ocular pharmacology for optical std.pptx

pharmacology

1. OCULAR PHARMACOLOGY

2. Pharmacokinetics Study of chemical alteration of drug in the body Absorption Distribution Metabolism Excretion

3. Absorption Absorption is the movement of the drug from its site of administration to the target tissue (to produce the desired effect). Not only the fraction of administered dose that gets absorbed but the rate of absorption is also important.

4. Factors influencing absorption of drug Drug concentration and solubility : higher the concentration better will be the penetration. Viscosity : increases the contact time with the cornea. Addition of methylcellulose and polyvinyl alcohol increases the viscosity of drug. Lipid solubility : higher the lipid solubility more will be the penetration.

5. Surfactants : the preservatives used in ocular preparations alter cell membrane in the cornea and increase drug permeability eg - Benzylalkonium and Thiomersal pH : the normal tear pH is 7.4 and if the drug pH is different, it will cause reflex tearing. when an alkaloid drug is put in relatively alkaline medium, the proportion of the uncharged form will increase, thus more penetration

6. Barrier for intraocular transport of drugs Corneal epithelium and stroma : most imp Blood ocular barriers: blood retinal barrier blood aqueous barrier Blink rate Absorption through conjunctival vessels and mucosa Nasolacrimal drainage of tears

7. Distribution Once the drug is absorbed, it has the potential to penetrate most compartments of the body known as distribution. Distribution largely depends on the route of administration.

8. Distribution: Topical Transcorneal absorption Accumulation in aqueous humor Distribution to intraocular structures Trabecular Meshwork Distribution in systemic circulation

9. Factors affecting distribution Physiochemical properties of drug: Acidic/basic Binding to plasma proteins Binding to tissue proteins Relative blood flow to different tissues

10. Metabolism Drugs are metabolized to facilitate clearance & activate prodrugs for enhanced permeability Enzymatic biotransformation Eg : Esterases , ketone reductase & phase 1 &2 oxidizing and conjugating enzymes Eg . 1. Dipivefrine hydrochloride - Epinephrine 2. Latanoprost (isopropyl ester)- acid 3. Nepafenac 0.1% - Amfenac

11. Many of the drugs metabolized and excreted via kidneys or liver mostly Timolol – Liver Mannitol – kidneys Acetazolamide – kidneys Latanoprost (PG)- liver Local anesthetics- liver/ plasma

12. Routes of administration Topical Periocular Intraocular Solutions Subconjunctival Intracameral Gels Subtenon Intravitreal Ointments Peribulbar Contact lens Retrobulbar

13. Therapeutic applications

14. DRUGS FORMULATION INDICATION Onset of action& Duration of action ATROPINE 0.5%, 1% & 2% solution. 1% ointment Cycloplegia Mydriasis Cycloplegic retinoscopy OA: 30-40 mins Mydriasis -15 days Cycloplegia -120 mins HOMATROPINE 2% & 5% solution Cycloplegia Mydriasis Same as above SCOPALAMINE 0.25% solution Cycloplegia Mydriasis Mydriasis-7 days Cycloplegia-30-60 mins CYCLOPENTOLATE 0.5% & 1% solution Cycloplegia Mydriasis OA: 15-30 mins Mydriasis -1day Cycloplegia-20-45 mins PHENYLEPHRINE 2.5% solution Mydriatic only Mydriasis-4-6 hrs TROPICANAMIDE 0.5% & 1% solution Cycloplegia Mydriasis OA: 15-30 mins Mydriasis -4-5 hrs Cycloplegia-15miins Diagnostic purposes

15. Fluorescein dye Corneal epithelial defects & corneal ulcers. Applanation tonometry - Goldmann tonometer /Perkins hand-held tonometer Seidel's test: Concentrated fluorescein dye  Jones dye test for assessment of lacrimal passage functional potency. Fundus fluoroscein angiography: 10%-20% i /v Fluorometry Tear film break up time(TBUT)

16. Rose Bengal dye Rose bengal is actually a derivative of fluorescein Stains the devitalized cells only  Unlike fluoroscein , it’s a true histological stain which binds strongly and selectively to cellular components 1% liquid rose bengal dye via dry impregnated paper strips DRY EYE SJOGREN’S SYN- KERATOCONJUNTIVITIS SICCA

17. DENDRITIC KERATITIS

18. Lissamine green Stains membrane-damaged or devitalized cells- GREEN There is no stinging or discomfort such as that associated with rose bengal . Stains the edges of the dendritic ulcer while fluoroscence stains the central bed Concentration of 1% lissamine strips. DRY EYE DENDRITIC ULCER

