23.3 Glaucoma Medications: Classes, Mechanisms & Side Effects

The two levers

Every glaucoma drug does one of two things: reduces aqueous production or increases aqueous outflow. Knowing which lever a drug pulls predicts its side effects.

Prostaglandin analogues

Examples: latanoprost, travoprost, bimatoprost, tafluprost, latanoprostene bunod.

Why they are first-line: the strongest single-agent pressure reduction, once-nightly dosing that supports compliance, and minimal systemic effect.

Ocular side effects — and these generate patient complaints, so counsel in advance:

• Increased iris pigmentation — permanent, most noticeable in hazel or mixed-colour irides
• Periocular skin hyperpigmentation — usually reversible on stopping
• Eyelash growth — longer, thicker, darker lashes; the basis of a cosmetic product
• Conjunctival hyperaemia — common early, often settles
• Prostaglandin-associated periorbitopathy — deepening of the upper lid sulcus, periorbital fat atrophy, ptosis; asymmetric appearance in unilateral use
• Reactivation of herpes simplex keratitis; cystoid macular oedema in predisposed eyes, especially aphakia and pseudophakia with a compromised capsule

Beta-blockers

Examples: timolol (non-selective), levobunolol, carteolol, betaxolol (beta-1 selective).

Systemic side effects are the examinable point. Topical timolol is absorbed through the nasal mucosa into the circulation without first-pass metabolism and can cause:

• Bronchospasm — potentially fatal in asthma
• Bradycardia, heart block, hypotension, worsening heart failure
• Fatigue, depression, reduced exercise tolerance
• Masking of hypoglycaemic symptoms in insulin-treated diabetes
• Reduced libido

Contraindications: asthma, chronic obstructive pulmonary disease, sinus bradycardia, second or third degree heart block, cardiogenic shock and uncompensated heart failure. Betaxolol, being beta-1 selective, is relatively safer in reactive airways disease but is not risk-free.

This is why the medication and medical history matter. A patient handed a timolol sample without anyone asking about asthma is a genuine and documented cause of harm. Always teach punctal occlusion with a topical beta-blocker.

Tachyphylaxis — a diminishing response over weeks to months — is described with beta-blockers and is one reason for apparent treatment failure.

Alpha-2 adrenergic agonists

Examples: brimonidine, apraclonidine.

Mechanism: reduce aqueous production and increase uveoscleral outflow.

Side effects: ocular allergy is common — a follicular conjunctivitis developing weeks to months into treatment and the usual reason for discontinuation; also dry mouth, fatigue, drowsiness and hypotension.

Critical contraindication: brimonidine is contraindicated in infants and young children because it crosses the blood-brain barrier and causes central nervous system depression, apnoea, bradycardia and hypotension. It is also avoided with monoamine oxidase inhibitors.

Apraclonidine is used mainly for short-term pressure spikes, such as after laser trabeculoplasty or YAG capsulotomy, because tachyphylaxis and allergy limit chronic use. It also has the diagnostic role in Horner syndrome described earlier.

Carbonic anhydrase inhibitors

Topical: dorzolamide, brinzolamide. Oral: acetazolamide, methazolamide.

Mechanism: inhibit carbonic anhydrase in the ciliary epithelium, reducing aqueous production.

Topical side effects: stinging and a bitter metallic taste (from nasolacrimal drainage to the pharynx), transient blur, superficial punctate keratopathy. Use with caution in low endothelial cell counts, where corneal decompensation has been reported.

Oral acetazolamide side effects — a favourite examination topic:

• Paraesthesia of fingers, toes and around the mouth — almost universal
• Malaise, fatigue, anorexia, weight loss, depression — the "symptom complex"
• Metabolic acidosis and hypokalaemia
• Renal stones
• Gastrointestinal upset, altered taste (carbonated drinks taste odd)
• Rarely aplastic anaemia and Stevens-Johnson syndrome

All carbonic anhydrase inhibitors are sulphonamide derivatives — document a sulfa allergy carefully. Avoid in significant renal or hepatic impairment and in sickle cell disease, where acidosis promotes sickling.

Rho kinase inhibitors

Example: netarsudil.

Mechanism: relax the trabecular meshwork and increase conventional outflow; may also reduce episcleral venous pressure.

Side effects: conjunctival hyperaemia in the majority of patients, corneal verticillata (whorl-like deposits that are benign and reversible), and subconjunctival haemorrhage. Patients must be warned about the redness or they will stop the drug.

Miotics

Example: pilocarpine.

Mechanism: contracts the ciliary muscle, which pulls on the scleral spur and opens the trabecular meshwork; also contracts the pupil sphincter, which pulls the peripheral iris away from the angle — the reason it is used in angle closure.

Side effects: miosis causing dim vision and reduced night vision, accommodative spasm and brow ache (marked in young patients), induced myopia, and an increased risk of retinal detachment in predisposed eyes. Four-times-daily dosing makes compliance poor. Systemic cholinergic effects — sweating, salivation, bradycardia, bronchospasm, gastrointestinal cramps — occur with excess.

Hyperosmotics

Examples: intravenous mannitol, oral glycerol, oral isosorbide.

Use: acute angle closure and other acute pressure emergencies, by osmotically drawing water out of the vitreous.

Cautions: volume overload and pulmonary oedema in cardiac or renal failure; glycerol is metabolised to glucose and must be used cautiously in diabetes, where isosorbide is preferred.

Fixed combinations

Combination bottles — a beta-blocker with a carbonic anhydrase inhibitor, a beta-blocker with brimonidine, a beta-blocker with a prostaglandin — reduce the drop burden and improve compliance, and eliminate the washout problem between drops. Their side-effect profiles are the sum of their components, so every contraindication of each component applies.