ANTI GLAUCOMA DRUGS

Bikash Sapkota16th batch B. Optometry

Maharajgunj Medical CampusNepal

Presentation Layout

Introduction to glaucoma Anti glaucoma drugs: Classification Indications Contraindications Summary

Introduction

VISUAL FIELD LOSS

OPTIC NERVE

DAMAGE

GLAUCOMA

INCREASE

IOP

Glaucoma refers to a group of diseases characterized by

• Optic neuropathy• Specific pattern of visual field

defect• Raised IOP

Aqueous production and drainage Secretion of aqueous humour -ciliary body (posterior chamber) Route of drainage -primary (90%) : trabecular meshwork -uveo-scleral outflow(10%)

Purpose of initiating glaucoma therapy

The ultimate goal of glaucoma treatment is

To preserve enough vision during the patient’s lifetime to meet their functional needs

Ideally, treatment should also delay glaucomatous process

MEDICAL ASPECTS OF GLAUCOMA THERAPY

o When to treat ? - when glaucomatous damage is documented or future

damage is likelyo What to prescribed ? - best to try one drug with least ocular & systemic side

effects

- use least amount of medication

- in emergency use 2 drugs

Mechanisms of action of anti glaucoma agents

Chief therapeutic measure is to lower IOP to the target level either by o Reducing aqueous production in the ciliary bodyo Promoting aqueous humour outflow through the

trabecular meshwork o Promoting aqueous humour outflow via the uveoscleral

pathway

Beta blockers e.g. timolol, carteolol, betaxolol,levobunolol and metipranolol

Classification of anti glaucoma drugs

Adrenergic agonists e.g. epinephrine, dipivefrin, brimonidine and apraclonidine

Prostaglandin analoguee.g. latanoprost, bimatoprost ,unoprostone

Cholinergic agents e.g. pilocarpine, carbachol,demecarium bromide and echothiophate iodide

Carbonic anhydrase inhibitors e.g. dorzolamide and brinzolamide

Topical Drops

Carbonic anhydrase inhibitors e.g. acetazolamide and methazolamide

Osmotic agents e.g. glycerine, mannitol and urea

Systemic Drops

Beta blockers First drug of choice for POAG Lower IOP by reducing aqueous secretion due to their

effect on β2 receptors

Non selective β1 & β2

Timolol

Levobunolol

Metipranolol

Carteolol

Selective β1 blockers

Betaxolol

Pindolol

Metaprolol

β-blockers are ineffective during sleep

Topical β-blockers reduce aqueous formation by 24% to 48% in

awake humans

Antagonize the effect of catecholamines

Reduction in aqueous secretion

Mechanism of action

Beta blockers TimololMost commonly used agentNon-selective β blockerAs a salts of : maleate, Hemihydrate Efficacy oIOP decrease : 20% to28%oPeak – 2-3 hrsoWashout : 1 month

Concentration: 0.25% & 0.5%,

1-2 times daily

Beta blockers Short term escape:

Marked initial fall in IOP followed by transient rise with moderate fall in IOP

Long term drift:

Slow rise in IOP in patients who were well controlled with many months of therapy

Beta blockers Carteolol Non selective beta blockerAs effective as timolol Intrinsic sympathomimetic activity and ability to partially

activate β-receptors in the absence of catecholamines

Advantages oLess stingingoBest choice in pt. with POAG having associated hyperlipidemias

or atherosclerotic cardiovascular disease

Concentration : 1% drop, 1-2 times daily

Beta blockers Levobunolol Reduces IOP by oReducing aqueous humor formation

Advantage oAction lasts the longest, so is more reliable for once a day use than timolol

Contraindications oPts. predisposed to cardiac or respiratory disease

Concentration : 0.25 – 0.50% drop,

once daily

Beta blockers Betaxolol First selective β1 blocker used

in ophthalmology Long term effect is slightly less than Timolol and Levobunolol

Advantage oInitial therapy in pts. with asthma and other pulmonary problems

Concentration : 0.25% drop,

2 times daily

Adverse effects of β-blockers

Cardiovascular-Bradycardia-Conduction arrhythmias-Hypotension-Raynaud’s phenomenon-Fluid retention

Pulmonary-Bronchoconstriction/ bronchospasm-Asthma-Dyspnea

Central nervous systemAmnesiaDepressionConfusionHeadacheImpotenceInsomniaMigraine prophylaxisMyasthenia gravis

