Dr Mahmood Fauzi ASSIST PROF OPHTHALMOLOGY AL MAAREFA COLLEGE

 Define glaucoma  Estimate magnitude of visual morbidity from glaucoma  Explain aqueous humor dynamics in glaucoma development  Outline features of open and close angle glaucoma  Contract case studies in open and close angle glaucoma  Review autonomic effects on the glaucomatous eye.  Treatment rationale  Reasoning through drug mechanism of action: decrease aqueous production vs.. increase aqueous outflow

Glaucoma is Optic neuropathy that is commonly associated with elevated intraocular pressure (IOP), but the disease can occur in normal IOP Glaucomatous Optic neuropathy is the leading cause of irreversible blindness in the world Major types are open angle and closed angle Differences among various types of glaucoma complicate the nomenclature Our understanding and treatment of the disease is very focused on IOP

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 Aqueous is produced by secretion and ultrafiltration from the ciliary processes into the posterior chamber.  It then passes through the pupil into the anterior chamber to leave the eye predominantly via the trabecular meshwork, Schlemm’s canal and the episcleral veins (the conventional pathway).

 A small proportion of the aqueous (4%) drains across the ciliary body into the supra-choroidal space and into the venous circulation across the sclera (uveoscleral pathway)  The intraocular pressure level depends on the balance between production and removal of aqueous humour.

Presentation AcquiredCongenital Ocular association PrimarySecondary Angle OpenClosed Course AcuteChronic

Complete history Complete examination IOP Gonioscopy Optic disc Visual Fields

Tonometers Goldmann Contact applanation Perkins Portable contact applanation Pulsair 2000 (Keeler) Air-puff Schiotz Portable non-contact applanation Non-contact indentation Contact indentation Tono-Pen portable contact applanation

 The normal pressure is 15.5 mmHg.  The limits are defined as 2 standard deviations above and below the mean (11–21 mmHg).

Date Author Title14

Optic nerve signs of glaucoma progression  Increasing C:D ratio  Development of disk pallor  Disc hemorrhage (60% will show progression of VF damage)  Vessel displacement  Increased visibility of lamina cribosa

 Mechanical theory  Compression of axons leads to axonal death  Vascular theory  Ischemia causes axonal necrosis Direct damage due to Pr. Capillary Occlusion Interference to Axoplasmic flow

 Axonal necrosis leading to cupping  Loss of supporting glial tissue  Normally leads to disc pallor Histology of Normal and Glaucomatous Optic nerve

Types of physiological excavation Small dimple central cup Larger and deeper punched-out central cup Cup with sloping temporal wall

Pallor and cupping Cupping and pallor correspond Pallor - maximal area of color contrast Cupping is greater than pallor pallor pallor Cupping - bending of small blood vessels crossing disc

 Affects 1 in 200 subjects over the age of 40.  Affecting males and females equally.  There may be a family history.  The prevalence among blacks is 3 to 4 times higher than whites.  Symptomless unless the patient becomes aware of a severe visual deficit.

Obstruction at the level of the trabecular meshwork Progressive loss of visual field over time from periphery to center Presence of hollowed out optic disc (‘cupping’) due to retinal ganglion cell death Open anterior chamber angle Majority of patients have IOP > 21 mmHg, asymptomatic

 Affects 1 in 1000 subjects over 40 years.  Females more commonly affected than males.  Strong family history.  Prevalence is more common among Asians and Eskimos.  Patients are likely to be hyperopic.  In acute cases, patient may have sever pain, photophobia, vision loss and nausea.

 On examination visual acuity is reduced,  Eye is red,  Cornea is cloudy  Pupil oval, fixed and dilated.

Apposition of iris and trabecular meshwork Parasympatholytics (pupillary dilation) can precipitate attack Increase risk with age, increase in volume of lens Acute onset, patient complains of nausea, headache (rather than eye ache), malaise, general distress Requires immediate treatment

Open angle:  Blood (hyphema), following blunt trauma.  Inflammatory cells (uveitis).  Pigment from the iris.  Deposition of material produced by the epithelium of the lens, iris and ciliary body in the trabecular meshwork (pseudoexfoliative glaucoma).  Steroid-induced glaucoma.  Raised episcleral venous pressure. Closed angle:  Abnormal iris blood vessels may obstruct the angle and cause the iris to adhere to the peripheral cornea, closing the angle (rubeosis iridis).  A large choroidal melanoma may push the iris forward.  A cataract may pushing the iris forward (phacomorphic).  Uveitis may cause the iris to adhere to the trabecular meshwork.

