Pharmacology_Katzung

Pharmacology_Katzung. 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, preventing 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 previously passed through, and a reentry arrhythmia is established.


Pharmacology_Katzung

Pharmacology_Katzung. which cause an increase in extracellular potassium that partially depolarizes the resting membrane potential, slowing sodium channel recovery from inactivation and prolonging the refractory period in the affected area. (3) Finally, conduction time around the circuit must be long enough so that by the time the impulse returns to the site after traveling around the obstacle, the tissue is no longer refractory. In other words, conduction time around the circuit must exceed the effective refractory period duration in the area of unidirectional block. Representative ECGs of important arrhythmias are shown in Figures 14–7 and 14–8. Unidirectional block can be caused by prolongation of refractory period duration due to depression of sodium channel activity in atrial, ventricular, and Purkinje cells. In the AV node, it may also be a result of depressed calcium channel activity. Drugs that Panel 1: Normal sinus rhythm Panel 2: Atrial flutter Panel 3:


Pharmacology_Katzung

Pharmacology_Katzung. Panel 1: Normal sinus rhythm Panel 2: Atrial flutter Panel 3: Panel 4: Ventricular tachycardia (starting at arrow) Panel 5: Ventricular fibrillation


Pharmacology_Katzung

Pharmacology_Katzung. Panel 2: Atrial flutter Panel 3: Panel 4: Ventricular tachycardia (starting at arrow) Panel 5: Ventricular fibrillation FIGURE 14–7 Electrocardiograms of normal sinus rhythm and some common arrhythmias. Major deflections (P, Q, R, S, and T) are labeled in each electrocardiographic record except in panel 5, in which electrical activity is completely disorganized and none of these deflections is recognizable. (Adapted, with permission, from Goldman MJ: Principles of Clinical Electrocardiography, 11th ed. McGraw-Hill, 1982. Copyright © The McGraw-Hill Companies, Inc.) abolish reentry may do so by further reducing excitability by blocking sodium (Figure 14–4) or calcium channels, thus converting an area of unidirectional block to bidirectional block. Drugs that block repolarizing potassium currents may also be effective in converting a region of unidirectional block to bidirectional block by prolonging action potential duration, and thereby increasing the refractory period duration.


Pharmacology_Katzung

Pharmacology_Katzung. Mechanisms of Action Arrhythmias are caused by abnormal pacemaker activity or abnormal impulse propagation. Thus, the aim of therapy of the arrhythmias is to reduce ectopic pacemaker activity and modify conduction or refractoriness in reentry circuits to disable circus movement. The major pharmacologic mechanisms currently available for accomplishing these goals are (1) sodium channel blockade, (2) blockade of sympathetic autonomic effects in the heart, (3) prolongation of the effective refractory period, and (4) calcium channel blockade.


Pharmacology_Katzung

Pharmacology_Katzung. Antiarrhythmic drugs decrease the automaticity of ectopic pacemakers more than that of the SA node. They also reduce conduction 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 channels of depolarized cells (Figure 14–9). Therapeutically useful channel-blocking drugs bind readily to activated channels (ie, during phase 0) or inactivated channels (ie, during phase 2) but bind poorly or not at all to rested channels. Therefore, these drugs block electrical activity when there is a fast tachycardia (many channel activations and inactivations per unit time) or when there is significant loss of resting potential (many inactivated channels during rest). This type of drug action is often described as use-dependent or state-dependent; that is, channels that are being used frequently, or are in an inactivated state, are more susceptible to


Pharmacology_Katzung

Pharmacology_Katzung. rest). This type of drug action is often described as use-dependent or state-dependent; that is, channels that are being used frequently, or are in an inactivated state, are more susceptible to block. Channels in normal cells that become blocked by a drug during normal 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 resting potential more positive than −75 mV) recover from block very slowly if at all (see also right panel, Figure 14–4).


Pharmacology_Katzung

Pharmacology_Katzung. In cells with abnormal automaticity, most of these drugs reduce the phase 4 slope by blocking either sodium or calcium channels, 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). Beta-adrenoceptor-blocking drugs indirectly reduce the phase 4 slope by blocking the positive chronotropic action of norepinephrine in the heart. In reentry arrhythmias, which depend on critically depressed conduction, most antiarrhythmic agents slow conduction further by one or both of two mechanisms: (1) steady-state reduction in


Pharmacology_Katzung

Pharmacology_Katzung. 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. Copyright © The McGraw-Hill Companies, Inc.) the number of available unblocked channels, which reduces the excitatory currents to a level below that required for propagation (Figure 14–4, left); and (2) prolongation of recovery time of the channels still able to reach the rested and available state, which increases the effective refractory period (Figure 14–4, right). As a result, early extrasystoles are


Pharmacology_Katzung

Pharmacology_Katzung. of recovery time of the channels still able to reach the rested and available state, which increases the effective refractory period (Figure 14–4, right). As a result, early extrasystoles are unable to propagate at all; later impulses propagate more slowly and are subject to bidirectional conduction block.


Pharmacology_Katzung

Pharmacology_Katzung. By these mechanisms, antiarrhythmic drugs can suppress ectopic automaticity and abnormal conduction occurring in depolarized cells—rendering them electrically silent—while minimally affecting the electrical activity in normally polarized parts of the heart. However, as dosage is increased, these agents also depress conduction in normal tissue, eventually resulting in drug-induced arrhythmias. Furthermore, a drug concentration that is therapeutic (antiarrhythmic) under the initial circumstances of treatment may become “proarrhythmic” (arrhythmogenic) during fast heart rates (more development of block), acidosis (slower recovery from block for most drugs), hyperkalemia, or ischemia.


Pharmacology_Katzung

Pharmacology_Katzung. The most widely used scheme for the classification of antiarrhythmic drug actions recognizes four classes: 1. Class 1 action is sodium channel blockade. Subclasses of this action reflect effects on the action potential duration (APD) and the kinetics of sodium channel blockade. Drugs with class 1A action prolong the APD and dissociate from the channel with intermediate kinetics; drugs with class 1B action shorten the APD in some tissues of the heart and dissociate from the channel with rapid kinetics; and drugs with class 1C action have minimal effects on the APD and dissociate from the channel with slow kinetics. 2. Class 2 action is sympatholytic. Drugs with this action reduce β-adrenergic activity in the heart. 3. Class 3 action manifests as prolongation of the APD. Most drugs with this action block the rapid component of the delayed rectifier potassium current, IKr. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Class 3 action manifests as prolongation of the APD. Most drugs with this action block the rapid component of the delayed rectifier potassium current, IKr. 4. Class 4 action is blockade of the cardiac calcium current. This action slows conduction in regions where the action potential upstroke is calcium dependent, eg, the SA and AV nodes. A given drug may have multiple classes of action as indicated by its membrane and ECG effects (Tables 14–2 and 14–3). For example, amiodarone shares all four classes of action. Drugs are usually discussed according to the predominant class of action. Certain antiarrhythmic agents, eg, adenosine and magnesium, do not fit readily into this scheme and are described separately. Drugs with local anesthetic action block sodium channels and reduce the sodium current, INa. They are the oldest group of anti-arrhythmic drugs and are still widely used.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs with local anesthetic action block sodium channels and reduce the sodium current, INa. They are the oldest group of anti-arrhythmic drugs and are still widely used. By blocking sodium channels, procainamide slows the upstroke of the action potential, slows conduction, and prolongs the QRS duration of the ECG. The drug also prolongs the APD (a class 3 action) by nonspecific blockade of potassium channels. The drug


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 14–9 Stateand 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 activations and


Pharmacology_Katzung

Pharmacology_Katzung. 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 activations and inactivations) and depolarization of the resting potential (more channels in the I state) will favor blockade of the channels and selectively 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 progressively 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. Copyright Elsevier.) may be somewhat less effective than quinidine (see below) in sup-particularly with


Pharmacology_Katzung

Pharmacology_Katzung. block of sodium channels in excitable membranes by local anesthetics. Biophys J 1984;46:15. Copyright Elsevier.) may be somewhat less effective than quinidine (see below) in sup-particularly with intravenous use. However, in therapeutic concenpressing abnormal ectopic pacemaker activity but more effective trations, its peripheral vascular effects are less prominent than those in blocking sodium channels in depolarized cells. of quinidine. Hypotension is usually associated with excessively rapid procainamide infusion or the presence of severe underlying left ventricular dysfunction.


Pharmacology_Katzung

Pharmacology_Katzung. Procainamide’s cardiotoxic effects include excessive action poten-Procainamide has direct depressant actions on SA and AV tial prolongation, QT-interval prolongation, and induction of nodes, and these actions are only slightly counterbalanced by torsades de pointes arrhythmia and syncope. Excessive slowing of drug-induced vagal block. conduction can also occur. New arrhythmias can be precipitated. A troublesome adverse effect of long-term procainamide therapy is a syndrome resembling lupus erythematosus and usually consisting of arthralgia and arthritis. In some patients, pleuritis, Procainamide has ganglion-blocking properties. This action pericarditis, or parenchymal pulmonary disease also occurs. reduces peripheral vascular resistance and can cause hypotension, Renal lupus is rarely induced by procainamide. During long-term TABLE 14–2 Membrane actions of antiarrhythmic drugs. 1Not available in the USA. na, data not available.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 14–2 Membrane actions of antiarrhythmic drugs. 1Not available in the USA. na, data not available. therapy, serologic abnormalities (eg, increased antinuclear antibody titer) occur in nearly all patients, and in the absence of symptoms, these are not an indication to stop drug therapy. Approximately one third of patients receiving long-term procainamide therapy develop these reversible lupus-related symptoms. Other adverse effects include nausea and diarrhea (in about 10% of cases), rash, fever, hepatitis (<5%), and agranulocytosis (approximately 0.2%).


Pharmacology_Katzung

Pharmacology_Katzung. Other adverse effects include nausea and diarrhea (in about 10% of cases), rash, fever, hepatitis (<5%), and agranulocytosis (approximately 0.2%). Procainamide can be administered safely by intravenous and intramuscular routes and is well absorbed orally. A metabolite (N-acetylprocainamide, NAPA) has class 3 activity. Excessive accumulation of NAPA has been implicated in torsades de pointes during procainamide therapy, especially in patients with renal failure. Some individuals rapidly acetylate procainamide and develop high levels of NAPA. However, the lupus syndrome appears to be less common in these patients.


