarization (arises from the resting must be long enough that the retrograde impulse does not enter potential) refractory tissue as it travels around the obstacle; that is, the con- duction time must exceed the effective refractory period. It is important to note that reentry depends on conduction that has been depressed by some critical amount, usually as a result of –70 injury or ischemia. If conduction velocity is too slow, bidirectional block rather than unidirectional block occurs; if the reentering FIGURE 14–5 Two forms of abnormal activity, early (top) and impulse is too weak, conduction may fail, or the impulse may delayed afterdepolarizations (bottom). In both cases, abnormal arrive so late that it collides with the next regular impulse. On the depolarizations arise during or after a normally evoked action poten- other hand, if conduction is too rapid—ie, almost normal—bidi- tial. They are therefore often referred to as “triggered” automaticity; rectional conduction rather than unidirectional block will occur. that is, they require a normal action potential for their initiation. Even in the presence of unidirectional block, if the impulse travels around the obstacle too rapidly, it will reach tissue that is still refractory. Representative electrocardiograms of important arrhyth- multiple reentry circuits, determined by the varying properties of the mias are shown in Figures 14–7 and 14–8. cardiac tissue, may meander through the heart in apparently random Slowing of conduction may be due to depression of sodium paths. The circulating impulse often gives off “daughter impulses” current, depression of calcium current (the latter especially in the that can spread to the rest of the heart. Depending on how many AV node), or both. Drugs that abolish reentry usually work by Forward impulse Retrograde obstructed and extinguished impulse Purkinje twig Depressed region A. Normal conduction B. Unidirectional block FIGURE 14–6 Schematic diagram of a reentry circuit that might occur in small bifurcating branches of the Purkinje system where they enter the ventricular wall. A: Normally, electrical excitation branches around the circuit, is transmitted to the ventricular branches, and becomes extinguished at the other end of the circuit due to collision of impulses. B: An area of unidirectional block develops in one of the branches, pre- venting anterograde impulse transmission at the site of block, but the retrograde impulse may be propagated through the site of block if the impulse finds excitable tissue; that is, the refractory period is shorter than the conduction time. This impulse then reexcites tissue it had previ- ously passed through, and a reentry arrhythmia is established.  CHAPTER 14 Agents Used in Cardiac Arrhythmias 235 Panel 1: aVF P R T BASIC PHARMACOLOGY OF Normal sinus THE ANTIARRHYTHMIC AGENTS rhythm Mechanisms of Action P' P' P' R P' P' P' Panel 2: Arrhythmias are caused by abnormal pacemaker activity or abnor- V2 Atrial mal impulse propagation. Thus, the aim of therapy of the arrhyth- flutter mias is to reduce ectopic pacemaker activity and modify conduction or refractoriness in reentry circuits to disable circus movement. S The major pharmacologic mechanisms currently available for T T T accomplishing these goals are (1) sodium channel blockade, (2) V1 blockade of sympathetic autonomic effects in the heart, (3) pro- longation of the effective refractory period, and (4) calcium chan- nel blockade. Panel 3: Before digitalis Antiarrhythmic drugs decrease the automaticity of ectopic pace- Atrial S S S makers more than that of the SA node. They also reduce conduction fibrillation V 1 and excitability and increase the refractory period to a greater extent in depolarized tissue than in normally polarized tissue. This is accomplished chiefly by selectively blocking the sodium or calcium After digitalis channels of depolarized cells (Figure 14–9). Therapeutically useful S S channel-blocking drugs bind readily to activated channels (ie, dur- R R R Panel 4: V1 ing phase 0) or inactivated channels (ie, during phase 2) but bind Ventricular poorly or not at all to rested