2/1/2020 Glaucoma Pharmacology: Old, New and What to Do? Joseph Sowka, OD Greg Caldwell, OD Rho-Kinase White 1 2 GLAUCOMA EPIDEMIOLOGY AND AQUEOUS HUMOR DYNAMICS TREATMENT IOP – A Complex Homeostasis Current Medical Treatments for OAG Aqueous formation in ciliary body – passive diffusion, ultrafiltration and active secretion Cornea Aqueous Production Aqueous Outflow Conventional Outflow – Trabecular Meshwork → Schlemm’s Canal → Conventional Unconventional Episcleral Venous System Trabecular Meshwork Prostaglandin Non-Conventional Outflow – Schlemm’s -blocker Cholinergic agonist analog Canal Uveoscleral Episcleral CAI NO-donating PGA NO-donating Veins 2-agonist RhoKinase inhibitor PGA 2-agonist Uveoscleral Outflow Updated 1/7/18 Ciliary Processes 3 4 PROSTAGLANDINS: PROSTAGLANDINS OCULAR ADVERSE EFFECTS ▪ Prostaglandins are not indicated ideal in secondary inflammatory glaucoma or any ▪ Hyperemia clinical entity that has anterior segment ▪ Increased iris coloration inflammation as a component ▪ Periorbitopathy: skin darkening, Sulcus ▪ Prostaglandins are important in that they deepening flatten the diurnal IOP curve as well as giving - Hyperemia is reversible with medication cessation. Iris color lingering IOP reduction even as much as 60 changes appear to be irreversible. Periorbitopathy may be reversible if the medication is stopped soon enough, but may hours after dosing. Thus, they are more indeed be permanent. forgiving of patients that miss dosages. ▪ Hypertrichosis ▪ Punctate keratopathy, dry eye ▪ Uveitis, CME, and dendritic keratitis? 5 6 1 2/1/2020 • Xalatan® (latanaprost 0.005%) – Generic latanoprost…APPROVED 3-22-2011 • Travatan-Z® (travoprost 0.004%) – Preserved with Sofzia • Lumigan® (bimatoprost 0.01%) • Zioptan ® (tafluprost 0.0015%)- Merck – Preservative free • Vyzulta™ (latanoprostene bunod 0.024%) – Approved 11/2/17 – NO donating PGA 7 8 9 10 VYZULTA™ (latanoprostene bunod ophthalmic solution, 0.024%) • First prostaglandin analog with one of its metabolites being nitric oxide (NO) • QD dosing • Dual mechanism of action – metabolizes into two moieties, latanoprost acid, which primarily works within the uveoscleral pathway to increase aqueous humor outflow, and butanediol mononitrate, which releases NO to increase outflow through the trabecular meshwork and Schlemm's canal. – Blocks RhoKinase and calcium signaling 11 12 2 2/1/2020 Sorting out the prostaglandins: The XLT study • The first study performed that simultaneously Results of Meta-Analyses of Studies Assessing the compared the clinical outcomes associated Comparative Efficacy of Prostaglandin Analogs with the use of latanoprost, bimatoprost, and travoprost • Compared not only the effectiveness of IOP reduction of the three medications, but also examined the adverse effects and tolerability of the medications Parrish R, Palmberg P, Sheu WP, and the XLT Study Group. A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular Bean GW, Camras CB. Commercially available prostaglandin analogs for the reduction of intraocular pressure: similarities and pressure: A 12-week, randomized, differences. SurvOphthalmol. 2008 Nov;53 Suppl1:S69-84. masked-evaluator multicenter study. Am J Ophthalmology 2003; 135 (5):688-703 13 14 The XLT study “Great, but can you tell me something • IOP was significantly reduced from baseline for all that maybe I didn’t already know?” three medications. – Magnitude of the reduction was not statistically significant between the medications • There was no significant difference between the medications in the persistence of pressure lowering or for the mean diurnal pressure throughout the study 15 16 PGA in Chronic Angle Closure Glaucoma • Mechanism is unknown, but results are impressive PGA for chronic angle closure • Aqueous may gain access to CB face/ is an exceptional therapeutic uveoscleral meshwork via still open part of option. angle- or another pathway unknown • PGA have demonstrated pronounced effect in Remember that LPI still needs eyes even with complete PAS angle closure to be performed. –May decrease IOP through uveoscleral tissues other than ciliary face Kook MS et al. Efficacy of latanoprost in patients with chronic angle-closure glaucoma and no visible ciliary body face. A preliminary study. J Oc Pharm and Therapeutics; 2005; 21(1):75-84 17 18 3 2/1/2020 Autonomics Sympathetics • Alpha 1 • Sympathetic Agents – Blood vessels of ciliary body: vasoconstriction, which reduces blood – Adrenergic agonists flow and aqueous production. – Sympathomimetic – Epinephrine-like drugs – Norepinephrine based – Adrenergic antagonist • Alpha 2 – Sympatholytic – Nerve terminal • Beta 1 • Parasympathetic Agents – Heart: increased – Parasympatomimetics • Beta 2 – Cholinergic agonists – Lungs: relaxed- increased