Pharmacology_Katzung

Pharmacology_Katzung. Procainamide is eliminated by hepatic metabolism to NAPA and by renal elimination. Its half-life is only 3–4 hours, which necessitates frequent dosing or use of a slow-release formulation (the usual practice). NAPA is eliminated by the kidneys. Thus, procainamide dosage must be reduced in patients with renal failure. The reduced volume of distribution and renal clearance associated with heart failure also require reduction in dosage. The half-life of NAPA is considerably longer than that of procainamide, 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.


Pharmacology_Katzung

Pharmacology_Katzung. If a rapid procainamide effect is needed, an intravenous loading dose of up to 12 mg/kg can be given at a rate of 0.3 mg/kg/ min or less rapidly. This dose is followed by a maintenance dosage of 2–5 mg/min, with careful monitoring of plasma levels. The risk of gastrointestinal (GI) or cardiac toxicity rises at plasma concentrations greater than 8 mcg/mL or NAPA concentrations greater than 20 mcg/mL. To control ventricular arrhythmias, a total procainamide dosage of 2–5 g/d is usually required. In an occasional patient who accumulates high levels of NAPA, less frequent dosing may be possible. This is also possible in renal disease, where procainamide elimination is slowed.


Pharmacology_Katzung

Pharmacology_Katzung. Procainamide is effective against most atrial and ventricular arrhythmias. However, many clinicians attempt to avoid long-term therapy because of the requirement for frequent dosing and the common occurrence of lupus-related effects. Procainamide is the drug of second or third choice (after lidocaine or amiodarone) in most coronary care units for the treatment of sustained ventricular arrhythmias associated with acute myocardial infarction. TABLE 14–3 Clinical pharmacologic properties of antiarrhythmic drugs. 1May suppress diseased sinus nodes. 2Anticholinergic effect and direct depressant action. 3Especially in Wolff-Parkinson-White syndrome. 4May be effective in atrial arrhythmias caused by digitalis.


Pharmacology_Katzung

Pharmacology_Katzung. 1May suppress diseased sinus nodes. 2Anticholinergic effect and direct depressant action. 3Especially in Wolff-Parkinson-White syndrome. 4May be effective in atrial arrhythmias caused by digitalis. Quinidine has actions similar to those of procainamide: it slows the upstroke of the action potential, slows conduction, and prolongs the QRS duration of the ECG, by blockade of sodium channels. The drug also prolongs the action potential duration by blockade of several potassium channels. Its toxic cardiac effects include excessive QT-interval prolongation and induction of torsades de pointes arrhythmia. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed conduction throughout the heart. It also has modest antimuscarinic actions in the heart.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse GI effects of diarrhea, nausea, and vomiting are observed in one third to one half of patients. A syndrome of headache, dizziness, and tinnitus (cinchonism) is observed at toxic drug concentrations. Idiosyncratic or immunologic reactions, including thrombocytopenia, hepatitis, angioneurotic edema, and fever, are observed rarely. Quinidine is readily absorbed from the GI tract and eliminated by hepatic metabolism. It is rarely used because of cardiac and extracardiac adverse effects and the availability of better-tolerated antiarrhythmic drugs. The effects of disopyramide are very similar to those of procainamide and quinidine. Its cardiac antimuscarinic effects are even more marked than those of quinidine. Therefore, a drug that slows AV conduction should be administered with disopyramide when treating atrial flutter or fibrillation.


Pharmacology_Katzung

Pharmacology_Katzung. Toxic concentrations of disopyramide can precipitate all of the electrophysiologic disturbances described under quinidine. As a result of its negative inotropic effect, disopyramide may precipitate heart failure de novo or in patients with preexisting depression of left ventricular function. Because of this effect, disopyramide is not used as a first-line antiarrhythmic agent in the USA. It should not be used in patients with heart failure. Disopyramide’s atropine-like activity accounts for most of its symptomatic adverse effects: urinary retention (most often, but not exclusively, in male patients with prostatic hyperplasia), dry mouth, blurred vision, constipation, and worsening of preexisting glaucoma. These effects may require discontinuation of the drug.


Pharmacology_Katzung

Pharmacology_Katzung. These effects may require discontinuation of the drug. In the USA, disopyramide is only available for oral use. The typical oral dosage of disopyramide is 150 mg three times a day, but up to 1 g/d has been used. In patients with renal impairment, dosage must be reduced. Because of the danger of precipitating heart failure, loading doses are not recommended. Although disopyramide has been shown to be effective in a variety of supraventricular arrhythmias, in the USA, it is approved only for the treatment of ventricular arrhythmias. Lidocaine has a low incidence of toxicity and a high degree of effectiveness in arrhythmias associated with acute myocardial infarction. It is used only by the intravenous route.


Pharmacology_Katzung

Pharmacology_Katzung. Lidocaine has a low incidence of toxicity and a high degree of effectiveness in arrhythmias associated with acute myocardial infarction. It is used only by the intravenous route. Lidocaine blocks activated and inactivated sodium channels with rapid kinetics (Figure 14–10); the inactivated state block ensures greater effects on cells with long action potentials such as Purkinje 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. In depolarized cells, the increased inactivation and slower unbinding kinetics result in the selective depression of conduction. Little effect is seen on the ECG in normal sinus rhythm.


Pharmacology_Katzung

Pharmacology_Katzung. Lidocaine is one of the least cardiotoxic of the currently used sodium channel blockers. Proarrhythmic effects, including SA node arrest, worsening of impaired conduction, and ventricular arrhythmias, are uncommon with lidocaine use. In large doses, especially in patients with preexisting heart failure, lidocaine may cause hypotension—partly by depressing myocardial contractility.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 14–10 Computer simulation of the effect of resting membrane potential on the blocking and unblocking of sodium channels by lidocaine as the membrane depolarizes. Upper tracing: Action potentials in a ventricular muscle cell. Lower tracing: Percentage of channels blocked by the drug. An 800-ms time segment is shown. Extra passage of time is indicated by breaks in the traces. Left side: At the normal resting potential of −85 mV, the drug combines with open (activated) and 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: Metabolic injury is simulated, eg, ischemia due to coronary occlusion, that causes gradual depolarization over time. With subsequent action potentials arising from more depolarized potentials, the fraction of channels blocked increases because more channels remain in the inactivated state at


Pharmacology_Katzung

Pharmacology_Katzung. over time. With subsequent action potentials arising from more depolarized potentials, the fraction of channels blocked increases because more channels remain in the inactivated state at less negative potentials (Figure 14–4, left), and the time constant for 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 “sick” (depolarized) tissue is selectively suppressed.


Pharmacology_Katzung

Pharmacology_Katzung. Lidocaine’s most common adverse effects—like those of other local anesthetics—are neurologic: paresthesias, tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, and convulsions. These occur most commonly in elderly or otherwise vulnerable patients or when a bolus of the drug is given too rapidly. The effects are dose-related and usually short-lived; seizures respond to intravenous diazepam. In general, if plasma levels above 9 mcg/mL are avoided, lidocaine is well tolerated.


Pharmacology_Katzung

Pharmacology_Katzung. Because of its extensive first-pass hepatic metabolism, only 3% of orally administered lidocaine appears in the plasma. Thus, lidocaine must be given parenterally. Lidocaine has a half-life of 1–2 hours. In adults, a loading dose of 150–200 mg administered over about 15 minutes (as a single infusion or as a series of slow boluses) should be followed by a maintenance infusion of 2–4 mg/min to achieve a therapeutic plasma level of 2–6 mcg/mL. Determination of lidocaine plasma levels is of great value in adjusting the infusion rate. Occasional patients with myocardial infarction or other acute illness require (and tolerate) higher concentrations. This may be due to increased plasma α1-acid glycoprotein, an acute-phase reactant protein that binds lidocaine, making less free drug available to exert its pharmacologic effects.


Pharmacology_Katzung

Pharmacology_Katzung. In patients with heart failure, lidocaine’s volume of distribution and total body clearance may both be decreased. Therefore, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased; the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Although steady-state concentrations may be achieved in 8–10 hours in normal patients and patients with heart failure, 24–36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates


Pharmacology_Katzung

Pharmacology_Katzung. may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so 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 lidocaine disposition.


Pharmacology_Katzung

Pharmacology_Katzung. Lidocaine is the agent of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia. However, routine prophylactic use of lidocaine in this setting may actually increase total mortality, possibly by increasing the incidence of asystole, and is not the standard of care. Most physicians administer IV lidocaine only to patients with arrhythmias.


Pharmacology_Katzung

Pharmacology_Katzung. Mexiletine is an orally active congener of lidocaine. Its electro-physiologic and antiarrhythmic actions are similar to those of lidocaine. (The anticonvulsant phenytoin [see Chapter 24] exerts similar electrophysiologic effects and has been used as an antiarrhythmic.) Mexiletine is used in the treatment of ventricular arrhythmias. The elimination half-life is 8–20 hours and permits administration two or three times per day. The usual daily dosage of mexiletine is 600–1200 mg/d. Dose-related adverse effects are seen frequently at therapeutic dosage. These are predominantly neurologic, including tremor, blurred vision, and lethargy. Nausea is also a common effect. Mexiletine has also shown significant efficacy in relieving chronic pain, especially pain due to diabetic neuropathy and nerve injury. The usual dosage is 450–750 mg/d orally. This application is off label.


Pharmacology_Katzung

Pharmacology_Katzung. Flecainide is a potent blocker of sodium and potassium channels with slow unblocking kinetics. (Note that although it does block certain potassium channels, it does not prolong the action potential or the QT interval.) It is currently used for patients with otherwise normal hearts who have supraventricular arrhythmias. It has no antimuscarinic effects.


Pharmacology_Katzung

Pharmacology_Katzung. Flecainide is very effective in suppressing premature ventricular 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 previous myocardial infarction and ventricular ectopy. This was dramatically demonstrated in the Cardiac Arrhythmia Suppression Trial (CAST), which was terminated prematurely because of a two and one-half-fold increase in mortality rate in the patients receiving flecainide and similar group 1C drugs. Flecainide is well absorbed and has a half-life of approximately 20 hours. Elimination is both by hepatic metabolism and by the kidney. The usual dosage of flecainide is 100–200 mg twice a day.


Pharmacology_Katzung

Pharmacology_Katzung. Propafenone has some structural similarities to propranolol and possesses weak β-blocking activity. Its spectrum of action is very similar to that of quinidine, but it does not prolong the action potential. Its sodium channel-blocking kinetics are similar to those of flecainide. Propafenone is metabolized in the liver, with an average half-life of 5–7 hours. The usual daily dosage of propafenone is 450–900 mg/d in three divided doses. The drug is used primarily for supraventricular arrhythmias. The most common adverse effects are a metallic taste and constipation; arrhythmia exacerbation can also occur. Moricizine is an antiarrhythmic phenothiazine derivative that was used for treatment of ventricular arrhythmias. It is a relatively potent sodium channel blocker that does not prolong action potential duration. Moricizine has been withdrawn from the US market.


