Medical Treatment of

Glaucoma Fritz Allen ,MD

Visionary Ophthalmology

September 7th 2014

Medical Management of

Glaucoma Beta-adrenergic Antagonists (Beta

Blockers)

Parasympathomimetic Agents

Carbonic Anhydrase Inhibitors (CAI)

Adrenergic Agonists

Prostaglandin Analogues

Combined Medications

Hyperosmotic Agents

A 64-year-old male with POAG is taking

timolol, dorzolamide, brimonidine, and

latanoprost OU. He must begin phenelzine, a

systemic monoamine oxidase (MAO)

inhibitor. Which one of the following should

be discontinued?

• Latanoprost

• Brimonidine

• Dorzolamide

• Timolol

Which of the following glaucoma

medications is contraindicated for use in

children younger than age 2?

• Timolol

• Levobunolol

• Brimonidine

• Dorzolamide

Adrenergic Agonists Indications

Non-selective agonists (epinephrine,

dipivefrin)

Selective adrenergic agonists

(apraclonidine, brimonidine) IOP lowering

OAG / ocular hypertension

Prophylaxis against post-op pressure

spikes

Prior to and immediately after

laser treatment (laser

trabeculoplasty, laser PI, Nd:YAG

capsulotomy)

Cataract surgery

Acute ACG Miosis after refractive surgery (off-label

use)

Adrenergic Agonists Contraindications and precautions

Non-selective Narrow AC angles- may precipitate

pupillary block

Blepharoptosis surgery- stimulates

Müller’s muscle, inadequate correction

Retrobulbar anesthesia

Local – risk of vasospasm &

occlusion of ophthalmic or central

retinal artery

Systemic – tachyarrhythmias, death Aphakia- CME risk (13-30%)

Adrenergic Agonists Selective

Proven sensitivity to these agents

Concomitant use of monoamine oxidase

inhibitors (MAOI)

Infants and children < 2 years: brimonidine

is an absolute contraindication due to apnea,

bradycardia, dyspnea

Pediatric (ages 2-7) usage reports:

convulsions, cyanosis, hypoventilation,

lethargy; brimonidine is relatively

contraindicated

Precaution in patients with severe

cardiovascular disease

Precaution in patients with depression,

cerebral or coronary insufficiency,

Raynaud’s phenomenon, orthostatic

hypotension

Pregnancy: category B drug- use only if

potential benefits justify potential risk

Adrenergic Agonists Method of action

Non-selective-mixed α and ß adrenergic

agonist; effect varies over time, initially

raising IOP slightly, followed by reduction

lasting 12-24 hours

Selective-alpha adrenergic receptor agonist;

reduction of aqueous humor production is

primary mechanism of action Fluorophotometric studies suggest that

Brimonidine tartrate also increases

uveoscleral outflow

Controversial neuroprotective effect:

prevent demise of retinal ganglion cells due

to trauma or toxins

Adrenergic Agonists Complications of therapy

Non-selective Local - conj injection, follicular

conjunctivitis, burning, stinging, mydriasis,

blurry vision, headache

Cardiovascular - tachycardia, arrhythmias,

hypertension

Selective Local - hyperemia, follicular conjunctivitis,

conjunctival blanching

Systemic - dry mouth, fatigue, anxiety,

respiratory depression in neonates

Adrenergic Agonists Contraindications and precautions

Non-selective Narrow AC angles- may precipitate

pupillary block

Blepharoptosis surgery- stimulates

Müller’s muscle, inadequate correction

Retrobulbar anesthesia

Local – risk of vasospasm &

occlusion of ophthalmic or central

retinal artery

Systemic – tachyarrhythmias, death Aphakia- CME risk (13-30%)

Adrenergic Agonists Selective

Proven sensitivity to these agents

Concomitant use of monoamine oxidase

inhibitors (MAOI)

Infants and children < 2 years: brimonidine

is an absolute contraindication due to apnea,

bradycardia, dyspnea

Pediatric (ages 2-7) usage reports:

convulsions, cyanosis, hypoventilation,

lethargy; brimonidine is relatively

contraindicated

Precaution in patients with severe

cardiovascular disease

Precaution in patients with depression,

cerebral or coronary insufficiency,

Raynaud’s phenomenon, orthostatic

hypotension

Pregnancy: category B drug- use only if

potential benefits justify potential risk

Adrenergic Agonists Method of action

Non-selective-mixed α and ß adrenergic

agonist; effect varies over time, initially

raising IOP slightly, followed by reduction

lasting 12-24 hours

Selective-alpha adrenergic receptor agonist;

