What it is:glaucoma is an optic neuropathy. The disease is damage to the optic nerve head with matching visual field loss, not simply "high eye pressure." Elevated intraocular pressure (IOP) is the biggest modifiable risk factor and the only thing you can actually treat, but you can have glaucoma with a normal IOP and elevated IOP without glaucoma.
The core problem:IOP is set by the balance between aqueous humor flowing in (produced by the ciliary body) and flowing out (through the trabecular meshwork/Canal of Schlemm, or the uveoscleral pathway). In primary open-angle glaucoma (POAG), the drain is anatomically open but works poorly over years. In primary angle-closure glaucoma (PACG), the drain is physically blocked by the iris, and pressure can spike in hours.
What you do about it:every drug class either turns down the faucet (production) or opens one of the two drains (outflow). Lower IOP by at least 20-25% from baseline and you cut the risk of further nerve damage, even though there's no cure and no way to reverse damage already done.
Think of IOP control as one faucet, two drains.Faucet (production):beta blockers, alpha2 agonists, carbonic anhydrase inhibitors (CAIs) all shut down aqueous production in the ciliary body. Drain 1 (trabecular/conventional outflow, ~80-90% of flow):cholinergic agonists (pilocarpine) and the Rho kinase inhibitor netarsudil physically open this pathway. Drain 2 (uveoscleral/unconventional outflow, ~10-20% of flow):prostaglandin analogs and, to a lesser degree, alpha2 agonists push fluid out this route. Once you can place a drug on this map, its dosing, side effects, and place in therapy all make sense instead of needing to be memorized cold.
"Glaucoma" is not one disease. The angle anatomy (open vs closed) and the IOP/disc/field relationship both matter, and mixing them up is a common trap.
| Term | What it means | IOP |
|---|---|---|
| POAG | Chronic, bilateral (often asymmetric), open drainage angle that just works poorly. 60-70% of all glaucomas and 90-95% of primary glaucomas in the US. | Usually elevated, but not required for diagnosis |
| Ocular hypertension | Elevated IOP with nodisc changes and novisual field loss. Not glaucoma yet, but the single biggest risk factor for developing it. | >21 mm Hg (2.8 kPa) |
| Normal-tension glaucoma | Disc changes and visual field loss present, IOP never measured elevated. Proof that IOP is not the whole story. | <21 mm Hg (2.8 kPa) |
| PACG | The iris physically obstructs the trabecular meshwork. Can be chronic/intermittent or a true acute crisis. | Markedly elevated when symptomatic, 40-90 mm Hg (5.3-12 kPa) |
| Secondary glaucoma | Same mechanics, but caused by another disease, trauma, surgery, or a drug rather than being primary/inherited. | Variable |
Ocular hypertension and normal-tension glaucoma are mirror images.Ocular hypertension = pressure up, nerve fine (yet). Normal-tension glaucoma = nerve damaged, pressure "normal." Both prove that IOP is a risk factor you can measure and treat, not a diagnostic requirement. You can be told "IOP was 18" and still be looking at glaucoma if the disc and fields say so.
Secondary OAG is classified by wherethe outflow problem sits. Pretrabecular:an abnormal membrane covers the meshwork before flow even reaches it (some inflammatory and neovascular disease). Trabecular:the meshwork itself is altered or clogged (pigment dispersion syndrome, exfoliation syndrome, steroid response, trauma, uveitis debris). Posttrabecular:the meshwork is fine, but pressure backs up because episcleral venous pressure is elevated downstream (thyroid eye disease, carotid-cavernous fistula, Sturge-Weber). Knowing which tier is broken tells you why a given drug will or won't help, since drugs that boost trabecular outflow are useless if the block is downstream of the trabecular meshwork.
