Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 4 THE PHARMACOLOGY OF THE AUTONOMIC NERVOUS SYSTEM
Table 4.5 Muscarinic receptors
Receptor Location Cellular response Functional response Agonists Antagonists
M 1
M 2
M 3
Gastric and salivary
glands, CNS
Heart, GI, smooth
muscle
Exocrine glands, SM of
the eye and GI tract,
vascular
endothelium
Activation of G q/11 /PLCβ/IP 3 /DAG,
Ca 2+ ↑, K + conductance↓
Activation of G i , cAMP↓,
K + conductance↑
Activation of G q/11 /PLCβ/IP 3 /DAG,
Ca 2+ ↑
Glandular secretion↑, CNS
excitation
Cardiac inhibition, neural
inhibition, central
muscarinic effects
Glandular secretion↑, GI SM
constriction, ocular
accommodation,
vasodilation
ACh, CCh
ACh, CCh
ACh, CCh
Atropine, pirenzepin
Atropine, gallamin
Atropine
PLCβ, phospholipase Cβ; IP 3 , inositol triphosphate; DAG, diacylglycerol; cAMP, cyclic adenosine monophosphate; GI, gastrointestinal;
SM, smooth muscle; ACh,acetylcholine; CCh, carbamylcholine (carbachol).
effects causing tremor and hypothermia via activation
of M 1 receptors in the brain. The procognitive effects of
central M 1 receptor activation by selective M 1 agonists
have led to the investigation of such compounds as
antidementia drugs in humans. Modifications of the
basic chemical structure of muscarinic agonists as outlined
above have yielded drugs with increased cholinesterase
resistance and higher selectivity for muscarinic
receptors (acetylcholine versus bethanechol).
Whilst muscarine has no clinical applications, other
M-selective parasympathomimetic drugs (e.g. bethanechol)
have limited clinical use in situations of reduced
smooth muscle tone such as hypomotility disorders of
the gut and reduced bladder tone.
Pilocarpine, a nonpolar tertiary ammonium compound,
which is readily absorbed via mucous membranes,
can be used for the treatment of increased
intraocular pressure (glaucoma) (see Chapter 25). Pilocarpine
is not approved for veterinary use in the US or
UK but can be applied topically to the eye in companion
animals as extra-label use or under the requirements of
the UK/European prescribing cascade. It predominantly
constricts the smooth muscle of iris and ciliary body,
leading to improved drainage of aqueous humor via the
drainage angle. In the past another parasympathomimetic,
arecoline, was used to aid removal of intestinal
parasites in dogs. However, the clinical use of arecoline
has been superseded by newer, safer and more efficacious
anthelmintics (see Chapter 10).
Muscarinic antagonists
Antimuscarinic agents are competitive antagonists at
muscarinic acetylcholine receptors. The general lack of
M-receptor subtype selectivity of these parasympatholytic
drugs helps to explain the similar responses seen
after administration of muscarinic antagonists, which
include the reversal of parasympathetic cardiac inhibition,
mydriasis, bronchial, biliary and urinary tract
smooth muscle relaxation, inhibition of exocrine glandular
secretions and, at higher doses, reduction in GI
motility.
Antagonists of M acetylcholine receptors such as the
plant alkaloids atropine (Atropa belladonna, deadly
nightshade) and hyoscine (Hyoscyamus niger, thorn
apple) share a similar basic chemical structure with
acetylcholine, but the replacement of the acetyl side
chain by a bulky aromatic group results in high affinity
but abolished intrinsic activity at M-receptors. Compared
to parasympathomimetics, muscarinic antagonists
are nonpolar tertiary amines which are readily absorbed
and cross the blood–brain barrier. Atropine, for
example, the archetypal muscarinic antagonist, is widely
distributed but not readily metabolized in most species
(the exception is rabbits which, as a consequence, can
safely eat deadly nightshade) and therefore has a long
duration of action.
Atropine is clinically used as an anesthetic premedication
to manage bradycardia and excessive bronchial
secretion associated with the use of anesthetics and
opioids. Atropine and other muscarinic antagonists are
also used for the treatment of organophosphate and
carbamate toxicity. Organophosphate and carbamate
pesticides inhibit cholinesterase, causing excessive generalized
parasympathetic neurotransmission. Atropine
plays an important role in the symptomatic relief of
these intoxication states, the lack of M subtype selectivity
being advantageous as it causes antagonism of anticholinergic
effects in all parts of the parasympathetic
system.
Other muscarinic antagonists occasionally used in
veterinary medicine include propantheline bromide,
hyoscine and isopropamide in antiemetic and antidiarrheal
preparations (see Chapter 19) or for management
of bradyarrhythmias (see Chapter 17).
Ipratropium, a quaternary ammonium compound, is
under scrutiny as an inhalant for cats with asthma.
68