reduction of aqueous humor production is

primary mechanism of action Fluorophotometric studies suggest that

Brimonidine tartrate also increases

uveoscleral outflow

Controversial neuroprotective effect:

prevent demise of retinal ganglion cells due

to trauma or toxins

Adrenergic Agonists Complications of therapy

Non-selective Local - conj injection, follicular

conjunctivitis, burning, stinging, mydriasis,

blurry vision, headache

Cardiovascular - tachycardia, arrhythmias,

hypertension

Selective Local - hyperemia, follicular conjunctivitis,

conjunctival blanching

Systemic - dry mouth, fatigue, anxiety,

respiratory depression in neonates

Adrenergic Agonists -

Allergy

Adrenergic Agonists -

Allergy

Adrenergic Agonists -

Allergy A 64-year-old male with POAG is taking

timolol, dorzolamide, brimonidine, and

latanoprost OU. He must begin phenelzine, a

systemic monoamine oxidase (MAO)

inhibitor. Which one of the following should

be discontinued?

• Latanoprost

• Brimonidine

• Dorzolamide

• Timolol

Which of the following glaucoma

medications is contraindicated for use in

children younger than age 2?

• Timolol

• Levobunolol

• Brimonidine

• Dorzolamide

A 52-year-old woman with ocular

hypertension is started on a monocular trial

with a glaucoma medication. Which

glaucoma medication is most likely to

produce a decrease in IOP in the contralateral

(untreated) eye?

• Dorzolamide

• Latanoprost

• Timolol

• Brimonidine

Which class of glaucoma

medications should be avoided in

myasthenia gravis? • Miotics

• Prostaglandin analogues

• Beta blockers

• Topical CAIs

Beta-adrenergic

Antagonists (Beta

Blockers) Agents

Non-selective Timolol maleate (Timoptic)

Timolol hemihydrate (Betimol)

Levobunolol HCL (Betagan)

Carteolol HCL (Ocupress)

Metipranolol HCL (Optipranolol)

Selective Betaxolol (Betoptic-S)

Beta-adrenergic

Antagonists (Beta

Blockers) Indications

First line and adjunctive therapy to lower

IOP All types of glaucoma

Before or after laser surgery

After cataract surgery

Contraindications Proven sensitivity to agents

Reactive airway disease Bronchospasm

COPD

Greater than first degree heart block

Beta-adrenergic

Antagonists (Beta

Blockers) Relative contraindications

Congestive heart failure

Bradycardia

Method of action

1- and 2- receptors are on the ciliary

processes. Receptor blockade reduces

aqueous humor production via direct action Direct effect on non-pigmented ciliary

epithelium to decrease secretion via

inhibition of cyclic adenosine

monophosphate

Decreases local capillary perfusion to

reduce ultrafiltration

Beta-adrenergic

Antagonists (Beta

Blockers) Administration

Good corneal penetration

Peak aqueous concentration within 1-2

hours of topical dose. IOP effect peaks at 2

hours and lasts at least 24 hours Short-term escape

Dramatic reduction in IOP after

initial use followed by small

pressure rise that plateaus within

few days

May be due to increase in

receptors during first few days

Wait approximately 1 month to

evaluate response Long-term drift / tachyphylaxis

Approximately 3 months after

initiating therapy, some patients

have a mild decrease in IOP

response

Some will regain responsiveness

after a

drug holiday

Beta-adrenergic

Antagonists (Beta

Blockers) Efficacy

Non-selective 1- and 2- antagonists:

20-30% IOP reduction

1- selective antagonist: 14-17% IOP

reduction

Decreased efficacy possible when used

concomitantly with oral beta-blockers

Systemic absorption may result in IOP

lowering in contralateral eye

Beta-adrenergic

Antagonists (Beta

Blockers) Complications

Ocular toxicity Burning, hyperemia

Corneal anesthesia, punctate keratopathy,

erosions, toxic keratopathy

Periocular contact dermatitis

Dry eye

Cardiovascular 1 blockade slows pulse and decreases

cardiac contractility

May cause syncope, bradycardia,

arrhythmias, heart failure, decreased

exercise tolerance

Beta-adrenergic

Antagonists (Beta

Blockers) Respiratory

2 blockade produces contraction of

bronchial smooth muscle

May cause bronchospasm and airway

obstruction, especially in asthmatics

May cause dyspnea and apneic spells

especially in young children

Central nervous system Depression, anxiety, confusion,

hallucinations, lightheadedness, drowsiness,

fatigue, weakness, disorientation

Beta-adrenergic

Antagonists (Beta

Blockers) Cholesterol levels

Alterations in plasma lipid profile have

been reported with timolol when

administered without punctal occlusion

Decreases plasma high density lipoprotein

and possibly increases risk of coronary

artery disease

Other Exacerbation of myasthenia gravis

May mask awareness of hypoglycemia in

diabetics

GI distress

Dermatologic disorders

Sexual impotence

Beta-adrenergic

Antagonists (Beta

Blockers) Prevention of complications

Avoid use of beta-blockers in high-risk

patients

Nasolacrimal occlusion

Use topical beta-blockers with special

properties Betaxolol – 1- selective antagonist

Decreased incidence of respiratory

side effects in patients with

bronchospastic disease Carteolol – intrinsic sympathomimetic

activity

Adrenergic agonist effect that may

partially protect against adverse

effects of beta-blockade

Has less adverse affect on plasma

lipid profile

Beta-adrenergic

Antagonists (Beta

Blockers) Management of complications

Discontinue drug

Consider switch to beta-blocker with

special properties if indicated

A 52-year-old woman with ocular

hypertension is started on a monocular trial

with a glaucoma medication. Which

glaucoma medication is most likely to

produce a decrease in IOP in the contralateral

(untreated) eye?

• Dorzolamide

• Latanoprost

• Timolol

• Brimonidine

Which class of glaucoma

medications should be avoided in

myasthenia gravis? • Miotics

• Prostaglandin analogues

• Beta blockers

• Topical CAIs

Carbonic Anhydrase

Inhibitors Agents

Oral Acetazolamide 125 mg, 250 mg, 500 mg

Methazolamide 25 mg, 50 mg

Topical Dorzolamide 2%

Brinzolamide 1%

Carbonic Anhydrase

Inhibitors Indications

Reduction of chronically elevated IOP in

adults and children Monotherapy

Additive therapy

Prophylaxis of elevated IOP after a surgical

intervention

Reduction of acutely elevated IOP

Carbonic Anhydrase

Inhibitors Contraindications

Sulfa allergy

Kidney stones

Aplastic anemia

Thrombocytopenia

Sickle cell disease

History of blood dyscrasia

Carbonic Anhydrase

Inhibitors Method of action

Block aqueous production by inhibition of

carbonic anhydrase

> 90% must be blocked to decrease

aqueous production

Possible effects on ocular blood flow

Carbonic Anhydrase

Inhibitors Complications

Burning and stinging

Metallic taste

Cautious use of topical CAI for history of

sulfa allergy or kidney stones

Corneal toxicity

Paresthesias

Stevens-Johnson syndrome

Blood dyscrasias (aplastic anemia and

sickle cell disease)

Hypokalemia (after systemic use)

Conjunctival injection

Periocular contact dermatitis

Carbonic Anhydrase

Inhibitors

Carbonic Anhydrase

Inhibitors

Carbonic Anhydrase

Inhibitors

Carbonic Anhydrase

Inhibitors Prevention of complications

Monitor blood potassium, especially with

systemic CAIs

Consider pre-treatment blood counts,

especially with systemic CAIs

Avoid CAIs for diseased corneas with

marginal endothelium

No CAIs for history of sulfa allergy, blood

dyscrasia or kidney stones

Carbonic Anhydrase

Inhibitors Management of complications

Stop the medication

Topical toxicity Change topical therapy

Consider brinzolamide instead of

dorzolamide

Oral CAIs

Systemic toxicity Decrease the dose of oral medication

Change to topical therapy

Change from acetazolamide to

methazolamide

Medical consult for serious side effects

Switch to acetazolamide sequels

Combined Medications Agents

Dorzolamide HCL/Timolol maleate

Brinzolamide/Brimonidine

Brimonidine/Timolol

Latanoprost/Brimonodine/Timolol (outside

the US)

Indications Reduction of elevated IOP in patients with

OAG or ocular hypertension who are

insufficiently responsive to beta-blockers

Patients who have difficulty taking

multiple medications

Combined Medications Method of action

Dorzolamide hydrochloride Inhibitor of human carbonic anhydrase II,

which decreases aqueous humor secretion

Timolol maleate Nonselective beta-blocker which decreases

aqueous humor secretion

Combined Medications Complications

Most frequently reported ocular adverse

events Taste perversion, ocular burning/stinging,

conjunctival hyperemia, blurred vision,

superficial punctate keratitis, pruritis

Most frequently reported systemic adverse

events Worsening of restrictive airway disease,

fatigue, arrhythmia, syncope, heart block,

palpitation, insomnia, impotence, memory

loss, confusion

Prevention of complications Discussion of potential side effects with

patient

Nasolacrimal occlusion

Emphasis on correct dosing

Combined Medications Glycerin is a hyperosmotic agent

that should be avoided in patients

with which systemic disease? • Hypertension

• Diabetes mellitus

• Hyperthyroidism

• Anemia

Hyperosmotic Agents Dosing technique

Oral agents

Glycerin (Osmoglyn)

50% solution

4-7 oz.

