OCULAR PHARMACOLOGY for variou pathology.pptx

various drugs used for various pathology of the eyes
including glaucoma, corneal ulcer, hyphema, CRVO,BRVO ,

1. OCULAR PHARMACOLOGY -2 Dr. Aswathi Venugopal (Post Diploma DNB Resident, BMHRC) Moderator : Dr Anjali Sharma (Professor, BMHRC).

2. Contents Corticosteroid Anti- Glaucoma Drugs Immunosuppressive agents Local anaesthetic drugs Drugs used in the treatment of Dry eyes Ocular Diagnostic Drugs

3. Corticosteroid CLASSIFICATION Short Acting Hydrocortisone, Cortisone, Prednisolone. Intermediate acting Triamcinolone, Fluprednisolone Long acting Dexamethasone, Betamethasone.

4. Topical -Systemic. Allergic conjunctivitis - Posterior uveitis Scleritis - Optic neuritis Uveitis -Corneal graft rejection Allergic keratoconjunctivitis After intraocular & extra ocular surgeries.

5. Routes of administration Topical Periocular : Subconjunctival , Sub tenons , Transeptal, Orbital floor, retrobulbar injection Intraocular: Suprachoroidal, intravitreal, Systemic

6. Advantages and Disadvantage of 3 routes of Corticosteroid administration .

7. Mechanism of action Corticosteroids through Glucocorticoid receptor enter cell Binds to DNA Activates/represses gene transcription through various mechanism Transcription of mRNA Synthesis of new protein Lipocortin

8. Pharmacological effects : Anti Inflammatory (PGE2 Inhibition, Anti TNF alpha) Immunosuppression (IL-2, cell mediated immunity) Therapeutic uses

9. Ocular Indication for intra vitreal use To deliver high concentration to treat inflammation involving anterior and posterior segments. Used in Diabetic Macular Oedema, CME, ARMD, Retinal vascular occlusion and uveitis . Side effects : Increased IOP Post subcapsular cataract formation

10. Adverse effects Ocular Corticosteroid induced ocular hypertension and glaucoma Posterior subcapsular cataract Retardation of corneal epithelium Paradoxical ocular inflammation of anterior segment Epithelial toxicity, Crystalline keratopathy, Orbital fat atrophy. limitation of ocular movement. Systemic Hypertension Increased blood sugar Peptic ulcer Osteoporosis Activation of tuberculosis.

11. CONTRAINDICATION Viral infection Fulminant bacterial infection fungal Injuries and glaucoma

12. Anti – Glaucoma Drugs

13. TOPICAL DRUGS SYSTEMIC DRUGS Prostaglandin Analogues - Hyperosmotic agents Beta Blockers - Carbonic Anhydrase Inhibitors Alpha Agonist Carbonic Anhydrase Inhibitors Cholinergic Agents

14. Anti Glaucoma Drug DRUG MECHANISM OF ACTION OCULAR SIDE EFFECTS POINTS TO BE NOTED Beta-Blockers (20-30% IOP reduction from baseline) Non- selective beta blockers Timolol (0.25%,0.5%) Levobunolol hydrochloride0.25% & 0.50% Carteolol Hydrochloride 1% Selective beta 1-blocker Betaxolol (0.5%) Decrease aqueous production, by inhibiting Camp in Ciliary epithelium. Allergic blepharoconjunctivitis Superficial punctate keratitis Corneal anaesthesia Contraindicated in Asthma, CHF, Diabetes

15. PROSTAGLANDIN ANALOGUES ( Prostanoids , Prostamides , Docosanoids ) (25-30% reduction in IOP) Latanoprost (0.05%) Bmitaprost (0.03%) Travoprost (0.004%) Tafluprost (0.0015%)(preservative free Increased uveoscleral outflow Hyperchromic heterochromia iridis Hypertrichosis Uveitis Iris cysts Conjunctival hyperaemia (max- bimatoprost ) Cystoid macular oedema Contraindicated in hypertensive uveitis Bimatoprost –FDA approved for treatment of hypotrichosis

16. α Adrenergic Agonists ( 20-30% decrease in IOP) Apraclonidine (0.5%, 1%) Brimonidine (0.2%) (Dual action) Dipivefrin (0.1%) Decrease aqueous production Follicular Conjunctivitis Mydriasis Lid retraction Ocular allergies Black conjunctival pigmentation Bradycardia, hypotension apnea, drowsiness and CNS depression thus CI in children(brimonidine) Contraindicated in Parkinson's disease