GastrointestinalDiarrheaNausea

DermatologicAlopeciaNail pigmentationUrticariaLichen planus

Ocu

lar

side

eff

ects

Beta blockers Allergic blepharoconjunctivitis

Dry eye/decreased tear breakup time

Corneal anesthesia

Macular edema (aphakics)Macular hemorrhage/retinal

detachmentUveitis

Cataract progression

Allergic blepharoconjunctivitisDry eye/decreased tear breakup

timeCorneal anesthesia

Macular edema (aphakics)Macular hemorrhage/retinal

detachmentUveitis

Cataract progression

Beta blockers Open angle Glaucoma

Angle closure Glaucoma

Secondary Glaucoma

Glaucoma in children

Indications

Beta blockers

Bronchial asthmaHistory of bronchial asthmaSevere COPDBradycardia Severe heart blockOvert cardiac failureChildren & infants

Contraindications

Beta blockers

Clinical issues Preferred drugBest IOP control Avoid BetaxololCost Generic Timolol

MetipranololTimolol hemihydrate

Comfort CarteololHypercholesterolemia CarteololCOPD BetaxololPregnancy Avoid all

Selection of β-Blockers

Adrenergic agonist Mode of action Decreasing aqueous formation by constricting the

ciliary blood vessels Increasing uveoscleral outflow by an increase in

prostaglandin synthesis

Adrenergic agonist

α and β agonist

Epinephrine

Dipivefrin

Phenylephrine

α2 selective

Apraclonidine

Brimonidine

Adrenergic agonist

EpinephrineNonselective α- and β-adrenergic agonist Onset of action occurs at 1 hr Peak effect at 4 hours Ocular hypotensive effect may last up to 72 hoursIOP control : 20 -25 %

Concentration : 0.5-2% drop,

2 times daily

Adrenergic agonist Side effects of epinephrine StingingBrowacheConjunctival hyperemiaAdenochrome depositsAllergic lid reactions Macular edema Blepharoconjuntivitis Systemic hypertensionArrythmia

Contraindications o Severe Hypertensiono Cardiac Diseaseso Thyrotoxicosis

Adrenergic agonist DipivefrinProdrugPenetration across the cornea is 17 times more than epinephrineBetter tolerated than epinephrineOnset of action : 30 minutes, Peak effect : 1hr IOP reduction :20-24%

AdvantageoLower cardiovascular side effects oCan be used in pts. of asthma, in young pts. intolerant to

miotics and in those with cataracts

Concentration : 0.1% drop,

2 times daily

Adrenergic agonist Phenylephrine Acts on α1 adrenergic receptors MOA : Induce vasoconstriction and mydriasis to break posterior

synechiae Can produce mydriasis even in pts. treated with strong

miotics

Concentration : 0.125-10 %drop

Adrenergic agonist Apraclonidineα2-adrenergic agonist Para amino derivative of clonidineIOP control : 20 % -30 % Maximal effect is produced 3-5 hours after dosing

Not used as primary treatment due to significant tachyphylaxis Mainly indicated in acute pressure spikes in case of laser iridotomy, trabeculoplasty, and posterior capsulotomy

Concentration : 1% and 0.5%, twice daily

Adrenergic agonist BrimonidineSmall effect on uveoscleral

outflowNeuroprotection IOP control: 20-30%

AdvantageoCan be used as primary drug in POAGoLess tachyphylaxis & less rate of allergic

reactions than apraclonidine

Concentration :tartrate 0.2%, tartrate in purite 0.1%BD, TID

Adrenergic agonist

OcularoAllergyoContact dermatitis oBlurred visionoBurning/ stingingoFollicular conjunctivitisoHyperemia/itchingoPhotophobia

Side effects SystemicoDry mouthoFatigueoDrowsinessoHeadacheoHypotensionoBradycardia in neonatesoHypothermia in neonates

Cholinergic drugs

contraction of the longitudinal fibers of the ciliarymuscle, producing tension on the scleral spur: (Opening the trabecular meshwork) and facilitating aqueous outflow

Contraction of the circular fibers of the ciliary muscle, relaxing the zonular tension on thelens equator : Accommodation

Contraction of the iris sphincter: Constricts the pupil (miosis)

Mec

hani

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f acti

on

Classification of Cholinergic AgonistsDirect-actingAcetylcholineMethacholinePilocarpine ▪ drop- 0.5, 1, 2, 4, 6 %,gel-4%

Carbachol ▪ drop-1.5, 3%

Indirect-acting (cholinesterase inhibitors)ReversiblePhysostigmineNeostigmineEdrophoniumDemecariumIrreversibleEchothiophate ▪ drop-0.125%Diisopropylfluorophosphate

