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Glaucoma Therapy: The “Art” of Medical Management J. James Thimons,O.D.,FAAO Medical Director, Ophthalmic Consultants of CT The Role of IOP Management in Glaucoma PEAK Effect with Evening Dose Once daily drug: • Peak effect (8 mm Hg) at 12-14 hrs post dose • Trough effect (2 mm Hg) at 22-24 hrs post dose 9 IOP Reduction (mm Hg) 8 7 6 5 4 Trough 3 2 1 Office hours 0 0 200 2:00 400 4:00 600 6:00 800 8:00 am am am am 1000 1800 2000 2200 10:00 1200 12:00 1400 2:00 1600 4:00 6:00 8:00 10:00 2400 12:00 am pm pm Time of Day (hr) Time of Day (hr) pm pm pm pm am Dose Courtesy of David B. Yan, M.D., F.R.C.S.(C) 3 IOP Variability Highest (peak) IOP may commonly occur outside of usual clinic office hours1,2 In spite of achieving target IOP during office hours patients may experience: – “damaging”/above target IOPs at other times of the day – disease progression Are we missing IOP spikes, peak, damaging IOP, IOPs at other times of day3? 1. Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204. 2. Mosaed S, et al. Am J Ophthalmol. 2005; 139(2): 320–324. 3. Hughes E, et al. J of Glaucoma 2003; 12: 232-236. 4 Peak IOP Outside Office Hours PURPOSE: To determine the relationship between office IOP and peak IOP METHODS (Study One)1: 42 patients with OAG Treated with 3 different IOP lowering eye drops 24 hr IOP values obtained in sitting position with Goldmann applanation tomography at 3 hr intervals METHODS (Study Two)2: 103 patients with OAG (including 35 untreated) 24 hr IOP values obtained at 2 hr intervals using a pneumatometer, in sitting and supine positions during the diurnal/wake period and in the supine position during the nocturnal/sleep period 1.Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204. 2.Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320-324. 5 Peak IOP Outside Office Hours Study 1 Study 2 Times at which maximum and minimum IOP occurred in a 24hr period1: Number of eyes 40 • 30 10 8 28 20 10 0 19 23 20 3am6am 67% of peak IOP occurs outside office hours2 10 12 9am12pm 3pm6pm 9pm12am Time of minimum IOP in 24-hour Time of maximum IOP in 24-hour 1.Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204. 2.Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320-324. 6 IOP is Higher at Night Habitual IOP of glaucomatous eyes Habitual IOP of healthy eyes n=24 Clock Time IOP (mm Hg) Diurnal Sitting 3:30 PM 5:30 PM 7:30 PM 9:30 PM 11:30 PM 1:30 AM 3:30 AM 5:30 AM 7:30 AM 9:30 AM 11:30 AM 1:30 PM IOP (mm Hg) 26 25 24 23 22 21 20 19 18 17 16 15 14 Diurnal Sitting Nocturn al Supine Diurnal Sitting Noctur nal Supine 26 25 24 23 22 21 20 19 18 17 16 15 14 Diurnal Sitting n=24 *Error bars = SEM 3:30 AM 5:30 AM 7:30 AM 9:30 AM 11:30 AM 1:30 PM Higher nocturnal supine IOP than diurnal sitting IOP (healthy and OAG) Supine IOP higher than sitting IOP, regardless of time of day 3:30 PM 5:30 PM 7:30 PM 9:30 PM 11:30 PM 1:30 AM Clock Time Liu JH et al. Invest Ophthalmol Vis Sci. 2003; 44: 1586-1590. 7 Diurnal Fluctuations in IOP: Independent Risk Factor? PURPOSE: To study the risk associated with diurnal IOP variations in patients with OAG METHODS: • 64 patients with OAG and IOP below 25 mm Hg (over 5 year follow-up) • Patients successfully performed tonometry with a self-tonometer 5 times a day for 5 days • Baseline status and time to progression of visual field loss identified from clinical charts • Level and variability of diurnal IOP characterized and risk of progression analyzed using a nonparametric time-to-event model Asrani S, et al. J Glaucoma 2000; 9: 134-142. 