channels. Therefore, these drugs block tachycardia (starting at electrical activity when there is a fast tachycardia (many channel arrow) activations and inactivations per unit time) or when there is signifi- cant loss of resting potential (many inactivated channels during rest). This type of drug action is often described as use-dependent QS QS T T T or state-dependent; that is, channels that are being used frequently, Panel 5: V4 or in an inactivated state, are more susceptible to block. Channels Ventricular in normal cells that become blocked by a drug during normal fibrillation activation-inactivation cycles will rapidly lose the drug from the receptors during the resting portion of the cycle (Figure 14–9). Channels in myocardium that is chronically depolarized (ie, has a FIGURE 14–7 Electrocardiograms of normal sinus rhythm and some common arrhythmias. Major deflections (P, Q, R, S, and T) are resting potential more positive than −75 mV) recover from block labeled in each electrocardiographic record except in panel 5, in very slowly if at all (see also right panel, Figure 14–4). which electrical activity is completely disorganized and none of these In cells with abnormal automaticity, most of these drugs reduce deflections is recognizable. (Modified and reproduced, with permission, from the phase 4 slope by blocking either sodium or calcium channels, Goldman MJ: Principles of Clinical Electrocardiography, 11th ed. McGraw-Hill, 1982.) thereby reducing the ratio of sodium (or calcium) permeability to potassium permeability. As a result, the membrane potential during phase 4 stabilizes closer to the potassium equilibrium potential. In addition, some agents may increase the threshold (make it more positive). β-Adrenoceptor–blocking drugs indirectly reduce the further slowing depressed conduction (by blocking the sodium or phase 4 slope by blocking the positive chronotropic action of nor- calcium current) and causing bidirectional block. In theory, accel- epinephrine in the heart. erating conduction (by increasing sodium or calcium current) In reentry arrhythmias, which depend on critically depressed would also be effective, but only under unusual circumstances conduction, most antiarrhythmic agents slow conduction fur- does this mechanism explain the action of any available drug. ther by one or both of two mechanisms: (1) steady-state Lengthening (or shortening) of the refractory period may also reduction in the number of available unblocked channels, make reentry less likely. The longer the refractory period in tissue which reduces the excitatory currents to a level below that near the site of block, the greater the chance that the tissue will required for propagation (Figure 14–4, left); and (2) prolonga- still be refractory when reentry is attempted. (Alternatively, the tion of recovery time of the channels still able to reach the rested shorter the refractory period in the depressed region, the less likely and available state, which increases the effective refractory period it is that unidirectional block will occur.) Thus, increased disper- (Figure 14–4, right). As a result, early extrasystoles are unable to sion of refractoriness is one contributor to reentry, and drugs may propagate at all; later impulses propagate more slowly and are suppress arrhythmias by reducing such dispersion. subject to bidirectional conduction block. 236 SECTION III Cardiovascular-Renal Drugs Polymorphic ventricular tachycardia (torsade de pointes) NSB Prolonged QT interval FIGURE 14–8 Electrocardiogram from a patient with the long QT syndrome during two episodes of torsades de pointes. The polymorphic ventricular tachycardia is seen at the start of this tracing and spontaneously halts at the middle of the panel. A single normal sinus beat (NSB) with an extremely prolonged QT interval follows, succeeded immediately by another episode of ventricular tachycardia of the torsades type. The usual symptoms include dizziness or transient loss of consciousness. (Reproduced, with permission, from Basic and Clinical Pharmacology, 10th edition, McGraw-Hill, 2007.) By these mechanisms, antiarrhythmic drugs can