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

1780 Transcorneal and transconjunctival/scleral absorption are the
desired routes for localized ocular drug effects. The time period
between drug instillation and its appearance in the aqueous humor is
defined as the lag time. The drug concentration gradient between the
tear film and the cornea and conjunctival epithelium provides the
driving force for passive diffusion across these tissues. Other factors
that affect a drug’s diffusion capacity are the size of the molecule,
chemical structure, and steric configuration. Transcorneal drug penetration
is conceptualized as a differential solubility process; the
cornea may be thought of as a trilaminar “fat-water-fat” structure
corresponding to the epithelial, stromal, and endothelial layers. The
epithelium and endothelium represent barriers for hydrophilic substances;
the stroma is a barrier for hydrophobic compounds. Hence,
a drug with both hydrophilic and lipophilic properties is best suited
for transcorneal absorption.
Drug penetration into the eye is approximately linearly related
to its concentration in the tear film. Certain disease states, such as
corneal epithelial defects and corneal ulcers, may alter drug penetration.
Medication absorption usually is increased when an anatomical
barrier is compromised or removed. Experimentally, drugs may be
screened for their potential clinical utility by assessing their corneal
permeability coefficients. These pharmacokinetic data combined with
the drug’s octanol/water partition coefficient (for lipophilic drugs) or
distribution coefficient (for ionizable drugs) yield a parabolic relationship
that is a useful parameter for predicting ocular absorption.
Of course, such in vitro studies do not account for other factors that
affect corneal absorption, such as epithelial integrity, blink rate, dilution
by tear flow, nasolacrimal drainage, drug binding to proteins and
tissue, and transconjunctival absorption; hence, these studies have
limitations in predicting ocular drug absorption in vivo.
Distribution. Topically administered drugs may undergo systemic
distribution primarily by nasal mucosal absorption and possibly by
local ocular distribution by transcorneal/transconjunctival absorption.
Following transcorneal absorption, the aqueous humor accumulates
the drug, which then is distributed to intraocular structures as well as
potentially to the systemic circulation via the trabecular meshwork
pathway (Figure 64–3B). Melanin binding of certain drugs is an
important factor in some ocular compartments. For example, the
mydriatic effect of adrenergic–receptor agonists is slower in onset
in human volunteers with darkly pigmented irides compared to those
with lightly pigmented irides. In rabbits, radiolabeled atropine binds
significantly to melanin granules in irides of non-albino animals. This
finding correlates with the fact that atropine’s mydriatic effect lasts
longer in non-albino rabbits than in albino rabbits and suggests that
drug-melanin binding is a potential reservoir for sustained drug
release. Another clinically important consideration for drug-melanin
binding involves the retinal pigment epithelium. In the retinal pigment
epithelium, accumulation of chloroquine (see Chapter 49)
causes a toxic retinal lesion known as a “bull’s-eye” maculopathy,
which is associated with a decrease in visual acuity.
Metabolism. Enzymatic biotransformation of ocular drugs may be
significant because a variety of enzymes, including esterases, oxidoreductases,
lysosomal enzymes, peptidases, glucuronide and
sulfate transferases, glutathione-conjugating enzymes, catechol-Omethyl-transferase,
monoamine oxidase, and 11-hydroxysteroid
dehydrogenase are found in the eye. The esterases have been of particular
interest because of the development of prodrugs for enhanced
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
corneal permeability; e.g., dipivefrin hydrochloride is a prodrug for
epinephrine, and latanoprost is a prodrug for prostaglandin F 2
(PGF 2
); both drugs are used for glaucoma management. Topically
applied ocular drugs are eliminated by the liver and kidney after systemic
absorption, but enzymatic transformation of systemically
administered drugs also is important in ophthalmology.
Toxicology. All ophthalmic medications are potentially absorbed into
the systemic circulation (Figure 64–6), so undesirable systemic side
effects may occur. Most ophthalmic drugs are delivered locally to
the eye, and the potential local toxic effects are due to hypersensitivity
reactions or to direct toxic effects on the cornea, conjunctiva,
periocular skin, and nasal mucosa. Eyedrops and contact lens solutions
commonly contain preservatives such as benzalkonium chloride,
chlorobutanol, chelating agents, and thimerosal for their
antimicrobial effectiveness. In particular, benzalkonium chloride
may cause a punctate keratopathy or toxic ulcerative keratopathy
(Grant and Schuman, 1993). Thimerosal is used rarely due to a high
incidence of hypersensitivity reactions.
THERAPEUTIC AND DIAGNOSTIC
APPLICATIONS OF DRUGS IN
OPHTHALMOLOGY
Chemotherapy of Microbial Diseases
in the Eye
Antibacterial Agents
General Considerations. A number of antibiotics have
been formulated for topical ocular use (Table 64–4).
The pharmacology, structures, and kinetics of individual
drugs have been presented in detail in Section VI.
Appropriate selection of antibiotic and route of administration
is dependent on the patient’s symptoms, the
clinical examination, and the culture/sensitivity results.
Specially formulated antibiotics also may be extemporaneously
prepared by qualified pharmacists for serious
eye infections such as corneal infiltrates or ulcers
and endophthalmitis.
Therapeutic Uses. Infectious diseases of the skin, eyelids,
conjunctivae, and lacrimal excretory system are
encountered regularly in clinical practice. Periocular
skin infections are divided into preseptal and postseptal
or orbital cellulitis. Depending on the clinical setting
(i.e., preceding trauma, sinusitis, age of patient,
relative immunocompromised state), oral or parenteral
antibiotics are administered. The microbiological spectrum
for orbital cellulitis is changing; e.g., there has
been a sharp decline in Haemophilus influenzae after
the introduction in 1985 of the H. influenzae vaccine
(Ambati et al., 2000).
Dacryoadenitis, an infection of the lacrimal gland, is most
common in children and young adults. It may be bacterial (typically