17. CARBONIC ANHYDRASE INHIBITORS (20% mean IOP reduction) Dorzolamide (2%) Brinzolamide (1%) (suspension) Acetazolamide Methazolamide Decreased aqueous production (inhibit CA II isoform on ciliary muscle and sphincter pupillae Metabolic acidosis & hypokalaemia Superficial punctate keratopathy Urolithiasis Contra indicated in sulfa allergy Not available topically

18. Cholinergic Agonists Pilocarpine (1%) Increased trabecular & uveoscleral outflow (m3 muscarinic receptor on ciliary muscle and sphincter pupillae) Uveitis Pseudo myopia Brow ache Punctal occlusion Useful in open angle glaucoma and angle closure glaucoma

19. RHO KINASE INHIBITORS Netarsudil (0.02%) ( Rhopressa ) Ripasudil Increases Trabecular outflow by Promoting actin-myosin contraction Increasing actin stress fibres & focal adhesions & lowers episcleral venous pressure Decrease aqueous production by inhibition of norepinephrine transport Decreases aqueous secretion. Conjunctival hyperaemia Cornea verticillate Conjunctival haemorrhage

20. NITRIC OXIDE DONATING PROSTAGLANDIN ANALOGUEKSS Latanoprostenebunod (0.024%) Latanoprostene bunod Latanoprost Butanediol uveoscleral outflow Mononitrate Relaxes TM Same as prostaglandin F2 α analogues

21. Hyperosmotic Agents Mannitol, Glycerol. Mechanism of Action-

22. Immunosuppressive Agents in Uveitis Class of Drug MOA Dose Routes of Administration Complication Uses A. Antimetabolite Agents Methotrexate (MTX) Inhibits enzyme Dihydrofolate reductase thus interferes with DNA synthesis, repair & cellular replication. Inhibition of purine metabolism Inhibition of T cell activation Starting dose of 7.5mg/week with a maximum of 1.5mg/wk. Oral, Subcutaneous, intramuscular, intravenous. GI Upset, fatigue, hepatotoxicity, pneumonitis, teratogenic drug GI Upset, fatigue, hepatotoxicity, pneumonitis, teratogenic drug Uveitis associated with JIA, Chronic uveitis, Scleritis, Sarcoidosis, Idiopathic Uveitis, reactive arthritis VKH Sympathetic ophthalmia Azathioprine Purine analogue 2mg/kg/day Per Oral GIUpset,hepatitis.pancreatitis,BM toxicity GIUpset,hepatitis.pancreatitis,Bm Bechetsuveitis,VKH,SO,OCP .

23. Class of Drug MOA Dose Routes of Administration Complication Uses Mycophenolate mofetil/ Cellcept . Inhibits Inosine-5'-monophosphate dehydrogenase- alters purine metabolisms 1-3g qD PO in empty stomach Per Oral Diarrhoea, nausea, GI ulceration Scleritis, methotrexate nonresponsive noninfectious uveitis in adults and children, adjuvant to cyclosporine in BSCR' [2]

24. Inhibitors of T cell signaling Cyclosporine A Calcineurin inhibitor 2.5- 5mg/kg/day PO Per Oral Hypertension Nephrotoxicity Hyperlipidaemia/hypercholesterolemia Hirsutism Hyperplasia of gum Hyperuricemia Hyperglycemia /diabetes BSCR, sarcoidosis, pars planitis , VKH, MS, SO, idiopathic posterior uveitis, PUK

25. Tacrolimus/FK 506 Calcineurin inhibitor 0.05-0.2mg/kg/day PO Per Oral Nephrotoxicity Chronic posterior uveitis , intermediate uveitis, VKH,SO Voclosporine Calcineurin inhibitor 0.4mg/kg/day in divided dose PO Per Oral Similar to cyclosporine Noninfectious sight threatening uveitis, Evaluated in LUMINATE trial Sirolimus (Rapamycin) mTOR inhibitor Loading dose 6 mg/day, followed by Maintenance 2 mg/day, PO Per Oral GI distress Skin disorders Recalcitrant non-infectious uveitis[the intravitreal form is evaluated in SAVE and SAKURA study