Pharmacology_Katzung

Pharmacology_Katzung. Propranolol and similar drugs have antiarrhythmic properties by virtue of their β-receptor-blocking action and direct membrane effects. As described in Chapter 10, some of these drugs have selectivity for cardiac β1 receptors, some have intrinsic sympathomimetic activity, some have marked direct membrane effects, and some prolong the cardiac action potential. The relative contributions of the β-blocking and direct membrane effects to the antiarrhythmic effects of these drugs are not fully known. Although β blockers are fairly well tolerated, their efficacy for suppression of ventricular ectopic depolarizations is lower than that of sodium channel blockers. However, there is good evidence that these agents can prevent recurrent infarction and sudden death in patients recovering from acute myocardial infarction (see Chapter 10).


Pharmacology_Katzung

Pharmacology_Katzung. Esmolol is a short-acting β blocker used primarily as an anti-arrhythmic drug for intraoperative and other acute arrhythmias. See Chapter 10 for more information. Sotalol is a nonselective β-blocking drug that prolongs the action potential (class 3 action). These drugs prolong action potentials, usually by blocking potassium channels in cardiac muscle or by enhancing inward current, eg, through sodium channels. Action potential prolongation by most of these drugs exhibits the undesirable property of “reverse use-dependence”: action potential prolongation is least marked at fast rates (where it is desirable) and most marked at slow rates, where it can contribute to the risk of torsades de pointes.


Pharmacology_Katzung

Pharmacology_Katzung. Although most drugs in the class cause QT prolongation, there is considerable variability among drugs in their proarrhythmic tendency to cause torsades de pointes despite significant QT-interval prolongation. Recent studies suggest that excessive QT prolongation alone may not be the best predictor of drug-induced torsades de pointes. Other important factors in addition to QT prolongation include action potential stability and development of a triangular shape (triangulation), reverse use-dependence, and dispersion of repolarization time across the ventricles.


Pharmacology_Katzung

Pharmacology_Katzung. In the USA, amiodarone is approved for oral and intravenous use to treat serious ventricular arrhythmias. However, the drug is also highly effective in the treatment of supraventricular arrhythmias such as atrial fibrillation. As a result of its broad spectrum of antiarrhythmic action, it is very extensively used for a wide variety of arrhythmias. Amiodarone has unusual pharmacokinetics and important extracardiac adverse effects. Dronedarone, an analog that lacks iodine atoms, has US Food and Drug Administration (FDA) approval for the treatment of atrial flutter and fibrillation. Celivarone is another noniodinated benzofuran derivative similar to dronedarone that is currently undergoing clinical trials for the prevention of ventricular tachycardia recurrence.


Pharmacology_Katzung

Pharmacology_Katzung. Amiodarone markedly prolongs the action potential duration (and the QT interval on the ECG) by blockade of IKr. During chronic administration, IKs is also blocked. The action potential duration is prolonged uniformly over a wide range of heart rates; that is, the drug does not have reverse use-dependent action. Despite its present classification as a class 3 agent, amiodarone also significantly blocks inactivated sodium channels. Its action potential-prolonging action reinforces this effect. Amiodarone also has weak adrenergic and calcium channel-blocking actions. Consequences of these actions include slowing of the heart rate and AV node conduction. The broad spectrum of actions may account for its relatively high efficacy and its low incidence of torsades de pointes despite significant QT-interval prolongation. Amiodarone causes peripheral vasodilation. This action is prominent after intravenous administration and may be related to the action of the vehicle.


Pharmacology_Katzung

Pharmacology_Katzung. Amiodarone may produce symptomatic bradycardia and heart block in patients with preexisting sinus or AV node disease. The drug accumulates in many tissues, including the heart (10–50 times more so than in plasma), lung, liver, and skin, and is concentrated in tears. Dose-related pulmonary toxicity is the most important adverse effect. Even on a low dose of 200 mg/d or less, fatal pulmonary fibrosis may be observed in 1% of patients. Abnormal liver function tests and hypersensitivity hepatitis may develop during amiodarone treatment and liver function tests should be monitored regularly. The skin deposits result in a photodermatitis and a gray-blue skin discoloration in sun-exposed areas, eg, the malar regions. After a few weeks of treatment, asymptomatic corneal microdeposits are present in virtually all patients treated with amiodarone. Halos develop in the peripheral visual fields of some patients. Drug discontinuation is usually not required. Rarely, an optic neuritis may progress


Pharmacology_Katzung

Pharmacology_Katzung. in virtually all patients treated with amiodarone. Halos develop in the peripheral visual fields of some patients. Drug discontinuation is usually not required. Rarely, an optic neuritis may progress to blindness.


Pharmacology_Katzung

Pharmacology_Katzung. Amiodarone blocks the peripheral conversion of thyroxine (T4) to triiodothyronine (T3). It is also a potential source of large amounts of inorganic iodine. Amiodarone may result in hypothyroidism or hyperthyroidism. Thyroid function should be evaluated before initiating treatment and should be monitored periodically. Because effects have been described in virtually every organ system, amiodarone treatment should be reevaluated whenever new symptoms develop in a patient, including arrhythmia aggravation.


Pharmacology_Katzung

Pharmacology_Katzung. Amiodarone is variably absorbed with a bioavailability of 35–65%. It undergoes hepatic metabolism, and the major metabolite, desethylamiodarone, is bioactive. The elimination half-life is complex, with a rapid component of 3–10 days (50% of the drug) and a slower component of several weeks. After discontinuation of the drug, effects are maintained for 1–3 months. Measurable tissue levels may be observed up to 1 year after discontinuation. A total loading dose of 10 g is usually achieved with 0.8–1.2 g daily doses. The maintenance dose is 200–400 mg daily. Pharmacologic effects may be achieved rapidly by intravenous loading. QT-prolonging effect is modest with this route of administration, whereas bradycardia and AV block may be significant.


Pharmacology_Katzung

Pharmacology_Katzung. Amiodarone has many important drug interactions, and all medications should be reviewed when the drug is initiated and when the dose is adjusted. Amiodarone is a substrate for liver cytochrome CYP3A4, and its levels are increased by drugs that inhibit this enzyme, eg, the histamine H2 blocker cimetidine. Drugs that induce CYP3A4, eg, rifampin, decrease amiodarone concentration when coadministered. Amiodarone inhibits several cytochrome P450 enzymes and may result in high levels of many drugs, including statins, digoxin, and warfarin. The dose of warfarin should be reduced by one third to one half following initiation of amiodarone, and prothrombin times should be closely monitored.


Pharmacology_Katzung

Pharmacology_Katzung. Low doses (100–200 mg/d) of amiodarone are effective in maintaining normal sinus rhythm in patients with atrial fibrillation. The drug is effective in the prevention of recurrent ventricular tachycardia. It is not associated with an increase in mortality in patients with coronary artery disease or heart failure. In many centers, the implanted cardioverter-defibrillator (ICD) has succeeded drug therapy as the primary treatment modality for ventricular tachycardia, but amiodarone may be used for ventricular tachycardia as adjuvant therapy to decrease the frequency of uncomfortable cardioverter-defibrillator discharges. The drug increases the pacing and defibrillation threshold, and these devices require retesting after a maintenance dose has been achieved.


Pharmacology_Katzung

Pharmacology_Katzung. Dronedarone is a structural analog of amiodarone in which the iodine atoms have been removed from the phenyl ring and a methanesulfonyl group has been added to the benzofuran ring. The design was intended to eliminate action of the parent drug on thyroxine metabolism and to modify the half-life of the drug. No thyroid dysfunction or pulmonary toxicity has been reported in short-term studies. However, liver toxicity, including two severe cases requiring liver transplantation, has been reported. Like amiodarone, dronedarone has multichannel actions, including blocking IKr, IKs, ICa, and INa. It also has β-adrenergic-blocking action. The drug has a half-life of 24 hours and can be administered twice daily at a fixed dose of 400 mg. Dronedarone absorption increases twofold to threefold when taken with food, and this information should be communicated to patients as a part of the dosing instructions. Dronedarone elimination is primarily nonrenal. It inhibits tubular secretion of


Pharmacology_Katzung

Pharmacology_Katzung. when taken with food, and this information should be communicated to patients as a part of the dosing instructions. Dronedarone elimination is primarily nonrenal. It inhibits tubular secretion of creatinine, resulting in a 10–20% increase in serum creatinine; however, because the glomerular filtration rate is unchanged, no adjustments are required. Dronedarone is both a substrate and an inhibitor of CY3A4 and should not be co-administered with potent inhibitors of this enzyme, such as the azole and similar antifungal agents, and protease inhibitors.


Pharmacology_Katzung

Pharmacology_Katzung. Dronedarone restores sinus rhythm in a small percentage of patients (< 15%) with atrial fibrillation. It produces a 10-to 15-bpm reduction of the ventricular rate compared to placebo. In one report, dronedarone doubled the interval between episodes of atrial fibrillation recurrence in patients with paroxysmal atrial fibrillation. Initial studies suggested a reduction in mortality or hospitalization in patients with atrial fibrillation. However, a study of dronedarone’s effects in permanent atrial fibrillation was terminated in 2011 because of increased risk of death, stroke, and heart failure. Similarly, a trial of dronedarone in advanced heart failure was terminated prematurely because of an increase in mortality. The drug carries a “black box” warning against its use in acute decompensated or advanced (class IV) heart failure.


Pharmacology_Katzung

Pharmacology_Katzung. Sotalol has both β-adrenergic receptor-blocking (class 2) and action potential-prolonging (class 3) actions. The drug is formulated as a racemic mixture of dand l-sotalol. All the β-adrenergic-blocking activity resides in the l-isomer; the dand l-isomers share action potential prolonging effects. Beta-adrenergic-blocking action is not cardioselective and is maximal at doses below those required for action potential prolongation.


Pharmacology_Katzung

Pharmacology_Katzung. Sotalol is well absorbed orally with bioavailability of nearly 100%. It is not metabolized in the liver and is not bound to plasma proteins. Excretion is predominantly by the kidneys in the unchanged form with a half-life of approximately 12 hours. Because of its relatively simple pharmacokinetics, sotalol exhibits few direct drug interactions. Its most significant cardiac adverse effect is an extension of its pharmacologic action: a dose-related incidence of torsades de pointes that approaches 6% at the highest recommended daily dose. Patients with overt heart failure may experience further depression of left ventricular function during treatment with sotalol. Sotalol is approved for the treatment of life-threatening ventricular arrhythmias and the maintenance of sinus rhythm in patients with atrial fibrillation. It is also approved for treatment of supraventricular and ventricular arrhythmias in the pediatric age group. Sotalol decreases the threshold for cardiac defibrillation.