suppress ecto- 4. Class 4 action is blockade of the cardiac calcium current. This pic automaticity and abnormal conduction occurring in depolar- action slows conduction in regions where the action potential ized cells—rendering them electrically silent—while minimally upstroke is calcium dependent, eg, the SA and AV nodes. affecting the electrical activity in normally polarized parts of the A given drug may have multiple classes of action as indicated heart. However, as dosage is increased, these agents also depress by its membrane and electrocardiographic (ECG) effects (Tables conduction in normal tissue, eventually resulting in drug-in- 14–2 and 14–3). For example, amiodarone shares all four classes duced arrhythmias. Furthermore, a drug concentration that is of action. Drugs are usually discussed according to the predomi- therapeutic (antiarrhythmic) under the initial circumstances of nant class of action. Certain antiarrhythmic agents, eg, adenosine treatment may become “proarrhythmic” (arrhythmogenic) dur- and magnesium, do not fit readily into this scheme and are ing fast heart rates (more development of block), acidosis described separately. (slower recovery from block for most drugs), hyperkalemia, or ischemia. SODIUM CHANNEL-BLOCKING DRUGS (CLASS 1) SPECIFIC ANTIARRHYTHMIC Drugs with local anesthetic action block sodium channels and AGENTS reduce the sodium current, INa. They are the oldest group of anti- arrhythmic drugs and are still widely used. The most widely used scheme for the classification of antiarrhyth- PROCAINAMIDE (SUBGROUP 1A) mic drug actions recognizes four classes: 1. Class 1 action is sodium channel blockade. Subclasses Cardiac Effects of this action reflect effects on the action potential duration (APD) and the kinetics of sodium channel By blocking sodium channels, procainamide slows the upstroke blockade. Drugs with class 1A action prolong the APD of the action potential, slows conduction, and prolongs the QRS and dissociate from the channel with intermediate duration of the ECG. The drug also prolongs the APD (a class 3 kinetics; drugs with class 1B action shorten the APD in action) by nonspecific blockade of potassium channels. The drug some tissues of the heart and dissociate from the chan- may be somewhat less effective than quinidine (see below) in nel with rapid kinetics; and drugs with class 1C action suppressing abnormal ectopic pacemaker activity but more effec- have minimal effects on the APD and dissociate from the channel with slow kinetics. tive in blocking sodium channels in depolarized cells. 2. Class 2 action is sympatholytic. Drugs with this action O reduce β-adrenergic activity in the heart. H C2H5 H2N C N CH2 CH2 N 3. Class 3 action manifests as prolongation of the APD. Most C2H5 drugs with this action block the rapid component of the delayed rectifier potassium current, IKr. Procainamide  CHAPTER 14 Agents Used in Cardiac Arrhythmias 237 Unblocked R A I Blocked R-D A-D I-D 0 Sodium current (microamps / cm2) –460 –920 –1380 –1840 –2300 0 1 2 3 4 5 Time (ms) FIGURE 14–9 State- and frequency-dependent block of sodium channels by antiarrhythmic drugs. Top: Diagram of a mechanism for the selective depressant action of antiarrhythmic drugs on sodium channels. The upper portion of the figure shows the population of channels moving through a cycle of activity during an action potential in the absence of drugs: R (rested) → A (activated) → I (inactivated). Recovery takes place via the I → R pathway. Antiarrhythmic drugs (D) that act by blocking sodium channels can bind to their receptors in the channels, as shown by the vertical arrows, to form drug-channel complexes, indicated as R-D, A-D, and I-D. Binding of the drugs to the receptor varies with the state of the channel. Most sodium channel blockers bind to the active and inactivated channel receptor much more strongly than to the rested channel. Furthermore, recovery from the I-D state to the R-D state is much slower than from I to R. As a result, rapid activity (more activa- tions and inactivations) and depolarization of the resting potential (more channels in the I state) will favor