3What is glaucoma?Optic neuropathy that is the leading cause of irreversible blindness in the worldMajor types are open angle and closed angleGlaucoma is commonly associated with elevated intraocular pressure (IOP), but the disease can occur with normal IOPOur understanding and treatment of the disease is very focused on IOPThe diversity of diseases that fall under the name ‘glaucoma’ make a precise definition of the disease hard to come by. Most clinicians call any condition in which the intraocular pressure is elevated glaucoma. But, this is not a sufficient definition of the disease. Glaucoma is not a single entity.Glaucoma is the leading cause of irreversible blindness in this countryHowever, our understanding of the disease and approach to treatment is very centered around the intraocular pressure. As such, it is important that we understand the dynamics of aqueous humor flow.
4What is glaucoma?Clear liquid called aqueous humor circulates inside the front portion of the eyeTo maintain a healthy level of pressure within the eye, a small amount of aqueous humor is produced constantly, while an equal amount flows out of the eye through a microscopic drainage systemthe trabecular meshworkWith glaucoma, aqueous humor does not flow through the trabecular meshwork properlyOver time, eye pressure increases, damaging the optic nerve fibers
6Classification Two main categories of primary glaucoma: Open-angle glaucoma: the most common form of glaucomaClosed-angle glaucoma: a less common and more urgent form of glaucoma
7Open-angle glaucomaTrabecular meshwork becomes less efficient at draining aqueous humorIntraocular pressure (IOP) builds up, which leads to damage of the optic nerveDamage to the optic nerve occurs at different eye pressures among different patients.Typically, glaucoma has no symptoms in its early stages
8Closed-angle Glaucoma The drainage angle of trabecular meshwork becomes blocked by the iris (the colored part of the eye)IOP builds up very fastSymptoms include severe eye or brow pain, redness of the eye, decreased or blurred visionMust be treated as a medical emergencyWithout treatment, blindness in as little as one or two days
10Risk factors for glaucoma include: AgeFamily historyElevated eye pressure (IOP)Nearsightedness or farsightednessAfrican, Hispanic or Asian ancestryDiabetesPrevious eye injuryThin cornea
11Glaucoma Management Treatment Options: Medical: Surgical: Topical systemic medications (PO or IV)Laser:IridotomyIridoplastyTrabeculoplastySurgical:Filtration Surgery (e.g. Trabeculectomy)Tube shuntDestruction of the ciliary body (cyclodestruction)
12TREATMENT RATIONALE LOWER IOP BY: Decreasing Production of Aqueous HumorIncreasing Outflow of Aqueous Humor
13DRUGS THAT DECREASE AQUEOUS PRODUCTION 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 b1-selective betaxolol), depressionAlpha-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]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
14DRUGS THAT INCREASE AQUEOUS OUTFLOW 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, tachycardiaParasympathomimetics [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).Prostaglandins [latanoprost]-Mechanism: May uveoscleral outflow by relaxing ciliary body muscle-Side Effects: Iris color change
15TREATMENT: OPEN-ANGLE GLAUCOMA Several large, randomised controlled trials have demonstrated the benefits of early diagnosis and treatmentSome controversy exists as to whether the initial therapy of glaucoma should be surgical trabeculectomy (filtering procedure), or selective laser trabeculectomy, or medical therapyDrug therapy remains the most common initial treatment modalityDrug therapy of patients with documented glaucomatous change with either elevated or normal IOP is initiated in a stepwise manner
16TREATMENT: OPEN-ANGLE GLAUCOMA The goal of therapy is to prevent further visual lossA "target" IOP is chosen based on a patient baseline IOP and the amount of existing visual field loss as well as other risk factorsAn initial target IOP reduction of 20-30% is desiredGreater reductions (30–50%)may be desired for patients withvery high baseline IOPs or advanced visual field loss.Patients with normal baseline IOPs (normal-tension glaucoma) may have target IOPs of less than 10 to 12 mm Hg
18TREATMENT: OPEN-ANGLE GLAUCOMA Drug choiceThe prostaglandin (PG) analogues (bimatoprost, latanoprost and travoprost) are replacing beta-blockers as first-line agents.Brimonidine or topical carbonic anhydrase inhibitors (brinzolamide, dorzolamide) tend to be used as alternativesUnless there are contraindications to using beta-blockers or PG analoguesUse of pilocarpine is declining, although it may still be useful as adjunctive treatment
19Practice PointsUp to 50% of patients fail to use their medication correctlyOne strategy to aid compliance is to use an eye drop containing 2 drugs, eg timolol with a prostaglandin analogueSimple dosage regimens and patient education help complianceTo reduce systemic absorption (by up to 70%)close eyes and press on the tear duct for 3 minutes after instillation of each eye dropWhen >1 type of eye drop is to be instilled at the same time, separate administration by at least 5 minutes
21Comparative Information Drug classEffectDoses per daybeta-blocker, eg timolol+++1–2prostaglandin analogue, eg latanoprost1carbonic anhydrase inhibitor, eg dorzolamide++2–3alpha2 agonist, eg brimonidinecholinergic (pilocarpine)2–4
22Beta-blockers (eye)Timolol, levobunolol, metipranolol and carteolol are nonselectiveBetaxolol has β1-selective propertiesMode of actionReduce aqueous humour formation, probably by blockade of beta receptors on the ciliary epitheliumIndicationsAll types of glaucomaOcular hypertensionPrecautionsReversible airways disease, eg asthma—use is generally contraindicated, however cardioselective agents, ie betaxolol, may be used with care.
