Ocular pharmacology

1. Ocular Pharmacology
Guided By
Dr. V.M Motghare,
Prof. and Head
Department of pharmacology
G.M.C. Nagpur
& Dr . S.A. Pimpalkhute
Dr. Kundan Nivangune
JR3

2. Overview
Overview of ocular anatomy & Physiology
Pharmacokinetics & Toxicology of ocular therapeutic agents
Ocular Routes of Drug Administration
Therapeutic & Diagnostic applications of Drugs in Ophthalmology
Ophthalmic Effects of Selected Vitamin Deficiencies & Zinc Deficiency
Systemic Agents with Ocular Side Effects
New drug delivery systems in Ophthalmology
Conclusion

3. Anatomy of Eye

5. Tear Film

6. Pharmacokinetics of Ocular
Therapeutic Agents

7. Pharmacokinetics of Ocular Drugs
 Classical pharmacokinetic theory based on
systemically administered drugs does not fully
apply to all opthalmic drugs
Topical route – most commonly used

8. Absorption
Rate & extent of absorption of topically instilled
drugs depends upon –
1. Time the drug remains in the cul-de-sac &
precorneal tear film
“Drug penetration into the eye is
approximately 2. Elimination by linearly nasolacrimal related drainage
to its
concentration in the tear film.”
3. Drug binding to tear proteins
4. Drug metabolism by tear & tissue proteins
“”Drug penetration into the eye is approximately linearly related to
its concentration in the tear film.”
5. Diffusion across cornea & conjunctiva

9. Distribution
Transcorneal absorption
Accumulation in aqueous humor
Distribution to intraocular structures
Trabecular meshwork pathway
Distribution to systemic circulation

10. Distribution
Melanin binding of certain drugs –
- Ex:
1. Mydriatic effect of alpha adrenergic agonists
-- slower in onset - darkly pigmented irides compared
to those with lightly pigmented irides
2. Atropine’s mydriatic effect – long lasting in non-albino
rabbits than in albino rabbits
3. Accumulation of chloroquine in retinal pigment
epithelium – Bull’s eye maculopathy

11. Metabolism
Enzymatic biotransformation of ocular drugs-significant
Esterases – particular interest
Ex: Development of prodrugs for enhanced
ocular permeability
1. Dipivefrin hydrochloride
2. Latanoprost

13. Ocular Routes of Drug Administration
Sr.N
o
Route Special Utility Limitations &
Precautions
1. Topical --Convenient
-- Economical
--Relatively safe
--Compliance
--Corneal & conjunctival
toxicity
--Nasal mucosal toxicity
--Systemic side effects from
nasolacrimal absorption
2. Subconjunctival,
sub-Tenon’s &
Retrobulbar
injections
-Anterior segment
infections
-Posterior uveitis
-Cystoid Macular
Edema (CME)
-Local Toxicity
-Globe perforation
-Optic nerve trauma
-Central retinal artery or
vein occlusion
3. Intraocular
Injections
Anterior segment
surgery or infections
-Corneal toxicity
-Relatively short duration of
action
4. Intravitreal
Immediate local effect Retinal toxicity

14. Therapeutic applications of
Drugs in Ophthalmology

15. 1. Autonomic Drugs for Ophthalmic Use
2. Antimicrobial agents
3. Immunomodulatory & Antimitotic Drugs
4. Agents used to Assist in Ocular Diagnosis
5. Agents Used to treat Retinal
Neovascularization & Macular Degeneration
6. Drugs & Biological Agents Used in
Ophthalmic Surgery

16. Glaucoma
Definition:
Glaucoma is a chronic, progressive optic
neuropathy characterized by slow progressive
degeneration of the retinal ganglion cells and
the optic nerve axons leading to increased
deterioration of visual field.
• Parson’s.

17. History of Glaucoma
Hippocrates described "glaykoseis" as blindness
which occurs in the elderly.
The English ophthalmologist Banister - First to
establish the connection between increased
tension of the eyeball and glaucoma.
 In 1862, Donders - High intraocular pressure
caused blindness and called the disease
"Glaukoma simplex.“
Drug treatment started in 1875 with the discovery
of pilocarpine.