blockade of the channels and selec- tively suppress arrhythmic cells. Bottom: Progressive reduction of inward sodium current (downward deflections) in the presence of a lidocaine derivative. The largest curve is the initial sodium current elicited by a depolarizing voltage step; subsequent sodium current amplitudes are pro- gressively reduced owing to prior accumulated block and block during each depolarization. (Adapted, with permission, from Starmer FC, Grant AO, Strauss HC: Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics. Biophys J 1984;46:15.) Procainamide has direct depressant actions on SA and AV nodes, of torsades de pointes arrhythmia and syncope. Excessive slow- and these actions are only slightly counterbalanced by drug- ing of conduction can also occur. New arrhythmias can be induced vagal block. precipitated. A troublesome adverse effect of long-term procainamide Extracardiac Effects therapy is a syndrome resembling lupus erythematosus and usu- ally consisting of arthralgia and arthritis. In some patients, Procainamide has ganglion-blocking properties. This action pleuritis, pericarditis, or parenchymal pulmonary disease also reduces peripheral vascular resistance and can cause hypotension, occurs. Renal lupus is rarely induced by procainamide. During particularly with intravenous use. However, in therapeutic con- long-term therapy, serologic abnormalities (eg, increased anti- centrations, its peripheral vascular effects are less prominent than nuclear antibody titer) occur in nearly all patients, and in the those of quinidine. Hypotension is usually associated with exces- absence of symptoms, these are not an indication to stop drug sively rapid procainamide infusion or the presence of severe therapy. Approximately one third of patients receiving long- underlying left ventricular dysfunction. term procainamide therapy develop these reversible lupus- related symptoms. Toxicity Other adverse effects include nausea and diarrhea (in about Procainamide’s cardiotoxic effects include excessive action poten- 10% of cases), rash, fever, hepatitis (< 5%), and agranulocytosis tial prolongation, QT-interval prolongation, and induction (approximately 0.2%). 238 SECTION III Cardiovascular-Renal Drugs TABLE 14–2 Membrane actions of antiarrhythmic drugs. Block of Sodium Channels Refractory Period Calcium Effect on Depolarized Channel Pacemaker Sympatholytic Drug Normal Cells Cells Normal Cells Depolarized Cells Blockade Activity Action Adenosine 0 0 0 0 + 0 + Amiodarone + +++ ↑↑ ↑↑ + ↓↓ + Diltiazem 0 0 0 0 +++ ↓↓ 0 Disopyramide + +++ ↑ ↑↑ + ↓ 0 Dofetilide 0 0 ↑ ? 0 0 0 Dronedarone + + na na + na + Esmolol 0 + 0 na 0 ↓↓ +++ Flecainide + +++ 0 ↑ 0 ↓↓ 0 Ibutilide 0 0 ↑ ? 0 0 0 Lidocaine 0 +++ ↓ ↑↑ 0 ↓↓ 0 Mexiletine 0 +++ 0 ↑↑ 0 ↓↓ 0 Procainamide + +++ ↑ ↑↑↑ 0 ↓ + Propafenone + ++ ↑ ↑↑ + ↓↓ + Propranolol 0 + ↓ ↑↑ 0 ↓↓ +++ Quinidine + ++ ↑ ↑↑ 0 ↓↓ + Sotalol 0 0 ↑↑ ↑↑↑ 0 ↓↓ ++ Verapamil 0 + 0 ↑ +++ ↓↓ + Vernakalant + + + + na 0 na na, data not available. Pharmacokinetics & Dosage of gastrointestinal (GI) or cardiac toxicity rises at plasma concen- trations greater than 8 mcg/mL or NAPA concentrations greater Procainamide can be administered safely by intravenous and intra- than 20 mcg/mL. muscular routes and is well absorbed orally. A metabolite To control ventricular arrhythmias, a total procainamide dos- (N-acetylprocainamide, NAPA) has class 3 activity. Excessive age of 2–5 g/d is usually required. In an occasional patient who accumulation of NAPA has been implicated in torsades de pointes accumulates high levels of NAPA, less frequent dosing may be during procainamide therapy, especially in patients with renal possible. This is also possible in renal disease, where procainamide failure. Some individuals rapidly acetylate procainamide and elimination is slowed. develop high levels of NAPA. The lupus syndrome appears to be less common in these patients. Procainamide is eliminated by hepatic metabolism to NAPA Therapeutic Use and by renal elimination. Its half-life is only 3–4 hours, which Procainamide is effective against most atrial and ventricular necessitates frequent dosing