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Prostaglandin Analogs Prostaglandin Analogs 9/26/2017 Disclosure Statement “I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or Joseph Bergmann, MD provider(s) of commercial services discussed in this CME activity.” Medical Treatment Medical Treatment Is it effective / How does it work? Oral Is it safe / What are the side effects? Methazolamide Acetazolamide Is it expensive? Topical How do I take my drops Prostaglandins Do I need to do this my whole life? Beta-blockers Alpha-adrenergic Carbonic Anhydrase Inhibitors Cholinergic Agonists Rho Kinase Inhibitors Oral Carbonic Anhydrase Oral Carbonic Anhydrase Inhibitors Inhibitors Preparations/ Dosing Anatomy/ Physiology/ Pharmacokinetics Side Effects Cost 1 9/26/2017 Oral CAIs Oral CAI’s: Side Effects How is it available? Allergy Methazolamide ○ 25-50mg 2-3 times daily Rare Acetazolamide ○ 250-500 mg standard release dosed 4-6 hours Aplastic anemia, Thrombocytopenia, ○ 500 mg Sequels (standard release) dosed 12 hours Agranulocytosis How it works Decrease aqueous humor formation by direct antagonist activity on Hypokalemia ciliary epithelial carbonic anhydrase Create systemic acidosis Common 90% of enzyme must be inhibited for it to be effective Methazolamide is liver metabolized, acetazolamide is kidney GI: nausea, diarrhea, weight loss, metallic taste metabolized Nervous: Lethargy, depression, parathesias, Action Onset within 1 hour decreased libido Peak 2-4 hours (sustained release Renal: Kidney stones duration “Hangover” Oral CAI’s: Cost Prostaglandin Acetazolamide Regular and Sustained Release (Diamox Analogs Sequels) ○ $$$ Methazolamide $$$ Prostaglandin Analogs Prostaglandin Analogs How is it available? How it works Prostamides Improves aqueous outflow Bimatoprost, Latanoprost, Travaprost Pressure dependent and independent ○ Xalatan introduced in 1996 Elevated presence of metalloproteinases--- ○ Once daily dosing breaking down the collagen matrix within the uveoscleral region that surround the ciliary Decosanoid muscle bundles. Unoprostone isopropyl (Rescula) Increases uveoscleral outflow to >50% BID dosing 2 9/26/2017 Prostaglandin Analogs Prostaglandin Side Effects Effect of Prostaglandins Hyperemia Latanoprost / Travaprost 25-32% reduction in ? Cystoid Macular Edema IOP ○ Prodrugs metabolized in cornea Anterior Iritis Bimatoprost 27-33% reduction in IOP ? exacerbation of underlying herpes Unoprostone isopropyl 13-18% reduction in IOP keratitis Duration Dry eye Onset: slow Peak: 10-14 hours Duration: near 24 hours Prostaglandin Side Effects Cosmesis Eyelash changes Periorbital fat atrophy Periorbital Pigmentation Iris color changes Prostaglandin Analogs: Cost Beta-Blockers Latanoprost Travaprost Travatan Z Lumigan Rescula 3 9/26/2017 Beta-Blockers Beta-Blockers Timolol was intro in 1978 How it Works Nonselective Aqueous suppressant Timolol, levobunolol, carteolol, metipranilol inhibits synthesis of cyclic adenosine Selective monophosphate in the ciliary epithelium Betaxolol—preferentially binds beta-1 hepatic metabolism with renal excretion adrenergic receptors thus being cardio-selective Effect Multiple studies now support once daily 20% reduction in pressure dosing vs. BID Onset: 20 minutes AM dosing Peak: 1-2 hours ? Tachyphylaxisis Duration: nearly 24 hours Timolol: Side Effects Timolol: Cost Cardiac Cheap bradycardia, syncope, decreased BP, arrhythmia decrease HDL and increase total cholesterol Respiratory bronchospasm Central Nervous depression, hallucination, fatigue Ocular burning, dryness Other impotence, mask hypoglycemic sign Alpha-adrenergics Alpha-adrenergics Brimonidine (Alphagan/Alphagan-P) Dosed BID