8 Relative risk of disease progression within 5 years Diurnal Fluctuations Correlate with Visual Field Progression 6 5 4 5.76 3 2 1 0 1.0 Diurnal IOP range Diurnal IOP range 3.1 mm Hg 5.4 mm Hg Hazard ratio between higher quartile and lower quartile for “Range in Home IOP” was 5.7 Asrani S, et al. J Glaucoma 2000; 9: 134-142. 9 Patients on More Than One IOP-Lowering Medication 2 Medications 24.4% 3 Medications 5.6% 0.2% 4 Medications 69.8% 1 Medication Source: Verispan’s PDDA, MAT Nov 2006. Pathways to lower Intraocular Pressure Inflow –Alpha 2agonists –B1 blockers –CAI Outflow –Alpha 2– agonists –Cholinergics –Prostaglandins / Prostamindes Beta-blockers 30 year history of successfully lowering IOP Reduces aqueous humor formation Adrenergic agonists Lowers IOP 22-28% Ocularly well tolerated Beta Blockers Beta receptor in the ciliary body epithelium Beta 1 receptors >> Beta 2 receptors in the eye Beta receptors stimulate productions of aqueous. Beta blockers suppress aqueous production Beta-blockers Timolol maleate – Timoptic, Timoptic XE (1/2, 1/4 %) Carteolol – Ocupress 1% (Intrinsic sympathomimetic activity) Levobunolol – Betagan ½% Timolol hemihydrate – Betimol ¼, ½% Istalol ¼,1/2% - QD dosing indication Systemic Bradycardia Congestive heart failure Exacerbation of heart block Bronchospasm Mood change Impotence Lipid profile Contraindications Asthma Severs COPD CHF Heart block Myasthenia gravis Diabetes Lama study (AJO 11/02) Conclusions: – ...identifies no scientific studies supporting the development of worsening claudication, depression, hypoglycemia,sexual dysfunction or impaired neuromuscular transmission – Recommends careful medical history and checking pulse rate and rhythm So? Timolol Equally effective in AA’s and Whites IOP decrease 3060 min Long term drift – 47% decrease at 1 wk – 25% at 1 yr Carteolol (ocupress) Intrinsic sympathomimetic activity Less likely to increase systemic lipid profile Ocular Side Effects Punctate Corneal DESx) keratopathy anesthesia ( Watch for Blepharoconjunctititis Brimonidine 0.1% Alphagan alpha-2 Decrease aqueous production Also increase uveoscleral outflow (small amount) Not as effective as timolol but close May be neuroprotective More effective than or dorzolamide? Can cause mild mydriasis Comes in 0.1%, 0.15%, 0.2% Brimonidine: Dual Mechanism of IOP Lowering Enhances uveoscleral outflow Suppresses aqueous humor production (inflow) Toris et al. 1995 and 1999. Brimonidine Formulation Comparison ALPHAGAN® P Concentratio n of Brimonidine pH Preservative Viscosity agent Electrolytes ALPHAGAN® 0.1% 0.15% 0.2% 7.7 7.2 6.3-6.5 PURITE® BAK Carboxymethylcellul ose Polyvinyl alcohol Potassium chloride, calcium chloride dihydrate, magnesium chloride – Side effects 10-30% dry mouth 10% allergy rate Avoid with MAO inhibitors Alphagan P 0.1% – Better tolerated Mean IOP at Peak (10 am) Mean IOP (mm Hg) 30 28 Brimonidine-PURITE® 0.15% (N = 372) 26 Brimonidine 0.2%* (N = 376) 24 22 20 18 16 0 2 4 6 8 10 12 Months of treatment *Original ALPHAGAN® Katz. J Glaucoma. 2002. Mean IOP at Trough (8 am) 30 Brimonidine-PURITE® 0.15% (N = 372) Mean IOP (mm Hg) 28 Brimonidine 0.2%* (N = 376) 26 24 22 20 18 16 0 2 4 6 8 Months of treatment 10 12 *Original ALPHAGAN® Katz. J Glaucoma. 