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

250 animals after long- term exposure to organophosphates (De Bleecker
et al., 1992).
SECTION II
NEUROPHARMACOLOGY
THERAPEUTIC USES
Current use of anti- AChE agents is limited to four conditions
in the periphery:
• atony of the smooth muscle of the intestinal tract and
urinary bladder
• glaucoma
• myasthenia gravis
• reversal of the paralysis of competitive neuromuscular
blocking drugs (Chapter 11)
Long- acting and hydrophobic ChE inhibitors are
the only inhibitors with well- documented efficacy,
albeit limited, in the treatment of dementia symptoms
of Alzheimer’s disease. Physostigmine, with its shorter
duration of action, is useful in the treatment of intoxication
by atropine and several drugs with anticholinergic
side effects (discussed later); it also is indicated for
the treatment of Friedreich’s or other inherited ataxias.
Edrophonium has been used for terminating attacks of
paroxysmal supraventricular tachycardia.
Available Therapeutic Agents. The compounds described
here are those commonly used as anti- ChE drugs and
ChE reactivators in the U.S. Preparations used solely for
ophthalmic purposes are described in Chapter 64.
Conventional dosages and routes of administration are
given in the later discussion of therapeutic applications.
Physostigmine salicylate (ANTILIRIUM) is available for injection.
Physostigmine sulfate ophthalmic ointment and physostigmine
salicylate ophthalmic solution also are available. Pyridostigmine bromide
is available for oral (MESTINON) or parenteral (REGONOL, MESTI-
NON) use. Neostigmine bromide (PROSTIGMIN) is available for oral
use. Neostigmine methylsulfate (PROSTIGMIN) is marketed for parenteral
injection. Ambenonium chloride (MYTELASE) is available for
oral use. Tacrine (COGNEX), donepezil (ARICEPT), rivastigmine
(EXELON), and galantamine (REMINYL) have been approved for the
treatment of Alzheimer’s disease.
Pralidoxime chloride (PROTOPAM CHLORIDE) is the only AChE
reactivator currently available in the U.S. and can be obtained in a
parenteral formulation. HI-6 is available in several European and
Near Eastern countries.
Paralytic Ileus and Atony of the Urinary Bladder. In the
treatment of both these conditions, neostigmine generally
is preferred among the anti- ChE agents. Directly
acting muscarinic agonists (Chapter 9) are employed
for the same purposes.
Neostigmine is used for the relief of abdominal distension
and acute colonic pseudo- obstruction from a variety of medical and
surgical causes (Ponec et al., 1999). The usual subcutaneous dose
of neostigmine methylsulfate for postoperative paralytic ileus is
0.5 mg, given as needed. Peristaltic activity commences 10-30 minutes
after parenteral administration, whereas 2-4 hours are required after
oral administration of neostigmine bromide (15-30 mg). It may be
necessary to assist evacuation with a small low enema or gas with a
rectal tube.
When neostigmine is used for the treatment of atony of the
detrusor muscle of the urinary bladder, postoperative dysuria is
relieved, and the time interval between operation and spontaneous
urination is shortened. The drug is used in a similar dose and manner
as in the management of paralytic ileus. Neostigmine should
not be used when the intestine or urinary bladder is obstructed,
when peritonitis is present, when the viability of the bowel is
doubtful, or when bowel dysfunction results from inflammatory
bowel disease.
Glaucoma and Other Ophthalmologic Indications.
Glaucoma is a complex disease characterized by an
increase in intraocular pressure that, if sufficiently high
and persistent, leads to damage to the optic disc at the
juncture of the optic nerve and the retina; irreversible
blindness can result. Of the three types of glaucoma—
primary, secondary, and congenital— anti- AChE agents
are of value in the management of the primary as well
as of certain categories of the secondary type (e.g.,
aphakic glaucoma, following cataract extraction); congenital
glaucoma rarely responds to any therapy other
than surgery. Primary glaucoma is subdivided into
narrow- angle (acute congestive) and wide- angle
(chronic simple) types, based on the configuration of
the angle of the anterior chamber where the aqueous
humor is reabsorbed.
Narrow- angle glaucoma is nearly always a medical emergency
in which drugs are essential in controlling the acute attack,
but the long- range management is often surgical (e.g., peripheral or
complete iridectomy). Wide- angle glaucoma, on the other hand, has
a gradual, insidious onset and is not generally amenable to surgical
improvement; in this type, control of intraocular pressure usually is
dependent upon continuous drug therapy.
Since the cholinergic agonists and ChE inhibitors also block
accommodation and induce myopia, these agents produce transient
blurring of far vision, limited visual acuity in low light, and loss of
vision at the margin when instilled in the eye. With long- term administration
of the cholinergic agonists and anti- ChE agents, the compromise
of vision diminishes. Nevertheless, other agents without
these side effects, such as β adrenergic receptor antagonists,
prostaglandin analogs, or carbonic anhydrase inhibitors, have
become the primary topical therapies for open- angle glaucoma
(Alward, 1998), with AChE inhibitors held in reserve for the chronic
conditions when patients become refractory to the above agents.
Topical treatment with long- acting ChE inhibitors such as echothiophate
gives rise to symptoms characteristic of systemic ChE inhibition.
Echothiophate treatment in advanced glaucoma may be
associated with the production of cataracts (Alward, 1998).