19. Indocyanine green(ICG) Absorbs light at about 805 nm and emits 835nm infrared radiation These frequencies penetrate retinal layers allowing ICG angiography to image deeper patterns of circulation then FFA Tightly bound to plasma proteins, thus becomes confined to vascular system. 40mg in 2ml

20. VERTEPORFIN Verteporfin, a   benzoporphyrin  derivative Used as a  photosensitizer  for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular degeneration. CENTRAL SEROUS CHORIORETINOPATHY

21. Ocular infections Anti bacterials Anti fungals Anti virals Aminoglycosides cephalosporins Fluoroquinolone Macrolides Sulfonamides Others: Chloramphenicol Polyenes - Azoles Imidazole Triazole Acyclovir Valacyclovir Trifluridine Gancicyclovir Cidofovir Foscarnet Miconazole ketoconazole Fluconazole Itraconazole voriconazole Anti Parasitic: acanthamoeba Polyhexamethyl biguanide 0.02% Chlorhexidine 0.02% Hydrogen peroxide Benzalkonium chloride(BKC) Natamycin Ampho B

22. ANTIBACTERIALS

23. Anti Bacterials Anti Bacterials MOA Drugs available Aminoglycosides Protein synthesis inhibitors Gentamycin , Tobramycin & Amikacin Flouoroquinolones DNA gyrase inhibitors Ciprofloxacin, gati , moxi , besifloxacin etc Macrolides Protein synthesis inhibitors Azithromycin , erythromycin Sulphonamides Anti folate antibiotics Chloramphenichol , sulphaacetamide Cephalosporins Cell wall synthesis inhibitors cefazoline

24. Aminoglycoside (cont) Drugs Dosage Indication Side effects Gentamycin 0.3% every four hrs Conjunctivitis, keratitis , corneal ulcers, dacrocystitis etc Ocular burning & irritation, non specific conjuntivitis . Pregnancy & child Tobramycin 0.3% every four hrs Conjunctivitis, keratitis , corneal ulcers, dacrocystitis etc in children Tearing, swelling of eye, stinging or blurred vision fortified Amikacin 1.25%- 2.5% Severe bacterial infection Eg - mycobacterium chelonae keratitis Ototoxicity Nephrotoxicity Pregnancy-D

25. Generic name formulations Toxicity Indications Ciprofloxacin 0.3% solution 0.3% ointment Hypersensitivities Drug related corneal deposits Conjunctivitis Keratitis Corneal ulcer blephritis Dacrocystitis Ofloxacin 0.3% solution Hypersensitivity Conjunctivitis Corneal ulcers Fluroquinolones

26. Generic name formulations Toxicity Indications Gatifloxacin 0.3% solution Hypersensitivity Conjunctivitis, post op & pre op prophylaxis, corneal pathologies etc Moxifloxacin 0.5% solution Hypersensitivity same as above Besifloxacin 0.6% suspension Redness, blurring of vision, pain, irritation etc Same as above

27. Macrolides Generic name formulations Toxicity Indications Azithromycin 1% ointment Hypersensitivity Superficial infection involving cornea and conjunctiva Erythromycin 0.5% ointment Hypersensitivity Superficial infection involving cornea and conjunctiva MOA: Inhibits Protein synthesis by inhibiting the translocation on 50S ribosome

28. Sulphonamides Generic name Formulations Dosage Indications Chloramphenicol 0.5% solution 4-6 times daily Conjuntivitis Keratitis Sulfacetamide sodium 10%, 15% and 30% w/v Two hourly (for trachoma) Conjuntivitis , trachoma and other superficial ocular infections MOA : These are Anti folate antibiotics which inhibit folic acid synthesis

29. The use of fluoroquinolones as monotherapy for bacterial keratitis has proved as effective as combined fortified antibiotics However, serious complications such as corneal perforation, evisceration, or enucleation of the affected eye were more common with fluoroquinolone therapy (16.7%) compared with the fortified therapy (2.4%, p= 0.02). Caution should be exercised in using fluoroquinolones in large, deep ulcers in the elderly Gangopadhyay N, Daniell M, Weih L,Taylor HR. Fluoroquinolone and fortified antibiotics for treating bacterial corneal ulcers; Br J Ophthalmol 2000 ;84:378–384

30. Antibiotic Resistance Moxifloxacin resistance rates of coagulase negative (70% of endophthalmitis in cataract surgey ) are increasing. The mean resistance of moxi at a large university centre over past six years were almost 60%. -JAMA Ophthalmology, November 2014 “ Recent studies suggest that repeated short courses of post injection topical antibiotic do not decrease the risk of endophthalmitis but also actually increase antibiotic resistance among conjunctival flora -American Journal Of Ophthalmology, March 2014