Pharmacology_Katzung

Pharmacology_Katzung. Dofetilide has class 3 action potential prolonging action. This action is effected by a dose-dependent blockade of the rapid component of the delayed rectifier potassium current (IKr) and the blockade of IKr increases in hypokalemia. Dofetilide produces no relevant blockade of the other potassium channels or the sodium channel. Because of the slow rate of recovery from blockade, the extent of blockade shows little dependence on stimulation frequency. However, dofetilide does show less action potential prolongation at rapid rates because of the increased importance of other potassium channels such as IKs at higher frequencies.


Pharmacology_Katzung

Pharmacology_Katzung. Dofetilide is 100% bioavailable. Verapamil increases peak plasma dofetilide concentration by increasing intestinal blood flow. Eighty percent of an oral dose is eliminated unchanged by the kidneys; the remainder is eliminated in the urine as inactive metabolites. Inhibitors of the renal cation secretion mechanism, eg, cimetidine, prolong the half-life of dofetilide. Since the QT-prolonging effects and risks of ventricular proarrhythmia are directly related to plasma concentration, dofetilide dosage must be based on the estimated creatinine clearance. Treatment with dofetilide should be initiated in hospital after baseline measurement of the rate-corrected QT interval (QTc) and serum electrolytes. A baseline QTc of greater than 450 ms (500 ms in the presence of an intraventricular conduction delay), bradycardia of less than 50 bpm, and hypokalemia are relative contraindications to its use.


Pharmacology_Katzung

Pharmacology_Katzung. Dofetilide is approved for the maintenance of normal sinus rhythm in patients with atrial fibrillation. It is also effective in restoring normal sinus rhythm in patients with atrial fibrillation. Ibutilide, like dofetilide, slows cardiac repolarization by blockade of the rapid component (IKr) of the delayed rectifier potassium current. Activation of slow inward sodium current has also been suggested as an additional mechanism of action potential prolongation. After intravenous administration, ibutilide is rapidly cleared by hepatic metabolism and the elimination half-life averages 6 hours. The metabolites are excreted by the kidney.


Pharmacology_Katzung

Pharmacology_Katzung. Intravenous ibutilide is used for the acute conversion of atrial flutter and atrial fibrillation to normal sinus rhythm. The drug is more effective in atrial flutter than atrial fibrillation, with a mean time to termination of 20 minutes. The most important adverse effect is excessive QT-interval prolongation and torsades de pointes. Patients require continuous ECG monitoring for 4 hours after ibutilide infusion or until QTc returns to baseline. These drugs, of which verapamil is the prototype, were first introduced as antianginal agents and are discussed in greater detail in Chapter 12. Verapamil and diltiazem also have antiarrhythmic effects. The dihydropyridines (eg, nifedipine) do not share antiarrhythmic efficacy and may precipitate arrhythmias.


Pharmacology_Katzung

Pharmacology_Katzung. Verapamil blocks both activated and inactivated L-type calcium channels. Thus, its effect is more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current, such as the SA and AV nodes. AV nodal conduction time and effective refractory period are consistently prolonged by therapeutic concentrations. Verapamil usually slows the SA node by its direct action, but its hypotensive action may occasionally result in a small reflex increase of SA rate. Verapamil can suppress both early and delayed afterdepolarizations and may abolish slow responses arising in severely depolarized tissue. Verapamil causes peripheral vasodilation, which may be beneficial in hypertension and peripheral vasospastic disorders. Its effects on smooth muscle produce a number of extracardiac effects (see Chapter 12).


Pharmacology_Katzung

Pharmacology_Katzung. Verapamil’s cardiotoxic effects are dose-related and usually avoidable. A common error has been to administer intravenous verapamil to a patient with ventricular tachycardia misdiagnosed as supraventricular tachycardia. In this setting, hypotension and ventricular fibrillation can occur. Verapamil’s negative inotropic effects may limit its clinical usefulness in diseased hearts (see Chapter 12). Verapamil can induce AV block when used in large doses or in patients with AV nodal disease. This block can be treated with atropine and β-receptor stimulants. Adverse extracardiac effects include constipation, lassitude, nervousness, and peripheral edema. The half-life of verapamil is approximately 4–7 hours. It is extensively metabolized by the liver; after oral administration, its bioavailability is only about 20%. Therefore, verapamil must be administered with caution in patients with hepatic dysfunction or impaired hepatic perfusion.


Pharmacology_Katzung

Pharmacology_Katzung. In adult patients without heart failure or SA or AV nodal disease, parenteral verapamil can be used to terminate supraventricular tachycardia, although adenosine is the agent of first choice. Verapamil dosage is an initial bolus of 5 mg administered over 2–5 minutes, followed a few minutes later by a second 5 mg bolus if needed. Thereafter, doses of 5–10 mg can be administered every 4–6 hours, or a constant infusion of 0.4 mcg/kg/min may be used. Effective oral dosages are higher than intravenous dosage because of first-pass metabolism and range from 120 mg to 640 mg daily, divided into three or four doses.


Pharmacology_Katzung

Pharmacology_Katzung. Effective oral dosages are higher than intravenous dosage because of first-pass metabolism and range from 120 mg to 640 mg daily, divided into three or four doses. Supraventricular tachycardia is the major arrhythmia indication for verapamil. Adenosine or verapamil is preferred over older treatments (propranolol, digoxin, edrophonium, vasoconstrictor agents, and cardioversion) for termination. Verapamil can also reduce the ventricular rate in atrial fibrillation and flutter (“rate control”). It only rarely converts atrial flutter and fibrillation to sinus rhythm. Verapamil is occasionally useful in ventricular arrhythmias. However, intravenous verapamil in a patient with sustained ventricular tachycardia can cause hemodynamic collapse.


Pharmacology_Katzung

Pharmacology_Katzung. Diltiazem appears to be similar in efficacy to verapamil in the management of supraventricular arrhythmias, including rate control in atrial fibrillation. An intravenous form of diltiazem is available for the latter indication and causes hypotension or bradyarrhythmias relatively infrequently. Certain agents used for the treatment of arrhythmias do not fit the conventional class 1–4 organization. These include digitalis (see Chapter 13), adenosine, magnesium, and potassium. It is also becoming clear that certain nonantiarrhythmic drugs, such as drugs acting on the renin-angiotensin-aldosterone system, fish oil, and statins, can reduce recurrence of tachycardias and fibrillation in patients with coronary heart disease or congestive heart failure.


Pharmacology_Katzung

Pharmacology_Katzung. Adenosine is a nucleoside that occurs naturally throughout the body. Its half-life in the blood is less than 10 seconds. Its cardiac mechanism of action involves activation of an inward rectifier K+ current and inhibition of calcium current. The results of these actions are marked hyperpolarization and suppression of calcium-dependent action potentials. When given as a bolus dose, adenosine directly inhibits AV nodal conduction and increases the AV nodal refractory period but has lesser effects on the SA node. Adenosine is currently the drug of choice for prompt conversion of paroxysmal supraventricular tachycardia to sinus rhythm because of its high efficacy (90–95%) and very short duration of action. It is usually given in a bolus dose of 6 mg followed, if necessary, by a dose of 12 mg. An uncommon variant of ventricular tachycardia is adenosine-sensitive. The drug is less effective in the presence of adenosine receptor blockers such as theophylline or caffeine, and its effects are


Pharmacology_Katzung

Pharmacology_Katzung. An uncommon variant of ventricular tachycardia is adenosine-sensitive. The drug is less effective in the presence of adenosine receptor blockers such as theophylline or caffeine, and its effects are potentiated by adenosine uptake inhibitors such as dipyridamole.


Pharmacology_Katzung

Pharmacology_Katzung. It was recognized over 100 years ago that reentry in simple in vitro models (eg, rings of conducting tissues) was perma-nently interrupted by transecting the reentry circuit. This concept is now applied in cardiac arrhythmias with defined anatomic pathways—eg, atrioventricular reentry using accessory pathways, atrioventricular node reentry, atrial flutter, and some forms of ven-tricular tachycardia—by treatment with radiofrequency catheter ablation or extreme cold, cryoablation. Mapping of reentrant pathways and ablation can be carried out by means of catheters threaded into the heart from peripheral arteries and veins. Studies have also shown that paroxysmal and persistent atrial fibrillation may arise from one or more of the pulmonary veins. Both forms of atrial fibrillation can be cured by electrically isolating the pul-monary veins by radiofrequency or cryotherapy catheter ablation or during concomitant cardiac surgery. Because catheter ablation therapy can often permanently cure


Pharmacology_Katzung

Pharmacology_Katzung. by electrically isolating the pul-monary veins by radiofrequency or cryotherapy catheter ablation or during concomitant cardiac surgery. Because catheter ablation therapy can often permanently cure atrial fibrillation, and because it does not involve adverse effects of drugs, it has become a very common treatment for chronic atrial fibrillation. Another form of nonpharmacologic therapy is the implant-able cardioverter-defibrillator (ICD), a device that can auto-matically detect and treat potentially fatal arrhythmias such as ventricular fibrillation. ICDs are now widely used in patients who have been resuscitated from such arrhythmias, and several trials have shown that ICD treatment reduces mortality in patients with coronary artery disease who have an ejection fraction ≤ 30% and in patients with class II or III heart failure and no prior history of arrhythmias. The increasing use of nonpharmacologic antiarrhythmic therapies reflects both advances in the relevant technologies and an


Pharmacology_Katzung

Pharmacology_Katzung. with class II or III heart failure and no prior history of arrhythmias. The increasing use of nonpharmacologic antiarrhythmic therapies reflects both advances in the relevant technologies and an increasing appreciation of the dangers of long-term therapy with currently available drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Adenosine causes flushing in about 20% of patients and shortness of breath or chest burning (perhaps related to bronchospasm) in over 10%. Induction of high-grade AV block may occur but is very short-lived. Atrial fibrillation may occur. Less common toxicities include headache, hypotension, nausea, and paresthesias.


