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

830 nodal function permits a greater number of impulses to
penetrate the ventricle, and heart rate actually may
increase (Figure 29–9). Thus, atrial flutter rate may
drop from 300/minute, with 2:1 or 4:1 AV conduction
(i.e., a heart rate of 150 or 75 beats/minute), to 220 per
minute, but with 1:1 transmission to the ventricle (i.e.,
a heart rate of 220 beats/minute), with potentially disastrous
consequences. This form of drug-induced
arrhythmia is especially common during treatment with
quinidine because the drug also increases AV nodal
conduction through its vagolytic properties; flecainide
and propafenone also have been implicated. Therapy
with Na + channel blockers in patients with re-entrant
ventricular tachycardia after a myocardial infarction
(MI) can increase the frequency and severity of arrhythmic
episodes. Although the mechanism is unclear,
slowed conduction allows the re-entrant wavefront
to persist within the tachycardia circuit. Such drugexacerbated
arrhythmia can be very difficult to manage,
and deaths owing to intractable drug-induced
ventricular tachycardia have been reported. In this setting,
Na + infusion may be beneficial. Several Na + channel
blockers (e.g., procainamide, quinidine) have been
reported to exacerbate neuromuscular paralysis by D-
tubocurarine (Chapter 11).
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Action Potential Prolongation. Most drugs that prolong
the action potential do so by blocking K + channels,
although enhanced inward Na + current also can cause
prolongation. Enhanced inward current may underlie
QT prolongation (and arrhythmia suppression) by ibutilide.
Block of cardiac K + channels increases APD
and reduces normal automaticity (Figure 29–10D).
Increased APD, seen as an increase in QT interval,
increases refractoriness (Figure 29–11) and therefore
should be an effective way of treating re-entry (Task
Force, 1991). Experimentally, K + channel block produces
a series of desirable effects: reduced defibrillation
energy requirement, inhibition of VF owing to
acute ischemia, and increased contractility (Roden,
1993). As shown in Table 29–3, most K + channel–
blocking drugs also interact with β adrenergic receptors
(sotalol) or other channels (e.g., amiodarone, quinidine).
Amiodarone and sotalol appear to be at least as effective
as drugs with predominant Na + channel–blocking
properties in both atrial and ventricular arrhythmias.
“Pure” action potential–prolonging drugs (e.g.,
dofetilide, ibutilide) also are available (Murray, 1998;
Torp-Pedersen et al., 1999).
Toxicity of Drugs That Prolong QT Interval. Most of
these agents disproportionately prolong cardiac action
potentials when underlying heart rate is slow and can
cause torsades de pointes (Table 29–1 and Figure
29–9). While this effect usually is seen with QT-prolonging
anti-arrhythmic drugs, it can occur more rarely
with drugs that are used for noncardiac indications. For
such agents, the risk of torsades de pointes may become
apparent only after widespread use postmarketing, and
recognition of this risk has been a common cause for
drug withdrawal (Roden, 2004). Recent research has
shown that sex hormones modify cardiac ion channels
and help account for the clinically observed increased
incidence of drug-induced torsades de pointes in
women (Kurokawa et al., 2009).
Ca 2+ Channel Block. The major electrophysiologic effects
resulting from block of cardiac Ca 2+ channels are in
nodal tissues. Dihydropyridines, such as nifedipine,
which are used commonly in angina and hypertension
(Chapter 28), preferentially block Ca 2+ channels in vascular
smooth muscle; their cardiac electrophysiologic
effects, such as heart rate acceleration, result principally
from reflex sympathetic activation secondary to peripheral
vasodilation. Only verapamil, diltiazem, and
bepridil block Ca 2+ channels in cardiac cells at clinically
used doses. These drugs generally slow heart rate
(Figure 29–10A), although hypotension, if marked, can
cause reflex sympathetic activation and tachycardia.
The velocity of AV nodal conduction decreases, so the
PR interval increases. AV nodal block occurs as a result
of decremental conduction, as well as increased AV
nodal refractoriness. These latter effects form the basis
of the anti-arrhythmic actions of Ca 2+ channel blockers
in re-entrant arrhythmias whose circuit involves the AV
node, such as AV re-entrant tachycardia (Figure 29–7).
Another important indication for anti-arrhythmic
therapy is to reduce ventricular rate in atrial flutter or
fibrillation. Rare forms of ventricular tachycardia
appear to be DAD-mediated and respond to verapamil
(Sung et al., 1983). Parenteral verapamil and diltiazem
are approved for rapid conversion of PSVTs to sinus
rhythm and for temporary control of rapid ventricular
rate in atrial flutter or fibrillation. Oral verapamil may be
used in conjunction with digoxin to control ventricular
rate in chronic atrial flutter or fibrillation and for prophylaxis
of repetitive PSVT. Unlike β adrenergic receptor
antagonists, Ca 2+ channel blockers have not been
shown to reduce mortality after MI (Singh, 1990). In
contrast to other Ca 2+ channel blockers, bepridil
increases APD in many tissues and can exert an antiarrhythmic
effect in atria and ventricles. However,
because bepridil can cause torsades de pointes, it is not
prescribed widely and has been discontinued in the U.S.