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

covered by an episcleral vascular coat, by Tenon’s capsule, and by
the conjunctiva. The tendons of the six extraocular muscles insert
collagen fibers into the superficial scleral. Numerous blood vessels
pierce the sclera through emissaria to both supply and drain the
choroid, ciliary body, optic nerve, and iris.
Inside the scleral shell, the vascular choroid nourishes the outer
retina by a capillary system in the choriocapillaris. Between the outer
retina and the choriocapillaris lie Bruch’s membrane and the retinal
pigment epithelium, whose tight junctions provide an outer barrier
between the retina and the choroid. The retinal pigment epithelium
serves many functions, including vitamin A metabolism, phagocytosis
of the rod outer segments, and multiple transport processes.
Retina. The retina is a thin, transparent, highly organized structure of
neurons, glial cells, and blood vessels. Of all structures within the eye,
the neurosensory retina has been the most widely studied. The unique
organization and biochemistry of the photoreceptors have provided a
superb system for investigating signal transduction mechanisms. The
wealth of information about rhodopsin has made it an excellent model
for the G protein–coupled signal transduction. Such detailed understanding
holds promise for targeted therapy for some of the hereditary
retinal diseases.
Vitreous. Approximately 80% of the eye’s volume is the vitreous,
which is a clear medium containing collagen type II, hyaluronic acid,
proteoglycans, and a variety of macromolecules, including glucose,
ascorbic acid, amino acids, and a number of inorganic salts. Glutamate
in the vitreous has been suspected to have a possible relationship to
glaucoma. The ganglion cells appear to die in glaucoma via a process
of apoptosis (Quigley et al., 1995; Wax et al., 1998), and glutamate has
been shown to induce apoptosis via NMDA receptor excitotoxicity
(Sucher et al., 1997). Elevated glutamate levels have been noted in
experimental animal models (Dreyer et al., 1996; Yoles and Schwartz,
1998) and in humans with glaucoma (Dreyer et al., 1996), although
this has been questioned (Levkovitch-Verbin et al., 2002). Memantine,
a noncompetitive NMDA receptor antagonist (Vorwerk et al., 1996;
Seki and Lipton, 2008; Ju et al., 2008), is currently being investigated
clinically as a possible treatment for glaucoma.
Optic Nerve. The optic nerve is a myelinated nerve conducting the retinal
output to the central nervous system (CNS). It is composed of:
• an intraocular portion, which is visible as the optic disk in the retina
• an intraorbital portion
• an intracanalicular portion
• an intracranial portion
The nerve is ensheathed in meninges continuous with the
brain. At present, pharmacological treatment of optic neuropathies
usually is based on management of the underlying disease. For
example, nonarteritic ischemic optic neuropathy might be treated
with intravitreal glucocorticoids (Kaderli et al., 2007) and optic neuritis
may be best treated with intravenous glucocorticoids (Atkins
et al., 2007; Beck and Gal, 2008; Volpe, 2008). Unfortunately, these
guidelines have not yet become routine clinical practice (Biousse
et al., 2009). Glaucomatous optic neuropathy is medically managed
by decreasing IOP.
PHARMACOKINETICS AND TOXICOLOGY
OF OCULAR THERAPEUTIC AGENTS
Drug-Delivery Strategies
Properties of varying ocular routes of administration
are outlined in Table 64–3. A number of delivery systems
have been developed for treating ocular diseases.
Most ophthalmic drugs are delivered in solutions, but
Table 64–3
Some Characteristics of Ocular Routes of Drug Administration
ROUTE ABSORPTION PATTERN SPECIAL UTILITY LIMITATIONS AND PRECAUTIONS
Topical Prompt, depending on Convenient, economical, Compliance, corneal and conjunctival
formulation relatively safe toxicity, nasal mucosal toxicity, systemic
side effects from nasolacrimal absorption
Subconjunctival, Prompt or sustained, Anterior segment Local toxicity, tissue injury, globe
sub-Tenon’s, and depending on formulation infections, posterior perforation, optic nerve trauma, central
retrobulbar injections uveitis, cystoid retinal artery and/or vein occlusion,
macular edema
direct retinal drug toxicity with
inadvertent globe perforation, ocular
muscle trauma, prolonged drug effect
Intraocular Prompt Anterior segment surgery, Corneal toxicity, intraocular toxicity,
(intracameral) infections relatively short duration of action
injections
Intravitreal injection Absorption circumvented, Endophthalmitis, retinitis, Retinal toxicity
or device immediate local effect, age-related macular
potential sustained effect degeneration
See the text for a more complete discussion of individual routes.