Pharmacology_Katzung

Pharmacology_Katzung. The localized expression of the “funny” current If in the SA node and its important role in pacemaker activity provide an attractive therapeutic target for heart rate control. Ivabradine is a selective blocker of If. It slows pacemaker activity by decreasing diastolic depolarization of sinus node cells. It is an open channel blocker that shows use-dependent block. Unlike other heart rate-lowering agents such as β blockers, it reduces heart rate without affecting myocardial contractility, ventricular repolarization, or intracardiac conduction. At therapeutic concentrations, block of If is not complete. As a result, autonomic control of the sinus node pacemaker rate is retained.


Pharmacology_Katzung

Pharmacology_Katzung. Elevated heart rate is an important determinant of the ischemic threshold in patients with coronary artery disease and a prognostic indicator in patients with congestive heart failure. Antianginal and anti-ischemic effects of ivabradine have been demonstrated in patients with coronary artery disease and chronic stable angina. In controlled clinical trials, ivabradine proved as effective as β blockers in the control of angina. In patients with left ventricular dysfunction and heart rates greater than 70 bpm, ivabradine reduced mean heart rate and the composite end points of cardiovascular mortality and hospitalization.


Pharmacology_Katzung

Pharmacology_Katzung. Inappropriate sinus tachycardia is an uncommon disorder characterized by multiple symptoms, including palpitations, dizziness, orthostatic intolerance, and elevated heart rates. Conventional treatment includes β blockers and nondihydropyridine calcium channel blockers. Recent case reports and one clinical trial have shown that ivabradine provides an effective alternative to slow the heart rate in patients with inappropriate sinus tachycardia. The drug is administered in doses of 5–10 mg as needed. Visual disturbances attributable to the block of the If channels in the retina have been described. This side effect is limited by the low permeability of ivabradine in the blood-brain barrier. Ivabradine is in use elsewhere but is currently approved only for use in heart failure in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. Ranolazine was originally developed as an antianginal agent. Subsequent studies have demonstrated antiarrhythmic properties that are dependent on the blockade of multiple ion channels. The drug blocks the early INa and the late component of the Na+ current, INaL, the latter having a tenfold higher sensitivity to the drug. The block of both components of the sodium current is frequencyand voltage-dependent. Ranolazine also blocks the rapid component of the delayed rectifier K+ current IKr. The blockade of both INaL and IKr results in opposing effects on the APD; the net effect depends on the relative contribution of INaL and IKr to the APD. In normal ventricular myocytes, the net effect is prolongation of the APD and the QT interval. In myocytes isolated from mice bearing long QT-associated mutations, the net effect is APD shortening. In normal atrial myocytes, the net effect is prolongation of the APD. At rapid rates, eg, during tachycardia, the atrial action potential arises from the


Pharmacology_Katzung

Pharmacology_Katzung. mutations, the net effect is APD shortening. In normal atrial myocytes, the net effect is prolongation of the APD. At rapid rates, eg, during tachycardia, the atrial action potential arises from the incompletely repolarized membrane and results in voltage-dependent reduction of INa. Ranolazine has relatively little effect on ICa and the remaining K+ currents at therapeutic concentrations.


Pharmacology_Katzung

Pharmacology_Katzung. Ranolazine had been shown to have antiarrhythmic properties in both atrial and ventricular arrhythmias. It prevents the induction of and may terminate atrial fibrillation. It is currently undergoing clinical trials in combination with dronedarone for the suppression of atrial fibrillation. Ranolazine has been shown to suppress ventricular tachycardia in ischemic models and in a major clinical trial of its effects in coronary artery disease. The drug has not yet received FDA approval as an antiarrhythmic drug.


Pharmacology_Katzung

Pharmacology_Katzung. Vernakalant is a multi-ion channel blocker, placing it in several classes of antiarrhythmic action. It causes frequencyand voltage-dependent block of the early and late components of the sodium current. The muscarinic potassium current IKACh, which is constitutively activated in atrial fibrillation, is blocked by vernakalant. The early-activating potassium channels Ito and Ikur are also blocked by the drug. These potassium channel currents play a more prominent role in atrial than ventricular repolarization. As a result, vernakalant produces only mild QT-interval prolongation. It does not produce torsades de pointes. Though not yet approved by the FDA, vernakalant can be administered intravenously for the rapid termination of atrial fibrillation in patients with no or minimal structural heart disease. In a direct comparison trial, vernakalant proved more effective than placebo or amiodarone in terminating atrial fibrillation in a 90-minute period. This relatively rapid action


Pharmacology_Katzung

Pharmacology_Katzung. heart disease. In a direct comparison trial, vernakalant proved more effective than placebo or amiodarone in terminating atrial fibrillation in a 90-minute period. This relatively rapid action decreases the required observation period for untoward side effects following drug administration. Sinus bradycardia and hypotension are the only noticeable cardiovascular adverse effects.


Pharmacology_Katzung

Pharmacology_Katzung. Originally used for patients with digitalis-induced arrhythmias who were hypomagnesemic, magnesium infusion has been found to have antiarrhythmic effects in some patients with normal serum magnesium levels. The mechanisms of these effects are not known, but magnesium is recognized to influence Na+/ K+-ATPase, sodium channels, certain potassium channels, and calcium channels. Magnesium therapy appears to be indicated in patients with digitalis-induced arrhythmias if hypomagnesemia is present; it is also indicated in some patients with torsades de pointes even if serum magnesium is normal. The usual dosage is 1 g (as sulfate) given intravenously over 20 minutes and repeated once if necessary. A full understanding of the action and indications for the use of magnesium as an antiarrhythmic drug awaits further investigation.


Pharmacology_Katzung

Pharmacology_Katzung. The significance of the potassium ion concentrations inside and outside the cardiac cell membrane was discussed earlier in this chapter. The effects of increasing serum K+ can be summarized as (1) a resting potential depolarizing action and (2) a membrane potential stabilizing action, the latter caused by increased potassium permeability. Hypokalemia results in an increased risk of early and delayed afterdepolarizations, and ectopic pacemaker activity, especially in the presence of digitalis. Hyperkalemia depresses ectopic pacemakers (severe hyperkalemia is required to suppress the SA node) and slows conduction. Because both insufficient and excess potassium are potentially arrhythmogenic, potassium therapy is directed toward normalizing potassium gradients and pools in the body.


Pharmacology_Katzung

Pharmacology_Katzung. Several types of chloride channels have been identified. At present, no drugs acting on chloride channels are in clinical use for cardiac indications. However, the chloride channels involved in cystic fibrosis and other conditions are of great clinical importance and have been the subject of intensive research (see Box: A Cystic Fibrosis Link in the Heart?). The margin between efficacy and toxicity is particularly narrow for antiarrhythmic drugs. Risks and benefits must be carefully considered (see Box: Antiarrhythmic Drug-Use Principles Applied to Atrial Fibrillation). Several important steps must be taken before initiation of any antiarrhythmic therapy: 1.


Pharmacology_Katzung

Pharmacology_Katzung. Several important steps must be taken before initiation of any antiarrhythmic therapy: 1. Eliminate the cause. Precipitating factors must be recognized and eliminated if possible. These include not only abnormalities of internal homeostasis, such as hypoxia or electrolyte abnormalities (especially hypokalemia or hypomagnesemia), but also drug therapy and underlying disease states such as hyperthyroidism or cardiac disease. It is important to separate this abnormal substrate from triggering factors, such as myocardial ischemia or acute cardiac dilation, which may be treatable and reversible by different means. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Make a firm diagnosis. A firm arrhythmia diagnosis should be established. For example, the misuse of verapamil in patients with ventricular tachycardia mistakenly diagnosed as supraventricular tachycardia can lead to catastrophic hypotension and cardiac arrest. As increasingly sophisticated methods to characterize underlying arrhythmia mechanisms become available and are validated, it may be possible to direct certain drugs toward specific arrhythmia mechanisms. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Determine the baseline condition. Underlying heart disease is a critical determinant of drug selection for a particular arrhythmia in a particular patient. A key question is whether the heart is structurally abnormal. Few antiarrhythmic drugs have documented safety in patients with congestive heart failure or ischemic heart disease. In fact, some drugs pose a documented proarrhythmic risk in certain disease states, eg, class 1C drugs in patients with ischemic heart disease. A reliable baseline should be established against which to judge the efficacy of any subsequent antiarrhythmic intervention. Several methods are now available for such baseline quantification. These include prolonged ambulatory monitoring, electrophysiologic studies that reproduce a target arrhythmia, reproduction of a target arrhythmia by treadmill exercise, or the use of transtelephonic monitoring for recording of sporadic but symptomatic arrhythmias. A Cystic Fibrosis Link in the Heart?


Pharmacology_Katzung

Pharmacology_Katzung. Cystic fibrosis is a serious autosomal-recessive inherited disease that causes defective Cl− secretion in the lung. The defective Cl− secretion is caused by mutations of the CFTR (cystic fibrosis transmembrane conductance regulator) Cl− channel, resulting in the generation of thick and dehydrated mucus and chronic bacterial infections. Although more than 1600 types of muta-tions have been identified in the CFTR gene, most current therapies to treat cystic fibrosis lung disease target downstream consequences of the disease that are secondary to loss of CFTR Cl− channel function. Recently, the FDA approved the use of a new CFTR potentiator drug, ivacaftor, for treatment of a subset of cystic fibrosis patients (4%) with a specific (G551D) mutation. Ivacaftor improves CFTR channel function, resulting in better lung function. Another CFTR modulator, crofelemer, which inhibits CFTR Cl− channels, has recently been approved by the FDA for the treatment of diarrhea induced by antiviral drugs.


Pharmacology_Katzung

Pharmacology_Katzung. in better lung function. Another CFTR modulator, crofelemer, which inhibits CFTR Cl− channels, has recently been approved by the FDA for the treatment of diarrhea induced by antiviral drugs. Surprisingly, recent studies have demonstrated the expression of CFTR Cl− channels in the heart, where they appear to modulate action potential duration and membrane potential during sym-pathetic stimulation. Various animal models of cardiac disease have suggested that CFTR Cl− channels may play a role in hyper-trophy and heart failure and may be cardioprotective against ischemia and reperfusion damage. The physiologic and patho-physiologic roles of CFTR Cl− channels in human heart remain to be defined clearly. It is not known if there are significant cardiac alterations in cystic fibrosis patients, and the possible effects of the two new CFTR channel modulators, ivacaftor and crofelemer, on heart function remain to be determined.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Question the need for therapy. The mere identification of an abnormality of cardiac rhythm does not necessarily require that the arrhythmia be treated. An excellent justification for conservative treatment was provided by the Cardiac Arrhythmia Suppression Trial (CAST) referred to earlier. The benefits of antiarrhythmic therapy are difficult to establish. Two types of benefits can be envisioned: reduction of arrhythmia-related symptoms, such as palpitations, syncope, or cardiac arrest; and reduction in long-term mortality in asymptomatic patients. Among drugs discussed here, only β blockers have been definitely associated with reduction of mortality in relatively asymptomatic patients, and the mechanism underlying this effect is not established (see Chapter 10).