Aqueous humor is made continuously by the ciliary body epithelium, fills the posterior chamber, flows forward through the pupil into the anterior chamber, and then has to leave through one of two doors. Everything about glaucoma pharmacology is about that plumbing.
| Route | Share of outflow | How it works | Drugs that use it |
|---|---|---|---|
| Trabecular (conventional) | ~80-90% | Fluid filters through the trabecular meshwork into Canal of Schlemm and the venous system. Pressure-dependent. | Cholinergic agonists (contract ciliary muscle, mechanically stretch the meshwork open), Rho kinase inhibitors (relax meshwork cytoskeleton, lower episcleral venous resistance) |
| Uveoscleral (unconventional) | ~10-20% | Fluid seeps between ciliary muscle bundles into the suprachoroidal space. Not pressure-dependent, so it can keep working even when trabecular outflow is impaired. | Prostaglandin analogs (remodel ciliary muscle extracellular matrix to open channels), alpha2 agonists (partial contribution) |
Read the drug classes straight off the plumbing diagram. Shut the faucet:beta blockers, alpha2 agonists, and CAIs all reduce aqueous productionin the ciliary epithelium (beta blockers and alpha2 agonists via cAMP-linked signaling, CAIs by blocking the bicarbonate transport that drives fluid secretion). Open drain 1:cholinergic agonists (pilocarpine) contract the ciliary muscle, which mechanically tugs the trabecular meshwork open, and cholinesterase inhibitors (echothiophate) do the same thing indirectly by boosting endogenous ACh. Netarsudil, the newest class, relaxes the meshwork's actin cytoskeleton to open the same door by a different mechanism. Open drain 2:prostaglandin analogs increase matrix metalloproteinase activity in the ciliary muscle, loosening the extracellular matrix so fluid escapes uveoscleral. Nothing in this entire chapter works by "healing" the optic nerve. It is all about the pressure it sits under.
IOP is not constant. It has diurnal variation, typically lowest around 6 PM and highest right at waking, and it also shifts with pulse, blood pressure, coughing or forced expiration, neck compression, and posture. That's part of why a single office IOP reading is an imperfect snapshot and why elevated IOP is a poor predictor of who will actually lose visual field, even though the risk of field loss does rise as IOP rises. The rest of the damage picture, per the handbook, likely involves optic nerve ischemia, excitotoxicity, and autoimmune mechanisms that aren't fully understood and aren't things we currently have a drug for.
PACG happens when the iris physically bows forward and jams against the trabecular meshwork (pupillary block is the classic setup), sealing off the drain entirely. Because this is a mechanical obstruction and not a slow drainage inefficiency, pressure can rocket to 40-90 mm Hg within hours, which is why PACG is a surgical emergency (definitive fix is a hole in the iris) while POAG is a decades-long medication-management problem.
The two disease types present almost oppositely, and that contrast is itself high-yield.
| POAG | PACG | |
|---|---|---|
| Onset | Slow, over years | Can be intermittent/prodromal, or a sudden crisis |
| Symptoms early on | None. Genuinely asymptomatic until substantial field loss has already occurred | Intermittent blurred or hazy vision, halos around lights, occasional headache |
| Vision | Central acuity preserved even late; it's the peripheral field that goes first, which is why patients don't notice | Can be severely affected during an acute episode |
| Acute attack features | N/A, POAG doesn't crash acutely | Cloudy, edematous cornea; ocular pain; nausea, vomiting, abdominal pain; diaphoresis |
Severe eye pain, red eye, cloudy cornea, halos around lights, headache, and nausea/vomiting together is an ophthalmic emergency, not a routine eye complaint. The GI symptoms (nausea, vomiting, abdominal pain) trip people up because they sound like an abdominal problem, but here they're a downstream effect of extreme IOP elevation. Don't let a patient with this picture wait for a scheduled eye exam.
POAG is silent by design: it's bilateral, it's slow, and central vision (the part patients actually notice) is spared until very late. That's exactly why comprehensive eye exams and IOP checks matter for at-risk patients (family history, older age, Black or Latino/Hispanic ethnicity, high myopia) rather than waiting for symptoms to prompt a visit.
Diagnosis of POAG rests on the optic nerve and the visual field, with IOP as supporting (not defining) evidence.
From HEENT: miosisis pupil constriction, mydriasisis pupil dilation. Direct pupillary reaction is constriction of the eye you're shining light into; consensual reaction is the other eye constricting at the same time. These terms matter here because the entire glaucoma drug list is built around deliberately causing or avoiding miosis, and because mydriatic (dilating) drops and mydriasis-causing systemic drugs are exactly what can trigger an angle-closure attack in a susceptible eye.
Once-nightly dosing, best IOP reduction of any single agent, good tolerability, cheap generics available.