or use of a slow-release formulation arrhythmias. However, many clinicians attempt to avoid long- (the usual practice). NAPA is eliminated by the kidneys. Thus, term therapy because of the requirement for frequent dosing and procainamide dosage must be reduced in patients with renal fail- the common occurrence of lupus-related effects. Procainamide is ure. The reduced volume of distribution and renal clearance associ- the drug of second or third choice (after lidocaine or amiodarone) ated with heart failure also require reduction in dosage. The in most coronary care units for the treatment of sustained ven- half-life of NAPA is considerably longer than that of procainamide, tricular arrhythmias associated with acute myocardial infarction. and it therefore accumulates more slowly. Thus, it is important to measure plasma levels of both procainamide and NAPA, especially in patients with circulatory or renal impairment. QUINIDINE (SUBGROUP 1A) If a rapid procainamide effect is needed, an intravenous load- ing dose of up to 12 mg/kg can be given at a rate of 0.3 mg/kg/ Cardiac Effects min or less rapidly. This dose is followed by a maintenance dosage Quinidine has actions similar to those of procainamide: it slows the of 2–5 mg/min, with careful monitoring of plasma levels. The risk upstroke of the action potential, slows conduction, and prolongs  CHAPTER 14 Agents Used in Cardiac Arrhythmias 239 TABLE 14–3 Clinical pharmacologic properties of antiarrhythmic drugs. Effect on AV Usefulness in Arrhythmias Nodal Effect on SA Refractory QRS QT Supra– Drug Nodal Rate Period PR Interval Duration Interval ventricular Ventricular Half-Life Adenosine ↓↑ ↑↑↑ ↑↑↑ 0 0 ++++ ? < 10 s 1 Amiodarone ↓↓ ↑↑ Variable ↑ ↑↑↑↑ +++ +++ (weeks) Diltiazem ↑↓ ↑↑ ↑ 0 0 +++ – 4–8 h 1,2 2 2 Disopyramide ↑↓ ↑↓ ↑↓ ↑↑ ↑↑ + +++ 7–8 h Dofetilide ↓(?) 0 0 0 ↑↑ ++ None 7h Dronedarone ↑ +++ – 24 h Esmolol ↓↓ ↑↑ ↑↑ 0 0 + + 10 min Flecainide None,↓ ↑ ↑ ↑↑↑ 0 +3 ++++ 20 h Ibutilide ↓ (?) 0 0 0 ↑↑ ++ ? 6h Lidocaine None1 None 0 0 0 None 4 +++ 1–2 h 1 Mexiletine None None 0 0 0 None +++ 12 h 1 2 2 Procainamide ↓ ↑↓ ↑↓ ↑↑ ↑↑ + +++ 3–4 h Propafenone 0, ↓ ↑ ↑ ↑↑↑ 0 + +++ 5–7 h Propranolol ↓↓ ↑↑ ↑↑ 0 0 + + 5h Quinidine ↑↓1,2 ↑↓2 ↑↓2 ↑↑ ↑↑ + +++ 6h Sotalol ↓↓ ↑↑ ↑↑ 0 ↑↑↑ +++ +++ 7h Verapamil ↓↓ ↑↑ ↑↑ 0 0 +++ – 7h Vernakalant ↑ ↑ +++ – 2h 1 May suppress diseased sinus nodes. 2 Anticholinergic effect and direct depressant action. 3 Especially in Wolff-Parkinson-White syndrome. 4 May be effective in atrial arrhythmias caused by digitalis. 5 Half-life of active metabolites much longer. the QRS duration of the ECG, by blockade of sodium channels. and tinnitus (cinchonism) is observed at toxic drug concentra- The drug also prolongs the action potential duration by blockade tions. Idiosyncratic or immunologic reactions, including thrombo- of several potassium channels. Its toxic cardiac effects include cytopenia, hepatitis, angioneurotic edema, and fever, are observed excessive QT-interval prolongation and induction of torsades rarely. de pointes arrhythmia. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed Pharmacokinetics & Therapeutic Use conduction throughout the heart. Quinidine is readily absorbed from the GI tract and eliminated by hepatic metabolism. It is rarely used because of cardiac and extra- O CH3 cardiac adverse effects and the availability of better-tolerated anti- arrhythmic drugs. H N N C DISOPYRAMIDE (SUBGROUP 1A) CH CH2 OH Cardiac Effects Quinidine The effects of disopyramide are very similar to those of procain- amide and quinidine. Its cardiac antimuscarinic effects are even Extracardiac Effects more marked than those of quinidine. Therefore, a drug that slows Adverse GI effects of diarrhea, nausea, and vomiting are observed AV conduction should be administered with disopyramide when in one third to one half of patients. A syndrome of headache, dizziness, treating atrial flutter or fibrillation. 