Ocular PharmacologyGuided By

Dr. V.M Motghare,

Prof. and Head

Department of pharmacology

G.M.C. Nagpur

& Dr . S.A. Pimpalkhute

Dr. Kundan NivanguneJR3

OverviewOverview 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

Anatomy of Eye

Tear Film

Pharmacokinetics of Ocular Therapeutic Agents

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

Absorption

Rate & extent of absorption of topically instilled drugs depends upon –

“Drug penetration into the eye is approximately linearly related to its concentration in the tear film.”

1. Time the drug remains in the cul-de-sac & precorneal tear film

2. Elimination by nasolacrimal drainage

3. Drug binding to tear proteins

4. Drug metabolism by tear & tissue proteins

5. Diffusion across cornea & conjunctiva

“”Drug penetration into the eye is approximately linearly related to its concentration in the tear film.”

Distribution

Transcorneal absorption

Accumulation in aqueous humor

Distribution to intraocular structures

Trabecular meshwork pathway

Distribution to systemic circulation

DistributionMelanin 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

Metabolism

Enzymatic biotransformation of ocular drugs- significant

Esterases – particular interest

Ex: Development of prodrugs for enhanced ocular permeability

1. Dipivefrin hydrochloride

2. Latanoprost

Ocular Routes of Drug AdministrationSr.No

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 Injection

Immediate local effect Retinal toxicity

Therapeutic applications of Drugs in Ophthalmology

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

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.

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.

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

Types Of Glaucoma

Primary Glaucoma:Primary open angle glaucomaAngle closure glaucoma

Secondary Glaucomas

Congenital or developmental

Development of Glaucoma Animation, Open Angle

vs Angle Closure Glaucoma..mp4

Aim of Treatment

Decrease IOP

Decrease formation of aqueous Increase aqueous

drainage

-Beta blockers-Alpha agonists

-Carbonic anhydrase inhibitors (CAI)

PG analogsTopical miotics

Agents used for treatment of Open angle Glaucoma

1. Prostaglandin analogues

2. β receptor antagonists

3. α receptor agonists

4. Carbonic anhydrase inhibitors

Prostaglandin AnalogsFirst- line medical therapy for GlaucomaPGF2α 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

β Adrenergic blockers

Nonselective β blockers – Timolol maleate

- Levobunolol

- Metipranolol

- Carteolol

β -1 antagonists - Betaxolol

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

BETAXOLOL Less efficacious than

Timolol

TIMOLOL

20-35% fall in IOT within 1 hour & lasts for

12 hours30% patients - Additional

medication

BETAXOLOLLess efficacious than

TimololProtective effect on retinal neurons by

blocking some calcium channels & reducing reducing Na2+/Ca2+

influx

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

Carbonic anhydrase Inhibitors (CAI)

Topical CAI – Dorzolamide , BrinzolamideMOA – 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

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

Topical Miotics

Historically important in open angle glaucomaMOA - Ciliary muscle contraction

-Increase drainage through trabecular meshwork

Drugs----Pilocarpine Less useful drugs – Numerous side effects &

three to four times a day dosing

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

Angle closure Glaucoma

Angle closure Glaucoma1. 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

Newer agents for treatment of Glaucoma

NMDA Receptor antagonist – MemantineErythropoietin (EPO)Endothelin receptor antagonists – BosentanCalcium channel blockers Nitric oxide synthase inhibitors Neurotrophins

SR. NO.

DRUG FORMULATION

INDICATION FOR USE OCULAR SIDE EFFECTS

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

Chemotherapy of microbial diseases of the eye

Dacryocystitis - Infection of the lacrimal sac

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

Conjunctivitis – Inflammatory process of the conjunctiva

Blepharitis – Bilateral inflammatory process of the eyelids

Antibacterial Agents For Ophthalmic Use

Topical Antibacterial Agents Commercially Available for Ophthalmic

UseGeneric Name Formulation Toxicity Indication for Use

Azithromycin 1% solution H Conjunctivitis

Ciprofloxacin hydrochloride

0.3% solution;0.3% ointment

HD-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

Topical Antibacterial Agents Commercially Available for Ophthalmic Use…..