Give solution cold for improved

tolerability Isosorbide (Ismotic) currently unavailable

(1/2 - full 250 ml over ice)

Intravenous agents Mannitol (Osmitrol)

5-25% solution

2 g/kg body weight (intravenously)

Hyperosmotic Agents Indications

Short-term or emergency treatment of

elevated IOP

Useful in acute conditions of elevated IOP

(e.g. ACG)

Effective when elevated IOP renders iris

non-reactive to agents which combat

pupillary block such as the miotics (e.g.,

pilocarpine)

Used to lower IOP and/or reduce vitreous

volume prior to initiation of surgical

procedures

Hyperosmotic Agents Contraindications

Should not be used for long-term therapy

(becomes ineffective with repeated dosing) Some agents increase blood sugar levels

(may be contraindicated in patients with

diabetes)

Long-term use may perturb electrolytes

Of limited value when blood-ocular barrier

is disrupted

May cause rebound elevation in IOP if

agent penetrates eye and reverses osmotic

gradient

Hyperosmotic Agents Pre-therapy evaluation

Accurate measurement of IOP

Slit-lamp biomicroscopic exam: pupil/iris

evaluation for ischemic and non-reactive

iris sphincter muscle

Shallowing of AC pre-therapy (e.g., ACG)

with subsequent deepening of chamber

after therapy (from dehydration of

vitreous)

Gonioscopy to evaluate for signs of

refractory glaucoma necessitating

short-term hyperosmotic therapy prior to

surgery (e.g., traumatic glaucoma,

neovascular glaucoma)

Hyperosmotic Agents Alternatives

Aqueous suppressants (i.e., beta-blockers,

topical and/or oral CAIs, alpha-agonists)

Outflow enhancers (i.e., prostaglandin

analogues, miotic agents, epinephrine-like

agents)

Laser surgery procedures to correct acute

glaucoma (e.g., iridotomy and/or

iridoplasty for acute ACG)

Paracentesis

Glaucoma surgical procedure (e.g.,

trabeculectomy, tube shunts, etc.)

Hyperosmotic Agents Method of action

When given systemically, lowers IOP by

increasing blood osmolality (creates

osmotic gradient between blood and

vitreous humor)

The larger the dose and more rapid the

administration, the greater the reduction in

IOP (because of increased gradient)

Limited effectiveness and duration of

action when blood-aqueous barrier is

disrupted (osmotic agent enters the eye)

Hyperosmotic Agents Complications

Headache

Backache

Nausea and vomiting (oral agents)

Urination frequency and retention

Cardiac (chest pain, pulmonary edema,

congestive heart failure)

Renal impairment

Neurologic status (lethargy, seizures,

obtundation)

Subdural hemorrhage

Hypersensitivity reactions

Hyperkalemia or ketoacidosis (when

glycerin given to patients with diabetes)

Hyperosmotic Agents

Prevention of complications Consider alternative therapies

Use cautiously in patients with known

compromised cardiac, hepatic, or renal

status

Avoid use of glycerin in diabetics

Closely observe for complications

Management of complications Discontinue medication

Symptomatic relief of side effects until

resolution if applicable

Consider urinary catheter (if intravenous

mannitol is given preoperatively)

Hyperosmotic Agents Follow-up care

Closely monitor IOP (to determine efficacy

of hyperosmotic agents)