26. Alkylating agent Cyclophosphamide/Cytoxan. Causes DNA cross linking 1 mg/kg/day PO or1 g/m 2  (BSA) infusions q1-2 weeks (IV pulse) Per Oral Alopecia Hemorrhagic cystitis (due to a metabolite acrolein) Bone marrow toxicity ( anemia , leucopenia ) Sterility Secondary malignancy Necrotizing scleritis/PUK in GPA, RP, , RABilateral Mooren ulcer OCP SO

27. Chlorambucil/ Leukeran Ⓡ Causes DNA cross linking 2-12 mg/day PO Per Oral Bone marrow toxicity which may be reversible or irreversible Sterility Malignancy Opportunistic infection SO Uveitis in JIA Biologic Response modifiers TNF α Inhibitor Infliximab/RemicadeⓇ Inhibits TNF-alpha by binding Chimeric IgG1k anti-TNF α monoclonal antibody with a human constant and mouse variable region 3mg /day three times over 6 weeks, then 8 weekly IV Infusions Reactivation of infections (tuberculosis, fungal infection) which may be fatal Infusion reaction/ 'Remicade reaction' (pruritus, flushing, dyspnea , chest pain/tightness/discomfort, hypertension, myalgia, nausea, urticaria). Stop in serious infection or sepsis.Quantiferon TB Gold (interferon gamma release assay) before starting. Rule out active tuberculosis

28. Adalimumab/Humira. fully human anti-TNF-alpha monoclonal antibody 40mg SQ q2wk Subcutaneous Pain at injection site Headache Nausea, stomach upset Rash, anaphylaxis Sepsis Drug induced lupus Ocular inflammation in RA, JIA,AS, psoriatic arthritis and plaque psoriasis, BSCR, VKH, orbital pseudotumor Certolizumab/Cimzia. Recombinant humananti-TNFa antibody Fab’ fragment 400mg/ wk IV Serious infections [18]  including TB, fungus (histoplasmosis), bacterial sepsis, reactivation of hepatitis B virus, other opportunistic infections Secondary malignancy like lymphoma in children and adolescent- avoid in children To reduce anterior uveitis (AU) flares in subjects with active axial Spondyloarthritis ( axSpA ) in trial

29. Golimumab/Simponi. Fully human anti-TNF-alpha monoclonal antibody 50mg SQ q4wk Serious infections including TB, invasive fungal infection, bacterial sepsis, reactivation of hepatitis B virus, other opportunistic infections Secondary malignancy like lymphoma in children and adolescent Anaphylaxis, rash JIA associated uveitis idiopathic retinal vasculitis [

30. LOCAL ANESTHETICS IN OPHTHALMOLOGY Types of Local anaesthesia for ophthalmic procedures Retrobulbar block Peribulbar block Sub tenons block Local infiltration Topical Based on chemical structure anaesthetics are divided into Amino esters Amino amides

31. Topical Anaesthetics Preparation Class Formulation Onset Duration Commonly used preservative Tetracaine hydrochloride Ester 0.5% solution 1 minute 15-20 minutes Chlorobutanol 0.4% Proparacaine Hydrochloride Ester 0.5% solution 6-20 sec 10-15 minutes Benzalkonium chloride (0.01%) Cholorobutanol(0.2%) Proparacaracaine Hydrochloride with fluorescein Ester 0.5% solution with 0.25% Na fluorescein 6-20 sec 10-15 minutes Thimerosal (0.01%) Benoxinate hydrochloride with fluorescein Ester 0.4% solution with 0.25% Na Fluorescein. 1-2 minutes 10-15 minutes Cholorobutanol (1.0%) Lidocaine gel Amide 1.5,2,3.5, & 4 % gel 1-5 minutes 15-40 minutes Preservative free

32. Injectable anaesthetics Preparation Class Formulation (% solution) Onset (min) Duration Procaine Ester 1,2,10 7-8 30-45 Lipocaine Amide 0.5,1,1.5,2,4 4-6 40-60 Mepivacaine Amide 1,1.5,2 3-5 120-180 Bupivacaine Amide 0.25.0.5.0.75 5-10 240-720 Etidocaine Amide 1.1.5 3-5 180-600 Prilocaine Amide 4 2-3 150-108

33. Mechanism of Action Local anaesthetics acts by blocking the voltage-gated Na-channels in nerve fibres. Rapidly firing nerves are more Suspectable to action of LA.