multiple concentrations ○ higher concentration = more hypersensitivity Apraclonidine (Iopidine) Epinephrine and Dipivefrin HCL ○ nonselective, not used any longer 4 9/26/2017 Alpha-adrenergics Brimonidine: Side Effect How it works Ocular aqueous suppressant I improves uveoscleral outflow allergy (peak onset 12-18 months), alpha-2 adrenergic agonist activating g-coupled protein conjunctival blanching, dryness, mydriasis, receptors inhibiting adenylate cyclase thereby decreasing c-AMP eyelid retraction vasoconstriction also can cause acute lowering of IOP Systemic prolonged use leads to buildup of prostaglandins in eye thereby explaining improved uveoscleral outflow headache, dry mouth, fatigue, bradycardia, Effect hypotension Up to 26% reduction in IOP Children: NO! NO! NO! Onset: rapid Peak: 2 hours somnolence, apnea, hypotension, seizure Duration: up to 12 hours Tachyphylaxis Alpha-adrenergic Cost Topical CAIs Alphagan P Brimonidine (Generic) Iopidine Topical Carbonic Anhydrase Topical CAIs Inhibitors • Dorzolamide 2% (Trusopt) and How it works Brinzolomide 1% (Azopt) Aqueous suppressant inhibits carbonic anhydrase in ciliary body Both are now generic epithelium Both are BID or TID dosing 90%+ of enzyme must be inhibited for effective IOP control Effect 15-20% reduction in IOP Onset: relatively rapid Peak: 2 hours Duration: 8-12 hours 5 9/26/2017 Topical CAIs: Side Effects Topical CAIs Cost Sulfa Allergy? Azopt Ocular Trusopt blurred vision(myopic shift), irritation, Brinzolomide burning, pain, dermatitis Dorzolamide Systemic rhinitis, taste disturbance, fatigue Renal kidney stones Cholinergics Pilocarpine Cost Direct Acting Pilocarpine 1-6% solutions BID-to-QID dosing Indirect Acting (never seen these used) Echothiophate Iodide Demercarium Iodide Physostigmine Isoflurophate Cholinergics Pilocarpine Side Effects How it works Ocular increase trabecular outflow miosis (decrease vision) causes contraction of the longitudinal brow ache muscle in ciliary body thereby pulling on the scleral spur and stretching the trabecular myopic shift meshwork shallow anterior chamber Effect : 15-25% reduction in IOP retinal detachment Onset: 10-30 minutes inflammation Peak: 1.5-2 hours Systemic Duration: 4-8 hours essentially none...very safe 6 9/26/2017 Rho -Kinase Inhibitors Combinations The next revolution in medical glaucoma - • Cosopt Kinase Inhibitors care? Dorzolomide/timolol Increased outflow through trabecular meshwork Combigan How: reduces cellular stiffness Brimonidine/timolol May also be neuro-protective, anti- Simbrinza inflammatory and improve bloodflow to the Brimonidine/Brinzolomide optic nerve Not available yet: 2 US companies are in early clinical research--likely be years Combinations Preserative free Occudse Beta-blocker Cosopt-PF Combination timolol and dorzolamide Zioptan prostaglandin Medical Tx in Children Medical Tx in Pregnancy 1st Trimester NO Alphagan/Brimonidine Brimonidine is Class B (preferred) Caution with beta-blocker ? teratogenicity of all others 2nd Trimester CAIsoften acceptable Brimonidine and Beta-blockers are generallyOK Prostaglandins--premature labor Prostaglandinssafety CAI--fetal growth monitoring 3rd Trimester Brimonidine, beta-blockers, CAIs ok at least early Brimonidine not near labor--CNS depression Prostaglandin not recommended Post-partum CAIs and Beta-blockers rec by American Academy of Peds with breast feeding 7 9/26/2017 The Green Stuff Lifestyle Modification “Doc is there something I shouldn’t eat or that I should avoid?” “Doc is there an exercise that will help?” “I saw an advertisement for these supplements that treats/cures glaucoma” 8.
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