Glaucoma Drugs.pdf

Lecture 2: Glaucoma Drugs (Ocular Anti-Hypertensives) What is glaucoma: optic neuropathy initially provoked by multifactorial primary mechanisms of damage (PMOD) characterized by ONH Atrophy and secondary induced programmed retinal ganglion cell death causing a characteristic pattern of VF loss. Evi...

Lecture 2: Glaucoma Drugs (Ocular Anti-Hypertensives) What is glaucoma: optic neuropathy initially provoked by multifactorial primary mechanisms of damage (PMOD) characterized by ONH Atrophy and secondary induced programmed retinal ganglion cell death causing a characteristic pattern of VF loss. Evidence-Based Supported PMOD • Elevated intraocular pressure (EIOP) • Decreased Ocular Blood Flow (DOBF) What Causes EIOP? • Two outflow methods • Resistance to Trabecular Aqueous Outflow (TO) o Increased herniation of TM cytoskeleton o Decreased inflammatory signaling to EC Schlemm Canal o Increased Episcleral VP • Resistance to Uveoscleral Aqueous Outflow (USO) o USO Mechanism: Goes back to ciliary body through CB Band, through ciliary muscle bypassing muscle fibers which are restricted by collagen o Too much collagen o Prostaglandin agonists break down collagen between fibers, thus decreasing IOP (Metoproteinate is an enzyme that breaks down collagen fibers) Vascular Concept of OBF • OBF: Ocular Blood Flow • DBP: Diastolic BP • PPa: Perfusion Pressure of Artery • PPv: Perfusion Pressure of Vein • Lean and understand this formula • Refer to slide 7 in scribe notes for more detailed information Factors Involved in DOBF • Decreased DBP/Elevated IOP à Uncompensated DOPP à DOBF (ONH Damage) • Vasculospastic DX/Hyperviscosity Syndrome/EIOP (Migraines) à VA Dysfunction à DOBF (ONH Damage) What about Ocular Biomechanical Properties (OBMP)? • Cornea Viscoelastic Property (way to measure): ability to absorb, energy in absorption • Barriers: protective, rigidity characteristic, hold pressure • Prone to develop Glaucoma in pt with poor ocular biomechanics à poor viscoelastic property Biomechanical Concepts (key terms) • Corneal Hysteresis (CH)- Viscoelasticity o Increase value: better biomechanics and more ability to hold pressure • Corneal Resistance Factor (CRF)- relates to the overall ocular structural rigidity o More rigidity implies a higher IOP • Central Corneal Thickness (CCT)- extrapolated measurement to imply corneal rigidity; viewed as a protective factor • Ocular Response Analyzer (ORA): same principal of air puff tonometer o Will measure the pressure by applanation of the cornea o Resist force of applanation: § Rigid comeback-rigid § Long time comeback: flaccid Factors Involved in Altered OBMP Properties • Decreased CH à Decreased CRF à (two paths) o Decreased CCT à Decreased Corneal Rigidity o Decreased Corneal Rigidity • Decreased Corneal Rigidity à Decreased Protective Factor, Increased Risk Factor Secondary Mechanism of Damage Concept • Elevated IOP/Normal IOP + Mechanical Damage/Ischemic Insult à Optic Neuropathy à Neural Death o Where does neuronal damage come from? § Relation to Neurovascular coupling • Lack of blood flow related to nerve damage • Capillary BF is diminished • Electro-Retinogram measures action potential at different levels in retina • Glutamate Excitotoxicity (diminished glutamate transporter function • NMDA Receptor Activation (excitement): physiological open and close help autonomic flow o Healthy regulation of neurotransmitters in extracellular is key (Glutamate) o In glaucoma it is believed that Glutamate is too much extracellular, the receptor stays open by ligand Magnesium, leading to inflow to cell: Cell death by increase Ca § Re-uptake mechanism when glutamate increases extracellularly and closes to maintain homeostasis • Increases Ca+ Influx • Delayed Calcium deregulation: cell does not have the ability to take Ca+ out of the cell • Nitric Oxide Synthesis • Neurotrophion Depravation • Apoptosis Glaucoma Risk Factors • Elevated IOP • Suspicious Optic Disc o Cupping in relation to disc size o Normal disc size 1.8mm-2.5mm o 0.6/0.6-2.0mm: less risk o 0.4/0.4-1.5mm: more risk • Family History: siblings • Race: primary open angle-black, Hispanics • Increasing Age: 2x the risk • Myopia: long axial length- blood flow has to travel more turning into less blood flow • Diabetes: not really a strong factor • Systemic Vascular Disease: HBP and CRVO • CRVO: Raynaud's disease (decrease blood flow- blue nails and sensitivity to cold) Goals of Pharmacological Medical Therapy • Reduction in the mean IOP