Decades of use, solid efficacy and tolerability, but systemic beta-blockade risk (asthma, COPD, bradycardia).
Well-tolerated, effective, added when a first-line agent alone isn't enough or is contraindicated.
Effective but poorly tolerated relative to newer options; reserved for failure of better-tolerated combinations.
When two agents are needed, fixed-combination products(timolol-dorzolamide, timolol-brimonidine, brinzolamide-brimonidine, netarsudil-latanoprost) cut the number of daily doses. Fewer bottles means better adherence, it avoids the "washout effect" where a second drop given too soon after the first just gets diluted out before it can absorb, and it cuts total preservative exposure, which matters because chronic benzalkonium chloride exposure itself irritates the ocular surface over years of use.
1st lineagents are the default starting points; everything else is added or substituted as therapy escalates.
| Drug | Strength | Usual dose |
|---|---|---|
| Prostaglandin analogs 1st line- once nightly, best IOP reduction | ||
| Latanoprost | 0.005% | 1 drop every night |
| Latanoprostene bunod | 0.024% | 1 drop every night |
| Bimatoprost | 0.01%, 0.03% | 1 drop every night |
| Travoprost | 0.004% | 1 drop every night |
| Tafluprost (preservative-free) | 0.0015% | 1 drop every night |
| Beta blockers 1st line- all reduce aqueous production | ||
| Timolol | 0.25%, 0.5% | 1 drop daily to BID |
| Betaxolol (relatively β1-selective) | 0.5% soln / 0.25% suspension | 1 drop BID |
| Carteolol | 1% | 1 drop BID |
| Levobunolol | 0.25%, 0.5% | 1 drop BID |
| Metipranolol | 0.3% | 1 drop BID |
| Alpha2 agonists 2nd line- reduce production; brimonidine also boosts uveoscleral outflow | ||
| Brimonidine | 0.1%, 0.15%, 0.2% | 1 drop 2-3x daily |
| Apraclonidine (short-term / perioperative use) | 0.5%, 1% | 1 drop 2-3x daily |
| Carbonic anhydrase inhibitors 2nd line topical, last-resort oral | ||
| Dorzolamide (topical) | 2% | 1 drop 2-3x daily |
| Brinzolamide (topical) | 1% | 1 drop 2-3x daily |
| Acetazolamide (oral) | 125-250 mg tab | 125-250 mg 2-4x daily |
| Methazolamide (oral) | 25-50 mg tab | 25-50 mg 2-3x daily |
| Rho kinase inhibitor - newest class, opens trabecular outflow directly | ||
| Netarsudil | 0.02% | 1 drop every night |
| Cholinergic agonists 3rd line- open trabecular meshwork mechanically | ||
| Pilocarpine | 1%, 2%, 4% | 1 drop up to QID |
| Carbachol | 1.5%, 3% | 1 drop 2-3x daily |
| Cholinesterase inhibitor last resort | ||
| Echothiophate | 0.125% | 1 drop once to twice daily |
| Fixed-dose combinations | ||
| Timolol/dorzolamide | 0.5%/2% | 1 drop BID |
| Timolol/brimonidine | 0.5%/0.2% | 1 drop BID |
| Brinzolamide/brimonidine | 1%/0.2% | 1 drop TID |
| Netarsudil/latanoprost | 0.02%/0.005% | 1 drop every night |
They increase uveoscleral outflow by remodeling the ciliary muscle's extracellular matrix (increased matrix metalloproteinase activity loosens the tissue so fluid can escape between muscle bundles), with a smaller contribution from increased trabecular outflow as well. This is a pressure-independent pathway, which is part of why they work so reliably.
Latanoprostene bunoddeserves a special mention: it's a prodrug of latanoprost that is also metabolized to release a nitric-oxide-donating moiety, giving it two separate mechanisms for increasing outflow in one molecule.
Increased iris pigmentation(more melanin production, most visible in hazel/green/mixed-color irises turning browner) does not reverse when the drug is stopped. Eyelash growth and thickeningis the same mechanism and is actually marketed on its own as bimatoprost 0.03% (Latisse). Periorbital fat atrophy (a sunken-eye look with chronic use) and conjunctival hyperemia are also expected. Counsel patients on the iris color change specifically, since it's permanent and can be asymmetric if only one eye is treated.
