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Ocular pharmacology

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Ocular pharmacology

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Ocular pharmacology

  1. 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. 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. 3. Anatomy of Eye
  4. 4. Tear Film
  5. 5. Pharmacokinetics of Ocular Therapeutic Agents
  6. 6. 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
  7. 7. 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
  8. 8. Distribution Transcorneal absorption Accumulation in aqueous humor Distribution to intraocular structures Trabecular meshwork pathway Distribution to systemic circulation
  9. 9. 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
  10. 10. Metabolism Enzymatic biotransformation of ocular drugs-significant Esterases – particular interest Ex: Development of prodrugs for enhanced ocular permeability 1. Dipivefrin hydrochloride 2. Latanoprost
  11. 11. 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
  12. 12. Therapeutic applications of Drugs in Ophthalmology
  13. 13. 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
  14. 14. 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.
  15. 15. 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.
  16. 16. 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
  17. 17. Types Of Glaucoma Primary Glaucoma: Primary open angle glaucoma Angle closure glaucoma Secondary Glaucomas Congenital or developmental
  18. 18. Development of Glaucoma Animation, Open Angle vs Angle Closure Glaucoma..mp4
  19. 19. Aim of Treatment Decrease IOP Decrease formation of aqueous Increase aqueous drainage -Beta blockers -Alpha agonists -Carbonic anhydrase inhibitors (CAI) PG analogs Topical miotics
  20. 20. Agents used for treatment of Open angle Glaucoma 1. Prostaglandin analogues 2. β receptor antagonists 3. α receptor agonists 4. Carbonic anhydrase inhibitors
  21. 21. 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
  22. 22. β Adrenergic blockers Nonselective β blockers – Timolol maleate - Levobunolol - Metipranolol - Carteolol  β -1 antagonists - Betaxolol
  23. 23. 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
  24. 24. 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
  25. 25. 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
  26. 26. 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
  27. 27. 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
  28. 28. 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
  29. 29. 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
  30. 30. Angle closure Glaucoma
  31. 31. 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
  32. 32. Newer agents for treatment of Glaucoma NMDA Receptor antagonist – Memantine Erythropoietin (EPO) Endothelin receptor antagonists – Bosentan Calcium channel blockers  Nitric oxide synthase inhibitors Neurotrophins
  33. 33. 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
  34. 34. Chemotherapy of microbial diseases of the eye
  35. 35. Dacryocystitis - Infection of the lacrimal sac
  36. 36. Hordeolum/ Sty – Infection of the meibomian, Zeis or Moll gland
  37. 37. Conjunctivitis – Inflammatory process of the conjunctiva
  38. 38. Blepharitis – Bilateral inflammatory process of the eyelids
  39. 39. Antibacterial Agents For Ophthalmic Use
  40. 40. 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
  41. 41. 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
  42. 42. 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
  43. 43. 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
  44. 44. 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
  45. 45. Immunomodulatory Drugs A) Glucocorticoids – Topical glucocorticoids – Dexamethasone Prednisolone Fluorometholone Loteprednol Rimexolone Difluprednate
  46. 46. 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 )
  47. 47. 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
  48. 48. 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 ”
  49. 49. Nonsteroidal Anti- Inflammatory Agents Five Topical NSAIDs – Approved for ocular use 1. Flurbiprofen 2. Ketorolac 3. Diclofenac 4. Bromfenac 5. Nepafenac
  50. 50. 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
  51. 51. Immunosuppressive & Antimitotic Agents Agents commonly used – 1. 5-fluorouracil 2. Mitomycin C
  52. 52. 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
  53. 53. Immunomodulatory Agent Topical Cyclosporine – Approved for the treatment of chronic dry eye associated with inflammation -Decreases inflammatory markers in lacrimal gland & increases tear production
  54. 54. Agents used to Assist in Ocular Diagnosis Fluorescein dye - Epithelial defects of cornea & conjunctiva and aqueous humor leakage - IOP measurement  Mydriatrics - Dilated fundoscopic Examination
  55. 55. Agents Used to treat Retinal Neovascularization & Macular Degeneration 1. Verteporfin 2. Pegaptanib 3. Bevacizumab 4. Ranibizumab
  56. 56. Verteporfin - MOA • Verteporfin ( Intravenously ) • Light activation by non-thermal laser • Free radical generation • Vessel damage • Platelet activation & thrombosis • Occlusion of choroidal neovascularization
  57. 57. 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
  58. 58. 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
  59. 59. Ranibizumab Variant of Bevacizumab  Intravitreal injection weekly/monthly Use- Reserved for both classic & ocult choroidal neovascular membranes associated with ARMD
  60. 60. Anesthetics In Ophthalmic Procedures  Proparacaine & tetracaine drops – Uses – Tonometry - Removal of foreign bodies on conjunctiva & cornea - Superficial corneal surgery Lidocaine & Bupivacaine – Retrobulbar block anaestheia
  61. 61. Drugs & Biological Agents Used in Ophthalmic Surgery
  62. 62. 1. Povidone iodine 2. Viscoelastic substances 3. Ophthalmic Glue 4. Anterior Segment Gases 5. Vitreous Substitutes
  63. 63. 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.
  64. 64. 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
  65. 65. 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) -------
  66. 66. 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)
  67. 67. Toxicology
  68. 68. 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
  69. 69. 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
  70. 70. 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
  71. 71. Bulls eye
  72. 72. Visual field constriction Cataract
  73. 73. 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
  74. 74. 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
  75. 75. 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
  76. 76. 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)
  77. 77. 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.
  78. 78. 3/10/2014 Geriatric and Pediatric Pharmacology Dr Kundan 83

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