Transcript OCULAR PHARMACOLOGY

OCULAR
PHARMACOLOGY
Definitions
1) Bioavailability-% of unchanged drug delivered to site of potential
action regardless of route of administration
 2) Compartment-body space in which drug is homogeneously distributed
 3) Rate constants Ka- absorption rate constant (fraction of drug entering compartment per
unit time)
 Ke- elimination rate constant (fraction of drug eliminated from
compartment per unit time)
 4) Order of kinetics First order-rate of absorption and elimination are proportional to drug
concentration
 Zero order-rates are independent of concentration, related to a functional
capacity of body (true for most eyedrops)
 5) Tissue binding-renders drug unavailable for elimination and prolongs
its retention in a compartment

Relevant anatomic characteristics of the
eye
Cornea-functions as a trilaminar permeability barrier (does not
allowanisocoria drugs to cross by simple diffusion)
a) Properties of different corneal layers
Epithelium- hydrophobic
Stroma- hydrophilic
Endothelium- hydrophobic
b) Epithelium is main barrier to hydrophilic molecules
c) Nonionized molecules penetrate epithelium/endothelium well,
ionizedmolecules penetrate stroma well
d) For maximal corneal drug penetration a molecule must have
optimum ratio of hydro- and lipo- philicity
Relevant anatomic continue……

2) Sclera-due to intraocular pressure there is
typically a constant outward flow
across the sclera, therefore even sub-Tenon’s
injections penetrate the globe slowly

3) Blood ocular barrier-present due to tight
junctions of nonpigmented ciliary epithelium,
retinal pigment epithelium, and retinal capillary
endothelial cells
Vehicles of drug administration
Eyedrops-major route of ocular drug
administration
a) Drops are advantageous because they avoid
systemic toxicity by have the problem of a short
duration of availability in the tear film and need
to pass through a barrier with limited
permeability
 b) Characteristics of the cul-de-sac as a drug
compartment

Factors affecting availability of topical
meds
1. Surfactants-increase solubility of
hydrophilic drugs by altering
permeability of epithelial membranes
 2. Drug concentration-concentrated
solutions are used to maximize the
amount of drug entering the eye during
the limited availability provided by a drop

Factors affecting availability of topical
meds

3. Viscosity-high viscosity solutions increase drug contact
time on the cornea
4. pH-determines degree of ionization of a drug
(remember:
nonionized portion will be more lipid soluble, while
ionized portion will be more stable in the tears and better
penetrate stroma)
- since the pH of tears is slightly alkaline(7.4) many ocular
drugs are weak bases (alkaloids) existing in both
their charged and uncharged forms at that pH
- if the pH of the solution is made more basic then more
uncharged forms of the molecule are present, increasing
lipid solubility and epithelial penetration

Some Characteristics of Ocular Routes of Drug
Administration
ROUTE: Topical
ABSORPTION PATTERN: Prompt, depending on formulation
SPECIAL UTILITY: Convenient, economical, relatively safe
LIMITATIONS AND PRECAUTIONS: corneal and conjunctival
toxicity, nasal mucosal toxicity, systemic side effects from nasolacrimal
absorption
Some Characteristics of Ocular Routes of Drug
Administration
ROUTE: Subconjunctival, sub-Tenon's, and retrobulbar injections
ABSORPTION PATTERN: Prompt or sustained, depending on
formulation
SPECIAL UTILITY: Anterior segment infections, posterior uveitis,
cystoid macular edema
LIMITATIONS AND PRECAUTIONS: Local toxicity, tissue
injury, globe perforation, optic nerve trauma, central retinal artery and/or
vein occlusion, direct retinal drug toxicity with inadvertent globe
perforation, ocular muscle trauma, prolonged drug effect
Some Characteristics of Ocular Routes of
Drug Administration
ROUTE: Intraocular (intracameral) injections
ABSORPTION PATTERN: Prompt
SPECIAL UTILITY: Anterior segment surgery, infections
LIMITATIONS AND PRECAUTIONS: Corneal toxicity,
intraocular toxicity, relatively short duration of action
Some Characteristics of Ocular Routes of
Drug Administration

ROUTE: Intravitreal injection or device

ABSORPTION PATTERN: Absorption circumvented, immediate
local effect, potential sustained effect

