OCULAR PHARMACOLOGY

Gestina Aliska, MD, Clin Pharm

Department of Pharmacology and Therapeutic
Medical Faculty of Andalas University
Padang, February 8th 2017
Outlines

 Pharmacokinetic of ocular drugs

 Application drus for therapeutics and
diagnostic
 Antimicrobial
 Anti inflammatory
 Anti allergy
 Autonomic agents
 Anti glaucoma
 Drug for dry eyes
Scenario

 Seorang pasien laki-  Pasien perempuan usia

laki usia 35 tahun 48 tahun datang ke
datang ke poliklinik RS klinik dengan keluhan
dengan keluhan mata mata merah dan perih
kiri merah dan gatal sejak 1 hari yang lalu.
sejak 1 hari yang lalu. Pada pemeriksaan
Pasien juga ditemukan mata
mengeluhkan demam. kering.
 Bagaimana  Bagaimana
tatalaksana pasien ini? tatalaksana pasien ini?
Introduction
Farmakokinetik obat topikal mata

Nasolacrimal
Eliminasi drainage

Di tear film dan

Metabolisme protein jaringan

• Obat berikatan dengan

distribusi protein tear film
• Obat berdifusi melewati
kornea dan konjunctiva
Waktu  obat berada cul de sac dan precorneal tear
absorpsi film
 Absorption
conjunctival/s
corneal cleral route
route route

nasolacrimal absorption
pathway

Possible absorption pathways of an ophthalmic drug following topical application to the

eye.
 Absorption

 A drug's residence time be prolonged

 changing its formulation.
 Residence time  extended by blocking
the egress of tears from the eye by
closing the tear drainage ducts.
 Nasolacrimal drainage systemic
absorption of topically administered
ophthalmic medications.
 Absorption from the nasal mucosa 
systemic side effects may be caused by
topical medications
 Transcorneal & transconjunctival/scleral absorption  desired
routes for localized ocular drug effects.
 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 :
 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 trilamellar
"fat-water-fat" structure corresponding to the epithelial, stromal,
and endothelial layers.
 The epithelium & endothelium  barriers for hydrophilic
substances; the stroma is a barrier for hydrophobic compounds.
 A drug with both hydrophilic and lipophilic properties is best
suited for transcorneal absorption.
 Penetrasi obat pada mata  korelasi linier
dengan kadar obat pada tear film.
 Penyakit tertentu ulkus kornea dan defek epitel
kornea lain  ganggu penetrasi
 Absorpsi meningkat jika barrier berkurang atau
hilang.
 Other factors that affect corneal absorption:
 epithelial integrity, blink rate, dilution by tear flow,
nasolacrimal drainage, drug binding to proteins and
tissue, and transconjunctival absorption
 Distribusi
 Topically administered drugs may undergo systemic distribution
 primarily by nasal mucosal absorption
 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
 Melanin binding of certain drugs is an important factor in some ocular
compartments.
 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 nonalbino
animals.
 This finding correlates with the fact that atropine's mydriatic effect lasts longer in
nonalbino 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 causes a toxic
retinal lesion known as a "bull's-eye" maculopathy, which is associated with a
decrease in visual acuity.
Metabolisme
 Biotransformasi secara enzimatik di mata dapat signifikan terjadi
karena terdapat bbrp enzim di mata yang dapat memetabolisme
obat
 esterases, oxidoreductases, lysosomal enzymes, peptidases, glucuronide
and sulfate transferases, glutathione-conjugating enzymes, catechol-O-
methyl-transferase, monoamine oxidase, and 11-hydroxysteroid
dehydrogenase.
 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 F2; 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.
Pharmacokinetic
 Berbagai metode pemberian
obat untuk penyakit mata
Rute Absorpsi Penggunaan Keterbatasan dan
Perhatian khusus

Topikal Cepat, tergantung Ekonomis, relatif aman Kepatuhan, toksisitas

bentuk sediaan kornea dan konjunctiva,
mukosa hidung, efek
samping sistemik
melalui nasolakrimal
Injeksi Subkonjuctival, Cepat, tergantung Infeksi segmen anterior, Toksisitas lokal, trauma
sub-Tenon, dan bentuk sediaan uveitis posterior jaringan, trauma nervus
rektrobulbar optikus, oklusi arteri/
vena retina sentral,
trauma otot mata
Injeksi intraokular Cepat Bedah segmen anterior, Toksisitas kornea,
infeksi intraokular, masa kerja
obat singkat
Injeksi intra vitreal Efek lokal cepat Endolftalmitis, retinitis Toksisitas retina
APLIKASI KLINIS
Antibiotic for ophthalmic use

Goodman & Gilman’s The Pharmacological Basis of Therapeutics.