2002. Alpha Agonists-side effects Ocular– dermatitis, – lid retraction, – conjunctival blanching, – allergic reactions Systemic – dry mouth, – dry eye – lethargy, – apnea in children, – hypotension Contraindication Children MAO inhibitors Nocturnal Efficacy: Brimonidine Monotherapy PURPOSE: To investigate the effect of brimonidine monotherapy on IOP during the nocturnal/sleep period DESIGN: Prospective, open-label study METHODS: • Baseline data of 24 hr IOP in untreated patients collected in a sleep laboratory • Measurements of IOP taken using a pneumatonometer every 2 hrs in sitting and supine positions during the 16 hr diurnal period and in supine position during the 8 hr nocturnal period • Patients treated afterward with brimonidine 0.1% 3 times per day for 4 weeks, and 24 hr IOP data were collected under the same laboratory conditions Liu JH, et al. Ophthalmology 2010; 117: 2075–2079. 29 NOCTURNAL/SLE DIURNAL/WAK EP brimonidin E brimonidin e DIURNAL/WAK E brimonidin e 1.30PM 7.30AM 5.30AM 3.30AM 1.30AM 11.30PM 9.30PM 7.30PM 11.30AM Baseline Brimonidine Error bars = SEM N = 15 9.30AM e 5.30PM 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0 3.30PM Habitual IOP (mmHg) Brimonidine Efficacy During Nocturnal Period Clock Time Liu JH, et al. Ophthalmology 2010; 117: 2075–2079. 30 Glaucoma & Pregnancy BJO 2009; JD Ho: 244 pregnant women treated for glaucoma analyzed for birth weight 1,952 age matched controls No significant difference between women on BB’s vs: no Tx Herndon, L: D/C Brimonodine several weeks before d/t risk of apnea COMBIGAN™ (Brimonidine Tartrate/Timolol Maleate Ophthalmic Solution) 0.2%/0.5% Diurnal Mean IOP at Month 12 Dose all treatments Dose brimonidine Mean IOP (mm Hg) 20 16 * ** 12 * ** * ** * Brimonidine (n = 382)*** Timolol (n = 392)*** Fixed brimonidine/timolol (n = 385) 8 4 *P < .001 vs timolol **P < .001 vs brimonidine 0 8 AM 10 AM 3 PM 5 PM ***Brimonidine and timolol monotherapies are approved for first line therapy. Statistical significance does not necessarily correlate to clinical significance. Sherwood et al. Arch Ophthalmol. 2006. Treatment-Related Adverse Events 40 Fixed Brimonidine/Timolol BID (n = 385) Percentage of patients 35 Brimonidine 0.2% TID (n = 382)*** Timolol 0.5% BID (n = 392)*** 30 25 20 15 * P ≤ .03 vs brimonidine 0.2% TID ** P ≤ .02 vs timolol 0.5% BID * ** 10 * * * ** * ** 5 * 0 Conjunctival hyperemia Ocular stinging Eye pruritus Conjunctival Allergic follicles conjunctivitis Oral dryness ***Brimonidine and timolol monotherapies are approved for first line therapy. Sherwood et al. Arch Ophthalmol. 2006. COMBIGAN™ in Adjunctive Therapy With a PGA: Mean IOP Mean IOP (mm Hg) 24 21.9 Added to a PGA baseline -6.9 mm Hg (29%) 20 16 15.2 * 15.3 * 12 COMBIGAN™(brimonidine tartrate/timolol maleate 8 ophthalmic solution) 0.2%/0.5% + PGA (n = 37) 4 *P < .0001 vs baseline 0 0 1 2 3 Month 1Nixon and Hollander. 2AAO, 2007. Data on file, Allergan, Inc. COMBIGAN™ and ® Cosopt Randomized, investigator-masked, 3-month, parallel comparison Pooled data from 2 studies at 10 sites with identical protocols (Canada) Patients with OAG/OHT requiring additional IOP lowering Two subgroups – Monotherapy: COMBIGAN™(brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% (n = 54) and Cosopt® (dorzolamide hydrochloride-timolol maleate ophthalmic solution) (n = 47) – Adjunctive: COMBIGAN™ added to PGA (n = 37) and Cosopt® added to PGA (n = 42) IOP 2 hours after morning dose Visits at baseline, 1 month, and 3 months PGA = prostaglandin analogue 1Nixon and Hollander. AAO. 2007; 2Data on file, Allergan, Inc. COMBIGAN™ and Cosopt® as Monotherapy: Mean IOP Mean IOP (mm Hg) 24 23.6 20 23.0 17.2 16.3 * 16 