Discontinue therapy as soon as possible

Closely monitor ocular and systemic

symptoms and exam

Patient instructions Alert physician of any complications

Substitute IOP-lowering agents when

hyperosmotic agents no longer needed

Glycerin is a hyperosmotic agent

that should be avoided in patients

with which systemic disease? • Hypertension

• Diabetes mellitus

• Hyperthyroidism

• Anemia

What is the mechanism of action for

pilocarpine in reducing IOP? • Contraction of the ciliary muscle

resulting in increased outflow of

aqueous through the trabecular

meshwork

• Contraction of the ciliary muscle

resulting in a reduced rate of aqueous

production

• Inhibition of the enzyme

acetylcholinesterase with prolonged and

enhanced action of naturally secreted

acetylcholine

• Inhibition of carbonic anhydrase causing

a decreased rate of aqueous production

Echothiophate iodide (Phospholine

iodide) is an example of which type

of glaucoma medication? • Direct-acting parasympathomimetic agent

• Indirect-acting parasympathomimetic agent

• Beta blocker

• CAI

Indirect parasympathomimetics

initiate their effect by: • Binding directly to muscarinic receptors

• Suppressing acetylcholine release from

nerve terminals

• Suppressing enzymes that inactivate

acetylcholine

• Increasing the sensitivity of post-synaptic

nerve terminals to acetylcholine

Parasympathomimetic

Agents Agents

Carbachol

Pilocarpine HCL

Echothiopate iodide

Indications Increased IOP in patients with at least some

open filtering angle

Prophylaxis for ACG prior to iridotomy

Parasympathomimetic

Agents Contraindications

Patients with no trabecular outflow

Patients with peripheral retinal disease that

predisposes them to retinal detachment

Uveitic glaucoma

Acute infectious conjunctivitis

Proven sensitivity to these agents

Significant lens changes with chronic use

(relative contraindication)

Parasympathomimetic

Agents Method of action

Reduces IOP by causing contraction of the

ciliary muscle, which pulls the scleral spur

to tighten TM, increasing the outflow of

aqueous humor Direct-acting agents affect the motor end

plates in the same way as acetylcholine,

which is transmitted at postganglionic

parasympathetic junctions, as well as at

other autonomic, somatic, and central

synapses

Indirect-acting agents inhibit the enzyme

acetylcholinesterase, thereby prolonging

and enhancing the action of naturally

secreted acetylcholine

Parasympathomimetic

Agents Complications

Ocular More frequent

Induced myopia

Brow ache

Conjunctival and intraocular

vascular congestion

Cataracts

Paradoxical angle closure (by

inducing greater lenticular-pupillary

block)

Posterior synechiae

Corneal toxicity

Periocular contact dermatitis

Parasympathomimetic

Agents

Parasympathomimetic

Agents Less frequent

Iris pigment epithelial cysts

(cholinesterase inhibitors)

Lacrimal stenosis

Pseudopemphigoid

Fibrinous iritis (especially in post op

period)

Retinal detachment

Complications may be minimized by

titrating initial dosage and starting at lower

concentrations in those with blue eyes and

higher concentrations in those with darker

eyes

Compliance probably more problematic

than with other agents

Parasympathomimetic

Agents What is the mechanism of action for

pilocarpine in reducing IOP? • Contraction of the ciliary muscle

resulting in increased outflow of

aqueous through the trabecular

meshwork

• Contraction of the ciliary muscle

resulting in a reduced rate of aqueous

production

• Inhibition of the enzyme

acetylcholinesterase with prolonged and

enhanced action of naturally secreted

acetylcholine

• Inhibition of carbonic anhydrase causing

a decreased rate of aqueous production

Echothiophate iodide (Phospholine

iodide) is an example of which type

of glaucoma medication? • Direct-acting parasympathomimetic agent

• Indirect-acting parasympathomimetic agent

• Beta blocker

• CAI

Indirect parasympathomimetics

initiate their effect by: • Binding directly to muscarinic receptors

• Suppressing acetylcholine release from

nerve terminals

• Suppressing enzymes that inactivate

acetylcholine

• Increasing the sensitivity of post-synaptic

nerve terminals to acetylcholine

Prostaglandin

Analogues Contraindications

Uveitis/iritis (controversial)

Macular edema

Relative contraindications Aphakia or pseudophakia with open

posterior capsule, especially after

complicated surgery

Recent intraocular surgery

History of herpetic keratitis

Previous CME (multiple previous

surgeries/trauma)

Prostaglandin

Analogues Method of action

Latanoprost, travoprost, bimatoprost and

Rescula increase uveoscleral and TM

outflow Maximal IOP reduction by 12 hours, but

maximal effect may take 3-4 weeks

Prostaglandin

Analogues Complications

Darkening of iris and periocular skin Secondary to increased numbers of

melanosomes within melanocytes

Risk of iris pigmentation greatest in light

brown, blue-green, or two-toned irides;

least in blue irides

CME

Uveitis suspected

Exacerbations of underlying herpes

keratitis (pseudodendrites)

Prostaglandin

Analogues

Prostaglandin

Analogues

Exotic Drug Canasol (extract from Cannabis Sativa)

Thank you