GlaucomaViviany Taqueti and Scott Vafai

HST 150

What is glaucoma?• Optic neuropathy that 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

• Glaucoma is commonly associated with elevated intraocular pressure (IOP), but the disease can occur in the context of normal IOP

• Our understanding and treatment of the disease is very focused on IOP

From www.ahaf.org

Case 1

Mr. S presents to you with diminished peripheral vision. He complains that he feels like the world is closing in on him. He also notes that he has trouble looking at lights as they all appear to be surrounded by halos. You perform fundoscopic and gonioscopic exam with tonometry and diagnose glaucoma.

Open Angle Glaucoma

From http://www.merckfrosst.ca/e/health/glaucoma/glaucoma/classify/home.html

• 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

Case 2Mrs. P is a 65 yr. old female who has become acutely ill in the waiting room. An ophthalmologic assistant had dilated her eyes in preparation for examination. She is now complaining of nausea, diaphoresis and pain in her right eye, which is now red and swollen.

Closed Angle Glaucoma• 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

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

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SIDENOTE:

WHY WOULD YOU WANT TO DILATE MRS. P’s PUPILS WITH PHENYLEPHRINE VS. AN ANTICHOLINERGIC?

Modified from: Wood et al. NEJM 339:1298 (1998)

REVIEW: Autonomic NS Effect on the EyeRECEPTOR ACTIVATION WILL: TO LOWER IOP, AIM FOR:

IRIS, Circular Fibers mAchR : Constrict Pupil ActivityIRIS, Radial Fibers 1 R : Dilate Pupil ActivityCILIARY MUSCLES mAchR : Contract for Accomodation

2 R : Relax for Far Vision

ActivityActivity

Modified from: http://pharma1.med.osaka-u.ac.jp/textbook/Autonomic/Autonomic.html

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

LOWERING IOP SLOWS PROGRESSION OF VISUAL LOSS IN OPEN ANGLE GLAUCOMA

Early Manifest Glaucoma Trial: -1st (adequately powered) randomized trial with untreated control arm to evaluate effects of IOP reduction in patients with open-angle glaucoma. -Treatment significantly delayed progression.

Rx GLAUCOMA: ADDITIONAL CONSIDERATIONS

1. No single medication can be used in all patients2. 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 towardsIOP 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