18. Glaucoma…
 IOP – Not an accurate indicator of disease
Ocular Hypertension - IOPs in mid to high 20s
with no optic nerve damage
Normal or low- tension Glaucoma – Progressive
glaucomatous optic nerve damage despite having
IOPs in normal range

20. Types Of Glaucoma
Primary Glaucoma:
Primary open angle
glaucoma
Angle closure glaucoma
Secondary
Glaucomas
Congenital or
developmental

21. Development of Glaucoma Animation, Open
Angle vs Angle Closure Glaucoma..mp4

22. Aim of Treatment
Decrease IOP
Decrease formation
of aqueous
Increase aqueous
drainage
-Beta blockers
-Alpha agonists
-Carbonic anhydrase
inhibitors (CAI)
PG analogs
Topical miotics

23. Agents used for treatment of Open
angle Glaucoma
1. Prostaglandin analogues
2. β receptor antagonists
3. α receptor agonists
4. Carbonic anhydrase inhibitors

24. Prostaglandin Analogs
First- line medical therapy for Glaucoma
PGF2α analogs - Good efficacy , once daily application & absence of
systemic side effects
1.Latanoprost 2. Travoprost 3.Bimatoprost
MOA – Facilitate aqueous outflow through uveoscleral outflow pathway
Side effects - Ocular irritation & pain, Blurring of vision, increased iris
pigmentation, Macular edema

25. β Adrenergic blockers
Nonselective β blockers – Timolol maleate
- Levobunolol
- Metipranolol
- Carteolol
 β -1 antagonists - Betaxolol

26. Mechanism of Action of β Blockers
Lower IOT by reducing aqueous formation
-- Down regulation of adenylylcyclase due to β2
receptor blockade in ciliary epithelium
-- Reduction in ocular blood flow

27. BETAXOLOL
 Less efficacious than
Timolol
TIMOLOL
20-35% fall in IOT
within 1 hour & lasts for
12 hours
30% patients -
Additional medication
BETAXOLOL
Less efficacious than
Timolol
Protective effect on
retinal neurons by
blocking some calcium
channels & reducing
reducing Na2+/Ca2+
influx

28. Adverse Effects of Ocular β
Adrenergic blockers
Ocular
1. Stinging, redness &
dryness of eye
2. Corneal hypoesthesia
3. Allergic
blepharoconjunctivitis
4. Blurred vision
Systemic
1. Bronchospasm in
asthmatics & COPD
patients
2. Bradycardia &
accentuation of Heart
block
Minimization of systemic
adverse effects

29. Carbonic anhydrase Inhibitors
(CAI)
Topical CAI – Dorzolamide , Brinzolamide
MOA – Inhibit carbonic anhydrase (isoenzyme
II) on ciliary body epithelium → Reduces
formation of bicarbonate ions →
Reduces fluid transport → Reduces aqueous
formation → Decrease IOP
Use – Only as add on drug to topical β
blockers or PG analogs
Systemic CAI – Final medication option before
resorting to laser or incisional surgical treatment

30. Adrenergic Agonists
Dipivefrine
 Prodrug of Adrenaline
 Reduces aqueous
production
 Augments uveoscleral
outflow
 Ocular burning
 Infrequently used for
add on therapy
Apraclonidine
 Selective α2 agonist
 Highly ionized at
physiological pH
 Do not cross BBB
 Reduces aqueous
production
 Enhance uveoscleral
outflow

31. Topical Miotics
Historically important in open angle glaucoma
MOA - Ciliary muscle contraction
-Increase drainage through trabecular
meshwork
Drugs----Pilocarpine
Less useful drugs – Numerous side effects &
three to four times a day dosing