Pharmacology_Katzung

Pharmacology_Katzung. Antiarrhythmic therapy carries with it a number of risks. In some cases, the risk of an adverse reaction is clearly related to high dosages or plasma concentrations. Examples include lidocaineinduced tremor or quinidine-induced cinchonism. In other cases, adverse reactions are unrelated to high plasma concentrations (eg, procainamide-induced agranulocytosis). For many serious adverse reactions to antiarrhythmic drugs, the combination of drug therapy and the underlying heart disease appears important.


Pharmacology_Katzung

Pharmacology_Katzung. Several specific syndromes of arrhythmia provocation by antiarrhythmic drugs have also been identified, each with its underlying pathophysiologic mechanism and risk factors. Drugs such as quinidine, sotalol, ibutilide, and dofetilide, which act—at least in part—by slowing repolarization and prolonging cardiac action potentials, can result in marked QT prolongation and torsades de pointes. Treatment for torsades requires recognition of the arrhythmia, withdrawal of any offending agent, correction of hypokalemia, and treatment with maneuvers to increase heart rate (pacing or isoproterenol); intravenous magnesium also appears effective, even in patients with normal magnesium levels.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs that markedly slow conduction, such as flecainide, or high concentrations of quinidine can result in an increased frequency of reentry arrhythmias, notably ventricular tachycardia in patients with prior myocardial infarction in whom a potential reentry circuit may be present. Treatment here consists of recognition, withdrawal of the offending agent, and intravenous sodium to reverse unidirectional block. Conduct of Antiarrhythmic Therapy


Pharmacology_Katzung

Pharmacology_Katzung. Conduct of Antiarrhythmic Therapy The urgency of the clinical situation determines the route and rate of drug initiation. When immediate drug action is required, the intravenous route is preferred. Therapeutic drug levels can be achieved by administration of multiple slow intravenous boluses. Drug therapy can be considered effective when the target arrhythmia is suppressed (according to the measure used to quantify it at baseline) and toxicities are absent. Conversely, drug therapy should not be considered ineffective unless toxicities occur at a time when arrhythmias are not suppressed. Monitoring plasma drug concentrations can be a useful adjunct to managing antiarrhythmic therapy. Plasma drug concentrations are also important in establishing compliance during long-term therapy as well as in detecting drug interactions that may result in very high concentrations at low drug dosages or very low concentrations at high dosages.


Pharmacology_Katzung

Pharmacology_Katzung. Atrial fibrillation is the most common sustained arrhythmia observed clinically. Its prevalence increases from approximately 0.5% in individuals younger than 65 years of age to 10% in indi-viduals older than 80. Diagnosis is usually straightforward by means of an ECG. The ECG may also enable the identification of a prior myocardial infarction, left ventricular hypertrophy, and ven-tricular pre-excitation. Hyperthyroidism is an important treatable cause of atrial fibrillation, and a thyroid panel should be obtained at the time of diagnosis to exclude this possibility. With the clini-cal history and physical examination as a guide, the presence and extent of the underlying heart disease should be evaluated, pref-erably using noninvasive techniques such as echocardiography. Treatment of atrial fibrillation is initiated to relieve patient symptoms and prevent the complications of thromboembolism and tachycardia-induced heart failure, the result of prolonged uncontrolled heart rates. The


Pharmacology_Katzung

Pharmacology_Katzung. fibrillation is initiated to relieve patient symptoms and prevent the complications of thromboembolism and tachycardia-induced heart failure, the result of prolonged uncontrolled heart rates. The initial treatment objective is con-trol of the ventricular rate. This is usually achieved by use of a calcium channel-blocking drug alone or in combination with a β-adrenergic blocker. Digoxin may be of value in the presence of heart failure. A second objective is a restoration and maintenance of normal sinus rhythm. Several studies show that rate control (maintenance of ventricular rate in the range of 60–80 bpm) has a better benefit-to-risk outcome than rhythm control (conversion to normal sinus rhythm) in the long-term health of patients with atrial fibrillation. If rhythm control is deemed desirable, sinus rhythm is usually restored by DC cardioversion in the USA. This is also the preferred strategy in an emergency, eg, atrial fibrillation associated with hypotension or angina. For the


Pharmacology_Katzung

Pharmacology_Katzung. desirable, sinus rhythm is usually restored by DC cardioversion in the USA. This is also the preferred strategy in an emergency, eg, atrial fibrillation associated with hypotension or angina. For the elective restora-tion of sinus rhythm, a single large oral dose of propefenone or flecainide may be used, provided that safety is initially docu-mented in a monitored setting. Intravenous ibutilide can also restore sinus rhythm promptly. The selection of a drug to maintain normal sinus rhythm depends on the presence and type of underlying heart disease. An example of an algorithm for drug selection is given in Figure 14–11. Antiarrhythmic drugs remain the preferred rhythm control strategy. However, a comparison of initial strategies for the mainte-nance of normal sinus rhythm is currently undergoing clinical trial. The pivotal role of oral anticoagulation in the prevention of stroke is established. Currently guidelines identify patients who are at particular risk and should undergo


Pharmacology_Katzung

Pharmacology_Katzung. undergoing clinical trial. The pivotal role of oral anticoagulation in the prevention of stroke is established. Currently guidelines identify patients who are at particular risk and should undergo long-term anticoagulation.


Pharmacology_Katzung

Pharmacology_Katzung. ESC: Heart failure, CAD, valvular heart disease, LVH ACCF/AHA/HRS: heart failure, CAD, valvular heart disease, LVH ESC: Includes LVH with preserved LV function CCS: Including CAD, LVH, and HFpEF disease with LVH AF AF Dronedarone Dronedarone ESC: Ablation possible Dronedarone Sotalol Amiodarone as first-line therapy Flecainide Amiodarone Dofetilide CCS: Sotalol when LVEF > 35%


Pharmacology_Katzung

Pharmacology_Katzung. Amiodarone Dofetilide CCS: Sotalol when LVEF > 35% FIGURE 14–11 Selection of rhythm control therapies depends on presence and nature of any underlying heart disease. Patients may be divided into two broad categories: those with and those without underlying heart disease. Patient with heart failure, left ventricular ejection fraction (LVEF) less than 35%, coronary artery disease (CAD), valvular heart disease, and left ventricular hypertrophy (LVH) fall into the first category. The second category includes patients with mild LVH and with heart failure but a preserved ejection fraction (HFpEF). The recommendations are based on the guidelines of the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), the Heart Rhythm Society (HRS), and the Canadian Cardiology Society (CCS). AF, atrial fibrillation; ESC, European Society of Cardiology; LV, left ventricle.


Pharmacology_Katzung

Pharmacology_Katzung. potential duration and dissociates from INa channel with intermediate arrhythmias • drug of second choice for most sustained ventricular arrhythmias associated with acute myocardial infarction Oral, IV, IM • eliminated by hepatic metabolism to N-acetylprocainamide (NAPA; see text) and renal elimination • NAPA implicated in torsades de pointes in patients with renal failure • Toxicity: Hypotension • long-term therapy Quinidine: Similar to procainamide but more toxic (cinchonism, torsades); rarely used in arrhythmias; see Chapter 52 for malaria Mexiletine: Orally active congener of lidocaine; used in ventricular arrhythmias, chronic pain syndromes Propafenone: Orally active, weak β-blocking activity; supraventricular arrhythmias; hepatic metabolism Moricizine: Phenothiazine derivative, orally active; ventricular arrhythmias, proarrhythmic. Withdrawn in USA. • Esmolol: Short-acting, IV only; used for intraoperative and other acute arrhythmias


Pharmacology_Katzung

Pharmacology_Katzung. Moricizine: Phenothiazine derivative, orally active; ventricular arrhythmias, proarrhythmic. Withdrawn in USA. • Esmolol: Short-acting, IV only; used for intraoperative and other acute arrhythmias Atrial arrhythmias and prevention of recurrent infarction and sudden death Oral, parenteral • duration 4–6 h • Toxicity: Asthma, AV blockade, acute heart failure • Interactions: With other cardiac depressants and hypotensive drugs


Pharmacology_Katzung

Pharmacology_Katzung. Oral, parenteral • duration 4–6 h • Toxicity: Asthma, AV blockade, acute heart failure • Interactions: With other cardiac depressants and hypotensive drugs CLASS 3 •AmiodaroneBlocks IKr, INa, ICa-L channels, βadrenoceptors Prolongs action potential duration andQTinterval•slowsheartrateandAVnodeconduction•lowincidence of torsades de pointes Serious ventricular arrhythmias and supraventricular arrhythmias Oral,IV•variableabsorptionandtissueaccumulation•hepaticmetabolism,eliminationcomplexandslow•Toxicity: Bradycardia and heart block in diseased heart, peripheral vasodilation, pulmonaryandhepatictoxicity•hyper-orhypothyroidism.•Interactions: Many, based on CYP metabolism •DofetilideIKr block Prolongs action potential, effective refractory period Maintenance or restoration of sinus rhythm in atrial fibrillation Oral•renalexcretion•Toxicity: Torsades de pointes (initiate in hospital with monitoring)•Interactions: Additive with other QT-prolonging drugs


Pharmacology_Katzung

Pharmacology_Katzung. Sotalol: β-Adrenergic and IKr blocker, direct action potential prolongation properties, use for ventricular arrhythmias, atrial fibrillation Ibutilide: Potassium channel blocker, may activate inward current; IV use for conversion in atrial flutter and fibrillation Dronedarone: Amiodarone derivative; multichannel actions, reduces mortality in patients with atrial fibrillation Vernakalant: Investigational in the USA, multichannel actions in atria, prolongs atrial refractoriness, effective in atrial fibrillation