to <15 mmHg** o **Actual target is one that stops progression o Has to be stable w no fluctuations • Control of diurnal fluctuation • High rate of response • No Tachyphylaxis (Tachyphylaxis: an acute, sudden drop in response to a drug after its administration) Topical Medication Classes and IOP Lowering Abilities • Prostaglandin Analogues: 6-8 mmHg • Alpha2-Adrenergic Agonists: 2-6 mmHg • Beta Blockers (Adrenergic Antagonists): 3-5 mmHg • Carbonic Anhydrase Inhibitors (CAIs): 2-4 mmHg • CAI/Beta Blocker Combo: 4-6 mmHg • Alpha2-Adrenergic Agonists/Beta Blocker Combo: 4-6 mmHg Prostaglandin Analogues (PGAs) • Travoprost • Bimatoprost (chemically different) • Latanoprost (highly unstable, refrigeration needed) • Tafluprost (not much receptiveness in patients) • PGAs are the first line of medical therapy • Greater efficacy: advise to use at night o More IOP reduction than beta blockers o Flatter diurnal curves vs other therapies o Better response o No tachyphylaxis • Additive to other agents • Good safety • Latanoprost (Xalatan 0.005%) o Mode of therapy: QD PM (refrigerate) o 35% in IOP reduction o Good adjunctive therapy w beta-blockers • Travanoprost (Travatan 0.004%) o Same indications as latanoprost o More stable solution o BAK-Free Travoprost (Travatan Z) § Same formulation, but preserved w SofZia instead of BAK • Bimatoprost (Lumigan 0.01%) o Chemically different o A prostamide o Mode of action § 35% increase in trabecular outflow § 50% increase in uveo-scleral outflow (main mechanism of prostaglandins) • Tafluprost (0.0015%, solution, PF) o Indications: for reducing elevated IOP in patients w open-angle glaucoma or ocular HTN o Clinical Trials: patients w open-angle glaucoma or ocular HTN and baseline IOP of 23-26 mmHg who were treated once daily in the evening demonstrated reductions in IOP at 3 and 6 months of 6-8 mmHg and 5-8 mmHg respectively How do PGAs Work? • Pro-drug: converts to active free fatty acids by corneal enzymes • Binds to FP receptors in ciliary body • Up-regulation of matrix metalloproteinase (MMPs) which degrade extracellular proteins of the ciliary muscle (increase uveo-scleral outflow) o An increase of collagen decreases uveo-scleral outflow o PG2 Receptors secrete prostaglandins (pro-inflammatory) • Also enhances TOP • IOP reductions of 30% • One third of patients achieve reductions of 40-50% Trabecular Outflow MOA • Inflammation always increases permeability • SLT Therapy (same outcome as prostaglandins à Bimatoprost-Lumigan) o Increases permeability of cells by signaling w application of laser o The counter to widely held belief that PGAs work via the uveo-scleral outflow pathway & MMPs o Indicates that PGAs have a direct effect on Schlemm’s canal endothelial cell barrier function and therefore the conventional trabecular meshwork aqueous outflow pathway o Regulates the integrity of the intracellular junctions and the permeability of the barriers formed by SCEs What to look out for when using PGAs • Periorbital absorption causes atrophy of eyelid receptors and periorbital fat cells o Bulb of eyelashes increases w PGA usage o Lashes fall because of increased density (Bimatoprost-Lumigan) • Conjunctival hyperemia • Periorbital hyperpigmentation (racoon eyes) • Anterior Uveitis • CME post-cataract surgery (cystoid macular edema) Ocular Surface Disease and the use of PGAs • Ocular surface disease is common in the glaucoma population (a big reason for noncompliance w meds) • Inflammation of the cornea (treat w AT) PGA Contraindications • Pregnancy: category C, potential benefits may warrant use o Weigh risk vs benefits o History of miscarriage? • Inflammatory conditions: this is a BIG ONE o Chronic Uveitis Sympathomimetics: Alpha Adrenergic Agonists (AAA) • 2nd line after PGA • Activate alpha 2 receptors (alpha 2 is inhibitory to AH production) • Inhibit beta 2 (b-2 increases AH production) • • MOA: reduces aqueous humor production, increase aqueous outflow (uveo-scleral) Indications o Brimonidine (Alphagan P) can be 1st line § Purine breakdown to oxygen and water, shrinking of cells can cause itchiness o Apraclonidine: exhibits tachyphylaxis adjunctive, also short-term adjunctive therapy prior to glaucoma therapy o Pre and Post SX use in IOP spikes to decrease them • Dosage is BID (in conjugation w other meds) or TID • Ocular Side Effects o Allergic Reactions: in the form of folliculitis (you will not see papillae) • Systemic Side Effects o HTN o Dysgeusia (bad taste in mouth) o Anxiety • Contraindications o