Medical Management in PACG: Differences from POAG Dr Parul Ichhpujani MS, MBA(HA), Fellow International Society of Spaeth Fellows, Associate Professor Glaucoma and Neuro ophthalmology Service Department of Ophthalmology Government Medical College and Hospital Chandigarh

Management of PACG Vs. POAG Differs because of the fundamentally different mechanisms of the two diseases Unlike POAG, PACG to some extent is a preventable disease. Common Goal: IOP lowering Additional Goal: Protect the anterior chamber angle and keep its drainage function (Main strategy for PACG). Medical treatment should not be used as a substitute for laser iridotomy or surgical iridectomy in patients with PAC or PACG. Friedman et al. Clin Exp Ophthalmol. 2012; 40: 381-7

Choice of management: Dependent on the stage of the disease. PACS and PAC: Aim is to modify the anterior segment configuration preventing angle closure and IOP elevation. PACG: Aim is to protect those yet not closed angle, and to lower the IOP to prevent the worsening of glaucomatous optic neuropathy and visual field loss.

Drugs: PACG Versus POAG Hyperosmotic agents: Mannitol, Glycerol Use in PACG: Mannitol, 1.5 to 2 g/kg/dose intravenously over 30 minutes Raise blood osmolality; create an osmotic gradient Required for IOP reduction in Acute attack of angle closure or used pre filtering surgery Use in POAG: Generally, not required for POAG May be used pre-filtering surgery Indian J Ophthalmol.2011; 59(Suppl1): S82–S87.

II. Beta Blockers: Timolol Still in the Game!! Use in PACG: In Acute ACG: Beta-blockers reduce IOP by around 20% to 30% within 1 hour of instillation. First Rx line for residual angle closure after LPI; with elevated IOP Timolol 0.5% eye drop Vs Timolol eye gel 0.1%: Equal efficacy Timolol Vs. Latanoprost: Metanalysis; 7RCTs; Greater mean and peak IOP reductions with latanoprost   J Med Assoc Thai. 2012 Apr;95 Suppl 4:S116-22. PLoS One. 2014 May 9;9(5):e96852.

Use in POAG: Beta-blockers constitute as much as 90% of prescriptions for POAG in India. Timolol Vs. Betaxolol/ Carteolol/ Levobunolol: Timolol better Used as Monotherapy or as a fixed combination (highly efficacious both at trough and peak) Indian J Pharmacol. 2013;45(2):117–20. Am J Ophthalmol 1986; 101: 535–41. Ophthalmology 1988; 95: 735–41. Dorzolamide-Timolol Study Group. Ophthalmology. 1998;105(10):1945-51. Combigan Study Group. J Ocul Pharmacol Ther. 2005;21(4):337-48.

Comparative effectiveness of first line drugs for POAG: Levobetaxolol, brinzolamide, dorzolamide, bimatoprost, latanoprost, travoprost, tafluprost, and unoprostone have been compared directly with timolol in 44 comparisons. Comparative effectiveness of first line drugs for POAG: 114 RCTs; 20275 patients; 14 drugs When a comparison-specific heterogeneity is assumed, PGs lowered IOP more than timolol @ 3 mths; difference in IOP compared with timolol ranged from 0.30 to 2.08 mmHg. Timolol ranked 6th in mean IOP reduction@ 3 mths. Ophthalmology. 2016 Jan;123(1):129-40

III. Miotics: Pilocarpine Use in PACG Prior to laser therapy in AACG/PACS/PAC/PACG In AACG, after IOP is controlled to allow for iris reperfusion 134 patients; Combination of intravenous acetazolamide followed by oral acetazolamide, as well as topical pilocarpine, timolol, and steroid drops. Medical Rx resulted in resolution of AACG within 12 h in 76.2% of the subjects and within 24 h in 89.2% of the subjects This success rate is lower at preceding time points: 21.5% at 3 hours, 44.6% at 6 hours. Given this slow rate of resolution, other techniques like anterior chamber paracentesis should be tried alongside Medical Rx. Ramli N. Eye (Lond). 2010 Oct;24(10):1599-602.