32. Stepped Medical Approach to
Treatment of Open Angle Glaucoma
Start monotherapy with Latanoprost or topical β
blocker
If target i.o.t. not attained, either change over to
alternative drug or use both the above
concurrently
Brimonidine/dorzolamide – Use only when there
are contraindications to PG analogs/ β blockers
or to supplement their action
Oral acetazolamide/Topical miotics – Last resort

33. Angle closure Glaucoma

34. Angle closure Glaucoma
1. Hypertonic Mannitol ( 20%) – IV infusion
1.5 -2 g/kg
2. Acetazolamide - 0.5 g iv followed by oral
twice daily started concurrently
3. Miotic - Pilocarpine (1-4%) instilled every 10
min
4. Timolol 0.5 % - instilled 12 hourly.
5. Latanoprost 0.005
Definitive treatment –
Surgical/ Laser iridotomy

35. Newer agents for treatment of
Glaucoma
NMDA Receptor antagonist – Memantine
Erythropoietin (EPO)
Endothelin receptor antagonists – Bosentan
Calcium channel blockers
 Nitric oxide synthase inhibitors
Neurotrophins

36. 5 Atropine 0.5%, 1% &
2% solution;
1% ointment
-Cycloplegia
-Mydriasis
-Cycloplegic retinoscopy
-Dilated fundoscopic Exam
-Photosensitivity
-Blurred vision
6 Scopolamine 0.25%
solution
Cycloplegia
-Mydriasis
Photosensitivity
-Blurred vision
7 Homatropine 2% & 5%
solution
Cycloplegia
-Mydriasis
Photosensitivity
-Blurred vision
8 Cyclopentolate 0.5% 1%
solution
Cycloplegia
-Mydriasis
Photosensitivity
-Blurred vision
9 Tropicamide 0.5% & 1%
solution
Cycloplegia
-Mydriasis
Photosensitivity
-Blurred vision

37. Chemotherapy of microbial
diseases of the eye

38. Dacryocystitis - Infection of the
lacrimal sac

39. Hordeolum/ Sty – Infection of the meibomian, Zeis
or Moll gland

40. Conjunctivitis – Inflammatory process of
the conjunctiva

41. Blepharitis – Bilateral inflammatory process of
the eyelids

42. Antibacterial Agents For
Ophthalmic Use

43. Topical Antibacterial Agents
Commercially Available for Ophthalmic
Use
Azithromycin 1% solution H Conjunctivitis
Ciprofloxacin
0.3% solution;
H
hydrochloride
0.3% ointment
D-RCD
-Conjunctivitis
-Keratitis
-Keratoconjunctivitis
-Corneal Ulcers
-Blepharitis
-Dacryocystitis
Erythromycin 0.5% ointment H -Superficial Ocular Infections
involving cornea or conjunctiva
Gatifloxacin 0.3% solution H Conjunctivitis
H- Hypersensitivity ; D-RCD – Drug Related Corneal Deposits

44. Topical Antibacterial Agents Commercially
Available for Ophthalmic Use…..
Gentamicin
sulfate
0.3%
solution
H Conjunctivitis, Keratitis
Levofloxacin 0.5% H Conjunctivitis
Levofloxacin 1.5% H Corneal Ulcers
Moxifloxacin 0.5%
solution
H Conjunctivitis
Ofloxacin 0.3%
solution
H Conjunctivitis
Corneal Ulcers
Tobramycin
sulfate
0.3%
solution
0.3%
ointment
H External infections of the eye

45. Antiviral Agents for Ophthalmic Use
Trifluridine Topical (1%
solution)
PK, H -Herpes simplex keratitis
- Keratoconjuctivitis
Acyclovir Oral (200 mg
capsules, 800 mg
tablets)
Intravenous
-Herpes zoster ophthalmicus
- Herpes simplex iridocyclitis
Valacyclovir Oral (500- & 1000
mg)
-Herpes simplex keratitis
-Herpes zoster ophthalmicus
Famciclovir Oral (125-,250 mg
tablets)
-Herpes simplex keratitis
-Herpes zoster ophthalmicus
PK – Punctate Keratopathy ; H - Hypersensitivity

