I. OVERVIEW

• Decreasing aqueous humor production
• Increasing aqueous humor outflow
• Decreasing episcleral venous pressure

II. CLASSIFICATION OF GLAUCOMA MEDICATIONS

A. PROSTAGLANDIN F2α ANALOGS (PGAs) - First-Line Agents

• Bind to prostaglandin F (FP) receptors on ciliary muscle cells
• Increase uveoscleral (unconventional) outflow of aqueous humor
• Induce smooth muscle relaxation and alter extracellular matrix within ciliary muscle bundles

• Dosing: Once daily, usually at bedtime (0.005% latanoprost, 0.004% travoprost, 0.03% bimatoprost)
• IOP Reduction: 30-35% (most effective single agents)
• Onset: 3-4 hours; peak effect at 8-12 hours
• Duration: 24 hours (allows once-daily dosing)
• Why First-Line:
  • Maximum IOP reduction with minimal systemic effects
  • Once-daily compliance improves adherence
  • Most cost-effective for long-term therapy

• Conjunctival hyperemia (most common, 25-50% of patients)
• Eyelash growth (hypertrichosis) and increased pigmentation
• Periocular skin darkening (iris pigmentation increase)
• Iris color change (in lighter eyes)
• Macular edema (in susceptible patients)
• Punctal hyperemia

• Minimal (drugs are locally administered with minimal systemic absorption)

• Active ocular inflammation/iritis (may worsen with PGAs and miotics)
• Sickle cell disease (avoid - may promote inflammation)

• Apply once daily in evening for maximum effectiveness
• Instruct patient: Wait 5 minutes between different eye drops to prevent washout
• Bimatoprost has slightly superior IOP reduction than latanoprost

B. BETA-ADRENERGIC BLOCKERS (Non-Selective)

• Block β-adrenergic receptors on ciliary body epithelium
• Decrease aqueous humor production
• Non-selective agents: block both β1 and β2 receptors (more effective)
• Selective agents (Betaxolol): block β1 only (safer in asthma/COPD)

• Dosing: 0.5% timolol twice daily (morning and evening)
• IOP Reduction: 20-25%
• Onset: Peak effect at 30 minutes to 2 hours
• Duration: 12-24 hours

• Well-established, inexpensive
• Fewer local side effects than PGAs
• Effective in patients who cannot tolerate PGAs

• Minimal local effects
• Ptosis (rare)
• Decreased corneal sensation

• Bradycardia (most common)
• Bronchospasm (contraindicated in asthma/COPD - use Betaxolol instead)
• Hypotension
• Fatigue, sexual dysfunction
• Mask symptoms of hypoglycemia (caution in diabetes)

• Asthma/COPD (use Betaxolol - β1 selective)
• Severe bradycardia or heart block
• Severe depression

• Apply gentle pressure on lacrimal sac for 1-2 minutes after instillation to reduce systemic absorption
• Avoid abrupt discontinuation (rebound hypertension possible)
• Often combined with PGAs as second agent

C. ALPHA-2 ADRENERGIC AGONISTS

• Stimulate α2A receptors: decrease aqueous humor production at ciliary body
• Stimulate α2C receptors: increase uveoscleral outflow
• Also decrease episcleral venous pressure

• Dosing: 0.2% brimonidine 2-3 times daily
• IOP Reduction: 20-25%
• Onset: 1 hour
• Duration: 12 hours
• Useful for: Refractory glaucoma when combined with other agents

• Allergic conjunctivitis (frequent - ~25%)
• Follicular conjunctivitis
• Dry eye

• Fatigue, drowsiness, headache
• Dry mouth
• Hypertension (especially at high doses)

• Infants < 2 years (risk of central apnea, respiratory depression, hypothermia)
• Monoamine oxidase inhibitor use (drug interaction risk)
• Uncontrolled hypertension

• Developed tachyphylaxis - effectiveness may decrease over time
• Better tolerance if used as add-on than monotherapy
• Apply gentle pressure on lacrimal sac for 1-2 minutes

D. CARBONIC ANHYDRASE INHIBITORS (CAIs)

Topical CAIs (First-line for CAI use)

