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

and hypotension, which can severely reduce coronary blood flow,
especially if it is already compromised. These contraindications and
adverse effects are generally of limited concern with topical administration
for ophthalmic use.
Toxicology
Poisoning from the ingestion of plants containing pilocarpine, muscarine,
or arecoline is characterized chiefly by exaggeration of their
various parasympathomimetic effects and resembles that produced
by consumption of mushrooms of the genus Inocybe (described in
the next section). Treatment consists of the parenteral administration
of atropine in doses sufficient to cross the blood-brain barrier
and measures to support the respiratory and cardiovascular systems
and to counteract pulmonary edema.
Mushroom Poisoning (Mycetism). Mushroom poisoning has been
known for centuries. The Greek poet Euripides (fifth century
B.C.E.) is said to have lost his wife and three children from this
cause. In recent years, the number of cases of mushroom poisoning
has been increasing as the result of the current popularity of
the consumption of wild mushrooms. Various species of mushrooms
contain many toxins, and species within the same genus may
contain distinct toxins.
Although Amanita muscaria is the source from which muscarine
was isolated, its content of the alkaloid is so low (~ 0.003%)
that muscarine cannot be responsible for the major toxic effects.
Much higher concentrations of muscarine are present in various
species of Inocybe and Clitocybe. The symptoms of intoxication
attributable to muscarine develop within 30-60 minutes of ingestion;
they include salivation, lacrimation, nausea, vomiting, headache,
visual disturbances, abdominal colic, diarrhea, bronchospasm,
bradycardia, hypotension, and shock. Treatment with atropine
(1-2 mg intramuscularly every 30 minutes) effectively blocks these
effects (Goldfrank, 2006; Köppel, 1993).
Intoxication produced by A. muscaria and related Amanita
species arises from the neurologic and hallucinogenic properties of
muscimol, ibotenic acid, and other isoxazole derivatives. These
agents stimulate excitatory and inhibitory amino acid receptors.
Symptoms range from irritability, restlessness, ataxia, hallucinations,
and delirium to drowsiness and sedation. Treatment is mainly supportive;
benzodiazepines are indicated when excitation predominates;
atropine often exacerbates the delirium.
Mushrooms from Psilocybe and Panaeolus species contain
psilocybin and related derivatives of tryptamine. They also cause
short-lasting hallucinations. Gyromitra species (false morels) produce
GI disorders and a delayed hepatotoxicity. The toxic substance,
acetaldehyde methylformylhydrazone, is converted in the body to
reactive hydrazines. Although fatalities from liver and kidney failure
have been reported, they are far less frequent than with amatoxincontaining
mushrooms.
The most serious form of mycetism is produced by Amanita
phalloides, other Amanita species, Lepiota, and Galerina species
(Goldfrank, 2006). These species account for > 90% of all fatal
cases. Ingestion of as little as 50 g of A. phalloides (deadly nightcap)
can be fatal. The principal toxins are the amatoxins (α- and β-amanitin),
a group of cyclic octapeptides that inhibit RNA polymerase II and
thereby block mRNA synthesis. This causes cell death, manifested
particularly in the GI mucosa, liver, and kidneys. Initial symptoms,
which often are unnoticed or when present are due to other toxins,
include diarrhea and abdominal cramps. A symptom-free period lasting
up to 24 hours is followed by hepatic and renal malfunction.
Death occurs in 4-7 days from renal and hepatic failure (Goldfrank,
2006). Treatment is largely supportive; penicillin, thioctic acid, and
silibinin may be effective antidotes, but the evidence is based largely
on anecdotal studies (Köppel, 1993).
Because the severity of toxicity and treatment strategies for
mushroom poisoning depend on the species ingested, their identification
should be sought. Often symptomatology is delayed, limiting
the value of gastric lavage and administration of activated charcoal.
Regional poison control centers in the U.S. maintain up-to-date
information on the incidence of poisoning in the region and treatment
procedures.
MUSCARINIC RECEPTOR ANTAGONISTS
The muscarinic receptor antagonists include: 1) the naturally
occurring alkaloids, atropine and scopolamine;
2) semisynthetic derivatives of these alkaloids, which
primarily differ from the parent compounds in their disposition
in the body or their duration of action; and
3) synthetic derivatives, some of which show selectivity
for subtypes of muscarinic receptors. Noteworthy
agents among the latter two categories are homatropine
and tropicamide, which have a shorter duration of
action than atropine, and methscopolamine, ipratropium,
and tiotropium, which are quaternized and do
not cross the blood-brain barrier or readily cross membranes.
The synthetic derivatives possessing some
degree of receptor selectivity include pirenzepine,
which shows selectivity for M 1
receptors; and darifenacin
and solifenacin, which show selectivity for M 3
receptors.
Muscarinic antagonists prevent the effects of ACh
by blocking its binding to muscarinic receptors on
effector cells at parasympathetic (and sympathetic
cholinergic) neuroeffector junctions, in peripheral ganglia,
and in the CNS. In general, muscarinic antagonists
cause little blockade of nicotinic receptors. However,
the quaternary ammonium antagonists generally exhibit
a greater degree of nicotinic blocking activity and therefore
are more likely to interfere with ganglionic or neuromuscular
transmission.
While many effects of muscarinic antagonists can
be predicted from an understanding of the physiological
responses mediated by muscarinic receptors at
parasympathetic (and sympathetic cholinergic) neuroeffector
junctions, paradoxical responses are sometimes
seen. For example, presynaptic muscarinic
receptors of variable subtype are present on postganglionic
parasympathetic nerve terminals. Since blockade
of presynaptic receptors generally augments
225
CHAPTER 9
MUSCARINIC RECEPTOR AGONISTS AND ANTAGONISTS