15.8 15.6 12 *P = 0.04 (mean change from baseline) Cosopt® (dorzolamide hydrochloride-timolol maleate ophthalmic solution) (n = 47) 8 4 COMBIGAN™ (brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% (n = 54) 0 0 1 2 3 Month Mean IOP reductions from baseline at month 3 were 7.7 mm Hg with COMBIGAN™ and 6.7 mm Hg with Cosopt® (P = .040) 1Nixon and Hollander. AAO. 2007; 2Data on file, Allergan, Inc. Percentage of patients with rating of moderate or severe COMBIGAN™ and Cosopt ® Tolerability and Comfort COMBIGAN™(brimonidine tartrate/timolol 40% maleate ophthalmic solution) 0.2%/0.5% (n = 85) Cosopt® (dorzolamide hydrochloride-timolol 30% maleate ophthalmic solution) (n = 86) 20% 10% 0% Stinging Burning Unusual taste P = .0001 P = .0149 P = .0047 1Nixon and Hollander. 2AAO, 2007. Data on file, Allergan, Inc. Carbonic Anhydrase Inhibitors 4 types of isoenzymes I erythrocytes and corneal epithelium II non pigmented ciliary body epithelium , iris retinas lens III skeletal muscle IV kidney Carbonic Anhydrase Inhibitors Aqueous humor formation depends on secretion of bicarbonate from the ciliary processes when bicarbonate is formed, it tied with sodium and water follows Similar process in CSF production and in kidney CAI Dorzolamide Brinzolamide Acetazolamide 500mg sequels Methazolamide 2% 1% 125, 250, 25, 50 mg Systemic Side Effects Oral Use Malaise and fatigue Weight loss Anorexia Loss of libido Depression Sulfa allergies Sickle cell Marked kidney/liver Low potassium Low sodium level Transient myopia – Swelling of CB Pregnancy Category C Paresthesia Tinitus Nausea Taste alterations Metabolic acidosis Contraindications to Oral Therapy Sulfa allergies Sickle cell Marked kidney/liver Low potassium Low sodium level Pregnancy Category C Metabolic acidosis CAIs make wonderful partners Feldman, et al 2006 – 1.5-1.8 mm lower IOP as compared to brimonidine 0.15% when added to travaprost This significance was present at all time points BID dosing Companion study #2 When compared to brimonidine 2% adding them to Travaprost... IOP lowered by 13% w/ brimonidine IOP lowered by 23% w/ brinzolamide Brinzolamide as an Adjunct to Latanoprost PURPOSE: To evaluate the IOP lowering effect of brinzolamide (1.0%) as an adjunctive therapy to latanoprost (0.005%) in patients with open-angle glaucoma or ocular hypertension METHODS: • 14 patients with open-angle glaucoma or ocular hypertension who had been using latanoprost for more than 6 months were initiated on adjunctive brinzolamide therapy • IOP values at 1, 2 and 3 months compared with baseline (beginning of adjunctive therapy) • Incidence of adverse events examined Shoji N, et al. Cur Med Res Opin 2005; 21: 503-507. 46 Brinzolamide as an Adjunct to Latanoprost Adjunctive therapy lowered IOP by an additional 5.2 mm Hg after 3 months 30 25 IOP (mmHg) ** 20 15 ** 21.1 ± 4.8 16.9 ± 4.5 10 16.6 ± 4.0 ** 15.9 ± 3.1 5 0 ** P < 0.01 (Wilcoxon signed ranked test) Baseline 1 Month 2 Months 3 Months Shoji N, et al. Cur Med Res Opin 2005; 21: 503-507. 47 DIURNAL/WAKE DIURNAL/WAKE NOCTURNAL/SLEEP 1.30PM 11.30AM 9.30AM 5.30AM 3.30AM 1.30AM 11.30PM 9.30PM 7.30PM 7.30AM latanoprost latanoprost + brinzolamide latanoprost + timolol N=26 Error bars = SEM 5.30PM 26 24 22 20 18 16 14 12 10 8 6 4 2 0 3.30PM Habitual IOP (mm Hg) Brinzolamide or Timolol: Adjunct to Latanoprost in an Open-Label Study Clock Time Liu JH, et al. Ophthalmology 2009; 116(3): 449-54. 