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

Table 9–1
Some Pharmacological Properties of Choline Esters and Natural Alkaloids
MUSCARINIC ACTIVITY
MUSCARINIC SUSCEPTIBILITY TO Cardio- Gastro- Urinary Eye Antagonism NICOTINIC
AGONIST CHOLINESTERASES vascular intestinal Bladder (Topical) by Atropine ACTIVITY
Acetylcholine +++ ++ ++ ++ + +++ ++
Methacholine + +++ ++ ++ + +++ +
Carbachol – + +++ +++ ++ + +++
Bethanechol – ± +++ +++ ++ +++ –
Muscarine a – ++ +++ +++ ++ +++ –
Pilocarpine – + +++ +++ ++ +++ –
a
Not used therapeutically
The major natural alkaloid muscarinic agonists—
muscarine, pilocarpine, and arecoline—have the same
principal sites of action as the choline esters. Muscarine
acts almost exclusively at muscarinic receptor sites, and
the classification of these receptors derives from the
actions of this alkaloid. Pilocarpine has a dominant muscarinic
action but is a partial rather than a full agonist;
the sweat glands are particularly sensitive to pilocarpine.
Arecoline also acts at nicotinic receptors. Although
these naturally occurring alkaloids are of great value as
pharmacological tools and muscarine has toxicological
significance (discussed later), present clinical use is
restricted largely to the employment of pilocarpine as a
sialagogue and miotic agent (Chapter 64).
History and Sources. The alkaloid muscarine was isolated from the
mushroom Amanita muscaria by Schmiedeberg in 1869; its toxicology
is discussed later. Pilocarpine is the chief alkaloid obtained from
the leaflets of South American shrubs of the genus Pilocarpus.
Although it was long known by the natives that the chewing of leaves
of Pilocarpus plants caused salivation, the first experiments were
apparently performed in 1874 by the Brazilian physician Coutinhou.
The alkaloid was isolated in 1875, and shortly thereafter the actions
of pilocarpine on the pupil and on the sweat and salivary glands were
described by Weber. Arecoline is the chief alkaloid of areca or betel
nuts, the seeds of Areca catechu. The red-staining betel nut is consumed
as a euphoretic by the natives of the Indian subcontinent and
East Indies in a masticatory mixture known as betel and composed
of the nut, shell lime, and leaves of Piper betle, a climbing species
of pepper. Methacholine was synthesized and studied by Hunt and
Taveau as early as 1911. Carbachol and bethanechol were synthesized
and investigated in the 1930s.
Absorption, Distribution,
and Elimination
The absorption and distribution of these compounds
may be predicted from their structures: muscarine and
the choline esters are quaternary amines; pilocarpine
and arecoline are tertiary amines (Figure 9–1).
Because they are quaternary amines, the choline
esters are poorly absorbed following oral administration
and have a limited ability to cross the blood-brain
barrier. Even though these drugs resist hydrolysis, the
choline esters are short-acting agents due to rapid elimination
by the kidneys.
Pilocarpine and arecoline, being tertiary amines,
are readily absorbed and can cross the blood-brain barrier.
In contrast, muscarine, a quaternary amine, is
poorly absorbed. Muscarine can still, however, be toxic
when ingested and can even have CNS effects.
Although the specific metabolic pathways have not
been elucidated, pilocarpine clearance is decreased in
patients with hepatic impairment, in whom doses may
need to be reduced. The natural alkaloids are primarily
eliminated by the kidneys; excretion of the tertiary
amines can be accelerated by acidification of the urine.
Therapeutic Uses of Muscarinic
Receptor Agonists
Muscarinic agonists are currently used in the treatment
of urinary bladder disorders and xerostomia and in the
diagnosis of bronchial hyperreactivity. They are also
used in ophthalmology as miotic agents and for the
treatment of glaucoma.
There is growing interest in the role of muscarinic
receptors in cognition. The potential utility of M 1
agonists
in treating the cognitive impairment associated
with Alzheimer’s disease has long been considered.
Other receptor subtypes including M 2
and M 5
also
appear to be involved in the regulation of cognitive
function, at least in animal models (Wess et al., 2007).