23Beta-blockers (eye) Cardiovascular Consider effects of systemic beta-blockadeUse is contraindicated in bradyarrhythmia or second- or third-degree atrioventricular block.Treatment with a systemic beta-blocker reduces intraocular pressure (but less than with a topical beta-blocker).Avoid treatment with verapamil due to potential for profound bradycardia
24Beta-blockers (eye) Elderly Systemic adverse effects are more common, e.g. hypotension (may cause falls)ChildrenMay cause apnea in neonates and bradycardia in children.PregnancyMay cause fetal bradycardia;BreastfeedingUnlikely to cause adverse effects at usual doses.
25Beta-blockers (eye) Adverse effects The most important adverse effects are systemicCommonStinging on instillation (especially betaxolol solution), bradycardia, blurred visionInfrequentdecreased corneal sensation, hypotension, syncope, fatigue, confusion, hallucinations, bronchospasm
26Beta-blockers (eye) Comparative information Timolol (nonselective beta1 and beta2 receptor blocker)Reduces intraocular pressure by 25% when used in 0.25% solution<local adverse effects than betaxololBetaxolol (selective for beta1 receptors)Reduces intraocular pressure by about 20%.?Less likely to cause bronchospasmSuspension less stinging than solution
27Beta-blockers (eye) Practice points Slight decrease in effect may occur during the first month of treatment;tolerance may develop after 1 year or more of treatmentAfter stopping topical beta-blockers intraocular pressure may not return to baseline for 2–4 weeksIf single daily dosage is required, consider timolol gel or Timoptol-XE®
28Beta-blockers (eye) Dosage – Betaxolol Adult, child, 1 drop twice daily.Dosage – TimololUse the same way for adults and children.Conventional drops, 1 drop of 0.25% once or twice daily.Maximum 1 drop of 0.5% twice daily.Timoptol-XE®, 1 drop of 0.25% once dailyif necessary, increase to 1 drop of 0.5% once daily.Gel 0.1%, 1 drop once dailyInfant <12 months1 drop of 0.25% (of either formulation) once daily
29Beta-blockers (eye) Counselling Gel: store bottle upside down after opening so that gel collects in the bottle neck and stops bubbles forming as it is applied.
30Prostaglandin analogues (eye) Ocular Hypotensive Lipids Bimatoprost , latanoprost and travoprostMode of actionReduce intraocular pressure by increasing uveoscleral outflow of aqueous humour.IndicationsGlaucomaOcular hypertension
31Prostaglandin analogues (eye) Ocular Hypotensive Lipids PregnancyAvoid use; no data available;BreastfeedingUnlikely to be of concern; latanoprost is safe to use.
33Prostaglandin analogues (eye) Ocular Hypotensive Lipids Iris hyperpigmentationGradual (over months to years), usually irreversible, increase in iris pigmentation in treated eyesEyelash changesGradual darkening, lengthening and thickening of the eyelashes; reversible when treatment stopped.
