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

246 The sites of action of anti- ChE agents of therapeutic
importance are the CNS, eye, intestine, and the
neuromuscular junction of skeletal muscle; other
actions are of toxicological consequence.
SECTION II
NEUROPHARMACOLOGY
Eye. When applied locally to the conjunctiva, anti- ChE
agents cause conjunctival hyperemia and constriction
of the pupillary sphincter muscle around the pupillary
margin of the iris (miosis) and the ciliary muscle (block
of accommodation reflex with resultant focusing to
near vision). Miosis is apparent in a few minutes and
can last several hours to days. Although the pupil may
be “pinpoint” in size, it generally contracts further
when exposed to light. The block of accommodation is
more transient and generally disappears before termination
of miosis. Intraocular pressure, when elevated, usually
falls as the result of facilitation of outflow of the
aqueous humor (Chapter 64).
GI Tract. In humans, neostigmine enhances gastric contractions
and increases the secretion of gastric acid.
After bilateral vagotomy, the effects of neostigmine on
gastric motility are greatly reduced. The lower portion
of the esophagus is stimulated by neostigmine; in
patients with marked achalasia and dilation of the
esophagus, the drug can cause a salutary increase in
tone and peristalsis.
Neostigmine also augments motor activity of the small and
large bowel; the colon is particularly stimulated. Atony produced by
muscarinic receptor antagonists or prior surgical intervention may
be overcome, propulsive waves are increased in amplitude and frequency,
and movement of intestinal contents is thus promoted. The
total effect of anti- ChE agents on intestinal motility probably represents
a combination of actions at the ganglion cells of Auerbach’s
plexus and at the smooth muscle fibers, as a result of the preservation
of ACh released by the cholinergic preganglionic and postganglionic
fibers, respectively (Chapter 46).
Neuromuscular Junction. Most of the effects of potent
anti- ChE drugs on skeletal muscle can be explained
adequately on the basis of their inhibition of AChE at
neuromuscular junctions. However, there is good evidence
for an accessory direct action of neostigmine and
other quaternary ammonium anti- ChE agents on skeletal
muscle. For example, the intra- arterial injection of
neostigmine into chronically denervated muscle, or
muscle in which AChE has been inactivated by prior
administration of DFP, evokes an immediate contraction,
whereas physostigmine does not.
Normally, a single nerve impulse in a terminal motor- axon
branch liberates enough ACh to produce a localized depolarization
(end- plate potential) of sufficient magnitude to initiate a propagated
muscle action potential. The ACh released is rapidly hydrolyzed by
AChE, such that the lifetime of free ACh within the nerve- muscle
synapse (~200 μsec) is shorter than the decay of the end- plate potential
or the refractory period of the muscle. Therefore, each nerve
impulse gives rise to a single wave of depolarization. After inhibition
of AChE, the residence time of ACh in the synapse increases, allowing
for lateral diffusion and rebinding of the transmitter to multiple
receptors. Successive stimulation of neighboring receptors to the
release site in the end plate results in a prolongation of the decay
time of the end- plate potential. Quanta released by individual nerve
impulses are no longer isolated. This action destroys the synchrony
between end- plate depolarizations and the development of the action
potentials. Consequently, asynchronous excitation and fasciculations
of muscle fibers occur. With sufficient inhibition of AChE, depolarization
of the end plate predominates, and blockade owing to depolarization
ensues (Chapter 11). When ACh persists in the synapse, it
also may depolarize the axon terminal, resulting in antidromic firing
of the motoneuron; this effect contributes to fasciculations that
involve the entire motor unit.
The anti- ChE agents will reverse the antagonism caused by
competitive neuromuscular blocking agents. Neostigmine is not
effective against the skeletal muscle paralysis caused by succinylcholine;
this agent also produces neuromuscular blockade by depolarization,
and depolarization will be enhanced by neostigmine.
Actions at Other Sites. Secretory glands that are innervated
by postganglionic cholinergic fibers include the
bronchial, lacrimal, sweat, salivary, gastric (antral G
cells and parietal cells), intestinal, and pancreatic acinar
glands. Low doses of anti- ChE agents augment secretory
responses to nerve stimulation, and higher doses
actually produce an increase in the resting rate of
secretion.
Anti- ChE agents increase contraction of smooth muscle
fibers of the bronchioles and ureters, and the ureters may show
increased peristaltic activity.
The cardiovascular actions of anti- ChE agents are complex,
since they reflect both ganglionic and postganglionic effects of accumulated
ACh on the heart and blood vessels and actions in the CNS.
The predominant effect on the heart from the peripheral action of
accumulated ACh is bradycardia, resulting in a fall in cardiac output.
Higher doses usually cause a fall in blood pressure, often as a consequence
of effects of anti- ChE agents on the medullary vasomotor
centers of the CNS.
Anti- ChE agents augment vagal influences on the heart. This
shortens the effective refractory period of atrial muscle fibers and
increases the refractory period and conduction time at the SA and AV
nodes. At the ganglionic level, accumulating ACh initially is excitatory
on nicotinic receptors, but at higher concentrations, ganglionic
blockade ensues as a result of persistent depolarization of the cell
membrane. The excitatory action on the parasympathetic ganglion
cells would tend to reinforce the diminished cardiac output, whereas
the opposite sequence would result from the action of ACh on sympathetic
ganglion cells. Excitation followed by inhibition also is
elicited by ACh at the central medullary vasomotor and cardiac centers.
All of these effects are complicated further by the hypoxemia
resulting from the bronchoconstrictor and secretory actions of