Practical dosing note:give at night. Efficacy is not compromised by nighttime dosing the way some other classes are, and once-daily dosing itself is a major adherence advantage over agents dosed 2-3 times a day.
Nonselective beta blockers (timolol, levobunolol, metipranolol, carteolol) block β1 and β2 receptors in the ciliary epithelium, cutting aqueous humor production. Betaxolol is relatively β1-selective, which trades a bit of IOP-lowering potency for a somewhat better pulmonary safety margin, though it's still not risk-free.
Topical eye drops drain through the nasolacrimal duct into the nasal mucosa, where they're absorbed straight into the systemic circulation, bypassing first-pass hepatic metabolism entirely. That's enough absorbed nonselective beta blockade to worsen bronchospasm in asthma/COPD and to cause or worsen bradycardia and heart block. Nasolacrimal occlusion(pressing on the inner corner of the eye for 1-2 minutes after instillation) cuts systemic absorption meaningfully and is worth teaching to any patient on a topical beta blocker, especially if they have any pulmonary or cardiac history.
Historically the first-line workhorse before prostaglandins existed, and still first-line today, particularly useful when a patient specifically shouldn't have the cosmetic prostaglandin side effects or needs once-nightly gelling-solution timolol for adherence.
Alpha2 agonists reduce aqueous production (same cAMP-linked mechanism logic as beta blockers, different receptor) and brimonidine specifically also increases uveoscleral outflow, giving it a dual mechanism. Only brimonidine carries a primary chronic-use indication for glaucoma; apraclonidine is mainly used short-term, for example to blunt the IOP spike after laser eye procedures.
Apraclonidine develops tachyphylaxis(loses efficacy) with chronic use and has a notably high rate of allergic conjunctivitison repeated dosing. Brimonidine was specifically developed with reduced CNS penetration compared to older systemic alpha2 agonists like clonidine, which cuts (but doesn't eliminate) sedation and dry mouth. Both facts explain the therapy split: apraclonidine for a short burst, brimonidine for the long haul.
Systemic caution:alpha2 agonists can cause sedation, fatigue, dry mouth, and orthostatic hypotension even topically, and their CNS-depressant effect is more pronounced in infants and young children, where topical brimonidine is generally avoided.
CAIs block carbonic anhydrase type II in the ciliary epithelium, which the cell needs to generate the bicarbonate gradient that drives aqueous fluid secretion. Block the enzyme, and production drops. Topical agents (dorzolamide, brinzolamide) act locally with minimal systemic absorption. Oral agents (acetazolamide, methazolamide) are far more potent but come with real systemic burden: paresthesias, metallic taste, fatigue, GI upset, and a real risk of kidney stones with chronic use, which is exactly why they're reserved for when topical multidrug therapy has already failed.
CAIs are sulfonamide-derivative drugs, so they carry a caution in patients with a documented sulfonamide allergy. The clinically important point is that this risk is genuinely lower than with antibiotic sulfonamides (the aromatic amine and N1 substitution that drive most sulfa antibiotic hypersensitivity aren't present in CAIs), but it's still standard practice to ask about the allergy history and use clinical judgment rather than assume zero cross-reactivity.
Topical CAIs sting on instillation, which is a common (if minor) adherence barrier worth warning patients about up front.
Pilocarpine, a direct-acting M1/M3 muscarinic agonist, contracts the iris sphincter (producing miosis) and the ciliary muscle. Contracting the ciliary muscle mechanically pulls the trabecular meshwork open, increasing conventional outflow. Echothiophate, an irreversible cholinesterase inhibitor, produces the same downstream effect indirectly by letting endogenous acetylcholine accumulate at the same receptors; it has a very long duration of action and limited systemic absorption, which is part of why it stayed useful topically even though systemic cholinesterase inhibitors are far more dangerous.
Forced miosis and ciliary spasm cause exactly the side effects you'd predict: dim/poor night vision (the constricted pupil lets in less light), blurred or fluctuating near vision from constant accommodative spasm, and browache/headache from sustained ciliary muscle contraction. Newer classes hit the same or better IOP reduction without these functional vision complaints, which is why pilocarpine and echothiophate were pushed down the algorithm rather than out of it entirely.
