The document discusses various medical treatments for glaucoma, including different drug classes and their mechanisms of action, indications, contraindications and side effects. It provides detailed information on adrenergic agonists, beta-adrenergic antagonists, carbonic anhydrase inhibitors, and combined medications used to treat glaucoma. Key points covered include how the drugs work to lower intraocular pressure, when they should and should not be used, and common adverse effects.
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Medical Treatment of Glaucoma
1. 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
2. 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
3. Prior to and immediately after laser treatment (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
4. 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 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
5. 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
6. 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
7. hypotension
Pregnancy: category B drug- use only if potential benefits justify 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
8. 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
9. 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 the contralateral (untreated) eye?
• Dorzolamide
• Latanoprost
• Timolol
10. • 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)
11. 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
12. 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 Short-term escape
Dramatic reduction in IOP after
13. 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
14. 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
15. 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
16. 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
17. 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 the contralateral (untreated) eye?
• Dorzolamide
18. • 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, 250 500 mg
Methazolamide 25 mg, 50 mg
Topical
Dorzolamide 2%
Brinzolamide 1%
19. 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
20. 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 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
21. 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
22. 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
23. 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
24. 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
25. 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
26. 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)
27. 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
28. vitreous humor)
The larger the dose and more rapid administration, the greater 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
29. 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 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
30. 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
31. • 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
32. 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)
33. 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 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
35. 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
36. 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
37. 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
38. 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