Generic Name Formulation Toxicity Indication for 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 ConjunctivitisCorneal Ulcers

Tobramycin sulfate

0.3% solution0.3% ointment

H External infections of the eye

Antiviral Agents for Ophthalmic Use

GENERIC NAME ROUTE OF ADMINISTRATION

OCULAR TOXICITY

INDICATIONS FOR 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

Antiviral Agents for Ophthalmic Use…

GENERIC NAME ROUTE OF ADMINISTRATION

OCULAR TOXICITY

INDICATIONS FOR USE

Foscarnet IntravenousIntravitreal

----- Cytomegalovirus Retinitis

Ganciclovir Intravenous, OralIntravitreal implant

----- Cytomegalovirus Retinitis

Valganciclovir Oral ------- Cytomegalovirus Retinitis

Cidofovir Intravenous ------ Cytomegalovirus Retinitis

Antifungal Agents for Ophthalmic Use

Drug Method of Administration Indications for Use

Amphotericin B 0.1-0.5% solution

0.8-1 mg Subconjunctival5 microgram intravitreal injectionIntravenous

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

Immunomodulatory Drugs

A) Glucocorticoids –

Topical glucocorticoids – Dexamethasone

Prednisolone

Fluorometholone

Loteprednol

Rimexolone

Difluprednate

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 )

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

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 ”

Nonsteroidal Anti- Inflammatory Agents

Five Topical NSAIDs – Approved for ocular use

1. Flurbiprofen

2. Ketorolac

3. Diclofenac

4. Bromfenac

5. Nepafenac

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

Immunosuppressive & Antimitotic Agents

Agents commonly used –

1. 5-fluorouracil

2. Mitomycin C

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

Immunomodulatory Agent

Topical Cyclosporine

– Approved for the treatment of chronic dry eye associated with inflammation

-Decreases inflammatory markers in lacrimal gland & increases tear production

Agents used to Assist in Ocular Diagnosis

Fluorescein dye - Epithelial defects of cornea

& conjunctiva and aqueous

humor leakage

- IOP measurement Mydriatrics - Dilated fundoscopic

Examination

Agents Used to treat Retinal Neovascularization & Macular Degeneration

1. Verteporfin

2. Pegaptanib

3. Bevacizumab

4. Ranibizumab

Verteporfin - MOA•Verteporfin ( Intravenously )

•Light activation by non-thermal laser

•Free radical generation

•Vessel damage

•Platelet activation & thrombosis

•Occlusion of choroidal neovascularization

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

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

Ranibizumab

Variant of Bevacizumab

Intravitreal injection weekly/monthly

Use-

Reserved for both classic & ocult choroidal neovascular membranes associated with ARMD

Anesthetics In Ophthalmic Procedures

Proparacaine & tetracaine drops –

Uses – Tonometry

- Removal of foreign bodies on conjunctiva & cornea

- Superficial corneal surgeryLidocaine & Bupivacaine – Retrobulbar block

anaestheia

Drugs & Biological Agents Used in Ophthalmic

Surgery

1. Povidone iodine2. Viscoelastic substances3. Ophthalmic Glue4. Anterior Segment Gases5. Vitreous Substitutes

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

adhesiveb) Fibrinogen Glue

Corneal ulcerations & Perforations

To secure conjunctiva & corneal grafts.

4 Anterior Segment Gasesa) Sulfur Hexafluoride (SF6)b) Perfluoropropane

Reattachment of descemet’s membrane to stroma of Cornea

5 Vitreous Substitutes Reattachment of retina following Vitrectomy.

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

Ophthalmic Effects of Selected Vitamin Deficiencies & Zinc Deficiency

Deficiency

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) -------

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)

Toxicology

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

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

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

Bulls eye

Visual field constriction

Cataract

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

LACRISERT

- Hydroxypropyl cellulose ophthalmic insert (LACRISERT) Patients with dry eyes (keratitis sicca)A substitute for artificial tearsPlaced in the conjunctival sac and softens within 1

h and completely dissolves within 14 to 18 hStabilizes and thickens the precorneal tear film and

prolongs the tear film break-up time

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

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)

Contd…Advantages1) Drug application convenient (Once a week)2) Stabilization of Diurnal variation in IOT.3) Guard against dangerously high IOT due to

irregularly instilled drops.

Disadvantages1) Foreign body sensation2) Difficulty in retention of device3) Increased cost4) Detailed instruction.

Geriatric and Pediatric Pharmacology Dr Kundan

833/10/2014