SPECIAL UTILITY: Endophthalmitis, retinitis

LIMITATIONS AND PRECAUTIONS: Retinal toxicity
Absorption.
After topical instillation of a drug, the rate and
extent of absorption are determined by :
1-the time the drug remains in the cul-de-sac and
precorneal tear film
2-elimination by nasolacrimal drainage
3-drug binding to tear proteins
4- drug metabolism by tear and tissue proteins
5-diffusion across the cornea and conjunctiva
Distribution

Melanin binding of certain drugs is an
important factor in some ocular
compartments. For example, the mydriatic
effect of a adrenergic receptor agonists is
slower in onset in human volunteers with
darkly pigmented irides compared to those
with lightly pigmented irides.
Distribution continue……………..

Another clinically important consideration
for drug-melanin binding involves the
retinal pigment epithelium. In the retinal
pigment epithelium, accumulation of
chloroquine causes a toxic retinal lesion
known as a "bull's-eye" maculopathy,
which is associated with a decrease in
visual acuity
Ointments

Ointments usually contain mineral oil and
a petrolatum base and are helpful in
delivering antibiotics, cycloplegic drugs, or
miotic agents
Ointments
a) Advantages
1. Increase drug contact time
 b) Disadvantages
1. May act as a barrier to vision and
penetration of other drops
2. Slow release of some meds from
ointment may result in
subtherapeutic levels of drug

3) Gel-made of high viscosity acrylics (ex.
Ocuserts)- slowly releases drug at a
steady state level at overall lower conc. and
less systemic side-effects
 4) Liposomes-synthetic lipid
microspheres into which drugs may be
incorporated for sustained release


5) collagen shields-also provide prolonged drug
contact time (rate of drug release may not be
constant)

6) Subconjunctival/retrobulbar injectionallows drug to bypass conj/corneal epithelial
barriers, can allow meds to reach therapeutic
levels behind the lens/iris diaphragm
7) Intraocular injection
 8) Systemic administration
Ability of blood borne agents to reach the
globe depends on:
 a) lipid solubility
 b) plasma protein binding (only unbound
form is bioavailable)
 c) molecular weight

MISCELLANEOUS

Packs

Sustain-release devices

Irrigations

Hypertonic agents

Chelating agent
Metabolism.

Enzymatic biotransformation of ocular
drugs may be significant since
a
variety of enzymes,including esterases,
oxidoreductases , lysosomal enzymes,
peptidases , glucuronide and sulfate
transferases , glutathione-conjugating
enzymes,catechol-O-methyl-transferase,
monoamine oxidase, and 11bhydroxysteroid dehydrogenase are
found in the eye.
Metabolism continue……..

The esterases have been of particular interest because
of the development of prodrugs for enhanced corneal
permeability; for example, dipivefrin hydrochloride is a
prodrug for epinephrine, and latanoprost is a prodrug
for prostaglandin F2a; 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 , so
undesirable systemic side effects may occur.

Most ophthalmic drugs are delivered locally to the
eye, and the potential local toxic effects are due :


hypersensitivity reactions
direct toxic effects on the cornea, conjunctiva,
periocular skin, and nasal mucosa.
Local toxicity of topically applied
ocular drugs
Some drugs are more prone to produce
hypersensitivity reactions such as
neomycin.
 Unfortunately some eyes, and some
individuals, have a genetic predisposition
to allergic reactions, particularly those
subjects who suffer from atopy or allergy
affecting other systems.

Continue……

Others may have known but atypical and
undesirable reactions to topical drops,
such as marked elevation of intraocular
pressure (IOP) associated with topical
corticosteroids.
systemic toxicity of topically applied
ocular drugs

The systemic toxicity of topical ocular
drugs can be significant, and topical
betablockers have been associated with
marked respiratory and cardiac depression
and exacerbation of respiratory conditions
such as asthma.
Presevatives

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 Thimerosal currently is used rarely
due to a high incidence of hypersensitivity
reactions.
APPLICATIONS OF DRUGS IN
OPHTHALMOLOGY
THERAPEUTIC
 DIAGNOSTIC
Some drugs have both effects therapeutic
and diagnostic( e.g. atropine homatropine
physostigmine and pilocarpine)

Chemotherapy of Microbial Diseases in the
Eye
Appropriate selection of antibiotic and
route of administration is dependent on
the patient's symptoms, the clinical
examination, and the culture/sensitivity
results.