31. “Use of only povidone iodine at the time of intravitreal injection without topical antibiotics appears to have the lowest risk of contributing to the wide spread problem of increasing endophthalmitis .” -American Journal of Ophthalmology, March 2014 For topical agents, the MIC value is considered the Gold standard measurement of antibiotic efficacy

32. Antifungal agents Drug Administration Toxicity Indications Natamycin 5% suspension 2hourly Hypersensitivity Irritation Yeast & fungal keratitis Amphoteracin B 0.1-0.5% solution 0.8-1mg subconjuctival 5 mcg intravitreal Hypokalemia Infusion related toxicity Yeast & fungal keratitis and endophthalmitis Ketoconazole Topical 1-2% Oral 200-600mg/d Allergic rash teratogenic Yeast keratitis & endophthalmitis Fluconazole Topical 1-2% Oral 200mg/d Allergic rash teratogenic Yeast keratitis & endophthalmitis Itraconazole Topical 1-2% Oral 200-400 mg Poor penetration so used in combination Yeast & fungal keratitis & endophthalmitis Voriconazole Extemporaneously prepared No damage to the eye Invasive Aspergillosis P O L Y E N S A Z O L E S

33. Antiviral agents Generic name Route of administration Ocular toxicity indications Trifluridine Topical 1% solution Punctate keratopathy hypersensitivity Herpes simplex keratitis , keratoconjtivitis Acyclovir Oral(200mg cap/ 800mg tab) Herpes zooster ophthalmicus , HS iridocyclitis Valacyclovir Oral (500-1000mg) HS Keratitis HZ ophthalmicus Famicyclovir Intravenous intravitreal HS Keratitis HZ ophthalmicus Vidarabine 3% ointment Lacrimation , foreign body sensation, photo-phobia etc HS Keratitis HZ ophthalmicus ACUTE &RECURRENT Gua-nosine nucleoside analogyes

34. Anti Parasitic : Protozoal keratitis Acanthamoeba Keratitis Specific treatment include Topical agents DRUGS Diamidines Propamidine isethionate 0.1% Hexamidine 0.1% Biguanides Polyhexamethyl biguanide 0.02% Chlorhexidine 0.02% Aminoglycosides Neomycin paromycin Imidazoles Clotrimazole Miconazole

35. Anti acanthamoeba for contact lens care Anti acanthamoeba agents (in contact lens solution) Presevatives Type of contact lens Polyaminopropyl biguanide , Sodium borate 0.11% disodium edentate soft Polyhexamethyl biguanide Preservative free soft Polyvinyl alcohol 0.004% BKC, sodium edeate Gas permeable Polyvinyl alcohol (25.0) 0.004% BKC Gas permeable & hard Hydrogen peroxide 3% soft

36. Drugs for CMV RETINITIS Cytomegalovirus infection can occur in general population but CMV retinitis occur usually with advanced immunosuppression (CD4 + cells<100/mm3) Treatment Anti viral agents Route Toxicity Ganciclovir & valganciclovir Topically, IV, intravitreal Headache, convulsion, behavioural change Cidofovir intravitreal Vitritis , hypotony & vision loss Foscarnet Intravitreal , IV Headache, tremors etc Fomiversen Intravitreal Iritis , vitritis , cataract & rise in IOP

37. Ocular inflammation Inflammation is a characteristic response of the mammalian tissue to injury Anti inflammatory agents: Steroidal Anti Inflammatory Drugs Non-Steroidal Anti Inflammatory Drugs

38. Action of steroids INCREASE THE SYNTHESIS OF LIPOCORTIN (-)PHOSPHOLIPASE A2 (-)ARACHIDONIC ACID (-) PROSTAGLANDIN & LEUKOTRIENE PATHWAYS (-) PROSTAGLANDINS : Inflammation, conjunctival hyperemia, change in IOP, break down of blood ocular barrier etc

39. PHOSPHOLIPIDS ARACHIDONIC ACID LIPOXYGENASES CYCLOOXYGENASE, COX-1 & COX-2 LEUKOTRINES LTB4, LTC4, LTD4 & LTE4 PROSTAGLANDINS PGD2, PGE2, PGF2, PGI2 & TXA2 STEROIDS NSAIDS

40. Steroids Inhibits Bradykinin Nitric oxide Antigen presenting cells & T-cell macrophages Histamine production Eosinophil release

