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

• in patients who have an increased risk of retinal detachment,
miotics should be used with caution because they have been
implicated in promoting retinal tears in susceptible individuals
(such tears are thought to be due to altered forces at the
vitreous base produced by ciliary body contraction induced by
the drug)
The goal is to prevent progressive glaucomatous optic-nerve
damage with minimum risk and side effects from either topical or
systemic therapy. With these general principles in mind, a stepped
medical approach may begin with a topical prostaglandin (PG) analog.
Due to their once-daily dosing, low incidence of systemic side
effects, and potent IOP-lowering effect, PG analogs have largely
replaced adrenergic–receptor antagonists as first-line medical therapy
for glaucoma. The PG analogs consist of latanoprost (XALATAN),
travoprost (TRAVATAN, TRAVATAN Z), and bimatoprost (LUMIGAN,
LATISSE). The chemical structure of latanoprost is shown below:
PGF 2
reduces IOP but has intolerable local side effects.
Modifications to the chemical structure of PGF 2
have produced
analogs with a more acceptable side-effect profile. In primates and
humans, PGF 2
analogs appear to lower IOP by facilitating aqueous
outflow through the accessory uveoscleral outflow pathway. The
mechanism by which this occurs is unclear. PGF 2
and its analogs
(prodrugs that are hydrolyzed to PGF 2
) bind to FP receptors that
link to G q11
and then to the PLC–IP 3
–Ca 2+ pathway. This pathway
is active in isolated human ciliary muscle cells. Other cells in the
eye also may express FP receptors. Theories of IOP lowering by
PGF 2
range from altered ciliary muscle tension to effects on trabecular
meshwork cells to release of matrix metalloproteinases and
digestion of extracellular matrix materials that may impede outflow
tracts. There also is less myocilin protein noted in monkey smooth
muscle after PGF 2
treatment (Lindsey et al., 2001).
The receptor antagonists now are the next most common
topical medical treatment. There are two classes of topical blockers.
The nonselective ones bind to both 1
and 2
receptors and
include timolol maleate and hemihydrate (hemihydrate is not available
in the U.S.), levobunolol, metipranolol, and carteolol. There is
one 1
-selective antagonist, betaxolol, available for ophthalmic use,
but it is less efficacious than the nonselective blockers because the
receptors of the eye are largely of the 2
subtype. However,
because the 1
receptors are found preferentially in the heart while
the 2
receptors are found in the lung, betaxolol is less likely to cause
breathing difficulty. In the eye, the targeted tissues are the ciliary
body epithelium and blood vessels, where 2
receptors account for
75-90% of the total population. How blockade leads to decreased
aqueous production and reduced IOP is uncertain. Production of
aqueous humor seems to be activated by a receptor–mediated
cyclic AMP–PKA pathway; blockade blunts adrenergic activation
of this pathway by preventing catecholamine stimulation of the
receptor, thereby decreasing intracellular cyclic AMP. Another
hypothesis is that blockers decrease ocular blood flow, which
decreases the ultrafiltration responsible for aqueous production
(Juzych and Zimmerman, 1997).
When there are medical contraindications to the use of PG
analogs or receptor antagonists, other agents, such as a 2
adrenergic–
receptor agonist or topical carbonic anhydrase inhibitor (CAI), may
be used as first-line therapy. The 2
adrenergic agonists improve the
pharmacological profile of the nonselective sympathomimetic agent
epinephrine and its derivative, dipivefrin (PROPINE, others).
Epinephrine stimulates both and adrenergic receptors. The drug
appears to decrease IOP by enhancing both conventional (via a 2
receptor mechanism) and uveoscleral outflow (perhaps via PG production)
from the eye. Although effective, epinephrine is poorly tolerated,
principally due to localized irritation and hyperemia.
Dipivefrin is an epinephrine prodrug that is converted into epinephrine
by esterases in the cornea. It is much better tolerated but is still
prone to cause epinephrine-like side effects (Fang and Kass, 1997).
The 2
adrenergic agonist clonidine is effective at reducing IOP but
also readily crosses the blood-brain barrier and causes systemic
hypotension; as a result, it no longer is used for glaucoma. In contrast,
apraclonidine (IOPIDINE) is a relatively selective 2
adrenergic
agonist that is highly ionized at physiological pH and therefore does
not cross the blood-brain barrier. Brimonidine (ALPHAGAN, others)
also is a selective 2
adrenergic agonist but is lipophilic, enabling
easy corneal penetration. Both apraclonidine and brimonidine reduce
aqueous production and may enhance some uveoscleral outflow.
Both appear to bind to pre- and postsynaptic 2
receptors. By binding
to the presynaptic receptors, the drugs reduce the amount of neurotransmitter
release from sympathetic nerve stimulation and thereby
lower IOP. By binding to postsynaptic 2
receptors, these drugs stimulate
the G i
pathway, reducing cellular cyclic AMP production,
thereby reducing aqueous humor production (Juzych et al., 1997).
The development of a topical CAI took many years but was
an important event because of the poor side-effect profile of oral
CAIs. Dorzolamide (TRUSOPT, others) and brinzolamide (AZOPT)
both work by inhibiting carbonic anhydrase (isoenzyme II), which
is found in the ciliary body epithelium. This reduces the formation
of bicarbonate ions, which reduces fluid transport and, thus, IOP
(Sharir, 1997).
Any of these four drug classes can be used as additive secondor
third-line therapy. In fact, the receptor antagonist timolol has been
combined with the CAI dorzolamide (see the structure below) in a single
medication (COSOPT, others) and with the 2
adrenergic agonist brimonidine
(COMBIGAN).
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CHAPTER 64
OCULAR PHARMACOLOGY