breathing ability – acetylcholine based • Beta 1 & 2 on ciliary body – miotics – Stimulation increases aqueous production – Blocking B1 & 2 receptors reduces aqueous production • Beta blockers 19 20 Parasympathetics Parasympathetics • Iris: miosis • Glands: increased activity • Ciliary body: accommodation and trabecular • Heart: reduced activity meshwork opening • Blood vessels: vasodilation • Trabecular meshwork: aqueous outflow • Lung: bronchiole constriction increase • Because these organs are more controlled by the sympathetic system, there is less systemic affects by • Ciliary meshwork (uveal meshwork- parasympathomimetic drugs than would be uveoscleral pathway)- aqueous outflow expected. decrease • Gastrointestinal tract: increased motility • Urinary tract: increased motility 22 23 Adrenergic Agonists: Adrenergic Agonists: 24 25 4 2/1/2020 Alpha-2 agonists Alpha-2 agonists • Brimonidine acts presynaptically to inhibit release of • The most significant side effects are norepinephrine and reduces adrenergic receptor stimulation. The reduced sympathetic activity in drowsiness and fatigue, headache, and dry ciliary body reduces aqueous production. mouth – Some increase in uveoscleral outflow • Other side effects: • TID dosing – Conjunctivitis (follicular), Blurring, Burning – Often used initially BID. – BID dosing can leave the patient with uncontrolled IOP at • Early and late onset Alphagan allergy certain times of the day. • This is significant for monotherapy – Patients on polytherapy may be able to get away with BID dosing 26 27 Brimonidine “Great, but can you tell me something that maybe I didn’t already know?” • No effect on blood pressure, pulse, or pulmonary function – Minimal cardiovascular and pulmonary responses- not frankly contraindicated in patients with cardiovascular disease, but use caution in patients with ischemic heart disease or prior MI • Concurrent use of MAO inhibitors (anti- depressants) are a contraindication to the use of Alphagan • Does not appear to have IOP lowering effects at night/during sleep 28 29 Brimonidine Beta Blockers • Crosses blood-brain barrier and has CNS effects • Adverse effects are most significant in smaller patients and children • This medication has induced fatigue, drowsiness and even coma in children • Contrary to what you might have heard, Alphagan is not proven neuroprotective 30 31 5 2/1/2020 Beta Blockers: Contraindications Beta Blockers: Adverse Effects • Asthma • Bradycardia: • Emphysema – Slowing of sinus nodal discharge with resultant dose- • Myasthenia gravis dependent bradycardia. In most cases, the degree of – Can worsen myasthenia gravis bradycardia is asymptomatic and does not impact a • Cerebrovascular insufficiency patient’s life. • Greater than 1st degree heart block • Patients using topical beta blockers who develop • Hypotension (<100/60) symptomatic bradycardia -- as manifested by • Beta blockers are bad for athletes as it prevents heart rate diminished capacity for physical activity or from exceeding 135 BPM. Athletes cannot train through this undiagnosed syncope -- likely have coexistent block. pathology of the sinus AV node or conduction • Every patient considered for a topical beta blocker needs pathways and should be referred to a cardiologist. baseline blood pressure and resting pulse measurement in addition to review of medical history. – Problem is not likely solely due to beta blockers 32 33 Beta Blockers Beta Blockers • Topical beta blocker therapy should be avoided in • The most significant contraindications are COPD, patients with asymptomatic bradycardia and heart asthma, emphysema, symptomatic bradycardia, block. and asymptomatic bradycardia with heart block. – Patients with symptomatic bradycardia often present with • Beta blockers can be considered in patients with syncope and dizziness, and are identified prior to CHF pending approval by the patient’s PCP. All ophthalmic examination. other contraindications can be considered • Asymptomatic patients without aerobic conditioning ‘relative’ and beta blockers can be used in many (i.e., athletes) with resting pulse rate under 55 beats per of these situations on a case-by-case basis. minute should be evaluated by a cardiologist. • If a ‘contraindication’ is present, it doesn’t mean – However, patients with normal resting pulse rates and with that beta blockers (or any medication for that no history of syncope or dizziness are unlikely to experience matter) cannot be used, but should be a lesser any serious bradycardia effects from topical beta blockers. choice. 34 35 Beta Blockers • Timoptic® (timolol maleate 0.25% & 0.5%) • Timoptic-XE® (timolol maleate gel-forming solution) • Istalol® (timolol maleate 0.5%) • Betimol® (timolol hemihydrate 0.5%) • Betagan®