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

experimental arrhythmias by increasing gap junction conductance
have been described.
State-Dependent Ion Channel Block
Recent advances have elucidated the structural and
molecular determinants of ion channel permeation and
drug block. This information has begun to play an
increasing role in analyzing the actions of available
and new anti-arrhythmic compounds (MacKinnon,
2003). A key concept is that ion channel–blocking
drugs bind to specific sites on the ion channel proteins
to modify function (e.g., decrease current) and that the
affinity of the ion channel protein for the drug on its
target site will vary as the ion channel protein shuttles
among functional conformations (or ion channel
“states”; see Figure 29–2). Physicochemical characteristics,
such as molecular weight and lipid solubility,
are important determinants of state-dependent binding.
State-dependent binding has been studied most extensively
in the case of Na + channel–blocking drugs. Most
useful agents of this type block open and/or inactivated
Na + channels and have very little affinity for channels
in the resting state. Most Na + channel blockers bind to
a local anesthetic binding site in the pore of Nav1.5,
and drug affinity is reduced with mutation to critical
residues in the pore (Fozzard et al., 2005). Thus, with
each action potential, drugs bind to Na + channels and
block them, and with each diastolic interval, drugs dissociate,
and the block is released.
As illustrated in Figure 29–12, the dissociation
rate is a key determinant of steady-state block of Na +
channels. When heart rate increases, the time available
for dissociation decreases, and steady-state Na + channel
block increases. The rate of recovery from block also
slows as cells are depolarized, as in ischemia. This
explains the finding that Na + channel blockers depress
Na + current, and hence conduction, to a greater extent
in ischemic tissues than in normal tissues. Open versus
inactivated-state block also may be important in determining
the effects of some drugs. Increased APD, which
results in a relative increase in time spent in the inactivated
state, may increase block by drugs that bind to
inactivated channels, such as lidocaine or amiodarone.
The rate of recovery from block often is expressed as a time
constant (τ recovery
, the time required for ~63% of an exponentially
determined process to be complete; Courtney, 1987). In the case of
drugs such as lidocaine, τ recovery
is so short (<<1 s) that recovery from
block is very rapid, and substantial Na + channel block occurs only in
rapidly driven tissues, particularly in ischemia. Conversely, drugs
such as flecainide have such long τ recovery
values (10 s) that roughly
the same number of Na + channels is blocked during systole and diastole.
As a result, marked slowing of conduction occurs even in normal
tissues at normal rates.
Classifying Anti-Arrhythmic Drugs
Classifying drugs by common electrophysiologic properties
emphasizes the connection between basic electrophysiologic
actions and anti-arrhythmic effects
(Vaughan Williams, 1992). To the extent that the
clinical actions of drugs can be predicted from their
basic electrophysiologic properties, such classification
schemes have merit. However, as each compound is
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CHAPTER 29
ANTI-ARRHYTHMIC DRUGS
KEY
Rest
Open (activated)
Inactivated
% Na + CHANNELS
BLOCKED
100
0
Na + channel blocker
Slower dissociation rate
increases Na + channel block
Tachycardia
increases Na + channel block
Figure 29–12. Recovery from block of Na + channels during diastole. This recovery is the critical factor determining extent of steadystate
Na + channel block. Na + channel blockers bind to (and block) Na + channels in the open and/or inactivated states, resulting in phasic
changes in the extent of block during the action potential. As shown in the middle panel, a decrease in the rate of recovery from
block increases the extent of block. Different drugs have different rates of recovery, and depolarization reduces the rate of recovery.
The right panel shows that increasing heart rate, which results in relatively less time spent in the rest state, also increases the extent
of block. (Modified from Roden et al., 1993, with permission from Wiley-Blackwell Publishing.)