Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

THE PARASYMPATHETIC NERVOUS SYSTEM – CHOLINERGIC SYNAPSES
Suxamethonium (succinylcholine), is a selective
agonist of the nicotinic muscle type receptor. It dissociates
readily from the nicotinic receptor but is not metabolized
by acetylcholinesterase. It can be used as a
short-acting neuromuscular blocking agent as continuous
activation of the ACh receptors results in functional
antagonism. It is sporadically used in dogs and cats
during anesthesia and for the diagnosis of malignant
hyperthermia.
Nicotinic antagonists
Nicotinic antagonists fall into two distinct groups: ganglion
blockers and peripheral muscle relaxants. The differences
between the nicotinic receptors at autonomic
ganglia and those at the neuromuscular junction mentioned
above form the basis of the distinct pharmacodynamic
actions of these two classes of drugs. Generally,
ganglion blockers have little or no effect on transmission
at the neuromuscular junction.
The prototypic ganglion blocker is hexamethonium,
which causes a fall in blood pressure as the result of
blockade of sympathetic ganglia that mediate some
control on arterial and venous blood pressure.
Hexamethonium in the past was used as an antihypertensive
agent but has been superseded by β-blockers and
other antihypertensive treatments. Trimetaphan, another
ganglion blocker, is now only occasionally used in
human medicine for controlled hypotension during
surgery.
The prototypic peripheral muscle relaxant is curare.
This is not a pure substance but a mixture of alkaloids
from the South American vine Chondodendron tomentosum.
The main active constituent, d-tubocurarine,
was isolated at the beginning of the last century and
many synthetic agents are now available. Some of the
older peripheral muscle relaxants, including tubocurarine
and gallamine, have mild ganglion-blocking
activity.
The group of antinicotinic peripheral muscle relaxants
used in veterinary medicine can be further subdivided
into nondepolarizing (pancuronium, atracurium
besylate, vecuronium) or depolarizing (suxamethonium/
succinylcholine, see above) agents. Nondepolarizing
peripheral muscle relaxants bind to nicotinic receptors
at the motor endplates, acting as classic competitive
antagonists with no intrinsic activity, thereby inhibiting
neuromuscular transmission. Depolarizing peripheral
muscle relaxants act as agonists at the nicotinic receptors
of the neuromuscular junction that cause muscle
paralysis by inducing sustained depolarization as a
result of extremely slow dissociation of the receptor–
ligand complex.
The neuromuscular blockade produced by nondepolarizing
blockers can be reversed with anticholinesterases.
The neuromuscular blockade produced by
depolarizing blockers cannot be reversed by this method.
This latter point is rarely a problem as depolarizing
blockade is very short-lived as suxamethonium is a substrate
for circulating pseudocholinesterases.
Drugs affecting muscarinic receptors
Muscarinic receptors generally mediate the effects of
acetylcholine release at postsynaptic parasympathetic
synapses, causing predominantly smooth muscle constriction
and glandular secretion. The only sympathetic
effect mediated by muscarinic receptors is the stimulation
of sweat glands by atypical cholinergic postganglionic
sympathetic nerves. As opposed to nicotinic
receptors, which are ligand-gated ion channels, muscarinic
receptors belong to the class of seven transmembrane-spanning
G protein-coupled receptors (7TMs)
which, depending on the subtype, can affect a plethora
of intracellular target molecules including ion channels,
protein kinases and transcription factors. Based on their
genetic sequence, five subtypes of muscarinic receptors
(M 1 –M 5 ) can be distinguished and the functional role of
the three most important ones (M 1 –M 3 ) has been well
characterized. The major characteristics of these receptor
subtypes are presented in Table 4.5.
Muscarinic agonists
Muscarinic agonists are often referred to as parasympathomimetics
as their action resembles generalized
stimulation of the parasympathetic system. Examples
of such agents include, of course, muscarine but also
other choline esters related to acetylcholine, such as
bethanechol and pilocarpine. These compounds are
agonists at both muscarinic and nicotinic receptors
that do, however, display higher potency at muscarinic
receptors.
Depending on their potency and selectivity for muscarinic
receptors, parasympathomimetics induce cardiac
slowing and reduce cardiac output and their action on
endothelial M 3 receptors contributes to a pronounced
reduction in arterial blood pressure. They increase the
tone of all smooth muscle apart from vascular smooth
muscle and smooth muscle forming the urinary bladder
sphincter, resulting in increased gastrointestinal motility,
bronchoconstriction, miosis and support of bladder
emptying. In combination with their prosecretory effects
on exocrine glands (bronchial, salivary, lacrimal, sweat),
the bronchoconstriction induced by muscarinic agonists
can severely impair respiratory function.
Generally parasympathomimetics are polar quarternary
ammonium compounds with a linked ester group.
These chemical properties limit their bioavailability and
prevent them from crossing the blood–brain barrier.
Less polar compounds which cross the blood–brain
barrier more easily, such as pilocarpine, display central
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