34Prostaglandin analogues (eye) Ocular Hypotensive Lipids Comparative informationBimatoprost, latanoprost and travoprost appear to have similar efficacy.CounsellingThese eye drops may slowly change the colour of your eye making the iris appear darker.This change is permanent and may be more noticeable when only one eye is being treated.Practice pointsInstil in the evening for optimal effectDrugs in this class are structurally different; if response to one is poor, consider trying anothera paradoxical increase in intraocular pressure may occur if 2 ocular prostaglandin analogues are used together; avoid combination
35Alpha2 agonists Brimonidine and apraclonidine Mode of action Reduce IOP by suppressing formation and increasing outflow of aqueous humourIndicationsChronic open-angle glaucomaPrevention of ocular hypertension following laser surgeryAcute closed-angle glaucoma (before laser iridotomy)
36Alpha2 agonists Precautions Severe cardiovascular disease—may worsen; use with caution.PregnancyApraclonidine: avoid use;Brimonidine: suitable if necessary;BreastfeedingNo data available; unlikely to be a concern.
37Alpha2 agonists Comparative information Apraclonidine Brimonidine Reduce IOP by 25%Effect declines after a monthShort-term use (up to 3 months)High incidence of allergic blepharoconjunctivitis with chronic useBrimonidineReduce IOP by 20%Effective and well tolerated on chronic use
39Topical Carbonic anhydrase inhibitors Dorzolamide and brinzolamideMode of actionInhibit carbonic anhydrase II (predominant subtype found in the eye), which reduces aqueous humour formationIndicationsOcular hypertensionOpen-angle glaucoma
40Topical Carbonic anhydrase inhibitors PrecautionsAllergy to sulfonamides—may increase risk of allergy to carbonic anhydrase inhibitorsPregnancyAvoid use; no human data available; Australian category B3.BreastfeedingNo human data available.
42Topical Carbonic anhydrase inhibitors CounsellingYour eye may feel uncomfortable for a little while after you have put in the drop.If you have blurred vision, avoid driving or operating machinery until your sight improves.Practice pointsMay be used when beta-blocker is ineffective or not toleratedMay be used in combination with ophthalmic beta-blockers
43Other Drugs for Glaucoma Acetazolamide (Systemic Carbonic Anhydrase Inhibitors)HyperosmoticsGlycerin, isosorbide, and mannitolCholinergic AgentsPilocarpine and carbacholNonselective Adrenergic AgonistsEpinephrine and its prodrug, dipivefrine
44Acetazolamide Systemic carbonic anhydrase inhibitor Mode of action Inhibits carbonic anhydrase and therefore bicarbonate synthesisIn the eye this reduces aqueous humour secretion and IOPIndicationsPerioperative reduction of intraocular pressure, eg acute closed-angle glaucomaChronic open-angle glaucoma where other treatments have failed
45Acetazolamide Precautions Adrenal or respiratory failure or metabolic acidosis—contraindicated (increased risk of profound acidosis).Sodium or potassium depletion—contraindicated (will worsen depletion).Gout—may worsen.Allergy to sulfonamides—may increase risk of allergy to acetazolamide; manufacturer contraindicates use.
46AcetazolamideRenalContraindicated when CrCl <10 mL/minute (increased risk of profound acidosis); reduce dose if CrCl 10–30 mL/minute.Acetazolamide increases risk of recurrence of urolithiasis.HepaticContraindicated in hepatic impairment or cirrhosis due to the risk of hepatic encephalopathy.ElderlyIncreased risk of adverse effects, eg metabolic acidosis.
47Acetazolamide Adverse effects Up to 50% of patients do not tolerate acetazolamide.Commonparaesthesia (of hands, face, feet or mucocutaneous junctions), fatigue, drowsiness, depression, decreased libido, bitter or metallic taste, nausea, vomiting, abdominal cramps, diarrhoea, black faeces, polyuria, renal stones, metabolic acidosis, electrolyte changes (hypokalaemia, hyponatraemia)Infrequenttransient myopia (ciliary body swelling), bullous skin eruptions (Stevens-Johnson syndrome)Rareaplastic anaemia (especially in the first 6 months), thrombocytopenia, agranulocytosis or neutropenia, anaphylaxis
48Mannitol Hyperosmotic agent Mode of action Increases plasma osmolality; dehydrates vitreous body. Produces a rapid (30 minutes) but temporary (6 hours) drop in intraocular pressure.IndicationsAcute closed-angle glaucoma unresponsive to conventional treatmentIntraocular pressure reduction before intraocular surgery (prevents prolapse of intraocular contents)
49Mannitol Adverse effects Adverse effects are generally infrequent Fluid and/or electrolyte shift can produce pulmonary congestion, acidosis, electrolyte loss, dry mouth, thirst, oedema, headache, blurred vision, seizures and heart failure.Nausea, vomiting, local pain, skin necrosis and thrombophlebitis (injection site), chills, dizziness, urticaria, hypotension, tachycardia, fever, angina-like chest painsDosage – MannitolAdult, IV 1–2 g/kg (5–10 mL/kg of 20% solution) over 30 minutes.