Pharmacology_Katzung

Pharmacology_Katzung. GENERIC NAME AVAILABLE AS SODIUM CHANNEL BLOCKERS Disopyramide Generic, Norpace, Norpace CR Flecainide Generic, Tambocor Lidocaine Generic, Xylocaine Mexiletine Generic, Mexitil Procainamide Generic, Pronestyl, Procan-SR Propafenone Generic, Rythmol Quinidine sulfate (83% quinidine base) Generic Quinidine gluconate (62% quinidine base) Generic Quinidine polygalacturonate (60% quinidine base) Cardioquin BETA BLOCKERS LABELED FOR USE AS ANTIARRHYTHMICS Acebutolol Generic, Sectral Esmolol Generic, Brevibloc Propranolol Generic, Inderal CALCIUM CHANNEL BLOCKERS Diltiazem Generic, Cardizem GENERIC NAME AVAILABLE AS ACTION POTENTIAL-PROLONGING AGENTS Amiodarone Generic, Cordarone Dofetilide Tikosyn Dronedarone Multaq Ibutilide Generic, Corvert Sotalol Generic, Betapace Verapamil Generic, Calan, Isoptin MISCELLANEOUS Adenosine Generic, Adenocard Magnesium sulfate Generic DRUGS THAT ACT ON CHLORIDE CHANNELS Ivacaftor (labeled for use in cystic fibrosis) Kalydeco Crofelemer (labeled for use in


Pharmacology_Katzung

Pharmacology_Katzung. Isoptin MISCELLANEOUS Adenosine Generic, Adenocard Magnesium sulfate Generic DRUGS THAT ACT ON CHLORIDE CHANNELS Ivacaftor (labeled for use in cystic fibrosis) Kalydeco Crofelemer (labeled for use in diarrhea induced by anti-HIV drugs) Fulyzaq PREP AR A TIONS A V AIL ABLE


Pharmacology_Katzung

Pharmacology_Katzung. Antzelevitch C, Burashnikov A: Overview of basic mechanisms of cardiac arrhythmia. Card Electrophysiol Clin 2011;3:23. Bezzina CR, Lahrouchi N, Priori SG: Genetics of sudden cardiac death. Circ Res 2015;116:1919. Burashnikov A, Antzelevitch C: Role of late sodium channel block in the management of atrial fibrillation. Cardiovas Drugs Ther 2013;27:79. Chinitz JS et al: Rate or rhythm control for atrial fibrillation: Update and controversies. Am J Med 2012;125:1049. Cho HC, Marban E: Biological therapies for cardiac arrhythmias: Can genes and cells replace drugs and devices? Circ Res 2010;106:674. Das MK, Zipes DP: Antiarrhythmic and nonantiarrhythmic drugs for sudden cardiac death prevention. J Cardiovasc Pharmacol 2010;55:438. Duan D: Phenomics of cardiac chloride channels: The systemic study of chloride channel function in the heart. J Physiol 2009;587:2163.


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Pharmacology_Katzung. Duan D: Phenomics of cardiac chloride channels: The systemic study of chloride channel function in the heart. J Physiol 2009;587:2163. Echt DS et al, for the CAST Investigators: Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781. El-Sherif N, Boutjdir M: Role of pharmacotherapy in cardiac ion channelopathies. Pharmacol Ther 2015;155:132. El-Sherif N, Turitto G: Electrolyte disorders and arrhythmogenesis. Cardiol J 2011;18:233. Fedida D: Vernakalant (RSD1235): A novel, atrial-selective antifibrillatory agent. Expert Opin Investig Drugs 2007;16:519. Fuster V et al: ACC/AHA/ESC Guidelines for the management of patients with atrial fibrillation. Circulation 2006;114:700. George AL: Molecular and genetic basis of sudden cardiac death. J Clin Invest 2013;123:75. Grant AO: Cardiac ion channels. Circ Arrhythmia Electrophysiol 2009;2:185.


Pharmacology_Katzung

Pharmacology_Katzung. George AL: Molecular and genetic basis of sudden cardiac death. J Clin Invest 2013;123:75. Grant AO: Cardiac ion channels. Circ Arrhythmia Electrophysiol 2009;2:185. Hondeghem LM: Relative contributions of TRIaD and QT to proarrhythmia. J Cardiovasc Electrophysiol 2007;18:655. Kolettis TM: Coronary artery disease and ventricular arrhythmias: Pathophysiology and treatment. Curr Opin Pharm 2013;13:210. Li A, Behr ER: Advances in the management of atrial fibrillation. Clin Med 2012;12:544. Marrus SB, Nerbonne JM: Mechanisms linking shortand long-term electrical remodeling in the heart … Is it a stretch? Channels 2008;2:117. McPhail GL, Clancy JP: Ivacaftor: The first therapy acting on the primary cause of cystic fibrosis. Drugs Today 2013;49:253. Mohler PJ, Gramolini AO, Bennett V: Ankyrins. J Cell Biol 2002;115:1565. Monfredi O, Maltsev VA, Lakatta EG: Modern concepts concerning the origin of the heartbeat. Physiology 2013;28:74.


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Pharmacology_Katzung. Mohler PJ, Gramolini AO, Bennett V: Ankyrins. J Cell Biol 2002;115:1565. Monfredi O, Maltsev VA, Lakatta EG: Modern concepts concerning the origin of the heartbeat. Physiology 2013;28:74. Morady F: Catheter ablation of supraventricular arrhythmias: State of the art. J Cardiovasc Electrophysiol 2004;15:124. Roubille F, Tardif J-C: New therapeutic targets in cardiology, heart failure and arrhythmia: HCN channels. Circulation 2013;127:1986. 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. Tradtrantip L, Namkung W, Verkman AS: Crofelemer, an antisecretory antidiarrheal proanthocyandin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol 2010;77:69. Veerakul G, Nademanec K: Brugada syndrome: Two decades of progress. Circ J 2012;76:2713.


Pharmacology_Katzung

Pharmacology_Katzung. Veerakul G, Nademanec K: Brugada syndrome: Two decades of progress. Circ J 2012;76:2713. Vizzardi E et al: A focus on antiarrhythmic properties of ranolazine. J Cardiovasc Pharm Ther 2012;17:353. Wehrens XHT, Lehnart SE, Marks AR: Ryanodine receptor-targeted anti-arrhythmic therapy. NY Acad Sci 2005;1047:366. Wolbrette D et al: Dronedarone for the treatment of atrial fibrillation and atrial flutter: Approval and efficacy. Vasc Health Risk Manag 2010;6:517.


Pharmacology_Katzung

Pharmacology_Katzung. The patient has significant symptoms during recurrent epi-sodes of atrial fibrillation. She has multiple risk factors for thromboembolism (age, female gender, and hypertension). Therefore, she is a candidate for lifelong anticoagulation. Warfarin was the standard drug. The factor Xa (eg, apixa-ban, rivaroxiban) and the direct thrombin (eg, dabigatran) inhibitors are newer classes of anticoagulants that offer more patient-acceptable alternatives but at a higher cost. The peak heart rate in this patient’s atrial fibrillation is not particularly high. Maintenance of sinus rhythm appears to be important in this patient. The echocardiogram demon-strates impairment of left ventricular function. Selection of a drug that is tolerated in heart failure and has documented ability to convert or prevent atrial fibrillation, eg, dofetilide or amiodarone, would be appropriate. The use of catheter ablation for treatment of the initial episode of atrial fibril-lation is not the standard of care but is


Pharmacology_Katzung

Pharmacology_Katzung. atrial fibrillation, eg, dofetilide or amiodarone, would be appropriate. The use of catheter ablation for treatment of the initial episode of atrial fibril-lation is not the standard of care but is undergoing clinical trials.


Pharmacology_Katzung

Pharmacology_Katzung. Ramin Sam, MD, Harlan E. Ives, MD, PhD, & David Pearce, MD A 65-year-old man has a history of diabetes and chronic kidney disease with baseline creatinine of 2.2 mg/dL. Despite five different antihypertensive drugs, his clinic blood pres-sure is 176/92 mm Hg; he has mild dyspnea on exertion and 2–3+ edema on exam. He has been taking furosemide 80 mg twice a day for 1 year now. At the clinic visit, hydrochlorothi-azide 25 mg daily is added for better blood pressure control and also to treat symptoms and signs of fluid overload. Two weeks later, the patient presents to the emergency depart-ment with symptoms of weakness, anorexia, and generalized malaise. His blood pressure is now 91/58 mm Hg, and he has lost 15 kg in 2 weeks. His laboratory tests are signifi-cant for a serum creatinine of 10.8 mg/dL. What has led to the acute kidney injury? What is the reason for the weight loss? What precautions could have been taken to avoid this hospitalization?


Pharmacology_Katzung

Pharmacology_Katzung. Abnormalities in fluid volume and electrolyte composition are common and important clinical disorders. Drugs that block specific transport functions of the renal tubules are valuable clinical tools in the treatment of these disorders. Although various agents that increase urine volume (diuretics) have been described since antiquity, it was not until 1937 that carbonic anhydrase inhibitors were first described and not until 1957 that a much more useful and powerful diuretic agent (chlorothiazide) became available.


Pharmacology_Katzung

Pharmacology_Katzung. Technically, a “diuretic” is an agent that increases urine volume, whereas a “natriuretic” causes an increase in renal sodium excretion and an “aquaretic” increases excretion of solute-free water. Because natriuretics almost always also increase water excretion, they are usually called diuretics. Osmotic diuretics and antidiuretic hormone antagonists (see Agents That Alter Water Excretion) are aquaretics and are not directly natriuretic. Most recently, an entirely new class of agents has been developed that block urea transport. These agents result in increased urine output and increased urea excretion but not increased excretion of electrolytes. Even though they are technically aquaretics, they have also been referred to as urearetics. These agents are not yet available for therapy but are in early investigational stages.


Pharmacology_Katzung

Pharmacology_Katzung. This chapter is divided into three sections. The first section covers major renal tubule transport mechanisms. The nephron is divided structurally and functionally into several segments (Figure 15–1, Table 15–1). Several autacoids, which exert multiple, complex effects on renal physiology (adenosine, prostaglandins, and urodilatin, a renal autacoid closely related to atrial natriuretic peptide), are also discussed. The second section describes the pharmacology of diuretic agents. Many diuretics exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (vaptans, or vasopressin antagonists). The physiology of each nephron segment is closely linked to the basic pharmacology of the drugs acting there, which is discussed in the second section. The third section of the chapter


Pharmacology_Katzung

Pharmacology_Katzung. antagonists). The physiology of each nephron segment is closely linked to the basic pharmacology of the drugs acting there, which is discussed in the second section. The third section of the chapter describes the clinical applications of diuretics.