Systemic CAIs (Refractory cases only)

• Inhibit carbonic anhydrase enzyme in ciliary body
• Reduce bicarbonate accumulation in posterior chamber
• Decrease aqueous humor production by 20-50%
• Also increase uveoscleral outflow slightly

• Dosing: Dorzolamide/Brinzolamide 2-3 times daily
• IOP Reduction: 15-20%
• Onset: 1 hour
• Duration: 8 hours
• Advantage: Minimal systemic effects with topical use

• Dosing: Acetazolamide 500 mg once or twice daily; Methazolamide 50-100 mg 2-3 times daily
• IOP Reduction: 20-30% (superior to topical CAIs)
• Use: Reserved for refractory glaucoma only (due to systemic side effects)
• Onset: 1-2 hours
• Duration: 12 hours (acetazolamide), longer for methazolamide

• Ocular: Stinging, bitter taste (drug drains to nasopharynx)
• Minimal systemic effects with proper instillation technique

• Metabolic acidosis (most significant)
• Hypokalemia (potassium wasting)
• Paresthesias (fingers, lips, toes)
• Renal calculi (kidney stones) - major side effect
• Aplastic anemia (rare but serious)
• Sulfonamide-type allergy possible
• Transient myopia
• Gastrointestinal upset

• Sulfonamide allergy (for all CAIs)
• Renal failure (accumulation risk)
• Hepatic cirrhosis
• Hypokalemia
• Sickle cell disease (topical/systemic CAIs may reduce aqueous pH, promoting sickling)

• Always ensure adequate hydration with systemic CAIs
• Monitor serum potassium and electrolytes
• Use topical CAIs as add-on agent, not monotherapy
• Systemic CAIs reserved for acute angle-closure or refractory cases

E. RHOKINASE INHIBITORS (Newest Class)

• Inhibit Rho-associated kinase (ROCK)
• Increase conventional outflow through trabecular meshwork
• Decrease aqueous humor production
• Decrease episcleral venous pressure (unique mechanism)
• Triple mechanism of IOP reduction

• Dosing: Netarsudil 0.02% twice daily
• IOP Reduction: 20-24%
• Onset: Rapid (as early as 2 hours)
• Duration: 24 hours
• Advantage: Multiple mechanisms; decreases episcleral venous pressure (unique)

• Conjunctival hyperemia (30-50% - similar to PGAs, usually mild and transient)
• Subconjunctival hemorrhage (rare)
• Corneal verticillata (rare)

• Can be used as monotherapy or combination therapy
• Do NOT apply within 5 minutes of other eye drops
• Newer agent; excellent safety profile
• Comparable efficacy to PGAs with different side effect profile

F. MIOTICS (Parasympathomimetics) - Limited Use

• Stimulate muscarinic receptors on ciliary muscle
• Cause ciliary muscle contraction (accommodation)
• Opens trabecular meshwork spaces
• Increase conventional aqueous outflow

• Dosing: 1-2% solution 3-4 times daily
• IOP Reduction: 20-25%
• Onset: 30 minutes
• Duration: 4-8 hours

• Blurred vision (due to accommodation/pupil constriction)
• Myopia (ciliary spasm)
• Retinal detachment risk (especially in high myopes)
• Headache (accommodation strain)
• Reduced night vision

• High myopia (risk of retinal detachment)
• Anterior uveitis/iritis
• Sickle cell disease
• Angle-closure glaucoma (can precipitate acute attack)

• Rarely used now - replaced by more effective agents with better side effect profiles
• Occasionally used in refractory cases or angle-closure glaucoma
• Avoided in acute trauma (can increase inflammation)

G. HYPEROSMOTIC AGENTS

• Create osmotic gradient between blood and vitreous
• Draw fluid from vitreous into bloodstream
• Reduce vitreous volume, thereby lowering IOP
• Does NOT reduce aqueous production or increase outflow

• Dosing: Mannitol 1-2 g/kg IV over 45 minutes once daily
• IOP Reduction: 30-50% (rapid, dramatic effect)
• Onset: 30 minutes
• Duration: 4-6 hours
• Use: Acute angle-closure glaucoma, acute IOP elevation post-trauma