 Causes ◦ Diabetes ◦ CRVO ◦ Carotid vascular disease ◦ CRAO ◦ Eales’ Disease ◦ Sickle cell anemia ◦ Coats disease Signs & symptoms Rubeosis iridis Ectropion uveae NV of angle

BOTTOM LINE:  IOP from  Aqueous Flow, 3 Sites 1. Obstructed Trabecular Mesh Open Angle: Age-related, genetic Closed Angle: Anatomic, exacerbated by: 2. Pupillary Block Dilation of pupil  iris flattens,  flow via pupil, iris forward  iris-cornea angle 3. Swelling of Ciliary Body SIDENOTE: W HY W OULD Y OU W ANT T O D ILATE M RS. P’s P UPILS W ITH P HENYLEPHRINE VS. AN A NTICHOLINERGIC ? Modified from: Wood et al. NEJM 339:1298 (1998)

REVIEW: Autonomic NS Effect on the Eye RECEPTOR ACTIVATION WILL:TO LOWER IOP, AIM FOR: IRIS, Circular Fibers mAchR : Constrict Pupil  Activity IRIS, Radial Fibers  1 R : Dilate Pupil  Activity CILIARY MUSCLES mAchR : Contract for Accomodation  2 R : Relax for Far Vision  Activity  Activity

1. Medical treatment. 2. Laser treatment. 3. Surgical treatment.

TREATMENT RATIONALE LOWER IOP BY: (1)Decreasing Production of Aqueous Humor (2)Increasing Outflow of Aqueous Humor Focus on Pharmacologic Rx: First-line

DRUGS THAT DECREASE AQUEOUS PRODUCTION I.Beta-Blockers [levobunolol, timolol, carteolol, betaxolol] -Mechanism: Act on ciliary body to  production of aqueous humor -Administration: Topical drops to avoid systemic effects -Side Effects: Cardiovascular (bradycardia, asystole, syncope), bronchoconstriction (avoid with  1-selective betaxolol), depression II.Alpha-2 Adrenergic Agonists [apraclonidine, brimonidine] -Mechanism:  production of aqueous humor -Administration: Topical drops -Side Effects: Lethargy, fatigue, dry mouth [apraclonidine is a derivative of clonidine (antihypertensive) which cannot cross BBB to cause systemic hypotension] III.Carbonic Anhydrase Inhibitors [acetazolamide, dorzolamide] -Mechanism: Blocks CAII enzyme production of bicarbonate ions (transported to posterior chamber, carrying osmotic water flow), thus  production of aqueous humor -Administration: Oral, topical -Side Effects: malaise, kidney stones, possible (rare) aplastic anemia

DRUGS THAT INCREASE AQUEOUS OUTFLOW I.Nonspecific Adrenergic Agonists [epinephrine, dipivefrin] -Mechanism:  uveoscleral outflow of aqueous humor -Administration: Topical drops -Side Effects: Can precipitate acute attack in patients with narrow iris- corneal angle, headaches, cardiovascular arrhythmia, tachycardia II.Parasympathomimetics [pilocarpine, carbachol, echothiophate] -Mechanism:  contractile force of ciliary body muscle,  outflow via TM -Administration: Topical drops or gel, (slow-release plastic insert) -Side Effects: Headache, induced miopia. Few systemic SE for direct-acting agonists vs. AchE inhibitors (diarrhea, cramps, prolonged paralysis in setting of succinylcholine). Why isn’t Ach used? III.Prostaglandins [latanoprost] -Mechanism: May  uveoscleral outflow by relaxing ciliary body muscle -Administration: Topical drops -Side Effects: Iris color change

 Drainage surgery (trabeculectomy) relies on the creation of a fistula between the anterior chamber and the subconjunctival space.  The operation is usually effective in substantially reducing intraocular pressure.  It is performed increasingly early in the treatment of glaucoma.

Rx GLAUCOMA: ADDITIONAL CONSIDERATIONS 1.No single medication can be used in all patients 2.Compliance -Critical: Rx often requires several agents, multiple times a day, everyday - Role of slow-release drug delivery devices (Langer) 3.Non-pharmacologic ways to lower IOP: - Laser (argon laser trabeculoplasty) -  aqueous outflow, loses effectiveness over time -Surgical (trabeculectomy) -Creates alternative path for aqueous outflow -Only definitive therapy for closed angle 4.Effectiveness of Rx measured by ability to lower IOP, but other factors may be (more) important: - Neuroprotection/increased blood flow to optic nerve

GLAUCOMA: Key Points Glaucoma: -Visual loss from optic neuropathy -Open angle chronic, Closed angle acute -Final common pathway:  IOP (usually) Drug Rx: -All directed towards  IOP either via: -  aqueous production: Beta blockers Alpha-2 agonists Carbonic anhydrase inhibitors -  aqueous outflow: (Adrenergic agonists, nonspecific) Parasympathomimetics Prostaglandins Treatment slows progression Understanding ANS effect on the eye is critical for reasoning through drug mechanisms of action Understanding ANS effect on the whole body is critical for predicting and avoiding dangerous side effects

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