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

826
A
B
Decreased
phase 4
slope
Increased
threshold
refractoriness (Task Force, 1991). In atrial and ventricular myocytes,
refractoriness can be prolonged by delaying the recovery of Na + channels
from inactivation. Drugs that act by blocking Na + channels generally
shift the voltage dependence of recovery from block (Figure
29–5B) and so prolong refractoriness (Figure 29–11).
Drugs that increase APD without direct action on Na + channels
(e.g., by blocking delayed-rectifier currents) also will prolong
refractoriness (Figure 29–11). Particularly in sinoatrial or AV nodal
tissues, Ca 2+ channel blockade prolongs refractoriness. Drugs that
interfere with cell–cell coupling also theoretically should increase
refractoriness in multicellular preparations; amiodarone may exert
this effect in diseased tissue (Levine et al., 1988). Acceleration of
conduction in an area of slow conduction also could inhibit re-entry;
lidocaine may exert such an effect, and peptides that suppress
A
SECTION III
C
Increased
maximum
diastolic
potential
Na +
channel
blockers
MODULATION OF CARDIOVASCULAR FUNCTION
D
KEY
Increased
action
potential
duration
Baseline
Drug effect
Figure 29–10. Four ways to reduce the rate of spontaneous discharge.
The blue horizontal line represents threshold potential.
B
Action
potentialprolonging
drug
KEY
25% of Na + channels
recovered from inactivation
No drug
Drug
ΔERP
ΔERP
In anatomically determined re-entry, drugs may terminate
the arrhythmia by blocking propagation of the action potential.
Conduction usually fails in a “weak link” in the circuit. In the example
of the WPW-related arrhythmia described earlier, the weak link is
the AV node, and drugs that prolong AV nodal refractoriness and slow
AV nodal conduction, such as Ca 2+ channel blockers, β adrenergic
receptor antagonists, or digitalis glycosides, are likely to be effective.
On the other hand, slowing conduction in functionally determined
re-entrant circuits may change the pathway without extinguishing the
circuit. In fact, slow conduction generally promotes the development
of re-entrant arrhythmias, whereas the most likely approach for
terminating functionally determined re-entry is prolongation of
Figure 29–11. Two ways to increase refractoriness. In this figure,
the black dot indicates the point at which a sufficient number of
Na + channels (an arbitrary 25%; see Figure 29–5B) have recovered
from inactivation to allow a premature stimulus to produce
a propagated response in the absence of a drug. Block of Na +
channels (A) shifts voltage dependence of recovery (see Figure
29–5B) and so delays the point at which 25% of channels have
recovered (red diamond), prolonging refractoriness. Note that if
the drug also dissociates slowly from the channel (see Figure
29–12), refractoriness in fast-response tissues actually can extend
beyond full repolarization (“postrepolarization refractoriness”).
Drugs that prolong the action potential (B) also will extend the
point at which an arbitrary percentage of Na + channels have
recovered from inactivation, even without directly interacting
with Na + channels. ERP, effective refractory period.