Prostaglandin Analogues: The First-Line Glaucoma Drug

The problem: a drain that has silted up

Glaucoma is a plumbing disease before it is a nerve disease. The ciliary body secretes aqueous humour continuously into the front of the eye. That fluid must leave at the same rate it is made, and it drains by two routes: the conventional pathway (through the trabecular meshwork into Schlemm's canal — the main highway) and the uveoscleral pathway (seeping out through the ciliary muscle — a quiet back road). In primary open-angle glaucoma the trabecular meshwork becomes resistant, the fluid backs up, pressure rises, and the raised IOP slowly strangles the optic nerve. As the Glaucoma-overview chapter explains, lowering IOP is the only proven way to protect the nerve — so every drug class exists to do one of two things: open a drain, or turn down the tap. Prostaglandin analogues take the first road, and they take the road nobody else was using.

Mechanism: opening the back road

Prostaglandin analogues are synthetic mimics of prostaglandin F2-alpha (PGF2α). They bind the prostanoid FP receptor on the ciliary muscle. That binding switches on matrix metalloproteinases which remodel and loosen the extracellular matrix packed between the muscle bundles — in effect, they widen the spaces of the uveoscleral back road so far more fluid can seep out that way. Because they enhance outflow rather than suppress secretion, they work with the eye's own physiology instead of against it, and there is no ceiling from a tap that is already turned down. The result is the largest single-agent pressure drop of any topical class — roughly a quarter to a third off baseline IOP — from one drop a day. The eicosanoid pathway they hijack is the same one taught in the Inflammation section, where prostaglandins are the villains that must be suppressed; here, remarkably, a prostaglandin is the drug.

The drugs, and why once-daily at night

Four molecules share one mechanism, given as one evening drop. The class is latanoprost, travoprost, bimatoprost and tafluprost. All are prodrugs or amides activated in the eye, all target the FP receptor, and all are dosed once daily in the evening — the long tissue action gives 24-hour cover from a single night-time drop, and dosing more often actually lowers efficacy (the receptors down-regulate). This once-a-day simplicity is a large part of why they became first-line: adherence to eye drops is dismal, and a single bedtime drop is the easiest regimen to keep. Tafluprost is available preservative-free, useful when the preservative benzalkonium chloride (BAK) irritates the ocular surface — a real problem for patients who will take these drops for the rest of their lives. Newer molecules push the mechanism further: latanoprostene bunod releases nitric oxide to also relax the trabecular meshwork (attacking both drains at once), and netarsudil is a Rho-kinase inhibitor that improves conventional outflow — the two are combined with latanoprost in fixed-combination bottles.

Why they beat the old first-line: the systemic escape

For decades the default first drop was timolol, a topical beta-blocker that turns down aqueous secretion. It works — but a drop on the eye drains through the nasolacrimal duct into the nose and is absorbed straight into the bloodstream, bypassing the liver's first-pass metabolism. So topical timolol can cause exactly what a systemic beta-blocker causes: bronchospasm in an asthmatic, bradycardia and heart block, fatigue, masked hypoglycaemia. Prostaglandin analogues have essentially no systemic footprint — their adverse effects are all local, at the eye and lids. That single fact is why they displaced beta-blockers as first-line, especially in the very patients glaucoma is commonest in: the elderly, who so often also have asthma, COPD, or a slow heart. The Beta-blocker and CAI chapter covers why timolol is now usually the add-on, not the opener.

The price: local, cosmetic, and mostly not dangerous

The side effects are visible, which makes counselling more important than treating. Conjunctival hyperaemia — a red eye — is the commonest complaint and often settles with time. The three effects that must be counselled before the first drop are all pigment- and growth-related. First, permanent iris darkening: the drug increases melanin in iris stromal melanocytes, and in a mixed-colour (hazel or green-brown) iris this can turn it visibly, irreversibly brown — dramatic and permanent if only one eye is treated. Second, periocular skin darkening (hyperpigmentation of the lids), which usually fades if the drug is stopped. Third, hypertrichosis — the lashes grow longer, thicker, darker and more numerous. A subtler effect is prostaglandin-associated periorbitopathy (PAP): fat atrophy that deepens the upper lid sulcus and can make the eye look sunken, sometimes with a drooping lid. None of these threaten sight, but a patient who is not warned will stop the drops the day they notice their eyes changing colour. Two cautions do matter clinically: prostaglandin analogues can reactivate herpetic (HSV) keratitis, and they may worsen intraocular inflammation, so they are used cautiously in active uveitis and in patients with a history of dendritic keratitis.

Read the ladder as a logic, not a list to memorize. The whole of glaucoma medical therapy hangs on the figure above. Start first-line with a prostaglandin analogue at night. If target pressure is not reached, add — do not swap — a drug from the other side of the ladder, so the two mechanisms stack: a beta-blocker or carbonic anhydrase inhibitor to reduce production, or an alpha-2 agonist (brimonidine) which does both a little. These add-on agents are the subject of the Beta-blocker/CAI and Alpha-agonist chapters. Pilocarpine, an old muscarinic agonist, pulls the trabecular meshwork open (conventional outflow) but is now rarely used chronically because of the small pupil and brow-ache. When two or three drops become a burden, fixed combinations put two mechanisms in one bottle to protect adherence. And when drops fail or pressure is dangerously high, the ladder ends in laser (selective laser trabeculoplasty) or surgery (trabeculectomy, drainage tubes, MIGS). One warning the ladder does not show: this is the open-angle ladder. Acute angle-closure is a different emergency with a different drug set — never assume a red, painful eye with high pressure just needs another glaucoma drop.