46. Antiviral Agents for Ophthalmic Use…
Foscarnet Intravenous
Intravitreal
----- Cytomegalovirus
Retinitis
Ganciclovir Intravenous, Oral
Intravitreal implant
----- Cytomegalovirus
Retinitis
Valganciclovir Oral ------- Cytomegalovirus
Retinitis
Cidofovir Intravenous ------ Cytomegalovirus
Retinitis

47. Antifungal Agents for Ophthalmic Use
Amphotericin B 0.1-0.5% solution
0.8-1 mg Subconjunctival
5 microgram intravitreal
injection
Intravenous
Yeast & fungal keratitis &
endophthalmitis
- Yeast & fungal endophthalmitis
- Yeast & fungal endophthalmitis
-Yeast & fungal endophthalmitis
Natamycin 5% topical suspension -Yeast & fungal blepharitis
-Conjunctivitis ; keratitis
Fluconazole Oral & Intravenous Yeast keratitis & endophthalmitis
Itraconazole Oral Yeast & fungal keratitis &
endophthalmitis
Ketoconazole Oral Yeast keratitis & endophthalmitis
Miconazole 1% topical solution Yeast & fungal keratitis

48. Immunomodulatory Drugs
A) Glucocorticoids –
Topical glucocorticoids – Dexamethasone
Prednisolone
Fluorometholone
Loteprednol
Rimexolone
Difluprednate

49. Therapeutic Uses of Topical
Glucocorticoids
1. Significant ocular allergy
2. Anterior uveitis
3. Postoperative inflammation following
refractive, corneal & intraocular surgery
4. To reduce potential scarring of surgical site
(After Glaucoma filtering surgery )

50. Steroids in ocular conditions……
 Systemic steroids & by sub-Tenon’s capsule
injection – Posterior Uveitis
Intravitreal injection –
-- Age-related Macular degeneration (ARMD)
-- Diabetic Retinopathy
-- Cystoid Macular Edema (CME)
Parenteral steroids followed by tapering oral
doses – Optic Neuritis

51. Toxicity of Steroids
1. Posterior subcapsular cataracts
2. Secondary infections
3. Secondary open-angle glaucoma
-- Positive family history of glaucoma
-- GLCIA gene
-- Reversible
“ Soft steroids (e.g., Loteprednol ) reduce the risk
of elevated IOP ”

52. Nonsteroidal Anti- Inflammatory
Agents
Five Topical NSAIDs – Approved for ocular
use
1. Flurbiprofen
2. Ketorolac
3. Diclofenac
4. Bromfenac
5. Nepafenac

53. Topical NSAIDs & their Ocular Uses
Sr.
No.
Topical NSAID Ocular Use
1 Flurbiprofen To counter unwanted intraoperative miosis during
cataract surgery
2 Ketorolac -Seasonal allergic conjunctivitis
-Cystoid Macular Edema (CME ) occuring after
cataract surgery
3 Diclofenac -Postoperative inflammation
-Cystoid Macular Edema (CME ) occuring after
cataract surgery
4 Bromfenac Postoperative pain & inflammation after cataract
surgery
5 Nepafenac Postoperative pain & inflammation after cataract
surgery

54. Immunosuppressive & Antimitotic
Agents
Agents commonly used –
1. 5-fluorouracil
2. Mitomycin C

55. Therapeutic Uses
1. In Glaucoma surgery, to improve success of
filtration surgery by limiting postoperative wound-healing
process.
2. In corneal surgery, topical mitomycin – To reduce
risk of scarring after excision of pterygium
3. Conjunctival papilloma & conjunctival tumours –
Interferon alpha- 2b
4. Uveitis & uveitic cystoid macular edema –
Intraocular Methotrexate

56. Immunomodulatory Agent
Topical Cyclosporine
– Approved for the treatment of chronic dry eye
associated with inflammation
-Decreases inflammatory markers in lacrimal gland &
increases tear production