240 SECTION III Cardiovascular-Renal Drugs Channels blocked (%) Membrane potential (mV) N 0 O CH(CH3)2 H2N C C CH2 CH2 N CH(CH3)2 –75 –70 –85 –80 –100 Disopyramide 100 Toxicity Toxic concentrations of disopyramide can precipitate all of the electrophysiologic disturbances described under quinidine. As a 0 result of its negative inotropic effect, disopyramide may precipi- 800 tate heart failure de novo or in patients with preexisting depression Time (ms) of left ventricular function. Because of this effect, disopyramide is FIGURE 14–10 Computer simulation of the effect of resting not used as a first-line antiarrhythmic agent in the USA. It should membrane potential on the blocking and unblocking of sodium channels not be used in patients with heart failure. by lidocaine as the membrane depolarizes. Upper tracing: Action potentials Disopyramide’s atropine-like activity accounts for most of its in a ventricular muscle cell. Lower tracing: Percentage of channels symptomatic adverse effects: urinary retention (most often, but blocked by the drug. An 800 ms time segment is shown. Extra passage of not exclusively, in male patients with prostatic hyperplasia), dry time is indicated by breaks in the traces. Left side: At the normal resting mouth, blurred vision, constipation, and worsening of preexisting potential of –85 mV, the drug combines with open (activated) and glaucoma. These effects may require discontinuation of the drug. inactivated channels during each action potential, but block is rapidly reversed during diastole because the affinity of the drug for its receptor is so low when the channel recovers to the resting state at –85 mV. Middle: Pharmacokinetics & Dosage Metabolic injury is simulated, eg, ischemia due to coronary occlusion, In the USA, disopyramide is only available for oral use. The typi- that causes gradual depolarization over time. With subsequent action cal oral dosage of disopyramide is 150 mg three times a day, but potentials arising from more depolarized potentials, the fraction of channels up to 1 g/d has been used. In patients with renal impairment, dos- blocked increases because more channels remain in the inactivated state age must be reduced. Because of the danger of precipitating heart at less negative potentials (Figure 14–4, left), and the time constant for failure, loading doses are not recommended. unblocking during diastole rapidly increases at less negative resting potentials (Figure 14–4, right). Right: Because of marked drug binding, conduction block and loss of excitability in this tissue result; that is, the Therapeutic Use “sick” (depolarized) tissue is selectively suppressed. Although disopyramide has been shown to be effective in a variety of supraventricular arrhythmias, in the USA it is approved only for greater effects on cells with long action potentials such as Purkinje the treatment of ventricular arrhythmias. and ventricular cells, compared with atrial cells. The rapid kinetics at normal resting potentials result in recovery from block between action potentials and no effect on conduction. The increased inac- LIDOCAINE (SUBGROUP 1B) tivation and slower unbinding kinetics result in the selective depression of conduction in depolarized cells. Little effect is seen Lidocaine has a low incidence of toxicity and a high degree of on the ECG in normal sinus rhythm. effectiveness in arrhythmias associated with acute myocardial infarction. It is used only by the intravenous route. Toxicity CH3 Lidocaine is one of the least cardiotoxic of the currently used O H C2H5 sodium channel blockers. Proarrhythmic effects, including SA node N C CH2 N arrest, worsening of impaired conduction, and ventricular arrhyth- C2H5 mias, are uncommon with lidocaine use. In large doses, especially in CH3 patients with preexisting heart failure, lidocaine may cause hypoten- Lidocaine sion—partly by depressing myocardial contractility. Lidocaine’s most common adverse effects—like those of other local anesthetics—are neurologic: paresthesias, tremor, nausea of Cardiac Effects central origin, lightheadedness, hearing disturbances, slurred speech, Lidocaine blocks activated and inactivated sodium channels with and convulsions. These occur most commonly in elderly or other- rapid kinetics (Figure 14–10); the inactivated state block ensures wise vulnerable patients or when a bolus of