Irfan Ahmad Khan Department of Pharmacology Anatomy of Eye Tear Film Pharmacokinetics of Ocular Therapeutic Agents Pharmacokinetics of Ocular Drugs Classical pharmacokinetic theory based on systemically administered drugs ID: 999073
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1. Ocular PharmacologyDr. Irfan Ahmad KhanDepartment of Pharmacology
2. Anatomy of Eye
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6. Tear Film
7. Pharmacokinetics of Ocular Therapeutic Agents
8. Pharmacokinetics of Ocular Drugs Classical pharmacokinetic theory based on systemically administered drugs does not fully apply to all opthalmic drugsTopical route – most commonly used
9. AbsorptionRate & 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.”Time the drug remains in the cul-de-sac & precorneal tear filmElimination by nasolacrimal drainageDrug binding to tear proteinsDrug metabolism by tear & tissue proteinsDiffusion across cornea & conjunctiva“”Drug penetration into the eye is approximately linearly related to its concentration in the tear film.”
10. Distribution2.Transcorneal absorption Accumulation in aqueous humor Distribution to intraocular structures Trabecular meshwork pathwayDistribution to systemic circulation 1. Nasal Mucosal Absorption
11. DistributionMelanin binding of certain drugs – Mydriatic effect of alpha adrenergic agonists -- slower in onset - darkly pigmented irides compared to those with lightly pigmented irides2. Atropine’s mydriatic effect – long lasting in non-albino rabbits than in albino rabbits3. Accumulation of chloroquine in retinal pigment epithelium – Bull’s eye maculopathy
12. MetabolismEnzymatic biotransformation of ocular drugs- significantEsterases – particular interestDevelopment of prodrugs for enhanced ocular permeabilityeg: Dipivefrin hydrochloride epinephrine Latanoprost PGF2α
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14. Ocular Routes of Drug AdministrationS. No. Route Special UtilityLimitations & Precautions1.TopicalConvenientEconomicalRelatively safeCorneal & conjunctival toxicity Nasal mucosal toxicitySystemic side effects from nasolacrimal absorption2.Subconjunctival, sub-Tenon’s & Retrobulbar injectionsAnterior segment infectionsPosterior uveitisLocal ToxicityGlobe perforationOptic nerve trauma3.Intraocular InjectionsAnterior segment surgery or infectionsCorneal toxicityRelatively short duration of action4.Intravitreal InjectionImmediate local effectRetinal toxicity
15. Therapeutic applications of Drugs in Ophthalmology
16. Autonomic Drugs for Ophthalmic UseAntimicrobial agentsImmunomodulatory DrugsAgents used to Assist in Ocular DiagnosisTear SubstitutesDrugs & Biological Agents Used in Ophthalmic Surgery
17. 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.
18. Aim of Treatment Decrease IOP Decrease formation of aqueous Increase aqueous drainage-Beta blockers-Alpha agonists-Carbonic anhydrase inhibitors (CAI)PG analogsTopical miotics
19. Agents used for treatment of Open angle Glaucoma Prostaglandin analoguesLatanoprost, Travoprost, Bimatoprost Side effects - Ocular irritation & pain, Blurring of vision, increased iris pigmentation, Macular edemaβ receptor antagonistsTimolol, Levobunolol, Betaxolol, Carteolol Ocular ADR: Stinging, redness & dryness of eye, Corneal hypoesthesia, Blurred visionα -agonists Dipivefrine, Apraclonidine4. Carbonic anhydrase inhibitorsTopical CAI – Dorzolamide , Brinzolamide
20. Angle closure Glaucoma
21. Angle closure GlaucomaHypertonic Mannitol ( 20%) – IV infusion-1.5 -2 g/kg Acetazolamide - 0.5 g iv followed by oral twice daily started concurrentlyMiotic - Pilocarpine (1-4%) instilled every 10 min Timolol 0.5 % - instilled 12 hourly.Definitive treatment – Surgical/ Laser iridotomy
22. Chemotherapy of microbial diseases of the eye
