DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

840 atrial fibrillation. However, dronedarone increases
mortality in patients with severe heart failure and is
contraindicated in patients with NYHA class 4 heart
failure and in patients with a recent decompensation of
heart failure requiring hospitalization.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
CH 3 SO 2 NH
O
O
C 4 H 9
O (CH 2 ) 3 N
C 4 H 9
C 4 H 9
DRONEDARONE
Pharmacologic Effects. Similar to amiodarone, dronedarone
is a potent blocker of multiple ion currents,
including the rapidly activating delayed-rectifier K +
current (I Kr
), the slowly activating delayed-rectifier K +
current (I Ks
), the inward rectifier K + current (I K1
), the
acetylcholine activated K + current, the peak Na + current,
and the L-type Ca 2+ current. It has stronger antiadrenergic
effects than amiodarone.
Adverse Effects and Drug Interactions. The most common adverse
reactions are diarrhea, nausea, abdominal pain, vomiting, and
asthenia. Dronedarone causes dose-dependent prolongation of QTc
interval, but torsades de pointes is rare. Dronedarone is metabolized
by CYP3A and is a moderate inhibitor of CYP3A, CYP2D6,
and P-glycoprotein. A potent CYP3A4 inhibitor such as ketoconazole
may increase dronedarone exposure by as much as 25-fold.
Consequently, dronedarone should not be co-administered with
potent CYP3A4 inhibitors (e.g., antifungals, macrolide antibiotics).
Co-administration with other drugs metabolized by CYP2D6 (e.g.,
metoprolol) or P-glycoprotein (e.g., digoxin) may result in
increased drug concentrations.
Esmolol. (BREVIBLOC, others) is a β 1
-selective agent that
is metabolized by erythrocyte esterases and so has a
very short elimination t 1/2
(9 minutes). Intravenous
esmolol is useful in clinical situations in which immediate
β adrenergic blockade is desired (e.g., for rate
control of rapidly conducted atrial fibrillation). Because
of esmolol’s very rapid elimination, adverse effects due
to β adrenergic blockade—should they occur—dissipate
rapidly when the drug is stopped. Although
methanol is a metabolite of esmolol, methanol intoxication
has not been a clinical problem. Its pharmacology
is described in detail in Chapter 12.
Flecainide. The effects of flecainide (TAMBOCOR, others)
therapy are thought to be attributable to the drug’s very
long τ recovery
from Na + channel block (Roden and
Woosley, 1986). In the CAST study, flecainide
increased mortality in patients convalescing from MI
(CAST Investigators, 1989). However, it continues to
be approved for the maintenance of sinus rhythm in
patients with supraventricular arrhythmias, including
atrial fibrillation, in whom structural heart disease is
absent (Anderson et al., 1989; Henthorn et al., 1991)
and for life-threatening ventricular arrhythmias, such
as sustained ventricular tachycardia.
CF 3 CH 2 O
CONHCH 2
OCH 2 CF 3
FLECAINIDE
Pharmacologic Effects. Flecainide blocks Na + current and
delayed-rectifier K + current (I Kr
) in vitro at similar concentrations,
1 to 2 M (Ikeda et al., 1985; Follmer and
Colatsky, 1990). It also blocks Ca 2+ currents in vitro.
APD is shortened in Purkinje cells, probably owing to
block of late-opening Na + channels, but prolonged in
ventricular cells, probably owing to block of delayedrectifier
current (Ikeda et al., 1985). Flecainide does not
cause EADs in vitro but has been associated with rare
cases of torsades de pointes. In atrial tissue, flecainide
disproportionately prolongs action potentials at fast
rates, an especially desirable anti-arrhythmic drug
effect; this effect contrasts with that of quinidine, which
prolongs atrial action potentials to a greater extent at
slower rates (Wang et al., 1990). Flecainide prolongs the
duration of PR, QRS, and QT intervals even at normal
heart rates. Flecainide also is an open channel blocker of
RyR2 Ca 2+ release channels and prevents arrhythmogenic
Ca 2+ release from the sarcoplasmic reticulum in
isolated myocytes (Hilliard et al., 2010). The blockade
of the RyR2 channel by flecainide targets directly the
underlying molecular defect in patients with mutations
in the ryanodine receptor and cardiac calsequestrin,
which may explain why flecainide suppresses ventricular
arrhythmias in CPVT patients refractory to standard
drug therapy (Watanabe et al., 2009).
Adverse Effects. Flecainide produces few subjective complaints in
most patients; dose-related blurred vision is the most common noncardiac
adverse effect. It can exacerbate congestive heart failure in
patients with depressed left ventricular performance. The most serious
adverse effects are provocation or exacerbation of potentially
lethal arrhythmias. These include acceleration of ventricular rate
in patients with atrial flutter, increased frequency of episodes of
re-entrant ventricular tachycardia, and increased mortality in patients
convalescing from MI (Crijns et al., 1988; CAST Investigators,
1989). As discussed earlier, it is likely that all these effects can be
attributed to Na + channel block. Flecainide also can cause heart
block in patients with conduction system disease.
Clinical Pharmacokinetics. Flecainide is well absorbed. The elimination
t 1/2
is shorter with urinary acidification (10 hours) than with
urinary alkalinization (17 hours), but it is nevertheless sufficiently
long to allow dosing twice daily (Table 29–5). Elimination occurs
by both renal excretion of unchanged drug and hepatic metabolism
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