▪ Formulated for topical ocular use

Activate cholinergic receptors directly at the neuroeffector junctions of the iris sphincter muscle and ciliary body

Exert their cholinergic effects primarily by inhibitingcholinesterase, thereby making increased amountsof acetylcholine available at cholinergic receptors

Cholinergic drugs Pilocarpine Derived from the plant Pilocarpus

MicrophyllusIOP decrease : 15-25%Peak : 1 ½ - 2hrsEffect lasts up to : 6-8 hrs Gel form at bedtime

Concentration : 0.25- 10% drop QID, 4% gel, ocusert:20-40µg/hr

Ocular pigmentation influences

Blue eyes show maximal ocular hypotensive responses

Darkly pigmented eyes demonstrate a relative resistance to IOP reduction

may require pilocarpine solutions in concentrations exceeding 4%

Cholinergic drugs

Cholinergic drugs

Acute and chronic narrow angle glaucoma Open angle glaucoma For prophylaxis of primary angle-closure glaucoma until a

peripheral iridotomy can be performed

Indications

Ocular Side Effects Accommodative spasm Miosis Follicular conjunctivitis Pupillary block with

secondary angle-closure glaucoma

Band keratopathy Allergic

blepharoconjunctivitis Retinal detachment Conjunctival injection Lid myokymia Anterior subcapsular

cataract Iris cyst formation

Systemic Side Effects Headache Browache Marked salivation Profuse perspiration Nausea Vomiting Bronchospasm Pulmonary edema Systemic hypotension Bradycardia Generalized muscular

weakness Abdominal pain, diarrhea

o Presence of cataracto Patients younger than 40 years of ageo Neovascular and uveitic glaucomao History of retinal detachmento Asthma or history of asthmao High myopiao Known hypersensitivity to the drug

Cholinergic drugs

Contraindications

It is a dual acting parasympathomimetic Direct action- by stimulation of end plate potential Indirect action- by inhibition of acetylcholine esterase

Ocular pain, impaired vision due to induced accommodation & myopia

1% for intracameral use during surgery

Carbachol

Acetylcholine

Cholinergic drugs Concentration : 0.75-3%, TID

Side effects

It is an indirect acting parasympathomimetic

Constriction of sphincter pupillae muscle around

the pupillary margin and thus increases aqueous outflow

Retinal detachment, miosis, cataract, pupillary

block glaucoma, iris cyst, browache and punctal stenosis

Physostigmine

Cholinergic drugs Concentration : 0.25-0.5% drop

Mechanism

Side effects

Prostaglandin AnalogueOriginally discovered in the eye as mediators of the ocular

inflammatory responsePro-drugsConverted to active compound by corneal esterasesMOA: Increases uveoscleral outflowPG stimulates collagenase and metalloproteinase to degrade the

extracellular matrix between ciliary muscle bundles, which in

turn leads to the reduction of hydraulic resistance to uveoscleral

flow

Prostaglandin analogueLatanoprost (Xalatan)

Lowers IOP 27-30% with peak at 10-14 hrs Maximum effect usually by 4-6 weeks, may have further

decrease after 3-4 months Latanoprost tends to be less effective in lowering IOP in

children than in adults

Concentration : 0.005% drop, Once daily

Prostaglandin analogue Travoprost (Travatan)

Lowers IOP 7-9 mmHg (27-33%) Maximum IOP lowering effect achieved within 2

weeks

.

Concentration : 0.004% drop, once daily in evening

Prostaglandin analogue

Bimatoprost (Lumigan)

Prostamide analog Better IOP control than Latanoprost Maximum IOP effect within 1-2 weeks

.

Concentration : 0.03% drop, Once in the evening

Prostaglandin analogue

Indications Contraindications

o Primary open angle glaucoma o Normal tension glaucoma o Chronic closed angle glaucoma o Pigment dispersion syndrome o Exfoliation glaucoma

o Allergy o Pregnant and nursing mothero Children o Uveitic glaucoma o Immediate postoperative

period o Pt. with healed or active

herpes simplex keratitis

Ocular side effects Systemic side effects

o Cornea: punctate erosions, corneal pseudodendrites, recurrent herpes keratitis

o Conjunctiva : hyperemiao Eyelash : lengthening, thickening,o hyperpigmentationo Iris : irreversible hyperpigmentation o periorbital skin : hyperpigmentationo CME after cataract surgeryo Allergyo Anterior uveitis

o Occasional headacheo Skin rasho URTI

AdvantageoOnce daily dosingoLack of cardiopulmonary side effectsoAdditivity to other anti glaucoma medications