 Pilihan antibiotik topikal
Fluoroquinolon  ciprofoksasin, ofloxacin tetes
mata,
 excellent activity against gram-negative aerobic
bacteria;
 they had limited activity against gram-positive
organisms.
 Spektrum  E. coli and various species of
Salmonella, Shigella, Enterobacter,
Campylobacter, Neisseria, P. aeruginosa
 Staphylococci, but not against methicillin-
resistant strains
 Kloramfenikol  tetes mata, salep mata
 bacteriostatic
 broad-spectrum antibiotic that is active against
both aerobic & anaerobic gram-positive and
gram-negative organisms
 Antibiotik lain
 Aminoglikosida  gram negatif
 Gentamisin
 Tobramisin
 Neomisin
 Anti inflammatory
Korticosteroid
 Kortikosteroid topikal  alergi, uveitis anterior, external
eye inflammatory diseases associated with some infections
and ocular cicatricial pemphigoid, & postoperative
inflammation following refractive, corneal, and intraocular
surgery.
 Menghambat wound-healing process dengan menurunkan
infiltrasi fibroblas  menurunkan terbentuknya scar pada
lokasi op  post glaucoma filtering surgery
 Uveitis posterior steroid sistemik dan injeksi kapsul sub-
Tenon
 Injeksi Intravitreal age-related macular degeneration,
diabetic retinopathy & cystoid macular edema.
 Steroid parenteral  diikuti dengan tapering ke dosis oral
untuk terapi neuritis optik.
NSAID TOPIKAL MATA

five topical NSAIDs approved for ocular use:

diclofenac (VOLTAREN),
 flurbiprofen (OCUFEN),
 ketorolac (ACULAR),
 bromfenac (XIBROM),
 nepafenac (NEVANAC)
Topical NSAIDs  associated with sterile corneal
melts and perforations, especially in older patients
with ocular surface disease, such as dry eye
syndrome.
 Antihistamine and Mast-Cell
Stabilizers

 Pheniramine & antazoline, both H1 receptor antagonists, are

formulated in combination with naphazoline, a
vasoconstrictor, for relief of allergic conjunctivitis.
 Topical antihistamines include emedastine difumarate &
levocabastine hydrochloride.
 Cromolyn sodium, which prevents the release of histamine and
other autacoids from mast cells  vernal conjunctivitis.
 Lodoxamidetromethamine and pemirolast , mast-cell
stabilizers, also are available for ophthalmic use.
 Epinastine antagonizes H1 and H2 receptors and exhibits mast
cell–stabilizing activity.
Autonomic agents in the eye
Agonis kolinergik Antikolinesterase Antagonis muskarinik
Asetilkolin Pisostigmin Atropin
Pilokarpin Echothiophate Scopolamine

Simpatomimetik
Epinefrin
Dipivefrin
Naphazoline
Tetrahydrozoline
Betaxolol
timolol
Autonomic agents in the eye
 Atropin  sikloplegik digunakan untuk
pemeriksaan funduskopi
 Pilokarpin  miotik
 Anti glaukoma
 Gol. Analog prostaglandin (PGF2α)
 Gol antagonis reseptor β
 Selektif
 Non selektif
 Agonis α2 adrenergik
 Inhibitor karbonik anhidrase
Drug Therapy of Primary Open Angle
(chronic simple) Glaucoma
 Miotics: ↑ the acqueous outflow.
 Direct : pilocarpine.
 Indirect: choline esterase inhibitors
 Sympathomimetics: ↓ acq.humour
production, & ↑ outflow
 Β-adrenoceptor blocking agents: ↓
acq.humour production  Timolol
 Oral Agents: Carbonic Anhydrase inhibitors.
↓ acq.humour production  Acetazolamide
 Drug Therapy of acute angle
closed (congestive) glaucoma

 Dehydrating agents infus larutan hipertonik

(Mannitol, Glycerol)
 Oral Acetazolamide
 Topical miotics  mis: pilocarpine
 Analgesics: pethidine or morphine (for pain)
 Drugs for dry eye
The current management of dry eyes usually includes
instilling artificial tears and ophthalmic lubricants.
• tear substitutes are hypotonic or isotonic solutions
composed of electrolytes, surfactants, preservatives, and
some viscosity-increasing agent  prolongs the
residence time in the cul-de-sac & precorneal tear film.

Common viscosity agents include cellulose polymers

(e.g., carboxymethylcellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
and methylcellulose), polyvinyl alcohol, polyethylene
glycol, polysorbate, mineral oil, glycerin, and dextran.
Some tear formulations also are combined with a
vasoconstrictor  naphazoline, phenylephrine, or
tetrahydrozoline.

Hyaluronic acid sometimes is used as a viscous agent

 Systemic Agents with Ocular
Side Effects
 Retina
 Hidroksiklorokuin & klorokuin  central retinal toxicity by an unknown mechanism.
Pada dosis normal toksisitas tidak muncul namun muncul setelah digunakan selama 6 tahun.
Stopping the drug will not reverse the damage, but will prevent further toxicity.
 Sildenafil (VIAGRA) penghambat PDE5 (th/ disfungsi ereksi)
 Obat ini juga hambat inhibits PDE6  mengontrol kadar cGMP pada retina  gangguan
penglihatan dan fotosensitivitas. Retinal damage (-).

 Optic Nerve
 Multiple medications can cause a toxic optic neuropathy characterized by gradually progressive
bilateral central scotomas and vision loss. There can be accompanying optic nerve pallor. These
medicines include ethambutol, chloramphenicol, and rifampin. Systemic or ocular steroids can cause
elevated IOP and glaucoma. If the steroids cannot be stopped, glaucoma medications, and even
filtering surgery, often are required.
 Anterior Segment
 Steroids also have been implicated in cataract formation If vision is reduced, cataract surgery
may be necessary.
 Rifabutin, if used in conjunction with clarithromycin or fluconazole for treatment of Mycobacterium
avium complex (MAC) opportunistic infections in HIV-positive persons, is associated with an
iridocyclitis and even hypopyon. This will resolve with steroids or by stopping the medication.
 Ocular Surface
 Isotretinoin (ACCUTANE) has a drying effect on mucous membranes and is associated with dry eye.
THANK YOU

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