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

anatomic
barrier
functional
barrier
Figure 29–8. Two types of re-entry. The border of a propagating
wavefront is denoted by a heavy black arrowhead. In anatomically
defined re-entry (top), a fixed pathway is present (e.g.,
Figure 29–7). The black area denotes tissue in the re-entrant circuit
that is completely refractory because of the recent passage
of the propagating wavefront; the gray area denotes tissue in
which depressed upstrokes can be elicited (see Figure 29–5A),
and the red area represents tissue in which restimulation would
result in action potentials with normal upstrokes. The red area
is termed an excitable gap. In functionally defined, or “leading
circle,” re-entry (bottom), there is no anatomic pathway and no
excitable gap. Rather, the circulating wavefront creates an area
of inexcitable tissue at its core. In this type of re-entry, the circuit
does not necessarily remain in the same anatomic position
during consecutive beats, and multiple such “rotors” may be
present.
localized ischemia or other electrophysiologic perturbations
that result in an area of sufficiently slow conduction
in the ventricle that impulses exiting from that
area, find the rest of the myocardium re-excitable in
which case re-entry may ensue. Atrial or ventricular fibrillation
(VF) is an extreme example of “functionally
defined” (or “leading circle”) re-entry: Cells are re-excited
as soon as they are repolarized sufficiently to allow
enough Na + channels to recover from inactivation. The
abnormal activation pathway subsequently provides
abnormal spatial heterogeneity of repolarization that
can cause other re-entrant circuits to form; this perpetuates
until neither organized activation patterns nor
coordinated contractile activity is present.
Common Arrhythmias and Their
Mechanisms
The primary tool for diagnosis of arrhythmias is the ECG.
More sophisticated approaches sometimes are used,
such as recording from specific regions of the heart
during artificial induction of arrhythmias by specialized
pacing techniques. Table 29–2 lists common
arrhythmias, their likely mechanisms, and approaches
that should be considered for their acute termination
and for long-term therapy to prevent recurrence.
Examples of some arrhythmias discussed here are
shown in Figure 29–9. Some arrhythmias, notably VF,
are best treated not with drugs but with direct current
(DC) cardioversion—the application of a large electric
current across the chest. This technique also can be
used to immediately restore normal rhythm in less serious
cases; if the patient is conscious, a brief period of
general anesthesia is required. Implanted cardioverter–
defibrillators (ICDs), devices that are capable of
detecting VF and automatically delivering a defibrillating
shock, are used increasingly in patients judged to
be at high risk for VF. Often drugs are used with these
devices if defibrillating shocks, which are painful,
occur frequently.
MECHANISMS OF ANTI-ARRHYTHMIC
DRUG ACTION
Anti-arrhythmic drugs almost invariably have multiple
effects in patients, and their effects on arrhythmias can
be complex. A drug can modulate additional targets in
addition to its primary mode of action. At the same
time, a single arrhythmia may result from multiple
underlying mechanisms (e.g., torsades de pointes
(Figure 29–9H) can result either from increased Na +
channel late currents or decreased inward rectifier currents).
Thus, anti-arrhythmic therapy should be tailored
to target the most relevant underlying arrhythmia mechanism.
Drugs may be anti-arrhythmic by suppressing
the initiating mechanism or by altering the re-entrant
circuit. In some cases, drugs may suppress the initiator
but nonetheless promote re-entry.
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CHAPTER 29
ANTI-ARRHYTHMIC DRUGS