Antiglaucoma medications

Guide: Dr Shobha PaiDr MadhurimaAnti-Glaucoma Medications

Classification

PROSTAGLANDINS Newer class of drugsIntroduced in the 1990sVery potent in reducing IOPEicosanoids

Mechanism of actionMixed pharmacological responses4 types- EP, FP, IP and TPTwo mechanismsRelaxation of ciliary muscle and increase in uveoscleral outflowRemodelling of trabecular meshwork extracellular matrix

Latanoprost:Potent prostaglandin F2 agonistFirst to be approved for use0.005% dose OD-bed time25-30% reduction in IOPEfficacy >Timolol BD >Timolol gel OD >Brimonidine

Latanoprost No adverse systemic side effectsEffects continue for 24 hours unlike Timolol which does not act in the nightIncrease in retinal microcirculation and pulsatile blood flowStorage: refrigeration when not opened, once opened can be stored in room temperature for 6 weeks

Bimatoprost Travoprost0.03% solutionOnce daily Chemical structure differs from other PGsApproved in 2001Efficacy is comparable to LatanoprostMore local side effects0.004% solutionTwice daily dose is also effectiveAvailable as BAK freeDuration of action can be more than 40 hours from once daily doseSuperior to Latanoprost and Timolol, in IOP control and visual field progression

Isopropyl Unoprostone22-Carbon moleculeTrabecular flowProdrug derived from pulmonary metaboliteEfficacy comparable to Timolol given twice daily0.12% solution BDReduces IOP by 11-23%

Drug combinationsAll agents can be combined with Timolol with evening dosingWith topical Carbonic Anhydrase inhibitorsWith BrimonidinePG + Brimonidine> Timolol + Dorzolamide

With cholinergics

Side effectsHyperpigmentationLashes-increase in length and numberConjunctival hyperemiaIris pigmentationDry eye, SPKReactivation of HerpesAcute uveitisCystoid macular edemaChoridal effusion

Contraindicated in inflammtory glaucoma

Adrenergic systemAdrenergic agonists have been used as ocular hypotensives since 1900, with sub conjunctival injection of epinephrineIn eye, stimulation of 1 receptors causes mydriasis, vasoconstriction, raise in IOP and eyelid retractionStimulation of 2 receptors decreases aqueous formation and probably increases outflowAssociated with prostaglandin action

Epinephrine and DipivefrinIncreases aqueous outflow by both conventional and uveoscleral outflowEpinephrine has a low solubility and hence decreased efficacy

Dipivefrin is a prodrug with increased lipid solubility and increased corneal penetration. As efficacious as betaxolol 0.5%

Side effects

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2 ADRENERGIC AGONISTSClonidine, a potent 2 agonist was found to have IOP reducing activityClonidine has ability to penetrate blood brain barrierNon selective adrenergic agonists are not approved for useMechanism of action: They reduce IOP by decreasing aqueous formation.

Apraclonidine Derivative of clonidine without systemic side effectsProdrugAnterior segment vasoconstriction and thus reduces aqueous production 1% - acute rise in IOP 0.5% - long term controlEfficacy comparable to Timolol

Brimonidine Potent ocular hypotensiveMore selective to 2 receptors0.15% solution BD/TIDNeuroprotective propertiesCan cause cardiovascular instability in children < 5 yearsSleepiness and lethargy- great caution in children less than 15 yearsNot to be given with NSAIDs

Side effectsOcular Systemic Follicular conjunctivitisApraclonidine has higher rates of tachyphylaxis and allergyHyperemia, itching and photophobiaBlurred vision

Dry mouthFatigue, drowsiness, headacheHypotensionBradycardia and hypothermia in neonates

Adrenergic antagonists1967- Phillips and co workers reported IV propranolol decreased IOPUntil the advent of prostaglandins, adrenergic antagonists were among the most useful drugsAct on 2 receptors present on the ciliary epithelium and decrease aqueous production

Timolol MaleateNon selective antagonistReduces IOP without change in refractive status, pupil size0.25%, 0.5% twice daily formulationAction begins in 20-30 minutes and lasts till 24-48 hoursLong term drift is seenAdditive properties with pilocarpine, carbonic anhydrase inhibitors and adrenergic agonistsTimolol Hemihydrate