48 Prostaglandins /Prostamides Uveal seleral outflow Affects many properties with the 1955-Ambache described irin which medicated ocular response to inflammation Naturally synthesized by trabecular endothelial cells/ciliary muscle cells May have only minor inflammatory Regulatory effects Prostaglandins /Prostamides Different receptor sites DP,EP,IP Prostaglandins E and F most effective in lowering IOP They seem to facilitate aqueous outflow via the uvealscleral pathway Latanoprost 0.005% Xalatan – Prostaglandin F 2a analogue – Prodrug Travoprost 0.004% Travatan – Prostaglandin F 2a analogue – Prodrug Brimatoprost 0.03% Lumigan – Synthetic prostamide analog – Not a prodrug Tafluprost Zioptan - Non-preserved unit dose XLT Study – Parrish, Palmberg, et al. (AJO, May 2003, Vol. 135, No.5) Multicenter study to compare IOP lowering efficacy of Bimatoprost vs Latanoprost vs Travaprost Also compared safety profiles of the 3 drugs Conclusions: All 3 drugs were comparable in their ability to lower IOP at all time periods. – Latanoprost exhibited greater ocular tolerability PGAs: IOP-Lowering Effects PURPOSE: To compare the IOP-lowering effect and safety of latanoprost, bimatoprost, and travoprost METHODS: 12-week, randomized, parallel-group study conducted at 45 US sites Previously treated patients with OAG or OH and an IOP ≥ 23 mm Hg in one or both eyes after washout Received either latanoprost (0.005%), bimatoprost (0.03%), or travoprost (0.004%) once daily in the evening At baseline and after 6 and 12 weeks of therapy, masked evaluators measured IOP in triplicate at 8:00 AM, noon, 4:00 PM, and 8:00 PM. The primary efficacy outcome measure was change between baseline and week 12 in the 8:00 AM IOP Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703. 57 Primary Outcome 8 A.M. IOP reduction (mm Hg) from baseline to week 12: Latanoprost: 8.6 ± 3.7 Travoprost: 7.9 ± 3.4 Bimatoprost: 8.7 ± 3.8 Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703. 58 Adverse Effects Latanoprost (n=136) Bimatoprost (n=137) Travoprost (n=138) n No. events n No. events n No. events hyperemia 64 71 94 110 80 90 Eye irritation 9 10 15 16 6 6 Vision blurred 0 0 5 5 2 2 Eye pain 2 2 1 1 4 4 Growth of lashes 0 0 4 4 1 1 Skin discoloration 2 2 4 4 4 4 Dry eye 2 2 3 3 2 2 Visual acuity 2 reduced Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703. 2 2 3 3 3 Pruritus 0 0 0 3 3 0 59 Look at their failure rate: Percent of pxs who didn’t reach their target IOP – Latanoprost – 14% – Bimatoprost- 6% – Travaprost – 8% Adverse Effects Changes to pigmented tissues – Iris pigmentation starts at pupil and spreads concentrically – Long thick lashes – Periobital pigment changes Caution with macular edema, iris/uveitis, keratitis Caution with renal/hepatic dysfunction Pregnancy category C Prostaglandin Side Effects Iris pigmentation – Is it reversible? – Is it pre-cancerous? Xalatan – 6.7% @ 6mths 16% @ 12mths Travatan – 3% @ 12 mths Lumigan – 1.9% @ 12mths Other Prostaglandin side effects CME Uveitis Reactivation of HSK Hypertrichosis Periorbital skin darkening One must take into consideration the benefits of low IOP with the risks of the side effects Travatan (Travoprost 0.004%) Lowers IOP 30-33% Contraindicated in pregnant woman Excellent responder rated in black pts No CME Responder rates in all patients 56.3% for IOP 17 mm Hg for travatan 49% for xalatan 39% for timolol PGAs: Effects on Circadian IOP PURPOSE: To compare 24 hr reduction in IOP with latanoprost, travoprost and bimatoprost in patients with OAG and ocular hypertension (OH) DESIGN: Randomized, double-masked, crossover study PARTICIPANTS: 24 OAG and 20 OH patients METHODS: • Patients treated with randomized cross-over sequence of latanoprost, travoprost and bimatoprost for 1 month each, with 30 day washout in between • 24 hr tonometric curves were recorded at baseline (prior to each treatment) and after each treatment period in seated and supine positions • Baseline and post-treatment IOP measured at 3:00, 6:00, 9:00 AM and noon and 3:00, 6:00, 9:00 PM and midnight Orzalesi N, et al. Ophthalmology 2006; 113: 239-246. 