When to exercise caution with Pilocarpine in Angle closure Young patients Increased headache Blurred vision secondary to fluctuating myopia Inflammatory conditions Increases flare in the AC Myopic patients More at risk for RD Patients with central cataracts Pupil constriction limits vision Small pupil can complicate cataract extraction

When not to use Pilocarpine In cases where it may exacerbate pupil block, i.e., where AC is secondary to lens-induced or retro-lenticular mechanisms. Pseudoexfoliation Phacomorphic glaucoma Aqueous misdirection

Use in POAG

Revisiting MOA of Pilocarpine: Pilo. 1% in healthy eyes; Pilo. 2% in POAG EDI-OCT Bscan @ Nasal corneoscleral limbus; 1 hr after instillation Expands Schlemm’s canal. No differences in the effect were identified between the 2 groups. Whether this finding results from a direct effect of pilocarpine on the SC or secondarily from its effect on the ciliary musculature and/or trabecular aqueous outflow remains to be determined. JAMA Ophthalmol. 2016 Sep 1;134(9):976-81. .

IV. Alpha Agonists: Brimonidine Dual action: Decreases aqueous production Increases outflow Reduces iris thickness with an increase in posterior chamber depth but does not alter the thickness and position of the lens; does not facilitate pupil block. RCT; Brimonidine and BTFC caused passive miosis; widening of most of the AC angle parameters without changing the AC depth, in both normals and POAG patients. Effects of BTFC on the angle were likely to be greater than those resulting from the pilocarpine. Journal Ocular Pharmacol Therapeutics. 1999;15(4):337-44. No effect on accomodation; passie paralysis of iris dilator; inhibits aplha 1 receptors by modulating NE Kim JM. Jpn J Ophthalmol.2011; 55: 356-61

Use in PACG In Acute ACG: Alpha-agonists reduce IOP by around 26% within 2 hours post- dose.   Brimonidine Vs. Apraclonidine in Angle closure: Comparable efficacy in preventing post LPI IOP spikes. Apraclonidine 1.0% tends to have a pupil dilating effect while brimonidine 0.2% tends to constrict the pupil. Use in POAG: Network meta-analysis of 28 RCTs; 8 different glaucoma drugs (brimonidine, bimatoprost, travoprost, latanoprost, timolol, dorzolamide, betaxolol Brimonidine had the 4th highest drop in IOP at peak, but had the lowest IOP reduction of the 8 drugs investigated at trough. Yuen NS. Jpn J Ophthalmol. 2005;49(2):89-92. J Clin Epidemiol 2009;62(12):1279-83

V. Prostaglandins Use in PACG: Effective at lowering IOP in chronic PACG Mech. Of Action in ACG: EXACT Study: Efficacy of Xalatan in Angle Closure Glaucoma therapy Exact MOA not known. Latanoprost enhanced aqueous access to the ciliary body by way of the still- open part of the AC angle or across the iris root. Delayed onset of action precludes its use in acute angle closure. Work even in eyes with no visible uveoscleral meshwork or ciliary face; PGs gains access through a yet unidentified pathway that possibly involves the iris, and that outflow of aqueous may involve something other than uveoscleral meshwork Aung T et al. Ophthalmology,2000; 107:1178-83 Aung T et al. Ophthalmology. 2004;111(3):427-34. J Ocul Pharmacol Ther. 2005 Feb;21(1):75-84. 


Efficacy in angle closure? No correlation was found between efficacy of PGs and the extent of synechial closed angle Even in eyes with 360 degrees of PAS, Latanoprost is still effective. Metanalysis: 17 studies; 807 patients: Latanoprost safe and efficacious in angle closure. Aung T.Ophthalmology,2005; 112: 267-71 Kook MS et al. J Ocul Pharmacol Ther,2005; 21:75-84 J Glaucoma. 2016 Mar;25(3):e134-44.

