Download - Ocular pharmacology
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