BetaxololSelective 1 antagonistIt is thought to decrease IOP by either acting on 2 receptors or through a non adrenergic pathway0.5% used twice dailyNeuroprotective effectSafe is asthmatics40% patients experience burningMicrosuspension forms

Levobunolol: Non selective antagonist, available in 0.5% given once dailyCarteolol: Preferred for cardiac patients. 1% and 2% solution, twice daily dosageMetipranolol : Non selective antagonist, 0.3% solution for twice daily dosage

Side effectsOcular Systemic Stinging, itching, burning Keratoconjunctivitis SiccaCorneal anaesthesia

Systemic side effects can be caused even with low concentrationCNS symptoms, CVS symptomsBronchoconstriction, Increase in serum tryglyceridesAltered response to hypoglycemiaFetal arrhythmiascontraindicated in pregnancy

CARBONIC ANHYDRASE INHIBITORSSulfonamides Only systemic group of drugs still approved for long term useAcetazolamide was first introduced in 1954 as an antiglaucoma drugMethazolamide, ethoxzolamide, dichlorphenamideDorzolamide, brinzolamide- Topical

Mechanism of actionThis enzyme is present in many tissues in the body-renal cortex, gastric mucosa, RBC, lung, pancreas, CNSType II isoenzyme is present in the ciliary epithelium, in the basolateral surfaceDecreases production of bicarbonate and decreased formation of aqueousAlso, intracellular pH that is needed for ion transport is disturbed by CAIs.

Topical CAIs

Acetazolamide Reduce the formation of aqueous by 40%Many other mechanisms proposed: buffer system, vasoconstriction of anterior uveal tractPenetrates cornea poorly250mg every 6 hours given orally125mg, 250mg and 500 mg, sustained release preparationEmergency ampuoles

Methazolamide It is a systemic CAILesser protein bound than acetazolamide25-50mg given twice daily Can cause urolithiasis

Advantages over Acetazolamide:Not actively secreted by kidney, can be given in patients with renal problemsDiffuses more easily into eyeDosing is convenient

Side effectsOcular side effects:Irritation, myopic shift, SPK

Systemic side effects:Paraesthesia around mouth and finger tips, Increased frequency urination, gastric irritationElectrolyte imbalanceMetabolic acidosisCaution: liver disease, adrenal insufficiency, sickle cell disorder, pregnancyBlood dyscrasias and Steven Johnson SyndromeContraindicated in Fuchs endothelial dystrophy

CHOLINERGIC DRUGSOldest effective anti glaucoma medicationsMechanism of actionIn angle closure: They constrict the pupil and pull the peripheral iris away from the trabeculum. In open angle: They contract the ciliary body thus opening the scleral spur and opening the trabecular meshwork

Directly acting agentsAcetyl choline:Prototype of this groupNot used topically

Pilocarpine:Most widely prescribed mioticAvailable in 0.25-10%, QID application1%- light irides2%- dark iridesVarious methods are devised to decrease the number of applications

METHACHOLINE: Used in the pastDiagnosis of Adies pupilSynthetic derivative acetyl cholineCARBACHOL:More powerful miotic than pilocarpineMore side effectsIntracameral injection in post opperative patientsACECLIDINE: Used in EuropeLess effective than piolcarpineLess ciliary spasm and accomodation

Indirectly acting agentsThey inhibit the enzyme acetylcholinesterase and potentiate the effect of endogenous acetylcholineMore side effects than directly acting agentsEchothiophate: cataract and iris epithelial cystDemecarium Bromide: Long actingIsoflurophate: Not in clinical usePhysostigmine and Neostigmine: Short acting agents

Side effectsOcular: Conjunctival injectionPeriocular painMiosis and dim illuminationFluctuating myopic shift Anterior subcapsular opacity and iris epithelial cystsAllergic blepharoconjunctivitisRetinal hole and detachmentVitreous abnormalities to be ruled out before starting on miotics

Pupil to be dilated twice a year to visualize the discvisualize peripheral retina prevent formation of posterior synichiae2.5% phenylephrine can be used without decreasing outflow capacityContraindicated in intraocular inflammation and hypersensitivityPeptic ulcer, retinal abnormalities, chronic obstructive pulmonary disease and high myopia-relative contraindications