57. Agents used to Assist in Ocular
Diagnosis
Fluorescein dye - Epithelial defects of cornea
& conjunctiva and aqueous
humor leakage
- IOP measurement
 Mydriatrics - Dilated fundoscopic
Examination

58. Agents Used to treat Retinal
Neovascularization & Macular Degeneration
1. Verteporfin
2. Pegaptanib
3. Bevacizumab
4. Ranibizumab

59. Verteporfin - MOA
• Verteporfin ( Intravenously )
• Light activation by non-thermal laser
• Free radical generation
• Vessel damage
• Platelet activation & thrombosis
• Occlusion of choroidal neovascularization

60. Pegaptanib
Approved for neovascular (wet ) ARMD
Selective Vascular endothelial growth factor
(VEGF ) antagonist.
VEGF 165 – Angiogenesis & increase vascular
permeability- Progression of wet ARMD
0.3 mg once every 6 weeks by intravitreous
route

61. Bevacizumab
 Monoclonal antibody against Vascular Endothelial
Growth Factor (VEGF)
 Inhibits vascular proliferation & tumor growth
 Intravitreal injection weekly/monthly
 Off label Uses of Bevacizumab
1. Proliferative Diabetic Retinopathy
2. Macular edema
3. Retinopathy of Prematurity
4. ARMD

62. Ranibizumab
Variant of Bevacizumab
 Intravitreal injection weekly/monthly
Use-
Reserved for both classic & ocult choroidal
neovascular membranes associated with ARMD

63. Anesthetics In Ophthalmic
Procedures
 Proparacaine & tetracaine drops –
Uses – Tonometry
- Removal of foreign bodies on
conjunctiva & cornea
- Superficial corneal surgery
Lidocaine & Bupivacaine – Retrobulbar block
anaestheia

64. Drugs & Biological Agents
Used in Ophthalmic
Surgery

65. 1. Povidone iodine
2. Viscoelastic substances
3. Ophthalmic Glue
4. Anterior Segment Gases
5. Vitreous Substitutes

66. Sr.
No.
Drugs & Biological
Agents
Use in Ophthalmic Surgery
1 Povidone iodine (5% solution) To prepare periocular skin & to irrigate
cornea, conjunctiva & palpebral fornices
2 Viscoelastic
substances(chondroitin
sulphate,
hudroxypropylmethylcellulose
)
Maintain spaces & protects surfaces
during anterior segment surgery
3 Ophthalmic Glue-a)
Cyanoacrylate tissue
adhesive
b) Fibrinogen Glue
Corneal ulcerations & Perforations
To secure conjunctiva & corneal grafts.
4 Anterior Segment Gases
a) Sulfur Hexafluoride (SF6)
b) Perfluoropropane
Reattachment of descemet’s membrane to
stroma of Cornea
5 Vitreous Substitutes Reattachment of retina following
Vitrectomy.

67. Botulinum Toxin Type A
FDA approved - Strabismus & Blepharospasm
associated with dystonia, facial wrinkles
(glabellar lines), axillary hyperhydrosis &
spasmodic Torticolis
MOA – Prevention of acetyl choline release at
neuromascular junction – temporary paralysis of
locally injected muscle

68. Ophthalmic Effects of Selected
Vitamin Deficiencies & Zinc Deficiency
Deficien
cy
Effects in Anterior
Segment
Effects in Posterior
Segment
Vitamin A Conjunctiva(Bitot’s spot, xerosis)
Cornea (Keratomalacia , Punctate
keratopathy)
Retina(Nyctalopia)
Retinal pigment epithelium
(hypopigmentation)
Vitamin B1 ---- Optic nerve (Visual field defects)
Vitamin B6 Cornea(Neovascularization) Retina (Atrophy)
Vitamin
B12
------ Optic nerve (Visual field defects)
Vitamin C Lens (? Cataract formation) -------

