Glaucoma medicines, SLT and MIGS

The contemporary management of glaucoma spans a sophisticated continuum ranging from targeted topical pharmacotherapy and biological laser trabeculoplasty to ab-interno micro-invasive implants and guarded incisional filtration surgery. Selecting the optimal intervention requires balancing efficacy, long-term diurnal stability, safety profiles, patient adherence, and individual lifestyle factors.

---

Medical Hypotensive Pharmacotherapy

Topical ocular hypotensive medications lower intraocular pressure either by suppressing aqueous humor secretion from the non-pigmented ciliary epithelium or by accelerating aqueous outflow through the conventional (trabecular) or unconventional (uveoscleral) pathways.

1. Prostaglandin Analogues (PGAs)

• Active Compounds: Latanoprost 0.005%, Bimatoprost 0.01% / 0.03% (prostamide), Travoprost 0.004%, and Tafluprost 0.0015% (preservative-free formulation).
• Mechanism of Action: Selective agonists of the prostanoid FP receptor located on ciliary muscle cells and scleral fibroblasts. Activation stimulates the transcription and upregulation of Matrix Metalloproteinases (MMPs: MMP-1, MMP-3, MMP-9). These enzymes degrade and remodel extracellular collagen between ciliary muscle bundles, markedly reducing resistance along the uveoscleral (unconventional) outflow pathway.
• Selection: Prostaglandin analogues are common initial medicines, often once daily; effect, dosing and suitability depend on drug, label and patient factors.
• Adverse Effects:
  • Ocular: Conjunctival hyperemia (bimatoprost $>$ travoprost $>$ latanoprost); irreversible hyperpigmentation of the iris stroma (melanogenesis stimulated in existing melanocytes, not cellular hyperplasia; common in hazel/green-brown irides); eyelash hypertrichosis (hypertrophy, lengthening, thickening, and darkening of cilia); Prostaglandin-Associated Periorbitopathy (PAP) characterized by orbital fat atrophy, deepening of the upper eyelid sulcus, enophthalmos, and mild ptosis; cystoid macular edema (CME, especially in pseudophakic eyes with posterior capsule tears); anterior uveitis; and reactivation of latent herpes simplex keratitis (HSV).

2. Beta-Adrenergic Antagonists (Beta-Blockers)

• Active Compounds: Timolol maleate 0.25% / 0.5% (non-selective $\beta_1$ and $\beta_2$); Betaxolol 0.25% suspension / 0.5% solution (cardioselective $\beta_1$); Carteolol 1% (non-selective with intrinsic sympathomimetic activity [ISA]).
• Mechanism of Action: Competitive antagonism of $\beta_2$-receptors on the non-pigmented ciliary epithelium, inhibiting Gs-protein activation of adenylyl cyclase, reducing cyclic AMP (cAMP), and decreasing aqueous humor secretion by 20% to 25%. Dosed once daily in the morning or twice daily.
• Nocturnal effect: Beta-blockers often lower nocturnal pressure less than daytime pressure because aqueous production falls during sleep. “Zero effect at night” is too absolute.
• Systemic Contraindications & Side Effects:
  • Respiratory: Severe bronchospasm and respiratory failure. ABSOLUTE CONTRAINDICATION in bronchial asthma and severe COPD.
  • Cardiovascular: Sinus bradycardia ($<50$ bpm), second-degree or third-degree atrioventricular (AV) heart block, cardiogenic shock, and overt congestive heart failure.
  • Metabolic / Neuropsychiatric: Masking of adrenergic warning signs of hypoglycemia (tachycardia, tremor) in insulin-dependent diabetics; fatigue, depression, sleep disturbances, exercise intolerance, and erectile dysfunction.
  • Betaxolol: Cardioselectivity ($\beta_1$) provides a safer pulmonary profile, but hypotensive efficacy is lower (~15–20% reduction).

