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

Quinidine metabolism is induced by drugs such as phenobarbital
and phenytoin (Data et al., 1976). In patients receiving these
agents, very high doses of quinidine may be required to achieve therapeutic
concentrations. If therapy with the inducing agent is then
stopped, quinidine concentrations may rise to very high levels, and
its dosage must be adjusted downward. Cimetidine and verapamil
also elevate plasma quinidine concentrations, but these effects usually
are modest.
Sotalol. Sotalol (BETAPACE, BETAPACE AF) is a nonselective
β adrenergic receptor antagonist that also prolongs
cardiac action potentials by inhibiting delayed-rectifier
and possibly other K + currents (Hohnloser and
Woosley, 1994). Sotalol is prescribed as a racemate; the
L-enantiomer is a much more potent β adrenergic receptor
antagonist than the D-enantiomer, but the two are
equipotent as K + channel blockers. Its structure is
shown below:
CH 3 SO 2 NH
OH
SOTALOL
CHCH 2 NHCH(CH 3 ) 2
In the U.S., sotalol is an orphan drug approved for use
in patients with both ventricular tachyarrhythmias
(BETAPACE) and atrial fibrillation or flutter (BETAPACE AF).
Clinical trials suggest that it is at least as effective as
most Na + channel blockers in ventricular arrhythmias
(Mason, 1993).
Sotalol prolongs APD throughout the heart and QT
interval on the ECG. It decreases automaticity, slows AV
nodal conduction, and prolongs AV refractoriness by
blocking both K + channels and β adrenergic receptors,
but it exerts no effect on conduction velocity in fastresponse
tissue. Sotalol causes EADs and triggered activity
in vitro and can cause torsades de pointes, especially
when the serum K + concentration is low. Unlike the situation
with quinidine, the incidence of torsades de
pointes (1.5-2% incidence) seems to depend on the dose
of sotalol; indeed, torsades de pointes is the major toxicity
with sotalol overdose. Occasional cases occur at low
dosages, often in patients with renal dysfunction, because
sotalol is eliminated by renal excretion of unchanged
drug. The other adverse effects of sotalol therapy are
those associated with β receptor blockade (see earlier in
this chapter and Chapter 12).
Vernakalant. Vernakalant (RSD1235, proposed tradename
KYNAPID) is an investigational inhibitor of several
ion channels that are preferentially expressed in
the atria, in particular the ultra-rapidly activating
delayed-rectifier K + current (I Kur
encoded by Kv1.5).
To a lesser extent, it also blocks the rapidly activating
delayed-rectifier K + current (I Kr
), the transient outward
K + current (I to
), the Na + current, and the L-type Ca 2+
current. Vernakalant selectively prolongs the atrial
refractory period without significantly affecting ventricular
refractoriness.
O
O
Vernakalant is effective for converting atrial fibrillation
of short duration to sinus rhythm (Roy et al., 2008).
Vernakalant (3 mg/kg) is administered as a 10-minute
infusion, followed by a second infusion of 2 mg/kg 15
minutes later if AF is not terminated. Vernakalant is not
effective in converting long-duration AF (7 days) or
atrial flutter. The intravenous formulation of vernakalant
was recommended for approval by an FDA
advisory committee in 2008, but the drug has not
received FDA approval at the time of this printing. An
oral formulation is currently in clinical trials for the
maintenance of sinus rhythm in patients with chronic
atrial fibrillation. Vernakalant seems to have little or no
proarrhythmic effects, with no reported cases of torsades
de pointes in phase II and III studies.
Vernakalant is metabolized by rapidly by CYP2D6 to one
major and inactive metabolite (RSD1385) via 4-O-demethylation
(Mao et al., 2009). There appears to be little difference in C max
between extensive and poor 2D6 metabolizers after single-dose IV
administration. However, average t 1/2
of vernakalant was much longer
in two poor metabolizers (8.5 hours) than in 10 extensive metabolizers
(2.7 hours). This profound difference in t 1/2
will be important if
vernakalant is used chronically to prevent atrial fibrillation.
BIBLIOGRAPHY
Akiyama T, Pawitan Y, Greenberg H, et al. Increased risk of
death and cardiac arrest from encainide and flecainide in
patients after non-Q-wave acute myocardial infarction in
the Cardiac Arrhythmia Suppression Trial. The CAST
Investigators. Am J Cardiol, 1991, 68:1551–1555.
Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic
amiodarone on mortality after acute myocardial
infarction and in congestive heart failure—Meta-analysis of
individual data from 6500 patients in randomised trials.
Lancet, 1997, 350:1417–1424.
Anderson JL, Gilbert EM, Alpert BL, et al. Prevention of symptomatic
recurrences of paroxysmal atrial fibrillation in patients
O
VERNAKALANT
N
OH
845
CHAPTER 29
ANTI-ARRHYTHMIC DRUGS