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presentation ocular drugs.pptx
- 1. COMMON OCULAR DRUGS AND DELIVERY METHOD IN CORNEA PRESENTER: DR. RAMESH BHANDARI 1ST YEAR RESIDENT DEPARTMENT OF OPHTHALMOLOGY BPKLCOS, MMC, IOM
- 2. CONTENTS ⢠Anatomical and physiological characteristics of cornea ⢠Factors influencing drug permeability across cornea ⢠Pharmacokinetics ⢠Barrier for ocular transport of Drugs ⢠Absorption And Distribution of Drugs ⢠Mode of delivery of drugs ⢠Topical ⢠Systemic ⢠New technologies 2
- 3. CORNEA 3
- 4. ANATOMICAL AND PHYSIOLOGICAL CHARACTERISTICS OF CORNEA 4 ⢠A trilaminar structure of tear film (precorneal tear film) acts as a permeability barrier, so it doesnât allow drug to cross by simple diffusion. ⢠Properties of different corneal layers: ⢠Epithelium â hydrophobic â permeable to lipid soluble molecule (unionized molecule) ⢠Stroma - hydrophilic - permeable to water soluble molecule (ionized molecule) ⢠Endothelium - hydrophobic - permeable to lipid soluble molecule (Unionized molecule)
- 5. 5
- 6. ANATOMICAL AND PHYSIOLOGICAL CHARACTERISTICS OF CORNEA ⢠Epithelium is a main barrier â permeability increased if epithelium is damaged or abraded ⢠The highest trans-corneal concentration is achieved when administered compound has both water and lipid soluble property 6
- 7. FACTORS INFLUENCING DRUG PERMEABILITY ACROSS CORNEA ⢠Lipid and water solubility of the drug ⢠Drug with amphipathic properties have more penetration ⢠Concentration of the drug ⢠Higher the concentration- better penetration ⢠Ionic form of the drug ⢠Nonionized drug penetrates epithelium and ionized drug pass through stroma of the cornea Note: Fluorescein is a negative charged ion which canât penetrate intact epithelium, hence basis of fluorescein 7
- 8. ⢠Tonicity of the solution ⢠Hypertonic solution increases permeability ⢠pH of the solution ⢠Normal pH of tear is 7.4 ⢠If the pH of drug is different, it will cause reflex tearing and alter permeability ⢠If alkaloid drug is kept in alkaline medium, unionized drug concentration increases, hence increasing permeability 8
- 9. ⢠Viscosity of the solution ⢠Increases contact time with cornea; addition of methyl cellulose and polyvinyl alcohol increases viscosity of the drug ⢠Surface active agents/ surfactants ⢠Reduce surface tension, increases corneal wetting and therefore presents more drug for absorption eg. Preservatives like Benzalkonium chloride and thiomersel ⢠Pro-drug form ⢠Prodrug form are lipophilic â absorption from epithelium- converted to active drug (hydrophilic) â absorbed by stroma eg. esterase ⢠Dipivefrine epinephrine 9
- 10. PHARMACOKINETICS ⢠Absorption, distribution, metabolism, and excretion of the drug ⢠A drug can be delivered to ocular tissue as: ⢠Locally: Eye drop Ointment Periocular injection Intraocular injection ⢠Systemically: Orally Intravenously 10
- 11. BARRIER FOR OCULAR TRANSPORT OF DRUG ⢠Corneal epithelium and stroma ⢠Blood ocular barriers:Blood retinal barrier Blood- aqueous barrier ⢠Blink rate ⢠Absorption from conjunctival vessel and mucosa ⢠Nasolacrimal drainage of tears 11
- 12. 12 Active Pharmaceutical Ingredient in Tear Fluid Systemic absorption (50-100% of the dose) ROUTES: -Conjunctiva -Nose -Lachrymal drainage -Pharynx -GI tract -Aqueous humor Ocular Absorption (5% of the dose) Corneal Routes -Primary routes -Lipophilic drugs Conjunctival and scleral route -Hydrophilic drugs Aqueous Humor Ocular tissues
- 13. ABSORPTION Rate & extent of absorption of topically instilled drugs depends upon 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 13
- 14. DISTRIBUTION 14 Trans-corneal absorption Accumulation in aqueous humor Distribution to intraocular structure Trabecular meshwork pathway Distribution to systemic circulation