Prostaglandin analogue

Carbonic anhydrase inhibitor

99% inhibition of CA – decrease aqueous production

• Inhibit enzyme carbonic anhydrase

• Reducing aqueous humour formation

Mechanism of actionMechanism

Carbonic anhydrase inhibitor

Systemic Acetazolamide

Methazolamide

Ethoxzolamide

Dichlorphenamide

Topical

Dorzolamide

Brinzolamide

Lodoxamide

Carbonic anhydrase inhibitor

Oral/IV preparationIOP decrease : 15-20% Peak : 2-4 hrs (oral), 30 mins (IV)Washout : 12 hrs (oral ),4 hrs (IV)

Acetazolamide

o Oral : 125mg & 250mg tablet- 6 hrlyo 500mg sustained-release capsules -2 timeso For children(5-10mg/kg)-6 to 8 hrlyo IV preparation- 500mg

Concentration

Systemic Numbness and tingling of

extremities and perioral region Metallic taste Symptom complex Decreased libido Depression Fatigue Malaise Weight loss Gastrointestinal irritation Metabolic acidosis Hypokalemia Renal calculi Blood dyscrasias Dermatitis

OcularTransient myopia

Side Effects of Acetazolamide

Clinically significant liver disease Severe chronic obstructive pulmonary

disease Certain secondary glaucoma Renal disease, including kidney stones Pregnancy Known hypersensitivity to sulfonamides

Contraindications to Acetazolamide

Carbonic anhydrase inhibitor

Potency > acetazolamide Improved intraocular penetration Higher water and lipid solubilities Increased half life and plasma concn

Can be given at lower doses than acetazolamideo Dose : 25-50mg x BD/TDSo Indication : chronic IOP reduction

Carbonic anhydrase inhibitorMethazolamide

Topical Dorzolamide 2% & Brinzolamide 1%Efficacy IOP decrease : 15-20%peak : 2-3 hrswashout : 10-18 hrsDose : 2-3 times daily

Carbonic anhydrase inhibitor

Carbonic anhydrase inhibitorOcular side effectsoInduced myopiaoStinging sensationoKeratitis, conjunctivitisoDermatitis

Contrainidications Pt with known hypersensitivity to sulfonamide

Systemic side effectso Similar to oral CAI but less likely

Hyperosmotic agents IV : Mannitol , urea Oral : glycerol, isosorbide

Mechanism of action

Increase blood osmolality

Osmotic gradient between blood and vitreous

Water is drawn out of vitreous

Hyperosmotic agents IV Preparation Mannitol

20% solution 1-2gm/kg or 5(2.5-7)ml/kg over 20 minOnset:15-30minPeak:30-60min Last : 6hrs

Hyperosmotic agents Oral Preparation

Glycerol50% solution ,1gm/kg or 1.5-3 ml/kgOnset: 20min Peak:45mins -2 hrs Duration:4-5hrscaution in Diabetics

Isosorbide

45% solution1.5-4 ml/kg

Hyperosmotic agents Side effects Gastrointestinal systemoNausea,vomiting,abdominal cramp

Cardiovascular systemoCHF,angina

CNSoSubdural hematoma, Headache, confusion,

disorientation,fever RenaloDiuresis, anuria, potassium loss

OthersoDiabetic ketoacidosis ,urticaria.

Summary

Open angle glaucoma

1.β-blockers :Timolol, Betoxolol, Levubunolol

2.Miotic : Pilocarpine

3.α adrenergic agonist : Adrenaline, Dipiverdine, Brimonidine

4.Carbonic anhydrase inhibitors : Acetazolamide, Dorzolamide

5.Prostaglandin : Latanoprost

Angle closure glaucomaCombination of vigorous therapy is employed

1.Beta blocker –Timolol eye drop

2.Miotic – Pilocarpine eye drop every 10 min

3.Hypertonic- mannitol injection (20%)

4.Acetazolamide orally

5.Apraclonidine eye drop

Summary

Mode of action of anti glaucoma drugs

Beta blocker-decrease aqueous secretionMiotics -increase trabecular outflowAdrenergic agonist-decrease aqueous secretionProstaglandin-increase trabecular and uveaoscleral outflowCarbonic anhydrase inhibitor-decrease aqueous secretion

Summary

References Clinical Ocular Pharmacology by Jimmy D Balett Ophthalmic Drugs by Graham Hopkins & Richard Pearson Comprehensive Ophthalmology by A.K. Khurana AAO-Section 10-Glaucoma AAO-Section 2-Fundamentals & Principles of Ophthalmology Internet