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

260 and the remainder of the muscle fiber membrane retain
their normal sensitivities to K + depolarization and direct
electrical stimulation.
SECTION II
NEUROPHARMACOLOGY
The steps involved in ACh release by the nerve action potential,
the development of miniature end-plate potentials (MEPPs), their
summation to form a postjunctional end-plate potential (EPP), the
triggering of the muscle action potential, and contraction are
described in Chapter 8. Biophysical studies with patch electrodes
reveal that the fundamental event elicited by ACh or other agonists is
an “all or none” opening of the individual receptor channels, which
gives rise to a square wave pulse with an average open-channel conductance
of 20-30 picosiemens (pS) and a duration that is exponentially
distributed around a time of ~1 ms. The duration of channel
opening is far more dependent on the nature of the agonist than is the
magnitude of the open-channel conductance (Sakmann, 1992).
Increasing concentrations of the competitive antagonist
tubocurarine progressively diminish the amplitude of the excitatory
postjunctional EPP. The amplitude of this potential may fall to below
70% of its initial value before it is insufficient to initiate the propagated
muscle action potential; this provides a safety factor in neuromuscular
transmission. Analysis of the antagonism of tubocurarine
on single-channel events shows that, as expected for a competitive
antagonist, tubocurarine reduces the frequency of channel-opening
events but does not affect the conductance or duration of opening
for a single channel (Katz and Miledi, 1978). At higher concentrations,
curare and other competitive antagonists block the channel
directly in a fashion that is noncompetitive with agonists and dependent
on membrane potential (Colquhoun et al., 1979).
The decay time of the MEPP is similar to the average lifetime
of channel opening (1-2 ms). MEPPs are a consequence of the
spontaneous release of one or more quanta of ACh (~10 5 molecules);
individual molecules of ACh in the synapse have only a transient
opportunity to activate the receptor and do not rebind successively to
receptors to activate multiple channels before being hydrolyzed by
acetylcholinesterase (AChE). The concentration of unbound ACh in
the synapse from nerve-released ACh diminishes more rapidly than
does the decay of the EPP (or current). In the presence of anticholinesterase
drugs, the EPP is prolonged up to 25-30 ms, which is
indicative of the rebinding of transmitter to neighboring receptors
before hydrolysis by AChE or diffusion from the synapse.
Simultaneous binding by two agonist molecules at the respective
αγ and αδ subunit interfaces of the receptor is required for activation.
Activation shows positive cooperativity and thus occurs over
a narrow range of concentrations (Changeux and Edelstein, 1998;
Sine and Claudio, 1991). Although two molecules of competitive
antagonist or snake α-toxin can bind to each receptor molecule at
the agonist sites, the binding of one molecule of antagonist to each
receptor is sufficient to render it nonfunctional (Taylor et al., 1983).
The depolarizing agents, such as succinylcholine,
act by a different mechanism. Their initial action is to
depolarize the membrane by opening channels in the
same manner as ACh. However, they persist for longer
durations at the neuromuscular junction primarily
because of their resistance to AChE. The depolarization
is thus longer-lasting, resulting in a brief period of
repetitive excitation that may elicit transient and repetitive
muscle excitation (fasciculations). This initial
depolarization is followed by block of neuromuscular
transmission and flaccid paralysis (called phase I
block). The block arises because, after an initial opening,
perijunctional sodium channels close and will not
reopen until the end plate is repolarized. At this point,
neural release of ACh results in the binding of ACh to
receptors on an already depolarized end plate. These
closed perijunctional channels keep the depolarization
signal from affecting downstream channels and effectively
shield the rest of the muscle from activity at the
motor end plate. In humans, depolarizing agents elicit
a sequence of repetitive excitation followed by block of
transmission and neuromuscular paralysis; however,
this sequence is influenced by such factors as the anesthetic
agent used concurrently, the type of muscle, and
the rate of drug administration. The characteristics of
depolarization and competitive blockade are contrasted
in Table 11–3.
In other animal species and occasionally in humans, depolarizing
agents produce a blockade that has unique features, some of which
combine those of the depolarizing and the competitive agents; this type
of action is termed a dual mechanism. In such cases, the depolarizing
agent initially produces characteristic fasciculations and potentiation
of the maximal twitch, followed by the rapid onset of neuromuscular
block. This phase I block is potentiated by anticholinesterase agents
(e.g., ambenonium, edrophonium, neostigmine, pyridostigmine,
donepezil, galantamine, rivastigmine, and tacrine): Inhibition of ACh
degradation results in additional depolarizing agent, in this case
endogenous ACh, at the neuromuscular junction. Following the onset
of blockade, there is a poorly sustained response to tetanic stimulation
of the motor nerve, intensification of the block by tubocurarine, and
lack of potentiation by anti-cholinesterase agents. The dual action of the
depolarizing blocking agents is also seen in intracellular recordings of
membrane potential; when agonist is applied continuously, the initial
depolarization is followed by a gradual repolarization, which in many
respects resembles receptor desensitization.
Under clinical conditions, with increasing concentrations of
succinylcholine and over time, the block may convert slowly from a
depolarizing phase I block to a non-depolarizing, phase II block
(Durant and Katz, 1982). The pattern of neuromuscular blockade
produced by depolarizing drugs in anesthetized patients appears to
depend, in part, on the anesthetic; fluorinated hydrocarbons may be
more apt to predispose the motor end plate to non-depolarization
blockade after prolonged use of succinylcholine (Fogdall and Miller,
1975). While the response to peripheral stimulation during phase II
block resembles that of the competitive agents, reversal of phase II
block by administration of anti-cholinesterase agents (e.g., with
neostigmine) is difficult to predict and should be undertaken with
much caution. The characteristics of phase I and phase II blocks are
shown in Table 11–1.
Although the observed fasciculations also may be a consequence
of stimulation of the prejunctional nerve terminal by the