- 15. Mode of delivery of drugs Topical â˘Eye drop â˘Eye ointment â˘Gel â˘Soft contact lens â˘Ocuserts Periocular â˘Subconjunct ival â˘Subtenon â˘Peribulbar â˘Retro bulbar Intraocular Intracamer al Intravitreal Systemi c Intravenou s Oral 15
- 16. IDEAL DRUG DELIVERY SYSTEM Following characteristics are required to optimize ocular drug delivery through cornea ⢠Good corneal penetration ⢠Prolong contact time with corneal tissue 16
- 17. TOPICAL ADMINISTRATION EYE DROP ⢠Simplest and most convenient ⢠Generally, 1 drop = 50 microliters ⢠Conjunctival sac capacity = 7 â 13 microliters ⢠Only 20% of administered drug is retained (i.e. 10 microlitres) 17
- 18. Delivery of larger volume of topical eye drops Reflex blinking Increased drainage rate to nasolacrimal canal Spilling on the cheeks, splashing the excess solution to the eyelashes Wasted amount of drug and possible negative side- effects due to high systemic absorption EYE DROP (CONTDâŚ) 18
- 19. ⢠Properties of eye drops like hydrogen ion concentration, osmolality, viscosity and instilled volume can influence the retention of solution in the eye. ⢠Method for instillation of eye drop: ⢠Hold the skin below the lower eye lid ⢠Pull it forward slightly ⢠Instill 1 drop 19 EYE DROP (CONTDâŚ)
- 20. ⢠Time duration that the drug remains in the tear reservoir and tear film is called the residence time of a medication ⢠Measures to increase drug absorption: ⢠Wait for 5 to 10 min between drops ⢠Compress the lacrimal sac by digital pressure at the medial canthus ⢠Keep the eye lid closed for 5 minutes after instillation 20 EYE DROP (CONTDâŚ)
- 21. OINTMENT ⢠Increase the contact time of ocular medication to ocular surface, thus better effect ⢠It has the disadvantage of delayed action, sticking of eyelids and temporary blurring vision ⢠Used at bed time ⢠The drug has to be highly lipid soluble with some water solubility to have maximum effect as ointment 21
- 22. GELS ⢠Gels composed of mucoadhesive polymers that provide localized delivery of an active ingredient to the eye. Such polymers have a property known as bio adhesion. ⢠These polymers extend the contact time of drug with the biological tissues and thereby improve ocular bioavailability. ⢠Advantage: Longer contact time Greater storage stability ⢠Disadvantage: Blurred vision (but less than ointment) Poor patient compliance 22
- 23. OCUSERT 23 ⢠Ocular inserts (ocuserts) are sterile preparation that prolong residence time of drug with a controlled release manner ⢠Lacrisert is a sterile rod shaped device for the treatment of dry eye syndrome and keratitis sicca. ⢠They act by imbibing water from the cornea and conjunctiva and form the hydrophilic film which lubricates the cornea.
- 24. SYSTEMIC DRUG ⢠Drugs used to treat corneal pathology can be given orally or intravenously ⢠Factors influencing systemic drug penetration into ocular tissue: ⢠Lipid solubility: more penetration ⢠Protein Binding: more effect with low protein binding ⢠Ocular inflammation: more penetration with ocular inflammation 24
- 25. NEW TECHNOLOGY IN DRUG DELIVERY MUCOADHESIVE ⢠Polyacrylic acid and hyaluronic acid ⢠Types: Naturally occurring (lectins and fibronectin) Synthetic: Carbopol ⢠Interacts with mucosal layer on cornea ⢠Increased retention of drug ⢠Aids in the localized delivery of topical ocular drugs and increases bioavailability due to prolonged contact and corneal layer. 25
- 26. COLLAGEN CORNEAL SHIELD ⢠Soluble ophthalmic inserts manufactured from porcine scleral tissue and molded into contact lens-like shields that are useful as a delivery system to prolong contact between drug and cornea ⢠The shield dissolves in 12- 72 hours, leading to higher concentration of drug in the corneal surface ⢠Used for the early treatment of bacterial keratitis as well as for antibiotics prophylaxis ⢠Disadvantage: poorly tolerated because they are very uncomfortable 26