34. Adverse effects Local: Mild stinging and burning sensation, Epithelial damage due to tear film instability (decreased reflex tearing, infrequent blinking), superficial punctate keratopathy, conjunctival hyperaemia, chemosis, swelling of eyelids, lacrimation & itching. Dense yellowish white stromal ring is characteristic of stromal damage by anaesthetic misuse. Systemic Uncommon, usually seen with drug overdose. Degree of systemic toxicity correlates with potency of anaesthetic agent CNS: Tinnitus, drowsiness, disorientation, slurred speech, muscle twitching, can cause even respiratory arrest & generalised CNS depression. CVS: Myocardial suppression & vasodilation cause decreased cardiac output.

35. Methemoglobinemia Causes cyanosis, found in case of high doses of prilocaine Allergic reaction Esters metabolize to PABA, which is responsible for allergic reactions such as dermatitis & rashes.

36. Contraindications Previous history of hypersensitivity should not be given same anaesthetic agent Amide type of LA is metabolised in liver hence given with caution in patients with impaired Liver Function. Collection of specimen from ocular surface to be done before installation of LA as many of them antimicrobial property. Patients with perforating injury LA cause endothelial damage(topical application). Ester type LA metabolised by plasma pseudocholinesterase, hence contraindicated in patients with genetic deficiency of enzyme.

37. Drugs Used in the Treatment of Dry Eyes

38. Aqueous Enhancement Therapy Commercially available artificial tear solution CMC,PEG,HPMC

39. Anti-Inflammatory Therapy Cyclosporin A Used for moderate to severe dry eye disease, contain fungal-derived peptide that prevents activation of transcription factors necessary for T-cell activation and IL-2 production. Density of goblet cells increased on the ocular surface. Corticosteroids. Acts by non-specifically inhibiting many aspects of the inflammatory response. Topical steroids are effective for achieving a quick response. Tetracycline A class of antibiotic that has anti-inflammatory properties, like reduced cytokines, nitric oxide & expression of HLA class 2 & Inhibition of MMP. Main side effects are increased skin photosensitivity & gastrointestinal complaints.

40. Secretagogues.

41. Hormonal Therapy Androgenic steroids have beneficial effect for ocular manifestation of Sjogren's syndrome. Systemic androgen has immunosuppressive effects on lacrimal gland Oestrogen appears to contribute to the development of dry eyes Effects of sex steroids on tear function are mediated through both meibomian & lacrimal glands. Nutritional Supplements Essential fatty acids: Reduce inflammation (omega 3 fatty acids) Alters the composition of meibomian lipids. Topical vitamin A (retinol) : topical retinol has been used in various forms of dry eye conditions.

42. Preservatives used in tear drops Benzalkonium chloride (0.01% for eye drops, 0.02% for CL solutions) Chlorbutanol Chlorhexidine Thiomerosal and mercuric oxide EDTA Methylparaben Propylparaben Purite

43. Ocular complications of preservatives Pigmentation (mercury deposits in lids- conj - cornea & lens) Irritation (redness- photophobia-lacrimation- burning) Allergic Dermatitis, urticaria & eczema Blepharitis Papillary & follicular conjunctivitis Pemphigoid Toxic Epith . Cell exfoliation. SPK

44. Drugs for Dry Eyes

45. ANTI-ALLERGIC DRUGS CATEGORY EXAMPLES COMMENTS Histamine receptor Antagonist. Levocabastine, emedastine difumarate, Pheniramine, antazoline Use for isolated acute allergic attacks Mast-cell stabilizers Cromolyn sodium, Iodoxamide, pemirolast, nedocromil sodium. Most useful for chronic allergies May take 1-2 weeks to be effective. Pemirolast and nedocromil have antihistamine effects as well. Anti – histamines with mast-cell stabilizing activity. Olopatadine, alcaftadine, bepotastine, ketotifen, fumarate, azelastine, epinastine. These medications combine the immediate effect of selective antihistamines with long-term effects of mast-cell stabilization. Topical NSAIDs Ketorolac, nepafenac, bromfenac. Can reduce itching, but stings when applied.( refrigerate to reduce stinging) Vasoconstrictors Naphazoline/pheniramine, naphazoline/antazoline Relieves redness, but not other symptoms. Topical corticosteroids Loteprednol, fluorometholone, rimexolone May be useful in serious cases or until control is achieved with other agents. Oral antihistamines Fexofenadine, loratadine, cetirizine, ebastine, mizolastine, desloratadine Useful when systemic allergic symptoms are present but may cause dry eyes.