3. Alpha-2 Adrenergic Agonists

• Active Compounds: Brimonidine tartrate 0.1% / 0.15% (with Purite preservative) / 0.2%; Apraclonidine 0.5% / 1.0% (used peri-procedurally to blunt post-laser IOP spikes).
• Mechanism of Action: Highly selective $\alpha_2$-adrenoreceptor agonist (selectivity $\alpha_2:\alpha_1$ is 1000:1). Acts via a dual mechanism: 1) decreases aqueous humor secretion through Gi-protein inhibition of adenylyl cyclase; and 2) increases uveoscleral outflow via stimulation of endogenous prostaglandin synthesis. Delivers 20% to 25% IOP reduction; dosed twice or three times daily.
• Adverse Effects & Black Box Pediatric Warning:
  • Local: High rate of allergic contact blepharoconjunctivitis (follicular conjunctivitis, erythema in 15–20% of chronic users).
  • Systemic: Xerostomia (dry mouth), fatigue, drowsiness, headache, hypotension, and bradycardia. Contraindicated with monoamine oxidase (MAO) inhibitors and tricyclic antidepressants.
  • FATAL PEDIATRIC WARNING: Strictly contraindicated in neonates, infants, and children under 2 years of age. Brimonidine readily crosses the immature blood-brain barrier, stimulating central $\alpha_2$-receptors to produce life-threatening central nervous system depression, profound somnolence, hypothermia, severe bradycardia, hypotension, and fatal respiratory arrest/apnea.

4. Carbonic Anhydrase Inhibitors (CAIs)

• Active Compounds: Topical: Dorzolamide hydrochloride 2%, Brinzolamide 1% (suspension, pH 7.5, causing significantly less stinging than dorzolamide, pH 5.6). Systemic: Acetazolamide (Diamox, oral/IV), Methazolamide.
• Mechanism of Action: Reversibly inhibits carbonic anhydrase II in the non-pigmented ciliary epithelium, slowing the conversion of $CO_2$ and $H_2O$ into bicarbonate ($HCO_3^-$). This impairs active sodium and water transport into the posterior chamber, suppressing aqueous production by 15% to 20% (topical) or 30% to 40% (systemic).
• Adverse Effects:
  • Topical: Bitter metallic dysgeusia, superficial punctate keratitis, stinging, and irreversible corneal endothelial decompensation in compromised corneas (e.g., Fuchs endothelial dystrophy).
  • Systemic: Paresthesias (tingling of extremities), metabolic acidosis, hypokalemia, malaise, anorexia, gastrointestinal distress, calcium phosphate nephrolithiasis, idiosyncratic acute transient myopia/choroidal effusion, and rare fatal idiosyncratic aplastic anemia, agranulocytosis, and Stevens-Johnson syndrome. Caution in sulfa allergy.

5. Rho Kinase (ROCK) Inhibitors

• Active Compounds: Netarsudil 0.02% (Rhopressa), Ripasudil 0.4%.
• Mechanism of Action: Inhibits Rho-associated protein kinase (ROCK-1 and ROCK-2), promoting actin stress fiber disassembly, focal adhesion breakdown, and cellular relaxation within the trabecular meshwork and Schlemm canal endothelium. This directly lowers conventional trabecular outflow resistance. Netarsudil secondarily lowers episcleral venous pressure (EVP) and inhibits the norepinephrine transporter (NET).
• Efficacy and adverse effects: Netarsudil response varies with baseline pressure and the patient. Hyperaemia, cornea verticillata and conjunctival haemorrhage can occur; reticular epithelial corneal oedema is also a recognized adverse effect. Use the locally authorized formulation and product information; do not promise a fixed 4–5 mmHg fall or assume every corneal change is harmless.

Laser Trabeculoplasty and the LiGHT Trial

Selective laser trabeculoplasty (SLT) targets pigmented trabecular cells with a short-pulsed 532-nm laser and stimulates an outflow response. It can be offered as initial therapy in suitable open-angle glaucoma or ocular hypertension, or as an adjunct. Discuss transient inflammation, pressure spikes, incomplete response and later need for medication or repeat treatment.

LiGHT compared an initial SLT strategy with drops in treatment-naive OHT/open-angle glaucoma. At three years, 74.2% of patients in the SLT group remained drop-free at target. The six-year report in Ophthalmology (2023) found 69.8% of SLT-group eyes remained at target without medical or surgical treatment; progression occurred in 19.6% versus 26.8% in the initial-drops group. Do not mix patient and eye denominators or attribute differences in cataract surgery to proven preservative causation.

SLT can be repeated in selected eyes, with variable response. Argon laser trabeculoplasty produces more thermal structural change; repeat options and safety differ. Check the angle, pigment, inflammation, baseline pressure and follow-up capacity before laser. See the six-year trial report.

Micro-Invasive Glaucoma Surgery (MIGS)

MIGS terminology varies. Many trabecular procedures use an ab-interno approach and preserve conjunctiva, but bleb-forming microstents and ab-externo microshunts have different anatomy and postoperative risks. Describe the actual route, pressure goal and evidence rather than applying a universal five-item definition to every small implant.