- 27. IONTOPHORESIS ⢠Physical process of moving charged molecules by electrical current is called as iontophoresis. ⢠Noninvasive method ⢠Transcorneal: delivers a high concentration of drug to anterior segment of eye (cornea, aqueous humor, iris, lens) ⢠Used for treatment of anterior segment disease such as dry eyes, keratitis, corneal ulcers 27
- 28. NANO PARTICLES AND MICRO PARTICLES ⢠Particulate polymeric drug delivery system include micro and nano particles designed to overcome the barriers ⢠Increase the drug penetration at the target site ⢠Improves the bioavailability of ophthalmic drug 28
- 29. 29
- 30. LIPOSOMES ⢠Liposomes are biocompatible and biodegradable lipid vesicles made up of natural lipids and about 25 â 10000nm in diameter ⢠They are having an intimate contact with the corneal and conjunctival surfaces which is desirable for drugs that are poorly absorbed thus increases the probability of ocular drug absorption 30
- 31. CYCLODEXTRIN ⢠Cyclodextrins manufactured by the enzymatic degradation of starch ⢠It occurs as a amorphous powder ⢠It is pharmacologically active material ⢠It increases solubility of poorly water soluble drugs ⢠It increases the absorption rate of the drug thus increasing bioavailability 31
- 32. COMMON DRUGS USED IN CORNEAL PATHOLOGY 32
- 34. ANTIBIOTICS 34
- 35. 35
- 37. ⢠Majority of the topically administered antibacterials cause hypersensitivity reaction. However fluoroquinolones (especially ciprofloxacin) can cause drug related corneal deposits. 37
- 38. FORTIFIED ANTIMICROBIAL EYE DROP ⢠Most of our available ophthalmic antibiotic preparations are in 0.3% concentration, which is not sufficient to attain minimum inhibitory concentration to halt the progression of resistant keratitis. ⢠Fortification means to intensify or strengthen the medication to achieve adequate drug concentration. ⢠For preparation of fortified antibiotics, a standard parenteral or lyophilized antibiotic preparation is combined with a compatible vehicle such that the antibiotic does not precipitate. 38
- 39. Need for Fortification: ⢠For resistant microbial keratitis, to attain appropriate drug concentration and to stop the fulminant rapid progression of keratitis. ⢠For moderate-to-severe corneal ulcers ⢠For drugs that are available only in parenteral form. For example - Vancomycin and Amphotericin B. 39
- 40. LIMITATIONS: ⢠High cost ⢠Contamination risk ⢠Since it is a preservative-free preparation, they have short shelf-life ⢠Need for refrigeration. 40
- 41. Medication/ composition Preparation technique Shelf life Fortified Tobramycin: 14mg/ml(1.4%) Add 2ml/80mg of parenteral tobramycin to commercially available tobramycin eye drops 0.3% 5 ml (15mg/5ml) 1 week in refrigerator at 4 degrees and 4 days in room temperature Fortified Gentamicin Eye Drops: 14mg/ml(1.4%) Add 2ml/80mg of parenteral gentamicin to commercial gentamicin ophthalmic solution 0.3% 5 ml (15mg/5ml) 1 week in refrigerator at 4 degrees C and 4 days in room temperature Fortified Amikacin Eye Drops: 2.5% Parenteral Amikacin 250mg/2ml is mixed with 8 ml artificial tears. 7 days under refrigeration at 4 Degrees Centigrade 42
- 42. 43 Medication/ composition Preparation technique Shelf life Fortified Cefazolin Eye Drops: 50mg/ml( 5%) Reconstitute parenteral Cefazolin 500mg with 2ml sterile water available with the injection and add to 8ml of artificial tears. 1week in refrigeration at 4 degrees C and 4 days in room temperature Fortified Ceftazidime eye drops: 50mg/ml( 5%) Reconstitute parenteral Ceftazidime 500mg with 2ml sterile water/BSS available with the injection and add to 8ml of artificial tears 1week under refrigeration at 4 degrees C and 3 days in room temperature Topical Vancomycin Eye Drops: 50mg/ml(5%) Reconstitute 500mg of vancomycin powder for injection with 2 ml sterile water/BSS. Add to 8ml of artificial tears. 28 days at 4 Degrees C