66 Bimatoprost and Travoprost: 12-Week Study Mean IOP at Week 12 Mean IOP (mm Hg) 24 20 16 12 Travoprost (n = 138) Bimatoprost (n = 136) 8 4 0 Baseline mean IOP comparable between groups Travoprost: 25.5, 23.8, 22.8, 22.0 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg) Bimatoprost: 25.7, 23.8, 22.8, 22.3 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg) 8 AM 12 PM 4 PM Time of Day 8 PM Parrish et al. Am J Ophthalmol. 2003. % of peak IOP reduction (@ 12 hr) Travoprost Appears Consistent Peak to Trough 100% 95% 90% 85% 80% 75% 70% 65% 60% Travoprost Latanoprost Bimatoprost 9:00 am 3:00 pm Time 12 hours post dose = peak IOP reduction 9:00 pm Peak-to-trough loss: • Bimatoprost = 38% • Latanoprost = 26% • Travoprost = 14% 24 hours post dose = trough IOP reduction Orzalesi N, et al. Ophthalmology 2006; 113: 239-246. 68 Effect of Travoprost on Diurnal and Nocturnal IOP PURPOSE: To assess the diurnal and nocturnal persistence of IOP reduction after omission of up to two doses of once-daily topical travoprost in patients with OAG or OH DESIGN AND METHODS: • Prospective, open-label study • 20 patients underwent 24 hr IOP monitoring at baseline prior to treatment and after 4 weeks or more of travoprost treatment Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133. 69 28 DIURNAL/WAKE NOCTURNAL/SLE EP DIURNAL/WAKE 26 24 22 20 18 16 Measured in the usual “habitual position” of the patients during those time periods – Diurnal period – sitting – Nocturnal period – supine 1:30 PM 11:30 AM 5:30 AM 3:30 AM 1:30 AM 9:30 PM 11:30 PM 7:30 PM 5:30 PM 3:30 PM 9:30 AM Error bars = SEM 14 7:30 AM Habitual IOP (mmHg) Effect of Travoprost on Diurnal and Nocturnal IOP Clock Time Baseline “On Treatment” Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133. 70 Bimatoprost and Travoprost: 6-Month Safety Results Both medications were well tolerated Most common adverse event: ocular redness – 16 patients (20.8%) in the bimatoprost group and 12 patients (14.8%) in the travoprost group (P = .326) Ocular itching reported for 7.4% of travoprost patients and 2.3% of bimatoprost patients (P = .278) Treatment-related adverse events leading to patient discontinuations – 8 patients in the travoprost group exited early: 4 for lack of efficacy, 2 for ocular redness and lid erythema, 1 for ocular dryness and itching, and 1 for allergic symptoms – 2 patients in the bimatoprost group exited early: 1 for blurry vision and 1 for ocular redness and lid erythema Cantor et al. Br J Ophthalmol. In press. Bimatoprost (Lumigan 0.03%) Lowers IOP 30-33% Favorable lowering of IOP with lumigan vs xalatan Side effects 15-45% hyperemia 15% ocular pruritis 45% Eyelash growth CME rare Percentage of Patients Reaching Target IOP at 10 AM, Month 12 Bimatoprost and Timolol 12-Month Study * 90 Target Pressures at Month 12 80 60 69 * * 47 40 69 61 58 *P < .010 vs timolol 50 * 77 * Timolol BID (n = 241) Bimatoprost QD (n = 474) 70 47 37 * 31 30 26 * 21 * 20 10 85 *7 2 12 16 9 5 0 ≤ 12 ≤ 13 ≤ 14 ≤ 15 ≤ 16 ≤ 17 Target IOP (mm Hg) ≤ 18 ≤ 19 ≤ 20 Higginbotham et al. Arch Ophthalmol. 