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

1798 and reduce the synthesis of others (e.g., collagenase, certain species
of keratin), and molecular evidence suggests that these actions can
be entirely accounted for by changes in nuclear transcription
(Mangelsdorf et al., 1994). Retinoic acid appears to be considerably
more potent than retinol in mediating these effects.
Retinoic acid influences gene expression by combining with
nuclear receptors. Multiple retinoid receptors have been described.
These are grouped into two families. One family, the retinoic acid
receptors (RARs), designated , , and , are derived from genes
localized to human chromosomes 17, 3, and 12, respectively. The
second family, the retinoid X receptors (RXRs), also is composed
of , , and receptor isoforms (Chambon, 1995). The retinoid
receptors show extensive sequence homology to each other in both
their DNA and hormone-binding domains and belong to a receptor
superfamily that includes receptors for steroid and thyroid hormones
and calcitriol (Mangelsdorf et al., 1994). Cellular responses
to thyroid hormones, calcitriol, and retinoic acid are enhanced by
the presence of RXR. Gene activation involves binding of the
hormone-receptor complex to promoter elements in target genes,
followed by dimerization with an RXR-ligand complex. The
endogenous RXR ligand is 9-cis-retinoic acid (Heyman et al., 1992;
Levin et al., 1992). No comparable receptor for retinol has been
identified; retinol may need to be oxidized to retinoic acid to produce
its effects within target cells.
Retinoids can influence the expression of receptors for certain
hormones and growth factors and thus can influence the growth,
differentiation, and function of target cells by both direct and indirect
actions (Love and Gudas, 1994).
Therapeutic Uses. Nutritional vitamin A deficiency causes xerophthalmia,
a progressive disease characterized by nyctalopia (night
blindness), xerosis (dryness), and keratomalacia (corneal thinning),
which may lead to corneal perforation; xerophthalmia may be
reversed with vitamin A therapy (WHO/UNICEF/IVAGG Task
Force, 1988). However, rapid, irreversible blindness ensues once the
cornea perforates. Vitamin A also is involved in epithelial differentiation
and may have some role in corneal epithelial wound healing.
Currently, there is no evidence to support using topical vitamin A
for keratoconjunctivitis sicca in the absence of a nutritional deficiency.
The current recommendation for retinitis pigmentosa is to
administer 15,000 IU of vitamin A palmitate daily under the supervision
of an ophthalmologist and to avoid high-dose vitamin E.
The Age-Related Eye Disease Study (AREDS) found a reduction
in the risk of progression of some types of ARMD for those randomized
to receive high doses of vitamins C (500 mg), E (400 IU),
-carotene (15 mg), cupric oxide (2 mg), and zinc (80 mg) (Age-
Related Eye Disease Study Research Group, 2001). Interestingly, zinc
has been found to be neuroprotective in a rat model of glaucoma. The
mechanism appears to be mediated by heat shock proteins and may
represent a novel treatment strategy for glaucoma (Park et al., 2001).
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
Wetting Agents and Tear Substitutes
General Considerations. The current management of dry eyes usually
includes instilling artificial tears and ophthalmic lubricants. In general,
tear substitutes are hypotonic or isotonic solutions composed of
electrolytes, surfactants, preservatives, and some viscosity-increasing
agent that prolongs the residence time in the cul-de-sac and precorneal
tear film. Common viscosity agents include cellulose polymers (e.g.,
carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose [hypromellose], and methylcellulose),
polyvinyl alcohol, polyethylene glycol, polysorbate, mineral
oil, glycerin, and dextran. The tear substitutes are available as
preservative-containing or preservative-free preparations. The viscosity
of the tear substitute depends on its exact formulation and can range
from watery to gel like. Some tear formulations also are combined
with a vasoconstrictor, such as naphazoline, phenylephrine, or tetrahydrozoline.
Tyloxapol (ENUCLENE) is marketed as an over-the-counter
ophthalmic preparation used to facilitate the wearing comfort of artificial
eyes.
The lubricating ointments are composed of a mixture of white
petrolatum, mineral oil, liquid or alcohol lanolin, and sometimes a
preservative. These highly viscous formulations cause considerable
blurring of vision, and consequently, they are used primarily at bedtime,
in critically ill patients, or in very severe dry eye conditions.
A hydroxypropyl cellulose ophthalmic insert (LACRISERT) that is
placed in the inferior cul-de-sac and dissolves during the day is available
to treat dry eyes.
Such aqueous, ointment, and insert formulations are only fair
substitutes for the precorneal tear film, which truly is a poorly understood
lipid, aqueous, and mucin trilaminar barrier (see “Absorption”).
Therapeutic Uses. Many local eye conditions and systemic diseases
may affect the precorneal tear film. Local eye disease, such as blepharitis,
ocular rosacea, ocular pemphigoid, chemical burns, or
corneal dystrophies, may alter the ocular surface and change the tear
composition. Appropriate treatment of the symptomatic dry eye
includes treating the accompanying disease and possibly the addition
of tear substitutes, punctal plugs (see “Absorption”), or ophthalmic
cyclosporine (see “Immunomodulatory Agent”). There also are a
number of systemic conditions that may manifest themselves with
symptomatic dry eyes, including Sjögren’s syndrome, rheumatoid
arthritis, vitamin A deficiency, Stevens-Johnson syndrome, and trachoma.
Treating the systemic disease may not eliminate the symptomatic
dry eye complaints; chronic therapy with tear substitutes,
ophthalmic cyclosporine, insertion of punctal plugs, placement of
dissolvable collagen implants, or surgical occlusion of the lacrimal
drainage system may be indicated. Ophthalmic cyclosporine (RESTA-
SIS) can be used to increase tear production in patients with ocular
inflammation associated with keratoconjunctivitis sicca.
Osmotic Agents
General Considerations. The main osmotic drugs for ocular use
include glycerin, mannitol, and hypertonic saline. With the availability
of these agents, the use of urea for management of acutely elevated
IOP is nearly obsolete.
Therapeutic Uses. Ophthalmologists occasionally use glycerin and
mannitol for short-term management of acute rises in IOP.
Sporadically, these agents are used intraoperatively to dehydrate the
vitreous prior to anterior segment surgical procedures. Many patients
with acute glaucoma do not tolerate oral medications because of nausea;
therefore, intravenous administration of mannitol and/or acetazolamide
may be preferred over oral administration of glycerin.
These agents should be used with caution in patients with congestive
heart failure or renal failure.
Corneal edema is a clinical sign of corneal endothelial dysfunction,
and topical osmotic agents may effectively dehydrate the
cornea. Identifying the cause of corneal edema will guide therapy,
and topical osmotic agents, such as hypertonic saline, may temporize