- 43. ANTIVIRALS 44
- 44. ANTIVIRALS: LOCAL APPLICATION 45 Drugs Dosage Effective against Complication Idoxuridine 1% drop Hourly in daytime, 2hrly in night time Herpes simplex Follicular conjunctivitis, punctate epithelial keratopathy, lacrimal punctal stenosis Acyclovir 3% ointment 5 times/ day Herpes simplex Herpes zoster punctate epithelial keratopathy. Ganciclovir 0.15% gel 5 times/ day Herpes simplex punctate epithelial keratopathy Ganciclovir Intravitrea CMV retinitis Increased IOP
- 45. ANTIVIRALS: SYSTEMIC APPLICATION 46 Drugs Dosage Effective against Complication Acyclovir 800mg 5 times/day 400mg 4 times/day Herpes zoster Herpes simplex Nephrotoxicity Valaciclovi r 500-700 mg 3 times/day Herpes zoster Nephrotoxicity Famiciclov ir 500-700mg 3 times/day Herpes zoster Headache, diarrhea, nausea, urticaria Ganciclovi r 5mg/kg body weight every 12 CMV retinitis Myelosuppresi on
- 46. ANTIFUNGAL 48
- 47. Drugs Administration MOA Toxicity Amphotericin B (AmB deoxycholate, AmB lipid complex, liposomal AmB, AmB colloidal dispersal) I.V. : 1mg/kg Intravitreal: 5-10 Âľgm Subconj: 750 Âľgm/ml Topical: 2.5 â 10mg/ml Binds to fungal cell wall ergosterol and disrupt it Hypokalemia, Infusion related toxicity, less penetration, renal toxicity Natamycin 5% suspension/ 2hrly drop Hypersensitivity Irritation Fluconazole Topical: 1-2% Oral: 200mg/day Inhibits ergosterol synthesis and causes direct damage to cell wall Hepatitis, cholestasis, rashes, hepatic failure Ketoconazole: gynaecomastia, GI upset Itraconazole Topical: 1-2% Oral: 200-400mg/day Ketoconazole Topical: 1-2% Oral: 200-600mg/day Voriconazole Topical: 1-2% Oral: 200mg/day Echinocandins: Caspofungins I.V Block fungal cell wall Beta glucan 49
- 48. 50 Medication/ composition Preparation technique Shelf life Topical Amphotericin B 0.15% Add 10 ml distilled or sterile water to parenteral 50mg of amphotericin B powder for injection. Draw 3 ml of this and add to 7ml of artificial tears eye drops. 7 days in refrigerator at 4 degrees C and 4 days in room temperature. Topical Voriconazole Eye Drops 1% Mix 20 ml ringer lactate to 200 mg voriconazole lyophilized powder. 30days at 4deg C or room temperature Antifungal drugs like Amphotericin B, Voriconazole etc can be given via intrastromal and intracameral routes for treatment of fungal ulcers
- 49. ANTIPARASITIC ďUsed to treat Acanthamoeba keratitis ďCauses of parasitic keratitis: ⢠contact lens users ⢠Trauma ⢠Corneal transplantation ⢠Exposure to infected lake water; sea water and hot tubs 51
- 50. ANTIPROTOZOAL AGENTS Agents Drugs preparation Diamidines Propamidine Isoethionate 0.1% Hexamidine 0.1% Biguanides Polyhexamethylbiguani de 0.02% Chlorhexidine 0.02% Aminoglycosides Neomycin 8mg/ml Paromycin 10mg/ml 52
- 51. MYDRIATIC AND CYCLOPLEGIC 53 1 Atropine 0.5%, 1% & 2% solution; 1% ointment -Cycloplegia -Mydriasis -Pain reliever in corneal pathology like corneal ulcer; -Following Removal of corneal foreign body and corneal scrapping. -Herpetic keratitis - Photosensitivit y -Blurred vision 2 Homatropin e 2% & 5% solution 3 Tropicamid e 0.5% & 1% solution
- 52. ANTI-INFLAMMATORY AGENTS Corticosteroids ⢠Prednisolone ⢠Dexamethasone ⢠Betamethasone ⢠Flurometholone ⢠Triamcinolone NSAIDS ⢠Indomethacin ⢠Flurbiprofen ⢠Ketorolac ⢠Diclofenac 54
- 53. NSAIDS NSAIDS Formulation Concentration Indomethacin Suspension 0.1% Flurbiprofen Eyedrop 0.3% Ketorolac Eye drop 0.5% Diclofenac Eye drop 0.1% 55