Pharmacology_Katzung

Pharmacology_Katzung. Sodium bicarbonate (NaHCO3), sodium chloride (NaCl), glucose, amino acids, and other organic solutes are reabsorbed via specific transport systems in the early proximal tubule Glomerulus tubule Proximal straight tubule Cortex Outer medulla Diuretics1 Acetazolamide/canagliflozin 2 Osmotic agents (mannitol, urearetics) 3 Loop agents (eg, furosemide) 4 Thiazides 5 Aldosterone antagonists 6 ADH antagonists Adenosine 2Thin descending limb H2O H2O H2O (+ADH) Inner medulla Loop of Henle Thin ascending limb Thick ascending limb Na+ K+ K+ 2Cl– Ca2+ Mg2+ convoluted tubule (+PTH) (+aldosterone) 124356277777 FIGURE 15–1 Tubule transport systems and sites of action of diuretics. ADH, antidiuretic hormone; PTH, parathyroid hormone.


Pharmacology_Katzung

Pharmacology_Katzung. (proximal convoluted tubule, PCT). Potassium ions (K+) are reabsorbed via the paracellular pathway. Water is reabsorbed passively, through both a transcellular pathway (mediated by a specific water channel, aquaporin-1 [AQP1]) and a paracellular pathway (likely mediated by claudin-2). Importantly, the water permeability of the PCT is very high, and hence, the osmolality of proximal tubular fluid is maintained at a nearly constant level, and the gradient from the tubule lumen to surrounding interstitium is very small. As tubule fluid is processed along the length of the proximal tubule, the luminal concentrations of most solutes decrease relative to the concentration of inulin, an experimental marker that is filtered but neither secreted nor absorbed by renal tubules. Approximately 66% of filtered sodium ions (Na+), 85% of the NaHCO3, 65% of the K+, 60% of the water, and virtually all of the filtered glucose and amino acids are reabsorbed by the proximal tubule in normal humans.


Pharmacology_Katzung

Pharmacology_Katzung. Of the various solutes reabsorbed in the proximal tubule, the most relevant to diuretic action are NaHCO3 and NaCl. Until recently, of the currently available diuretics, only one group (carbonic anhydrase inhibitors, which block NaHCO3 reabsorption) has acted predominantly in the PCT. Sodium bicarbonate reabsorption by the PCT is initiated by the action of a Na+/ exchanger (NHE3) located in the luminal membrane of the proximal tubule epithelial cell (Figure 15–2). This transport system allows Na+ to enter the cell from the tubular lumen in exchange for a proton (H+) from inside the cell. As in all portions of the nephron, Na+/K+-ATPase in the basolateral membrane pumps the reabsorbed Na+ into the interstitium in order to maintain a low intracellular Na+ concentration. The H+ secreted into the lumen combines with bicarbonate (HCO3−) to form H2CO3 (carbonic acid), which is rapidly dehydrated to CO2 and H2O by carbonic anhydrase. Carbon dioxide produced by dehydration of H2CO3 enters the


Pharmacology_Katzung

Pharmacology_Katzung. the lumen combines with bicarbonate (HCO3−) to form H2CO3 (carbonic acid), which is rapidly dehydrated to CO2 and H2O by carbonic anhydrase. Carbon dioxide produced by dehydration of H2CO3 enters the proximal tubule cell by simple diffusion, where it is then rehydrated back to H2CO3, facilitated by intracellular carbonic anhydrase. After dissociation of H2CO3, the H+ is available for transport by the Na+/H+ exchanger, and the HCO3− is transported out of the cell by a basolateral membrane transporter (Figure 15–2). Bicarbonate reabsorption by the proximal tubule is thus dependent on carbonic anhydrase activity. This enzyme


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 15–1 Major segments of the nephron and their functions. Glomerulus Formation of glomerular filtrate Extremely high None Proximal convoluted Reabsorption of 65% of filtered Na+/K+/ Very high Na/H1 (NHE3), carbonic tubule (PCT) CA2+, and Mg2+; 85% of NaHCO3, and nearly anhydrase; Na/glucose 100% of glucose and amino acids. Isosmotic cotransporter 2 (SGLT2) reabsorption of water. Proximal tubule, straight Secretion and reabsorption of organic acids Very high Acid (eg, uric acid) and segments and bases, including uric acid and most Carbonic anhydrase inhibi-tors, Adenosine antagonists (under investigation) Thin descending limb Passive reabsorption of water High Aquaporins None of Henle’s loop Thick ascending limb of Active reabsorption of 15–25% of filtered Very low Na/K/2Cl (NKCC2) Loop diuretics Henle’s loop (TAL) Na+/K+/Cl−; secondary reabsorption of CA2+


Pharmacology_Katzung

Pharmacology_Katzung. Thick ascending limb of Active reabsorption of 15–25% of filtered Very low Na/K/2Cl (NKCC2) Loop diuretics Henle’s loop (TAL) Na+/K+/Cl−; secondary reabsorption of CA2+ Distal convoluted tubule Active reabsorption of 4–8% of filtered Na+ Very low Na/Cl (NCC) Thiazides (DCT) and Cl−; CA2+ reabsorption under parathy-roid Cortical collecting Na+ reabsorption (2–5%) coupled to K+ and Variable2 Na channels (ENaC), K+-sparing diuretics tubule (CCT) H+ secretion K channels,1 H+ trans-Adenosine antagonists porter,1 aquaporins (under investigation) 1Not a target of currently available drugs. 2Controlled by vasopressin activity.


Pharmacology_Katzung

Pharmacology_Katzung. K channels,1 H+ trans-Adenosine antagonists porter,1 aquaporins (under investigation) 1Not a target of currently available drugs. 2Controlled by vasopressin activity. FIGURE 15–2 Apical membrane Na+/H+ exchange (via NHE3) and bicarbonate reabsorption in the proximal convoluted tubule cell. Na+/K+-ATPase is present in the basolateral membrane to maintain intracellular sodium and potassium levels within the normal range. Because of rapid equilibration, concentrations of the solutes are approximately equal in the interstitial fluid and the blood. Carbonic anhydrase (CA) is found in other locations in addition to the brush border of the luminal membrane. SGLT2, Na+/glucose transporter. can be inhibited by acetazolamide and other carbonic anhydrase inhibitors.


Pharmacology_Katzung

Pharmacology_Katzung. can be inhibited by acetazolamide and other carbonic anhydrase inhibitors. More recently, inhibitors of the sodium-glucose cotransporter, isoform 2 (SGLT2; Figure 15–2) have been approved to treat diabetes mellitus. The sodium-glucose cotransporter is responsible for reabsorbing much of the glucose that is filtered by the glomeruli. Although not indicated as diuretic agents, these drugs have diuretic properties accompanied by increased sodium and glucose excretion (see below). The diuretic properties are thought to result from mainly osmotic diuresis.


Pharmacology_Katzung

Pharmacology_Katzung. Organic acid secretory systems are located in the middle third of the straight part of the proximal tubule (S2 segment). These systems secrete a variety of organic acids (uric acid, nonsteroidal anti-inflammatory drugs [NSAIDs], diuretics, antibiotics, etc) into the luminal fluid from the blood. These systems thus help deliver diuretics to the luminal side of the tubule, where most of them act. Organic base secretory systems (creatinine, choline, etc) are also present, in the early (S1) and middle (S2) segments of the proximal tubule.


Pharmacology_Katzung

Pharmacology_Katzung. At the boundary between the inner and outer stripes of the outer medulla, the proximal tubule empties into the thin descending limb of Henle’s loop. Water is extracted from the descending limb of this loop by osmotic forces found in the hypertonic medullary interstitium. As in the proximal tubule, impermeant luminal solutes such as mannitol oppose this water extraction and thus have aquaretic activity. The thin ascending limb is relatively water-impermeable but is permeable to some solutes. Lumen-urine Thick ascending limb Interstitium-blood Na+ Na+ K+ K+ K+ K+ Cl – 2Cl– (+) Potential Mg2+, Ca2+ NKCC2 ATP FIGURE 15–3 Ion transport pathways across the luminal and basolateral membranes of the thick ascending limb cell. The lumen positive electrical potential created by K+ back diffusion drives divalent (and monovalent) cation reabsorption via the paracellular pathway. NKCC2 is the primary transporter in the luminal membrane.


Pharmacology_Katzung

Pharmacology_Katzung. The thick ascending limb (TAL), which follows the thin limb of Henle’s loop, actively reabsorbs NaCl from the lumen (about 25% of the filtered sodium), but unlike the proximal tubule and the thin descending limb of Henle’s loop, it is nearly impermeable to water. Salt reabsorption in the TAL therefore dilutes the tubular fluid, and for this reason, the TAL is called a diluting segment. Medullary portions of the TAL contribute to medullary hypertonicity and thereby also play an important role in concentration of urine by the collecting duct.


Pharmacology_Katzung

Pharmacology_Katzung. The NaCl transport system in the luminal membrane of the TAL is a Na+/K+/2Cl− cotransporter (called NKCC2 or NK2CL) (Figure 15–3). This transporter is selectively blocked by diuretic agents known as “loop” diuretics (discussed later in chapter). Although the Na+/K+/2Cl− transporter is itself electrically neutral (two cations and two anions are cotransported), the action of the transporter contributes to excess K+ accumulation within the cell. Back diffusion of this K+ into the tubular lumen (via the ROMK channel) causes a lumen-positive electrical potential that provides the driving force for reabsorption of cat-ions—including magnesium and calcium—via the paracellular pathway. Thus, inhibition of salt transport in the TAL by loop diuretics, which reduces the lumen-positive potential, causes an increase in urinary excretion of divalent cations in addition to NaCl.


Pharmacology_Katzung

Pharmacology_Katzung. Only about 10% of the filtered NaCl is reabsorbed in the distal convoluted tubule (DCT). Like the TAL of Henle’s loop, this segment is relatively impermeable to water, and NaCl reabsorption further dilutes the tubular fluid. The mechanism of NaCl FIGURE 15–4 Ion transport pathways across the luminal and basolateral membranes of the distal convoluted tubule cell. As in all tubular cells, Na+/K+-ATPase is present in the basolateral membrane. NCC is the primary sodium and chloride transporter in the luminal membrane. R, parathyroid hormone (PTH) receptor. transport in the DCT is an electrically neutral thiazide-sensitive Na+/Cl− cotransporter (NCC; Figure 15–4).


Pharmacology_Katzung

Pharmacology_Katzung. transport in the DCT is an electrically neutral thiazide-sensitive Na+/Cl− cotransporter (NCC; Figure 15–4). Because K+ does not recycle across the apical membrane of the DCT as it does in the TAL, there is no lumen-positive potential in this segment, and Ca2+ and Mg2+ are not driven out of the tubular lumen by electrical forces. Instead, Ca2+ is actively reabsorbed by the DCT epithelial cell via an apical Ca2+ channel and basolateral Na+/Ca2+ exchanger (Figure 15–4). This process is regulated by parathyroid hormone.