69. Ophthalmic Effects of Selected
Vitamin Deficiencies & Zinc Deficiency
Deficiency Effects in Anterior
Segment
Effects in Posterior Segment
Vitamin E -------- Retina & retinal pigment
epithelium (? Macular
degeneration)
Folic acid ------- Vein occlusion
Vitamin K Conjunctiva
(Hemorrhage)
Retina (Hemorrhage)
Zinc ------ Retina & retinal pigment
epithelium (? Macular
degeneration)

70. Toxicology

71. Toxicology
All opthalmic medications – Potentially absorbed
into systemic circulation – Undesirable systemic
side effects
 Ex Timolol (single eye drop) - Death
 Local toxic effects – Hypersensitivity reactions
-- Preservatives in eye drops & contact lens
solutions –
1. Benzalkonium chloride – Punctate Keratopathy
2. Thimerosal – Hypersensitivity reactions

72. Systemic Agents with Ocular Side
Effects
Sr.
No.
Name of Drug Ocular Side Effect
1. Topiramate Angle Closure Glaucoma
2. Hydroxychloroquine/Chloroquine Chloroquine amblyopia ( Bull’s Eye
Maculopathy )
3. Tamoxifen Crystalline Maculopathy
4. Vigabatrin Progressive & Permanent bilateral concentric
visual field constriction
5. Sildenafil/Vardenafil/tadalafil Nonarteritic Ischemic Optic Neuropathy
(NAION )
6. Ethambutol, Chloramphenicol ,
Rifampin
Toxic Optic Neuropathy (Progressive bilateral
central scotomas & vision loss )
7. Ocular Steroids Elevated IOP & Glaucoma
8. Steroids Cataract

73. Systemic Agents with Ocular Side
Effects……..
Sr.
No.
Name of Drug Ocular Side Effect
9. Rifabutin + Clarithromycin /
Fluconazole
Iridocyclitis & Hypopyon
10. Isotretinoin Dry eye & meibomian gland
dysfunction
11. Amiodarone Drug deposits in cornea ( Cornea
verticillata )
12. Chlorpromazine & Thioridazine Brown pigmentary deposits in the
cornea
13. Gold Chrysiasis ( gold deposits in cornea
& conjunctiva )
14. Tetracyclines Yellow discoloration of light-exposed
conjunctiva

74. Bulls eye

75. Visual field constriction
Cataract

77. Tear Substitutes
Hypotonic or isotonic solutions – electrolytes,
surfactants, preservatives & viscosity
increasing agent ( Carboxymethylcellulose,
Hydroxyethylcellulose, Polyvinyl alcohol)
Tyloxapol – Over-the-counter (OTC)
ophthalmic preparation – To facilitate wearing
comfort of artificial eyes

78. LACRISERT
 - Hydroxypropyl cellulose ophthalmic insert
(LACRISERT)
 Patients with dry eyes (keratitis sicca)
A substitute for artificial tears
Placed in the conjunctival sac and softens within 1
h and completely dissolves within 14 to 18 h
Stabilizes and thickens the precorneal tear film and
prolongs the tear film break-up time

79. Therapeutic Uses of Tear Substitutes
Eye diseases – Blepharitis
- Corneal dystrophies
- Chemical Burns
Systemic diseases – Sjogren’s syndrome
- Rheumatoid arthritis
- Vitamin A deficiency
- Stevens-Johnson syndrome

80. Ocusert
Pilocarpine, a parasympathomimetic agent for
glaucoma
Acts on target organs in the iris, ciliary body and
trabecular meshwork
Carrier for pilocarpine : alginic acid in core of
Ocusert
White annular border : titanium dioxide (pigment)
(easy for patient to visualize)

82. Contd… Advantages
1) Drug application convenient (Once a week)
2) Stabilization of Diurnal variation in IOT.
3) Guard against dangerously high IOT due to
irregularly instilled drops.
Disadvantages
1) Foreign body sensation
2) Difficulty in retention of device
3) Increased cost
4) Detailed instruction.

83. 3/10/2014
Geriatric and Pediatric Pharmacology
Dr Kundan
83