46. Antihistamines

47. Mast Cell Stabilizers

48. Miscellaneous Drugs Hyperosmotic Agents Used in the management of acute glaucoma & for reduction of corneal oedema . Systemic hyperosmotic agents lower IOP by : Reduction in the volume of vitreous humour through relative increase in the osmolality of the intravascular fluid. Secondary effect by stimulating osmoreceptors in the hypothalamic centre of CNS (this effect does not play significant role because of poor blood ocular barrier penetration. Systemic agents Topical agents Intravenous hyperosmotic agents Oral hyperosmotic agents 1.Mannitol 1.Glycerol 1.Hypertonic sodium chloride 2.Urea (not in use) 2.Isosorbide (not in use) 2.Glycerol

49. Therapeutic uses Acute glaucoma’s ( eg : Acute angle-closure glaucoma, malignant glaucoma, post-traumatic glaucoma) Short term or rapid reduction of IOP prior to definitive medical or surgical management. May also be used prior intra ocular surgery such as cataract surgery ,PK , Trabeculectomy, non-draining sclera buckling Topical hyperosmotic agents are indicated for reducing corneal oedema due to bullous keratopathy, acute angle closure glaucoma, corneal hydrops & Fuchs endothelial dystrophy.

50. Adverse Effects Systemic hyperosmotic Nausea & Vomiting especially with glycerol. Nausea may be avoided by administering glycerol with a flavoured vehicle Diuresis, urinary retention Dehydration Acidemia Anaphylactic shock Cardiovascular overload Pulmonary oedema Topical hyperosmotic . Temporary burning, irritation & blurring of vision on instillation . Contraindications : P atients with compromised cardiac function, Diabetic patients have increased risk of hyperglycaemia & ketosis .

51. Isosorbide : Used for short-term reduction of IOP to interrupt an acute attack of glaucoma Dosage & Administration: Initial dose is 1.5 g/Kg body wt. Of isosorbide 45% Onset of action is within 30 minutes, effect lasts for 3-5 hrs Topical Hyperosmotic Agents Topical Glycerol (Glycerine): used for temporarily clear an oedematous cornea. Dosage & administration: One or two drops of topical glycerol are administered prior to ophthalmic or gonioscopic examinations Topical Hypertonic Saline Used as sodium chloride 2, 3 and 5% ophthalmic eye drops or ointment. Used for temporary relief of corneal oedema caused by bullous keratopathy, Fuchs endothelial dystrophy and acute hydrops. Dosage & administration: 1 or 2 drops in the affected eyes every 3-4 hrs

52. OCULAR DIAGNOSTIC DRUGS Fluorescein dye Available as drops or strips Uses Stain corneal abrasions Applanation tonometry Detecting wound leak NLD obstruction. Fluorescein angiography. Caution: Stains soft contact lens Fluorescein drops can be contaminated by pseudomonas sp.

53. Rose Bengal stain 1.3 mg impregnated strips Stains devitalized epithelium Uses – severe dry eye, herpetic keratitis. Lissamine Green 1%, 2%, 3% liquid dyes. 1.5mg impregnated strips Preferred dye for staining the bulbar conjunctiva. High affinity for staining dead and degenerated cells, including mucous strands. Diagnosis of Dry eye disease. T o ascertain proper fitting of contact lens.

54. Trypan blue Anterior capsular staining- 0.06%. Posterior segment surgeries – 0.15%. Dyes does not penetrate the capsule, permitting visualization of anterior capsule. Used to stain the anterior capsule of lens during cataract surgeries. Stains epiretinal membrane after fluid/air exchange To stain and strip descements membrane in descements stripping endothelial keratoplasty (DSEK). Aid in stripping the corneal endothelium from the donor button in deep anterior lamellar keratoplasty. Selectively stains tenons capsule, hence is used after enucleation surgeries during layered closure, without entrapment of conjunctiva in tenons capsule.

55. References Textbook on Clinical Ocular Pharmacology and Therapeutics. Gupta, S. K., Agarwal, R., & Srivastava, S. Clinical Ocular Pharmacology (5th ed.). Bartlett, J. D., & Jaanus , S. D. (2008). Theory and Practice of Optics and Refraction. A K Khurana, Aruj K. Khurana, and Bhawna Khurana Corneal Ulcers: Diagnosis and Management. Namrata Sharma, Rasik B Vajpayee. Basic Clinical and Science Course. American Academy of Opthalmology .