Topical Antibacterial Agents Commercially
Available for Ophthalmic Use

Chloramphenicol, 0.5% solution,
Conjunctivitis, keratitis

Ciprofloxacin hydrochloride (CILOXAN).
1% ointment 3% solution, Conjunctivitis,
keratitis
Topical Antibacterial Agents

Gentamicin sulfate (GARAMYCIN) 0.3%
solution Conjunctivitis, blepharitis,
keratitis

Erythromycin 0.3%& 5% ointment
Blepharitis, Conjunctivitis
Topical Antibacterial Agents

Sulfacetamide sodium, 10, 15, 30%
solution Conjunctivitis, keratitis

Polymyxin B 10% ointment ,Various
solutions , Conjunctivitis, blepharitis,
keratitis
Antiviral Agents for Ophthalmic Use
Trifluridine Topical (1% solution) Herpes
simplex keratitis Herpes simplex
conjunctivitis
 idoxuridine-IDU-topical 0.1%, ointment
0.5%
 Acyclovir Oral, intravenous 400- and 800mg Herpes zoster ophthalmicus Herpes
simplex iridocyclitis
 Valacyclovir Oral Herpes simplex
keratitis , Herpes zoster ophthalmicus

Antiviral Agents continue………….
Famciclovir Oral Herpes simplex keratitis
 Foscarnet IV , Intravitreal
Herpes zoster ophthalmicus
Cytomegalovirus retinitis
 Ganciclovir IV, oral Cytomegalovirus
retinitis
 Formivirsen
Intravitreal injection Intravitreal implant
Cytomegalovirus retinitis

Antifungal Agents for Ophthalmic Use
Polyenes
Amphotericin B 0.1-0.5% (typically 0.15%)
topical solution , 0.8-1 mg subconjunctival
, 5-ug intravitreal & intravenous injection
Yeast and fungal endophthalmitis
Natamycin 5% topical suspension ,Yeast
and fungal blepharitis, conjunctivitis,
keratitis

Antifungal Agents for Ophthalmic Use
Imidazoles
 Fluconazole oral,,
 Itraconazole oral
 Ketoconazole oral
 Miconazole 1% topical solution Yeast and
fungal keratitis subconjunctival (5-10 mg)
intravitreal (10 ug) injection Yeast and fungal
endophthalmit

Table 10-3. Drugs used in open-angle glaucoma.
Mechanism
Methods of
Administratio
n
Cholinomimetics
Pilocarpine, carbachol,
physostigmine,
echothiophate,
demecarium
Ciliary muscle
contraction,
opening of
trabecular
meshwork;
increased outflow
Topical drops or
gel; plastic film
slow-release
insert
Increased outflow
Topical drops
Alpha agonists
Unselective
Epinephrine, dipivefrin
Alpha2-selective
Decreased aqueous
secretion
Apraclonidine
Topical, postlaser
only
Brimonidine
Topical
Timolol, betaxolol,
carteolol,
levobunolol,
metipranolol
Decreased
aqueous
secretion from
the ciliary
epithelium
Topical drops
Decreased
aqueous
secretion due to
lack of HCO3
Topical
Diuretics
Dorzolamide,
brinzolamide
Acetazolamide,
dichlorphenamide,
methazolamide
Oral
Prostaglandins
Latanoprost,
bimatoprost,
travoprost,
unoprostone
Increased
outflow
Topical
Glaucoma

young patients usually are intolerant of
miotic therapy secondary to visual blurring
from induced myopia

direct miotic agents are preferred over
cholinesterase inhibitors in "phakic"
patients (i.e., those patients who have
their own crystalline lens) because the
latter drugs can promote cataract
formation
Glaucoma continue…..

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)
Uveitis
Cyclopentolate (CYCYLOGYL, others),
 tropicamide (MYDRIACYL)
 Atropine, scopolamine and homatropine
frequently are used to prevent posterior
synechia formation between the lens and
iris margin and to relieve ciliary muscle
spasm that is responsible for much of the
pain associated with anterior uveitis.