Systemic side effectsNausea, vomiting, abdominal crampingSalivation, sweatingBradycardia, hypotension and bronchospasmMultiple applications should be avoided, punctal occlusionCholine apnoeaCholinergic toxicitiy:2mg Atropine s.c or i.vInj. Pralidoxime 25mg/kg infused over 2 hours

HYPEROSMOTIC AGENTSUseful in short term management of glaucoma

Osmoreceptors present in hypothalamus send efferent to the optic nerve

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Oral agentsSlow onset of action and less efficacious

Isosorbide: 45% solution, 1.5-4ml/kgIt is not metabolized; no effect on blood sugar levels

Absolute alcohol: 1-1.8ml/kg, 40-50% solution

Glycerol: most common. 50% solution, 1-3ml/kgPenetrates eye poorlyNausea and vomitingKetoacidosis

Intravenous agentsFaster action with more efficacy

Urea: 20% solution, 2-7ml/kgPenetrates eye better, less efficaciousOld solutions not to be used

Mannitol: agent of choice as intravenous agent2.5-7ml/kg of 20% solutionAction starts in 20-30 minutes, lasting for 6 hoursCellular dehydration in CNS- dementia and disorientationCongestive heart failure

Side effectsNausea, vomiting, headache and diuresisIntense diuresis- acute retentionPulmonary edema and congestive cardiac failureSubdural hematoma due to shrinkage of vesselsCellular dehydrationExtravasation of urea can lead to skin necrosis

Class of drugMechanism of actionConcentration % IOP reductionImportant side effectProstaglandins Latanoprost BimatoprostTravoprost Increase uveoscleral pathway0.005%0.03% HS0.004%25-32%HypertrichosisIncreased pigmentation Hyperemia antagonistsTimolol Levobunolol

Betaxolol Decrease aqueous production 0.5% BD20-30%

15-20%Bradycardia, heart block, bronchospasm

Stinging Adrenergic agonists ApraclonidineBrimonidne Decrease aqueous production Increase outflow0.5-1% BD, TID20-30%Hypotension, tachyphylaxis, follicular conjunctivitis

Class of drugMechanism of actionConcentration % IOP reductionImportant side effectCAIsAcetazolamideDorzolamideBrinzolamide Decrease aqueous production250mg QID2% BD,TID1% BD, TID15-20%SJS, blood dyscrasias

Miotics Pilocarpine Increase outflow1% QID15-25%Myopic shift,Retinal detachmentHyperosmotics Glycerol

Mannitol Draw water from eye to intravascular compartment50% solution 1.5-3ml/kg

20% solution 2,5-7ml/kgNausea, ketoacidosis

Urine retention, CCF

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Drug combinationsCombination Trade nameConcentration % IOP reductionTimolol/DorzolamideCosopt 0.5%/2% BD25-30%Timolol/ LatanoprostXalcom0.5%/0.005% HSGreater than monotherapy Timolol/TravoprostDuotrav0.5%/0.004% HSGreater than monotherapy Timolol/ Bimatoprost Ganfort0.5%/0.003% HSGreater than monotherapy Timolol/ BrimonidineCombigan0.5%/0.2% BDGreater than monotherapy

Newer investigational drugsNeuroprotective agents:

Anecoratve: Not in clinical use

Cannabinoids: Schedule I drug, many systemic side effects

Cellular skeletal modulators:Ethacrynic acid- corneal edemaLatrunculin B no corneal edema

Memantine: NMDA antagonistUsed for parkinconismPrevents calcium influxCompleted stage III clinical trial with promising results

Other cellular signaling pathwaysOlmesartanLomerizineNilvadipine

Nitrous oxide:Aminoguanidine-inhibitor of iNOSRat model studyNO generated by glial cellsProstanoid agents:TafluprostNot efficacious, withdrawnRho kinase inhibitorsIncrease aqeuous outflowIn clinical trials

ReferencesBecker Shaffers diagnosis and therapy of the glaucomas, 8th editionShields Textbook of Glaucoma, 6th editionAAO- Glaucoma, 2011-12Kanski and Bowling- Clinical Ophthalmology