50Mannitol Administration advice Mannitol crystallises at low temperatures (especially 20% solution); redissolve by warming in hot water and shaking vigorously; allow to cool to body temperature before giving via infusion set with filter.Practice pointsMannitol produces a marked osmotic diuresis; urinary catheterisation is required for anaesthetised or unconscious patientsThe hyperosmotic agent most often used in the treatment of acute ocular hypertension is IV mannitol (oral glycerol is used infrequently)
51Cholinergic Agents Mode of action Pilocarpine and carbacholMode of actionCholinergic effect contracts Iris sphincter and ciliary muscleIncreases outflow through the trabecular meshworkIndicationsChronic open-angle glaucomaAcute closed-angle glaucoma
52Cholinergic Agents Adverse effects Common Infrequent Rare Headache blurred vision, headache, ocular irritation (eg burning, itching), myopia, miosisInfrequentlacrimationRareretinal detachmentHeadacheAccommodative spasm and frontal headache (browache) are common initiallyusually decrease after 2–4 weeks; simple analgesics may reduce painMiosisCauses blurred vision, occurs infrequently but is potentially permanent with long-term use and may reduce vision in dim light, worsen the effect of a central visual opacity and constrict the visual field
53Nonselective Adrenergic Agonists DipivefrinePro-drug, enzymatically cleaved to epinephrineIncrease the outflow of aqueous humor through the trabecular meshworkReduce IOP by 15% to 25%Rarely used nowAdverse effectsOcular irritation (include allergic blepharoconjunctivitis)mydriasis, conjunctival hyperemia and frontal headacheNot used in patients with narrow angles since these agents can cause acute angle closure
54DRUG-INDUCED GLAUCOMAS AnticholinergicsSympathomimeticsSulfa-based drugsCorticosteroids increase IOPOphthalmic corticosteroid preparations carry the highest risk of increasing IOP
55TREATMENT: OCULAR HYPERTENSION Ocular hypertension; i.e., patients with IOP >22 mm Hg [>2.9 kPa]Ocular Hypertensive Treatment Study (OHTS) helped to identify risk factors for treatmentPatients withIOPs higher than 25 mm Hg (3.3 kPa)vertical cup-to-disk ratio of more than 0.5central corneal thickness of less than 555 µmAre at greater risk for developing glaucomaRisk factors such as family history of glaucoma, black ethnicity, severe myopia, and patients with only one eye must also be taken into consideration
56TREATMENT: OCULAR HYPERTENSION Patients with significant risk factors usually are treated with a well- tolerated topical agent such asβ-blockersProstaglandin analoga2-Adrenergic Agonist (brimonidine)Topical carbonic anhydrase inhibitorDepending on individual patient characteristics.
57TREATMENT: OCULAR HYPERTENSION Optimally, therapy is initiated in one eye to assess efficacy and toleranceUse of second- or third-line agents (e.g., pilocarpine or dipivefrin) when first-line agents fail to reduce IOP depends on the risk-to- benefit assessment of each patient
58Acute closed-angle glaucoma This is a rare ophthalmic emergencyTreatment is by peripheral laser iridotomyOral, IV, and topical medication is necessary to stabilise the eye and lower the pressure before laser iridotomyIV acetazolamide,Topical pilocarpine,A topical beta-blocker,IV Mannitol or oral glycerol
59Glaucoma surgeryLaser iridotomy: creates a small hole in the iris to improve flow of aqueous humor into drainage angle.
60Glaucoma surgeryLaser trabeculoplasty: stimulates the trabecular meshwork (drainage angle) to function more efficiently
61Glaucoma surgeryTrabeculectomy: creates new drainage channel for the eyeGoal is to stabilize disease and prevent further damage/vision lossDoes not reverse damage to the optic nervePerformed on an outpatient basis
62Regular Eye ExamsEveryone should regularly visit their ophthalmologist at the following intervals:Age years: At least once during this periodThose with risk factors for glaucoma (people of African descent or those who have a family history of glaucoma) should be seen every 3-5 yearsAge years: At least twice during this periodThose with risk factors for glaucoma (people of African descent or those who have a family history of glaucoma) should be seen every 2-4 yearsAge years: Every 2-4 yearsAge 65 years or older: Every 1-2 years