41. Corticosteroids CLASSIFICATION CLASSIFICATION Steroid Short acting Hydrocortisone, cortisone, prednisolone Intermediate acting Triamcinolone , fluprednisolone Long acting Dexamethasone & Betamethasone

42. Steroidal Anti Inflammatory agents Corticosteroids Strength (%) Indications Steroid responsive inflammatory condition of conjunctiva, cornea & ant seg of eye like Uveitis , allergic conjunctivitis, SPK, episcleritis , Corneal abrasion, ocular inflammation, corneal injury from diff burns, optic neuritis etc Dosage Prednisolone acetate, prednisolone soduim phophate 0.125 & 1.0 In tapering doses Dexamethasone sodium phosphate 0.1 In tapering doses Fluromethalone acetate 0.1 In tapering doses Loteprednol etabonate 0.5 & 0.2 In tapering doses Methyl prednisolone 1mg/kg IV

43. Side effects of steroids OCULAR SYSTEMIC Glaucoma Peptic ulcer Cataract Hypertension Activation of infection increases blood sugar Delayed wound healing Activation of TB Osteoporosis

44. Non-Steroidal Anti Inflammatory agents NSAIDS OCULAR USES Indomethacin To prevent miosis & CME after cataract sx Diclofenac Post operative inflammation Ketorolac Seasonal conjunctivitis, CME after cataract sx Nepafenac It’s a prodrug , 6 times faster permeation Flurbiprofen To counter unwanted intraoperative miosis during cataract surgery Piroxicam Activity is comparable & tolerance is better than diclofenac sodium(0.1%) INDOLE DERIVATIV ARYL ACETIC ACID DERIVATIVE ARYL PROPIONOC ACID DERIVATIVE ENOLIC ACID DERIVATIVE ANTI-INFLAMMATORY, ANALGESIC, ANTI-PYRETIC, FREE RADICAL SCAVENGING ACTIVITY etc

45. Ocular anti Allergic drugs Classification Drugs Allergy Seasonal allergic conjuntivitis (SAC) Perennial allergic conjuntivitis (PAC) Vernal keratoconjunctivitis (VKC) Atopic kerato conjunctivitis( AKC) Giant Papillary conjunctivitis(GPC) Anti histamines Pheniramine , antazoline , emedastine etc Mast cell stabilizers Cromolyn sodium, nedocromil , pemirolast , ketotifen Dual action anti allergic drugs Olapatidine ,, azelatine & epinastine NSAIDS Ketorolac Corticosteroids Loteprednol , fluromethalone , dexamethasone , prednisolone etc

46. ANTI GLAUCOMA DRUGS AIM OF TREATMENT DECREASE THE FORMATION OF IOP -Beta blockers -Alpha agonist -Carbonic anhydrase inhibitors INCREASE AQUEOUS DRAINAGE -Prostaglandins -Topical miotics

47. Cholinergics MOA : stimulates the muscarinic receptors producing increased aqueous outflow. Indiacation : pupillary block glaucoma Dosage : Pilocarpine 0.25%, 0.5% one drop two to three times a day

48. Anti cholinergics MOA : block the response of response of acetylcholine at the receptor Agents : Atropine Cyclopentolate Tropicanamide Not used routinely in glaucoma treatment Use: Inflammatory & Malignant glaucoma

49. Alpha adrenergics agonist MOA: stimulate alpha 2 receptors in the ciliary epithelium and thereby decrease the rate of aqueous production. Agents : Dipivefrin 0.1%, one drop 2-3 times a day Brimonidine 0.15% one drop 2-3 times a day

50. Beta blockers Mechanism of action: lower IOP by reducing aqueous formation Also reduces ocular outflow Non selective betablocker Selective beta 1 blockers Timolol maleate betaxolol Levobunolol Metipranolol Carteolol

51. TIMOLOL BETAXOLOL 20-35% fall in IOP within 1hr and last for 12 hours. 30% patients- additional medications Less efficacious than Timolol Protective effect on retinal neurons by blocking calcium channels

52. Adverse effects Ocular Stinging, redness & dryness of eyes Corneal hypothesia Allergic blephroconjuntivitis Blurred vision Systemic Bronchospasm in asthamatics & COPD patients Bradycadia and accentuation of heart block

53. Prostaglandins First line medical therapy for open angle glaucoma PGF2 alpha analogs Good efficacy, once daily, No systemic sideeffects MOA: facilitate aqueous outflow through uveoscleral outflow pathway