- 54. CORTICOSTEROIDS ⢠Corticosteroids can be administered locally in the form of drops, ointments or injections and systemically in the form of tablets/ injections. ⢠They are lipid soluble so easily diffuse through cell membrane ⢠Mechanism of Action: Inhibit phospholipase A2 in biosynthesis of Arachidonic acid; hence inhibits synthesis of various inflammatory mediators 56
- 55. Steroids formulation indication Prednisolone Suspension: 0.125% or 1% Solution: 0.125% or 1% Tablet: 5mg/10mg I.V.: 20mg/ml Steroid responsive inflammation condition of conjunctiva, cornea like allergic conjunctivitis; corneal injury; allergic keratitis etc. Dexamethasone Suspension: 0.1% Solution: 0.1% Tablet: 0.5mg I.V.: 4mg/ml Betamethasone Solution: 0.1% Ointment: 0.1% Tablet: 0.5mg/1mg Fluorometholone Suspension: 0.1% Ointment: 0.1% Triamcinolone Suspension :40mg/ml 57
- 56. POINTS PREDNISOLONE ACETATE PREDNISOLONE PHOSPHATE SOLUBILITY Water Insoluble Water soluble PENETRATION Higher penetration through Cornea Weaker penetration than Acetate. BIOAVAILABILITY Higher Less than Acetate EFFICACY High Low FORMULATION Suspension so requires shaking before use. Solution so does not require shaking before use. 58
- 57. ⢠Side-effects of steroid: 59 CORTICOSTEROIDS Ocular: ⢠Glaucoma ⢠Cataract ⢠Activation of infection (if given in fungal and bacterial keratitis) ⢠Delayed wound healing Systemic: ⢠Peptic ulcer ⢠Cushing syndrome ⢠Hypertension ⢠Diabetes mellitus ⢠Osteoporosis ⢠Mental changes
- 58. IMMUNOMODULATORS -Cyclosporins (0.05%) -Tacrolimus ⢠Used for the treatment of ocular inflammatory disease such as vernal keratoconjunctivitis, dry eye disease as well as for the treatment of corneal subepithelial infiltrates resistant to steroids therapy ⢠Side-effects: Gingival Hyperplasia Blurring of vision Renal impairment 61
- 59. DIAGNOSTIC DRUGS ⢠FLUORESCEIN DYE ⢠Available as drops/ strips ⢠Uses: stains corneal Epithelial Defect. 62
- 60. ⢠ROSE BENGAL STAIN ⢠Stains devitalized epithelium only ⢠Uses: severe dry eyes, herpetic keratitis ⢠LISSAMINE GREEN ⢠Stains membrane â damaged/ devitalized cells green ⢠Stains the edge of dendritic ulcer 63
- 61. LOCAL ANESTHETICS ⢠Local Anesthetics are widely used prior to removal of any corneal foreign bodies or surgical procedures. ⢠Blocks the conduction by inhibition of sodium channel, hence- inhibiting depolarization. 64 Concentrations Onset of action Duration of action Lignocaine Infiltration (1/2/3%) Topical 4% 5-10 min 10-35 sec 30-60 min 15-20 min Bupivacain e Infiltration (0.25 â 0.75%) Moderate 75-90 min
- 62. TEAR SUBSTITUTES ⢠Cellulose derivatives such as HPMC ( Hydroxy propyl methyl cellulose), methyl cellulose, hyaluronic acid, polyacrylic acid (carbomers), liquid paraffin, polyvinyl alcohol ⢠Have amphiphilic nature ⢠Used commonly for ocular irritation, dry eyes. 65
- 63. PRESERVATIVES ⢠Ophthalmic solutions and ointments must be sterile, so wide variety of preservatives are used -Benzalkonium chloride -Chlorbutol -Thiomersal -Chlorhexidine -Sorbic acid Adverse effects: ⢠Toxic to precorneal tear film and epithelium ⢠Impedes epithelial healing and disrupt film ⢠Direct cellular damage ⢠Decreases oxygen utilization of cornea 66
- 64. REFERENCES ⢠ANATOMY AND PHYSIOLOGY OF EYE- A.K. KHURANA ⢠MICHAEL J. DOUGHTY, OCULAR PHARMACOLOGY AND THERAPEUTICS, A PRIMARY CARE GUIDE, 1ST EDITION- 2001 ⢠COPELAND AND AFSHARIâS PRINCIPLES AND PRACTICE OF CORNEA VOLUME-1 1ST EDITION- 2013 ⢠KANSKIâS CLINICAL OPHTHALMOLOGY, A SYSTEMATIC APPROACH- EIGHTH EDITION ⢠NIXON HK. PREPARATION OF FORTIFIED ANTIMICROBIAL EYE DROPS. KERALA J OPHTHALMOLOGY 2018;30:152-4 ⢠VARIOUS INTERNET SOURCES AND JOURNALS 67
- 65. THANK YOU 68