Page 257 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 14 Agents Used in Cardiac Arrhythmias 243

to those of flecainide. Propafenone is metabolized in the liver, torsades de pointes. Other important factors in addition to QT
with an average half-life of 5–7 hours. The usual daily dosage of prolongation include action potential stability and development
propafenone is 450–900 mg/d in three divided doses. The drug of a triangular shape (triangulation), reverse use-dependence, and
is used primarily for supraventricular arrhythmias. The most dispersion of repolarization time across the ventricles.
common adverse effects are a metallic taste and constipation;
arrhythmia exacerbation can also occur.
AMIODARONE
MORICIZINE (SUBGROUP 1C) In the USA, amiodarone is approved for oral and intravenous use
to treat serious ventricular arrhythmias. However, the drug is also
Moricizine is an antiarrhythmic phenothiazine derivative that was highly effective in the treatment of supraventricular arrhythmias
used for treatment of ventricular arrhythmias. It is a relatively such as atrial fibrillation. As a result of its broad spectrum of
potent sodium channel blocker that does not prolong action poten- antiarrhythmic action, it is very extensively used for a wide variety
tial duration. Moricizine has been withdrawn from the US market. of arrhythmias. Amiodarone has unusual pharmacokinetics and
important extracardiac adverse effects. Dronedarone, an analog
BETA-ADRENOCEPTOR-BLOCKING that lacks iodine atoms, has US Food and Drug Administration
(FDA) approval for the treatment of atrial flutter and fibrillation.
DRUGS (CLASS 2) Celivarone is another noniodinated benzofuran derivative similar
to dronedarone that is currently undergoing clinical trials for the
Propranolol and similar drugs have antiarrhythmic properties prevention of ventricular tachycardia recurrence.
by virtue of their β-receptor-blocking action and direct mem-
brane effects. As described in Chapter 10, some of these drugs O I
H
have selectivity for cardiac β receptors, some have intrinsic C O CH CH N N C 2 5
1
sympathomimetic activity, some have marked direct membrane 2 2 C H
2 5
effects, and some prolong the cardiac action potential. The rela- I
tive contributions of the β-blocking and direct membrane effects O CH 2 CH 2 CH 2 CH 3
to the antiarrhythmic effects of these drugs are not fully known. Amiodarone
Although β blockers are fairly well tolerated, their efficacy for
suppression of ventricular ectopic depolarizations is lower than Cardiac Effects
that of sodium channel blockers. However, there is good evidence Amiodarone markedly prolongs the action potential duration (and
that these agents can prevent recurrent infarction and sudden the QT interval on the ECG) by blockade of I . During chronic
Kr
death in patients recovering from acute myocardial infarction administration, I is also blocked. The action potential duration
Ks
(see Chapter 10). is prolonged uniformly over a wide range of heart rates; that is,
Esmolol is a short-acting β blocker used primarily as an anti- the drug does not have reverse use-dependent action. Despite
arrhythmic drug for intraoperative and other acute arrhythmias. its present classification as a class 3 agent, amiodarone also sig-
See Chapter 10 for more information. Sotalol is a nonselective nificantly blocks inactivated sodium channels. Its action potential-
β-blocking drug that prolongs the action potential (class 3 action). prolonging action reinforces this effect. Amiodarone also has weak
adrenergic and calcium channel-blocking actions. Consequences
DRUGS THAT PROLONG of these actions include slowing of the heart rate and AV node
EFFECTIVE REFRACTORY PERIOD conduction. The broad spectrum of actions may account for its
relatively high efficacy and its low incidence of torsades de pointes
BY PROLONGING THE ACTION despite significant QT-interval prolongation.
POTENTIAL (CLASS 3)
Extracardiac Effects
These drugs prolong action potentials, usually by blocking potas- Amiodarone causes peripheral vasodilation. This action is promi-
sium channels in cardiac muscle or by enhancing inward current, nent after intravenous administration and may be related to the
eg, through sodium channels. Action potential prolongation by action of the vehicle.
most of these drugs exhibits the undesirable property of “reverse
use-dependence”: action potential prolongation is least marked Toxicity
at fast rates (where it is desirable) and most marked at slow rates,
where it can contribute to the risk of torsades de pointes. Amiodarone may produce symptomatic bradycardia and heart
Although most drugs in the class cause QT prolongation, block in patients with preexisting sinus or AV node disease. The
there is considerable variability among drugs in their proarrhyth- drug accumulates in many tissues, including the heart (10–50
mic tendency to cause torsades de pointes despite significant QT- times more so than in plasma), lung, liver, and skin, and is con-
interval prolongation. Recent studies suggest that excessive QT centrated in tears. Dose-related pulmonary toxicity is the most
prolongation alone may not be the best predictor of drug-induced important adverse effect. Even on a low dose of 200 mg/d or