Which PG is better? Travatan CACG Study Group: Travatan Better than Xalatan (p=0.162) Metanalysis: Latanoprost Vs.Others 10 RCTs; 1039 patients; Travoprost and bimatoprost are superior in IOP control than latanoprost, but latanoprost is better tolerated in patients with CACG. Asian J Ophthalmol. 2006;8:2-8 Eur J Ophthalmol. 2015;25(1):18-26.

Use in POAG: First Line therapy; Increase uveoscleral outflow 27-34% IOP reduction; Equivalent efficacy(Lat. Vs. Bimato. VS. Travop) Ther Adv Chronic Dis. 2014;5(1):30-43.

VI. CAI’s Use in PACG: Decrease aqueous production Oral CAIs: Acetazolamide Can open the angle, perhaps by a reverse pupillary block effect. Lowe RF. Aust J Ophthalmol. 1973;1:24–26. Topical CAIs: Dorzolamide, Brinzolamide Lack of clinical data on the use of topical CAIs in AACG. In AAC patients who are already on systemic CAI, adding a topical CAI may not have additional benefits. Can be used as Adjunctive therapy in chronic PACG. Rapid reduction in aqueous production lowers pressure in the posterior chamber compared with the anterior chamber. The momentary reversal of pressure gradient between the anterior and posterior chamber results in a concave iris configuration Rosenberg LF.Ophthalmology. 1998;105:88–92.

Use in POAG: 18-22% IOP reduction; Second/third line adjuncts; Monotherapy as well as Combination (BTFC/ DTFC) DTFC Vs BTFC in OAG: Greater IOP reduction; patients were more likely to achieve lower target pressures with DT than with BT. Indian J Ophthalmol. 2016 Feb;64(2):127-31.

Medical management of the different clinical types of angle closure glaucoma Acute attack of angle closure: RPC Data: 24.7% Acute presentation PGI data: 4.7% Acute presentation Initial IOP reduction with Hyperosmotics + Oral CAIs Topical Beta blockers followed by pilocarpine Topical Steroids to control inflammation Oral analgesics and antiemetics Medical therapy resulted in resolution of APAC within 12 h in 76.2% of the subjects and within 24 h in 89.2% of the subjects. Sihota et al. Indian J Ophthalmol. 1998;46:25–9. Ichhpujani et al. Indian J Ophthalmol. 2010;58(3):199-203. Eye (Lond). 2010 Oct;24(10):1599-602

Primary treatment is laser; LPI/ laser iridoplasty. II. Plateau Iris Primary treatment is laser; LPI/ laser iridoplasty. Low dose pilocarpine has a role in opening the angle as an alternative to iridoplasty. III. Phacomorphic glaucoma/Ectopia lentis Miotic therapy may worsen the angle closure IV. Malignant Glaucoma Concurrent use of Atropine drops, beta-blockers , alpha2- agonists, CAIs and hyperosmotics in full dosage from the beginning. Medical Rx is allowed time to work; if elevated IOP persists, go in for Surgery Am J Ophthalmol. 1999 Sep; 128(3):288-91.

Innovations in pipeline…...... Chitosan-g-poly(N-isopropylacrylamide) copolymers as delivery carriers for intracameral pilocarpine administration. Effective IOP reduction and pupillary constriction noted in rabbits intracamerally treated with pilocarpine-loaded poly(ε-caprolactone) nanoparticles. Collagen shields cross-linked with ZnO/PVP NPs release Pilocarpine HCl over a period of 14 days; offering a promising sustained release Rx option for glaucoma. Eur J Pharm Biopharm. 2017;113:140-148. Nanoscale. 2017;9(32):11754-64. Int J Pharm. 2016;501(1-2):96-101.

Take Home Message Medical treatment should not be used as a substitute for LPI. Treatment Options for Angle closure: Acute Presentation Oral CAIs and Hyperosmotic agents Topical beta-blocker and/or topical alpha-2 agonist Topical cholinergic agonists LPI after acute attack resolved; may consider lens extraction after acute attack resolved Ongoing or Chronic Angle-Closure Glaucoma Topical PGAs and/or topical beta-blocker and/or topical alpha-2 agonist CAIs Lens extraction surgery Trabeculectomy and/or tube shunt

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