2002. Additive IOP-Lowering Effect Additional Intraocular Pressure Lowering (mm Hg) Alpha Agonist 0 -0.5 -1 -1.5 -2 -2.5 -3 -3.5 -4 -4.5 N=23 Beta-blocker TCAI N=25 N=25 -2 -2.5 -3.9 O’Connor DJ, et al. Am J Ophthalmol. 2002; 133(6): 836-7. 74 Nocturnal Efficacy: Timolol vs. Latanoprost PURPOSE: To compare the nocturnal effects of oncedaily timolol and latanoprost on IOP DESIGN: Prospective, open-label, crossover study METHODS: 18 patients received topical treatments with timolol (0.5%), latanoprost (0.005%), and no IOP-lowering medication, for at least 4 weeks At the end of each treatment period, the patient was housed in a sleep laboratory for 24 hrs and IOP was measured every 2 hrs using a pneumotonometer Liu JH, et al. Am J Ophthalmol. 2004; 138: 389-395. 75 Supine Sitting No treatment N=18 Error bars = SEM 1.30PM 9.30AM 7.30AM 11.30AM Clock Time 5.30AM 3.30AM 1.30AM 11.30PM 9.30PM Timolol 7.30PM 5.30PM 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0 Sitting 3.30PM Habitual IOP (mm Hg) Timolol: Nocturnal IOP Liu JH, et al. Am J Ophthalmol. 2004; 138: 389-395. 76 Can There be Too much Prostaglandin? Alverado, J; Oct 2009 UCSF Laboratory Analysis of Effect of SLT on Trabecular Outflow SCE’s were exposed to six different IOP lowering drugs and SLT/TME’s The junction assembly/dissassembly was monitored by confocal flourescent time lapse microscopy Latanaprost, bimatoprost & Travaprost shared a common mechanism of action with SLT – Widening of the paracellular pathways – Induction of intercellular junction dissassembly – Decreased transepithelial flow across SCE’s Clinical impact: TME’s play a critical role in regulating SCE’s Non-Competing IOP agents may improve IOP spot SLT Cholinergics Cholinergics are bound by melanin and may need a high concentration to affect darker irides Anticholinesterases have similar effects to cholinergics These medications facilitate outflow via the trabecular meshwork Echothiophate iodine may prolong the effects of succinylcholine Cholinergics Generally contraindicated in synechial angle closure, neovascular glaucoma Uveitic glaucoma, retinal detachment of peripheral breaks Pilocarpine pregnancy category C Anticholinesterases contraindicated in pregnant women Cholingegics Cholinergics – Pilocarpine HCL – Pilocarpine nitrated – Pilocarpine ocuserts Cholinesterase Inhibit – Echothiophate 0.125% – Demecarium 0.25%-10% 1%, 2%, 4% 20%, 40% 0.03%, 0.06% 0.125%, 0.25% Mixed – Carbachol 3.% 0.75%,1.5%, 2.25%, Pilocarpine Low concentrations deepen chamber High concentrations may cause pupillary block Increase axial length of the lens, shallows AC Induce myopia Decrease uveosclearl outflow Pilocarpine Cilary block (malignant) glaucoma is worsened with miotis Increase permeability of blood aqueous barrier Increase post-op inflammation Need higher concentration in pigmented irides Max effect occurs in 2 hours last 8 hours; 12-15 hr still 14-15% reduction in IOP Pilo toxicity-Wet Salivation Lacrimation Sweating Vomiting/diarrhea Pulmonary edema/death Makes Parkinsons disease worse – (more acetylcholine than dopamine) 10 ml 1% pilocarpine, 100mg is dangerous Ocular Side Effects Conj hyperemia/follicle Miosis Brow aches Epitheliopathy Myopia Shallowing of the AC Iritis Pupillary cysts Lens opacities Retinal detachment Pemphigoid type reaction Systemic side effects Diarrhea Bradycardia Tearing Salivation Nausea Diaphoresis Cramps