23. Dacryocystitis - Infection of the lacrimal sac
24. Hordeolum/ Sty – Infection of the meibomian, Zeis or Moll gland
25. Conjunctivitis – Inflammatory process of the conjunctiva
26. Blepharitis – Bilateral inflammatory process of the eyelids
27. Topical Antibacterial Agents for Ophthalmic UseGeneric NameFormulationToxicityIndication for UseAzithromycin1% solutionHConjunctivitisCiprofloxacin hydrochloride0.3% solution;0.3% ointmentHD-RCD-Conjunctivitis-Keratitis-Keratoconjunctivitis-Corneal Ulcers-Blepharitis-DacryocystitisErythromycin0.5% ointmentH-Superficial Ocular Infections involving cornea or conjunctivaGatifloxacin0.3% solutionHConjunctivitisH- Hypersensitivity ; D-RCD – Drug Related Corneal Deposits
28. Topical Antibacterial Agents Available for Ophthalmic Use…..Generic NameFormulationToxicityIndication for UseGentamicin sulfate0.3% solution HConjunctivitis, KeratitisLevofloxacin0.5% HConjunctivitisLevofloxacin1.5% HCorneal UlcersMoxifloxacin0.5% solution HConjunctivitisOfloxacin0.3% solution HConjunctivitisCorneal UlcersTobramycin sulfate0.3% solution0.3% ointment HExternal infections of the eye
29. Antiviral Agents for Ophthalmic UseGeneric NameRoute of AdministrationOcular ToxicityIndications for UseTrifluridineTopical (1% solution)PK, H-Herpes simplex keratitis-KeratoconjuctivitisAcyclovirOral (200 mg capsules, 800 mg tablets)Intravenous-Herpes zoster ophthalmicus-Herpes simplex iridocyclitisValacyclovirOral (500- & 1000 mg)-Herpes simplex keratitis-Herpes zoster ophthalmicusFamciclovirOral (125-,250 mg tablets)-Herpes simplex keratitis-Herpes zoster ophthalmicusPK – Punctate Keratopathy ; H - Hypersensitivity
30. Antiviral Agents for Ophthalmic Use…Generic NameRoute of AdministrationOcular ToxicityIndications for UseFoscarnetIntravenousIntravitreal -----Cytomegalovirus RetinitisGanciclovirIntravenous, OralIntravitreal implant -----Cytomegalovirus RetinitisValganciclovirOral -------Cytomegalovirus RetinitisCidofovirIntravenous ------Cytomegalovirus Retinitis
31. Antifungal Agents for Ophthalmic Use DrugMethod of AdministrationIndications for UseAmphotericin B0.1-0.5% solution0.8-1 mg Subconjunctival5 microgram intravitreal injectionIntravenousYeast & fungal keratitis & endophthalmitisNatamycin5% topical suspensionYeast & fungal blepharitisConjunctivitis ; keratitisFluconazoleOral & IntravenousYeast keratitis & endophthalmitisItraconazoleOralYeast & fungal keratitis & endophthalmitisKetoconazoleOralYeast keratitis & endophthalmitisMiconazole1% topical solutionYeast & fungal keratitis
32. Immunomodulatory DrugsGlucocorticoids – Topical glucocorticoids – Dexamethasone Prednisolone Fluorometholone Loteprednol Rimexolone Difluprednate
33. Therapeutic Uses of Topical GlucocorticoidsOcular allergyAnterior uveitisPostoperative inflammation following refractive, corneal & intraocular surgeryTo reduce potential scarring of surgical site (After Glaucoma filtering surgery )
34. Steroids in ocular conditions……Systemic steroids & by sub-Tenon’s capsule injection – Posterior UveitisIntravitreal injection – Age-related Macular degeneration (ARMD) Diabetic Retinopathy Cystoid Macular Edema (CME)Parenteral steroids followed by tapering oral doses – Optic Neuritis
35. Toxicity of SteroidsPosterior subcapsular cataractsSecondary infectionsSecondary open-angle glaucomaPositive family history of glaucomaReversible“Soft steroids (e.g., Loteprednol ) reduce the risk of elevated IOP”
36. Nonsteroidal Anti- Inflammatory AgentsFive Topical NSAIDs – Approved for ocular useFlurbiprofenKetorolacDiclofenacBromfenacNepafenac