Bonus use:pilocarpine's ability to physically pull a mechanically obstructed iris away from the trabecular meshwork is exactly why it's part of acute angle-closure drug therapy (see below), even though it's rarely first choice for chronic POAG anymore.
Netarsudil is the first approved Rho kinase inhibitor for glaucoma. It relaxes the actin-myosin cytoskeleton of the trabecular meshwork cells themselves, opening the conventional outflow pathway directly, and also lowers episcleral venous pressure, a second contributor to outflow resistance that essentially no other glaucoma drug class touches. Efficacy is roughly comparable to a beta blocker, and it can be added on top of other classes (see the netarsudil-latanoprost fixed combination).
Signature side effects:conjunctival hyperemia (redness) is common and cosmetically bothersome enough to affect adherence, and corneal verticillata (a whorled corneal deposit pattern, generally visually insignificant) can appear with chronic use.
This is the one true ophthalmic emergency in this chapter. High IOP from a mechanically sealed drainage angle needs to come down fast, and definitive treatment is procedural, not pharmacologic.
In an acute closed-angle attack, miosis physically drags the peripheral iris away from the trabecular meshwork, which is exactly the mechanical fix the emergency needs. In chronic open-angle disease, the angle is already open, so you're just trading the modest outflow gain for the night-vision and accommodation side effects, which is why it's a last-line option there instead.
This table (from the handbook) is a favorite exam source and a genuinely useful med-rec checklist, because the two glaucoma types are provoked by almost opposite drug categories.
| Open-angle risk | Closed-angle risk |
|---|---|
| Corticosteroids(ophthalmic = high risk; systemic, nasal, and inhaled all carry some risk) | Anticholinergics(topical and systemic), including ipratropium |
| Fenoldopam | Sympathomimetics(topical and systemic) |
| Ophthalmic anticholinergics, succinylcholine | Heterocyclic antidepressants, low-potency phenothiazines, antihistamines |
| Vasodilators, cimetidine (both low risk) | SSRIs, imipramine, venlafaxine, topiramate |
| Benzodiazepines, theophylline, tetracyclines, CAIs, MAOIs, topical cholinergics, CNS stimulants, vasodilators (all lower risk, but still on the list) |
Open-angle risk = corticosteroids.Steroids increase resistance within the trabecular meshwork itself over weeks to months of use, mimicking POAG. This is dose- and duration-dependent, and ophthalmic steroids are the highest-risk route. Closed-angle risk = anything anticholinergic or sympathomimetic.Both classes cause pupillary dilation (mydriasis), and in a patient with an anatomically narrow/shallow angle to begin with, a dilated pupil is exactly what pushes the peripheral iris up against the meshwork and triggers a crisis. This is why a "shallow anterior chamber" on an eye exam is a flag to be cautious with anticholinergics, antihistamines, and decongestants, and why topiramatespecifically is a known trigger for acute secondary angle closure, distinct from and in addition to its mydriatic-drug mechanism.
| Parameter | When | Watching for |
|---|---|---|
| IOP | Every 4-6 weeksinitially; every 3-4 monthsonce pressures are acceptable; more often after any therapy change | Whether the 20-30% reduction target from baseline is being met |
| Visual field testing | Every 6-12 months, more often if disease is unstable or worsening | New or progressive field loss despite "controlled" IOP |
| Optic disc exam / imaging | Every 6-12 months, same cadence as visual fields | Progressive cupping or structural change |
| Adherence | Every visit | This is a leading cause of "treatment failure" in a disease that gives patients zero symptomatic feedback to remind them to use the drops |
| Systemic effects | Per class (heart rate/pulmonary status on beta blockers; sedation/BP on alpha2 agonists; electrolytes/renal function on oral CAIs) | Class-specific systemic toxicity from what's nominally an eye drop |
Because the correlation between IOP and actual nerve damage is imperfect, there's no single number that applies to every patient. The typical goal is a 25-30% reductionfrom baseline, with the actual target depending on disease severity: generally <21 mm Hg, but pushed as low as <10 mm Hgfor very advanced disease, continued damage despite already-lower pressures, normal-tension glaucoma, or patients whose pretreatment pressures were already only in the low-to-mid teens.