Uveitis
If posterior synechiae already have
formed, an adrenergic agonist may be
used to break the synechiae by enhancing
pupillary dilation.
 A solution containing scopolamine 0.3% in
combination with 10% phenylephrine
 Topical steroids usually are adequate to
decrease inflammation, but sometimes
they must be supplemented with systemic
steroids.

Use of Autonomic Agents in the Eye
Cholinergic agonists
Acetylcholine (MIOCHOL-E) 1% solution Intraocular
use for miosis in surgery (OCULAR SIDE
EFFECTS): is Corneal edema
Carbachol Intraocular use for miosis in surgery,
glaucoma
(O.S.E.) Corneal edema, miosis, induced myopia,
decreased vision, brow ache, retinal detachment

Anticholinesterase agents



Physostigmine (ESERINE) Glaucoma,
accommodative esotropia, louse and mite
infestation of lashes
(O.S.E.) Retinal detachment, miosis, cataract,
pupillary block glaucoma iris cysts, brow ache,
punctal stenosis of the nasolacrimal system
Echothiophate Glaucoma, accommodative
esotropia (O.S.E.) Same as for physostigmine
Muscarinic antagonists
Atropine Cycloplegic retinoscopy, dilated
funduscopic exam,
(O.S.E.) Photosensitivity, blurred vision
 Scopolamine , Homatropine ,
Cyclopentolate , Tropicamide effect and
side effect Same as for atropine

Sympathomimetic agents
Dipivefrin , Epinephrine , Brimonidine
Glaucoma (O.S.E.)Photosensitivity,
hypersensitivity
 Phenylephrine Mydriasis
 Apraclonidine Glaucoma, pre- & postlaser
prophylaxis of intraocular pressure spike

Sympathomimetic agents
Cocaine Topical anesthesia, evaluate
anisocoria
 Hydroxyamphetamine Evaluate anisocoria
 Naphazoline , Tetrahydrozoline
Decongestant (O.S.E.) Same as for
dipivefrin

THE EYE
Use of Immunomodulatory Drugs
for Ophthalmic Therapy








Glucocorticoids. Glucocorticoids have an important role in
managing ocular inflammatory diseases
Therapeutic Uses. antiinflammatory effects, topical
corticosteroids are used in managing significant ocular
allergy
Toxicity of Steroids. open-angle glaucoma cataract
c) ptosis
d) mydriasis
e) delayed wound healing
f) enhanced microbial proliferation
g) punctate keratopathy
Nonsteroidal Antiinflammatory
Agents. General Considerations
Ketorolac is given for seasonal allergic
conjunctivitis. An ophthalmic preparation
is available for ocular inflammatory
conditions
 Diclofenac is used for postoperative
inflammation.
 Both ketorolac and diclofenac have been
found to be effective in treating cystoid
macular edema occurring after cataract
surgery.

Diclofenac (Nonselective COX Inhibitors)

A 0.1% ophthalmic preparation is
recommended for prevention of
postoperative ophthalmic inflammation
and can be used after intraocular lens
implantation and strabismus surgery.

A topical gel containing 3% diclofenac is
effective for solar keratoses.
Bromfenac Ophtalmic
Bromfenac is a non-steroidal antiinflammatory drug (NSAID). Bromfenac
ophthalmic (for the eyes) is used to treat
swelling and pain caused by cataract
surgery.
 Side effect:
hives;difficult breathing;swelling of your
face, lips, tongue, or throat.

Nepafenac
Nepafenac is a
nonsteroidal antiinflammatory drug
(NSAID).
 It reduces pain and
inflammation in the
eyes.

Nepafenac

Nepafenac ophthalmic suspension is used
to reduce pain and swelling after cataract
surgery.

Nepafenac is a prodrug,after use
penetrates the cornea and is converted by
ocular tissue hydrolases to amfenac,
Antihistamines and Mast-Cell
Stabilizers



Pheniramine and antazoline, both H1-receptor
antagonists, are formulated in combination with
naphazoline, a vasoconstrictor, for relief of
allergic conjunctivitis.
Cromolyn sodium (CROLOM), which prevents the
release of histamine and other autacoids from
mast cells , has found limited use in treating
conjunctivitis that is thought to be allergenmediated, such as vernal conjunctivitis.
Lodoxamidetromethamine and pemirolast ,
mast-cell stabilizers, also are available for
ophthalmic use.