• Hypervolemia (fluid overload, pulmonary edema risk)
• Hyperkalemia (if renal function impaired)
• Headache, nausea, vomiting
• Renal failure (with repeated use)
• Thrombophlebitis (if IV infiltrates)

• Congestive heart failure
• Renal failure
• Severe dehydration
• Pulmonary edema

• Emergency drug only - rapid IOP reduction when immediate treatment needed
• Not for chronic use (systemic toxicity)
• Requires hospitalization
• Always use with topical/systemic medical therapy in acute angle-closure

III. TREATMENT ALGORITHMS

Primary Open-Angle Glaucoma (POAG)

• Start prostaglandin analog (latanoprost 0.005% once daily)
• OR timolol 0.5% twice daily (if PGA contraindicated)
• OR netarsudil 0.02% twice daily (newer option)

• Add beta-blocker (if not already used) + PGA
• OR add alpha-2 agonist + PGA
• OR add topical CAI (dorzolamide) + PGA + beta-blocker

• Consider systemic acetazolamide 500 mg once/twice daily
• Laser trabeculoplasty (can be first-line now)
• Surgical intervention (trabeculectomy, tube shunts)

Acute Angle-Closure Glaucoma (Emergency)

1. IV mannitol 1-2 g/kg (emergency IOP reduction)
2. Topical beta-blocker (timolol 0.5% twice daily)
3. Topical CAI (dorzolamide 2% 3 times daily)
4. Systemic acetazolamide 500 mg once/twice daily
5. Avoid: PGAs and miotics (may increase inflammation and worsen angle closure)
6. Followed by: Laser peripheral iridotomy (definitive treatment)

IV. DRUG INTERACTIONS & IMPORTANT NOTES

V. CLINICAL PEARLS FOR MBBS EXAMS

1. First-line: Prostaglandin analogs (PGAs) - highest efficacy, once-daily, minimal systemic effects
2. Most important side effect to remember:
   • PGAs → eyelash growth, iris darkening, conjunctival hyperemia
   • Beta-blockers → bronchospasm, bradycardia
   • Miotics → blurred vision, risk of retinal detachment
3. Combination therapy: Most glaucoma patients need 2-3 agents for optimal control
4. Key mechanism: All drugs either ↓ aqueous production OR ↑ aqueous outflow
5. Acute angle-closure: Use IV mannitol + medical therapy, then laser
6. Application technique: Press lacrimal sac 1-2 minutes after instillation to reduce systemic absorption
7. Patient adherence: Once-daily PGAs best for compliance vs. multiple daily beta-blocker dosing

VI. RECENT ADVANCES (2023-2025)

• Rho-kinase inhibitors (netarsudil) showing promise as monotherapy and combination agent
• Latanoprostene bunod (PGA with nitric oxide donor) - newer PGA with additional mechanism
• Fixed-combination drops reducing number of bottles/applications
• Laser trabeculoplasty now considered first-line option in many guidelines

1. Prostaglandin F2α analogs (latanoprost, travoprost, bimatoprost) - First-line agents with 30-35% IOP reduction
2. Beta-blockers (timolol, levobunolol) - 20-25% IOP reduction, beware systemic effects
3. Alpha-2 agonists (brimonidine, apraclonidine) - Avoid in infants <2 years
4. Carbonic anhydrase inhibitors (dorzolamide topical, acetazolamide systemic) - For refractory cases
5. Rho-kinase inhibitors (netarsudil) - Newest class with triple mechanism
6. Miotics (pilocarpine) - Rarely used now due to side effects
7. Hyperosmotic agents (mannitol) - Emergency use only

• PGAs are first-line due to efficacy, compliance, and safety
• Treatment algorithms differ for POAG vs. acute angle-closure
• Drug interactions are essential (e.g., beta-blockers with asthma, CAIs with sickle cell)
• Application technique matters - press lacrimal sac to reduce systemic absorption
• Most patients need combination therapy for target IOP