the drug is given too  CHAPTER 14 Agents Used in Cardiac Arrhythmias 241 rapidly. The effects are dose-related and usually short-lived; seizures arrhythmias. The elimination half-life is 8–20 hours and permits respond to intravenous diazepam. In general, if plasma levels above administration two or three times per day. The usual daily dosage 9 mcg/mL are avoided, lidocaine is well tolerated. of mexiletine is 600–1200 mg/d. Dose-related adverse effects are seen frequently at therapeutic dosage. These are predominantly Pharmacokinetics & Dosage neurologic, including tremor, blurred vision, and lethargy. Nausea is also a common effect. Because of its extensive first-pass hepatic metabolism, only 3% of orally administered lidocaine appears in the plasma. Thus, lido- CH3 caine must be given parenterally. Lidocaine has a half-life of 1–2 hours. In adults, a loading dose of 150–200 mg administered O CH2 CH CH3 over about 15 minutes (as a single infusion or as a series of slow NH2 boluses) should be followed by a maintenance infusion of 2–4 CH3 mg/min to achieve a therapeutic plasma level of 2–6 mcg/mL. Mexiletine Determination of lidocaine plasma levels is of great value in adjusting the infusion rate. Occasional patients with myocardial Mexiletine has also shown significant efficacy in relieving infarction or other acute illness require (and tolerate) higher con- chronic pain, especially pain due to diabetic neuropathy and centrations. This may be due to increased plasma α1-acid glyco- nerve injury. The usual dosage is 450–750 mg/d orally. This protein, an acute-phase reactant protein that binds lidocaine, application is off label. making less free drug available to exert its pharmacologic effects. In patients with heart failure, lidocaine’s volume of distribu- tion and total body clearance may both be decreased. Therefore, FLECAINIDE (SUBGROUP 1C) both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be Flecainide is a potent blocker of sodium and potassium channels increased as much as predicted from clearance changes alone. In with slow unblocking kinetics. (Note that although it does block patients with liver disease, plasma clearance is markedly reduced certain potassium channels, it does not prolong the action poten- and the volume of distribution is often increased; the elimina- tial or the QT interval.) It is currently used for patients with tion half-life in such cases may be increased threefold or more. otherwise normal hearts who have supraventricular arrhythmias. It In liver disease, the maintenance dose should be decreased, but has no antimuscarinic effects. usual loading doses can be given. Elimination half-life deter- O CH2 CF3 mines the time to steady state. Although steady-state concentra- O N tions may be achieved in 8–10 hours in normal patients and C NH CH2 patients with heart failure, 24–36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, O CH2 CF3 propranolol, cimetidine) reduce lidocaine clearance and so Flecainide increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on Flecainide is very effective in suppressing premature ventricular lidocaine disposition. contractions. However, it may cause severe exacerbation of arrhythmia even when normal doses are administered to patients with preexisting ventricular tachyarrhythmias and those with a Therapeutic Use previous myocardial infarction and ventricular ectopy. This was Lidocaine is the agent of choice for termination of ventricular dramatically demonstrated in the Cardiac Arrhythmia Suppression tachycardia and prevention of ventricular fibrillation after cardio- Trial (CAST), which was terminated prematurely because of a two version in the setting of acute ischemia. However, routine prophy- and one-half-fold increase in mortality rate in the patients receiv- lactic use of lidocaine in this setting may actually increase total ing flecainide and similar group 1C drugs. Flecainide is well mortality, possibly by increasing the incidence of asystole, and is absorbed and has a half-life of approximately 20 hours. Elimination not the standard of care. Most physicians administer IV lidocaine is both by hepa