MAOI Therapy Beta Blockers • MOA: reduce aqueous humor production • Indications: Could be 1st line but also adjunctive • All used BID o Betaxolol (B-1 selective)- does not affect bronchi, blocks Ca channelsà increase in BF to brain o Carteolol: TID, does not cross BBB (no depression) • Timolol (Timoptic) 0.5% • Betaxolol (Betopic-S) 0.25% • Carteolol (Ocupress) 1% • Levobunolol (Betagan) 0.25-0.5% • Metipranolol (OptiPranolol) 0.3% Things to know about Beta Blockers • Have Sulfonic Acid: CI in sulfa allergies • Numbs cornea (pts forget to blink) • Lipophilic • Masking of Hypoglycemic effect • Exasperation of Asthma • CHF • Cross Blood Brain Barrier, decreasing 5-HT à depression Non-Selective Beta Blockers • Timolol Maleate (Timoptic 0.25, 0.5; XE 0.5%, Ocudose PF; Betimol 0.5%) o New mode of therapy- 0.25% QD in the mornings o Maximum effect in 3 weeks o Washout period 1-2 months (time in a clinical trial receive no active medication so that all traces of the drug are washed out of a patient's system) o Liposoluble substance o Cosopt- Dorzolamide (AAA)/timolol • Levobunolol (Betagan 0.25%, 0.5%) o Same indications as Timolol o More effective in some patients o More SE in some patients • Carteolol (Ocupress 1%) o BID o Equally as effective as Timolol o Less effective than Betagan in some patients o Hydrosoluble substance (less side effects/ less risk of heart disease) o Increase the ratio of high density lipids to total cholesterol Cardio-Selective Beta Blockers • Betaxolol (Betoptic-S 0.25% suspension) o Beta-1 blocker (safer in asthmatic patients o BID o Calcium channel blocking activity o Caution in pts w sulfa allergies Beta Blocker Side Effects • Ocular o Corneal anesthesia related to dry eye (patients forget to blink) o Superficial Punctate Keratitis (SPK) • Systemic o CHF Exasperations o Depression • Contraindications o Sinus Bradycardia o CHF in diastolic hemodynamically unstable patients and systolic o Bronchial Asthma o COPD Carbonic Anhydrase Inhibitors • MOA: reduces aqueous production • Indication: adjunctive • Ocular Side Effects: SPK • Sympathetic Side Effects: (Dry mouth & eyes, bitter metallic taste, GI upset bc systemic absorption) • BID or TID • Dorzolamide (Trusopt) 2%: decrease AH Production, BID • Brinzolamide (Azopt) 1%: BID Do we still use Pilocarpine? • Not used in open angle glaucoma, used as a mechanism to prevent acute angle closure • Appositional closure: not impacted in the angle • Pilocarpine is a parasympathomimetic in autonomic NS (involuntary motor system) o Pupil will be miotic by muscarinic receptors on the pupil o Accommodation by constriction of ciliary muscle will increase the outflow of AH § Radial § Circular: involved in accommodation § Longitudinal: not associated w accommodation, but with flow at the scleral spur • Pulling on the scleral spur will open the trabecular meshwork Pilocarpine (Cholinergic) (Pilocar 1%, 2%, 4%, 6%; Ocusert) • Direct acting parasympathomimetic (causes pupil constriction-miosis) • Muscarinic receptor innervation at the sphincter and ciliary muscle • MOA: increase TO, not related to the degree of miosis • QID • Side Effects o Conjunctival Hyperemia o Enhancement of Inflammatory process o Posterior subcapsular cataracts o Bronchial Constriction Benefits of Combination Product Treatment (two drugs in one drop) • Increase compliance- simple dosing schedule • Cost of one medication vs two • Brinzolamide/Brimonidine Tartrate 1%/0.2% suspension • NEW: Alphagan w brinzolamide • Dorzolamide 2% / Timolol 0.5% (Cosopt) • Brimonidine 0.2% / Timolol 0.5% Compliance is a hindrance for treatment • 2 out of every 3 patients admit to missing at least 2 medication treatments per month • Over 40% of patients miss at least 10% of TID or QID doses • 15% of patients miss greater than 50% of doses New Medications • VYZULTA (Latanoprostene bunod ophthalmic solution) 0.024% o Dual MOA: metabolizes into two moieties § Latanoprost Acid à FP receptor à MMPs à Extracellular matrix remodeling § Butanediol Mononitrate (release NO to increase outflow through the TM and Schlemm’s Canal) à Soluble Guanylyl cyclase à cGMP/PKG à TM cell relaxation à increase TM/Schlemm’s Canal outflow • 1st line will be laser one day- Direct Selective Trabeculoplasty (DSLT) What else? • Rhopressa (netasudil) 0.02% solution o Rho Kinase (enzyme involved in herniation of TM) and NE transporter inhibitor (3 activates) o Triple Action o Clinical Trials: QD- lowered IOP by 5.7 mmHg from baseline o Not too accepted in practice