37. Topical NSAIDs & their Ocular UsesS. No. Topical NSAID Ocular Use1FlurbiprofenTo counter unwanted intraoperative miosis during cataract surgery2KetorolacSeasonal allergic conjunctivitisCystoid Macular Edema (CME ) occuring after cataract surgery3DiclofenacPostoperative inflammationCystoid Macular Edema (CME ) occuring after cataract surgery4BromfenacPostoperative pain & inflammation after cataract surgery5Nepafenac
38. Immunosuppressive & Antimitotic AgentsAgents commonly used – 1. 5-fluorouracil 2. Mitomycin C
39. Therapeutic UsesIn Glaucoma surgery, to improve success of filtration surgery by limiting postoperative wound-healing process.In corneal surgery, topical mitomycin – To reduce risk of scarring after excision of pterygiumConjunctival papilloma & conjunctival tumours – Interferon alpha- 2bUveitis & uveitic cystoid macular edema – Intraocular Methotrexate
40. Immunomodulatory AgentTopical Cyclosporine – Approved for the treatment of chronic dry eye associated with inflammation -Decreases inflammatory markers in lacrimal gland & increases tear production
41. Agents used to Assist in Ocular DiagnosisFluorescein dye Available as drops or strips Uses: stain corneal abrasions, tonometry, detecting wound leak, NLD obstructionCaution:stains soft contact lensFluorescein drops can be contaminated by Pseudomonas sp. Mydriatics - Dilated fundoscopic Examination
42. Anesthetics in Ophthalmic Procedures Proparacaine & tetracaine drops – Uses TonometryRemoval of foreign bodies on conjunctiva & corneaSuperficial corneal surgeryLidocaine & Bupivacaine – Retrobulbar block anaestheia
43. Drugs & Biological Agents Used in Ophthalmic Surgery
44. S. NoDrugs & Biological AgentsUse in Ophthalmic Surgery1Povidone iodine (5% solution)To prepare periocular skin & to irrigate cornea, conjunctiva & palpebral fornices2Viscoelastic substances (chondroitin sulphate, hyaluronate)Maintain spaces & protects surfaces during anterior segment surgery3Ophthalmic Glue-Cyanoacrylate tissue adhesiveFibrinogen GlueCorneal ulcerations & PerforationsTo secure conjunctival & corneal grafts.4Anterior Segment GasesSulfur Hexafluoride (SF6)PerfluoropropaneReattachment of descemet’s membrane to stroma of Cornea5Vitreous SubstitutesReattachment of retina following Vitrectomy.
45. Tear SubstitutesHypotonic or isotonic solutions – electrolytes, surfactants, preservatives & viscosity increasing agent (Carboxymethylcellulose, Hydroxyethylcellulose, Polyvinyl alcohol)
46. LACRISERTHydroxypropyl cellulose ophthalmic insert Patients with dry eyes (keratitis sicca)A substitute for artificial tearsPlaced in the conjunctival sac Stabilizes and thickens the precorneal tear film and prolongs the tear film break-up time
47. Therapeutic Uses of Tear SubstitutesEye diseases – Blepharitis - Corneal dystrophies - Chemical BurnsSystemic diseases – Sjogren’s syndrome - Rheumatoid arthritis - Vitamin A deficiency - Stevens-Johnson syndrome
48. Systemic Agents with Ocular Side EffectsSr. No.Name of DrugOcular Side Effect1. TopiramateAngle Closure Glaucoma2.Hydroxychloroquine/ChloroquineBull’s Eye Maculopathy3.TamoxifenCrystalline Maculopathy4.VigabatrinProgressive & Permanent bilateral concentric visual field constriction5.Sildenafil/Vardenafil/tadalafilNonarteritic Ischemic Optic Neuropathy (NAION )6.Ethambutol, Chloramphenicol, RifampinToxic Optic Neuropathy (Progressive bilateral central scotomas & vision loss )7.Ocular SteroidsElevated IOP & Glaucoma8.SteroidsCataract
49. Systemic Agents with Ocular Side Effects……..S. No. Name of DrugOcular Side Effect9.Rifabutin + Clarithromycin / FluconazoleIridocyclitis10.IsotretinoinDry eye & meibomian gland dysfunction11.AmiodaroneDrug deposits in cornea (Cornea verticillata )12.Chlorpromazine & ThioridazineBrown pigmentary deposits in the cornea13.TetracyclinesYellow discoloration of light-exposed conjunctiva
50. Bull’s Eye Maculopathy Visual field constriction
51. Digitalis induced chromatopsia (objects appear yellow)