Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

THE SYMPATHETIC NERVOUS SYSTEM – CATECHOLAMINERGIC SYNAPSES
Limited systemic uptake makes it a safe candidate to
induce bronchial smooth muscle relaxation without the
risk of generalized parasympathetic actions. The drug
is, however, not approved for the use in small animals
in the US and UK. Short-acting muscarinic antagonists
such as tropicamide are occasionally used as topical
applications in the eye (see Chapter 25).
Cholinesterase inhibitors
As indicated above, the inactivation of ACh at cholinergic
synapses following release of this neurotransmitter
involves the breakdown of ACh by synaptic acetylcholinesterase.
Together with butyrylcholinesterase, another
closely related serine hydrolase with ubiquitous tissue
and plasma distribution, acetylcholinesterase not only
terminates synaptic transmission but also reduces the
circulating levels of acetylcholine to virtually zero,
making acetylcholine a pure neurotransmitter. Both
cholinesterases are equally inhibited by a number of
naturally occurring and synthetic substances with similar
chemical structure to acetylcholine, which as a common
mode of action transfer an acetyl (short-acting anticholinesterases,
i.e. edrophonium), carbamyl (mediumduration
anticholinesterases, i.e. neostigmine) or
phosphate (irreversible anticholinesterases, i.e. parathion)
onto the catalytic site of the enzyme to block
hydrolytic activity. The difference in affinity of acetyl,
phosphate and carbamyl groups to this site determines
the duration of action of various anticholinesterases.
The clinical uses of these cholinesterase inhibitors are
very limited as the consequences of inhibiting these
enzymes are widespread central and peripheral parasympathomimetic
effects that are difficult to control.
These effects include enhanced transmitter activity at
postganglionic parasympathetic synapses (bradycardia,
bronchoconstriction, glandular secretion, gastrointestinal
hypermotility), depolarization block of the neuromuscular
junction, neurotoxicity and, if compounds can
cross the blood–brain barrier, initial excitation and convulsions
followed by depression.
There is, however, one important clinical use in veterinary
medicine. The short-acting drug edrophonium
is used to aid the diagnosis of myasthenia gravis, an
autoimmune disease in which antibodies directed against
muscle-type nicotinic receptors cause impaired cholinergic
transmission at the neuromuscular junction,
resulting in muscle weakness. Medium-duration anticholinesterases
such as neostigmine and pyridostigmine
are used in the clinical management of the disease in
combination with immunosuppressants.
Irreversible anticholinesterases such as parathion and
dichlorvos, which in some parts of the world are still
used as insecticides, can be the source of intoxication in
domestic animals.
THE SYMPATHETIC NERVOUS SYSTEM –
CATECHOLAMINERGIC SYNAPSES
Catecholaminergic neurotransmission mediates the
various actions of sympathetic nervous system activation
at postganglionic nerve terminals, which predominantly
regulate smooth muscle tone in a number of
organs and control cardiac function. Neurotransmitters
synthesized in catecholaminergic nerve terminals are
generally the catecholamines noradrenaline (norepinephrine),
dopamine and adrenaline (epinephrine),
which are synthesized from the amino acid precursor l-
tyrosine via a single enzymatic cascade. Out of these
three, noradrenaline (norepinephrine) is by far the most
important neurotransmitter in the autonomic nervous
system. As a result, postganglionic sympathetic synapses
are usually classified as noradrenergic synapses, despite
the presence of small amounts of dopamine and adrenaline
(epinephrine) in sympathetic nerve endings. Dopamine,
on the other hand, plays a more important role
as a modulatory neurotransmitter in the CNS, while
adrenaline (epinephrine), produced and secreted from
chromaffin cells of the adrenal medulla, acts predominantly
as a circulating hormone.
The basic synaptic processes of noradrenergic
neurotransmission are similar to those in cholinergic
synapses, the principal differences lying in the neurotransmitter
synthesis pathways, postrelease metabolism
and recycling (for details see below).
Figure 4.3 outlines the essential steps in the transmission
process at a noradrenergic synapse in the PNS.
Table 4.6 summarizes the drugs that can interfere with
the various stages of this process.
Apart from adrenoceptor antagonists and agonists
and to some extent monoamine oxidase (MAO) blockers,
these drugs have little or no clinical application in
veterinary medicine.
Adrenoceptors
The complex effects that sympathetic activation induces
in mammalian organisms via the release of mainly a
single neurotransmitter, especially the opposing effects
on smooth muscle tone in different organs, can only be
explained by the existence of distinct adrenoceptor subtypes.
However, a detailed understanding of the nature
and distribution of these catecholamine receptors lagged
a long way behind the systematic classification of nicotinic
and muscarinic acetylcholine receptors. Despite the
fact that Sir Henry Dale had made observations suggesting
the existence of such receptor subtypes (he realized
that in animals pretreated with certain ergot alkaloids,
adrenaline produced a paradoxical reduction in blood
pressure compared to the expected increase) as far back
as 1913, scientists were struggling to draw the right
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