54. Agents : Latanoprost : 0.005% HS Bimatoprost : 0.03% HS 3. Travoprost Adverse effects: Ocular irritation & pain Blurring of vision Increased iris pigmentation Macular edema

55. Carbonic anhydrase inhibitors Add on drugs to topical beta blockers or PG analogues MOA: inhibits carbonic anhydrase enzyme on ciliary body epithelium reduces formation of bicarbonate ions reduces fluid transport reduces aqueous formation decrease in IOP

56. Topical CAI: Dorzolamide Brinzolamide Systemic CAI: Acetazolamide 125-250 mg, two to four times a day Indication : open & closed angle glaucoma

57. Immunosuppressive & Anti Mitotic agents Agents commonly used 5- fluorouracil Mitomycin C Indications : Intermediate uveitis Peripheral ulcerative keratitis Ocular surface squamous neoplasia (OSSN) Trabeculectomy GVHD

58. Immunomodulators TOPICAL CYCLOSCPORINE -Approved for the treatment of Chronic dry eye associated with inflammation. Decreases inflammatory markers in lacrimal gland & increases tear production

59. Angle closure glaucoma Hypertonic Mannitol 20% IV infusion- 1.5-2 g/kg Acetazolamide 0.5g iv followed by oral twice daily started cncurrently Miotic : Pilocarpine 1-4% Timolol 0.5% Latanoprost DEFINITIVE TREATMENT: Surgical or Laser Iridotomy

60. Anti Angiogenic drugs VEGF Inhibitors ANGIOSTATIC STEROIDS BEVACIZUMAB RANIZUMAB PEGATINIB siRNA VEGF TRAP ANECORTAVE ACETATE SQUALINE

61. VEGF Inhibitors MOA: These are anti VEGF anti bodies that bind the VEGF receptors thereby blocks both increased vascular permeability and angiogenesis

62. VEGF Inhibitors Administration Indications Bevacizumab Intravitreal injection 1.25 mg/0.05ml WET ARMD Ranizumab Intravitreal injection every four wks Choroidal neovascularization due to ARMD Pegatanib Intravitreal injection every six wks WET ARMD Diabetic macular edema siRNA VEGF Trap Under clinical trail for WET ARMD

63. Ocular Lubricants Polymer composition of Artificial tears Hydroxymethyl cellulose/ carboxy methyl cellulose Carbomers ( polyacrylic acid) Hypomellose ( hydroxypropylmethyl cellulose) Liquid paraffin Polyvinyl alcohol Polyvinyl pyrrolidone polycarbophil Indications: Ocular irritation Dry Eyes

64. Preservatives Ophthalmic solutions and ointments must be sterile so wide variety of preservatives are used for anti-microbial activity PRESERVATIVES Benzalkonium chloride Chlorbutol Phenyl mercuric nitrate Stabilized oxychloro compound Thiomersal Chlorhexidine Sorbic acid

65. Adverse effects of preservatives Toxic to precorneal tear film and epithelium, thus impedes epithelial healing and disrupting the tear film Direct cellular damage Reduces oxygen utilization of cornea Hypersensitivity reaction Papillary conjunctivitis Punctate keratitis Corneal edema

66. Ophthalmic Anesthesia Requirements for ophthalmic surgeries Akinesia Profound analgesia Minimal bleeding Avoidance of oculocardiac reflex Control of IOP

67. Anaesthesia Techniques General Local : 1. Topical 2. Regional

68. Local Anaesthesia According to chemical nature ESTER group Procaine Cocaine Tetracaine Benzocaine AMIDE group Lidocaine Bupivacaine Ropivacaine Mepivacaine

69. LA ONSET OF ACTION DURATION OF ACTION CONCENTRATION Lignocaine 5-10 mins 10-35 secs 30-60 mins 15-20 mins Infiltration(1/2/3%) Topical 4% Proparacaine 15-30 secs 15-20 mins Topical (0.5%) Bupivacaine Moderate 75-90 mins Infiltration (0.25-0.75%) Ropivacaine Moderate 1.5-6hrs Infiltration 1%

70. In patients with uncomplicated cataract at high risk for thromboembolic events, phacoemulsification cataract surgery under topical anaesthesia was safely performed without discontinuing systemic anticoagulant and antiplatelet treatment. 40 pts of mean age 72yrs on anticoagulants had phaco surgery done and none had any hemmorhagic complications or a thromboembolic event during surgery or at 1 week followup Barequet IS etal,Risk assesment of simple phacoemulsification in patients on combined anticoagulant and antiplatelet therapy: J Cataract Refractive surgery, 2011

71. Thank you