Screening of Ophthalmic and Antiglaucoma Drugs

Screening of Ophthalmic and Antiglaucoma Drugs

1. Definition, scope & rationale of ocular drug screening

• Experimental ophthalmic pharmacology is the preclinical (in vitro / ex vivo / in vivo animal) evaluation of candidate drugs acting on the eye — chiefly intraocular-pressure (IOP)–lowering (antiglaucoma) agents, but also miotics/mydriatics, ocular anti-inflammatories, anti-cataract agents, corneal anaesthetics, and ocular-safety (irritation) profiling. This topic is the bench-and-animal-model methodology, NOT clinical ophthalmic pharmacotherapy (SK Gupta Ch.17, pp.278–89; Vogel V4 Part XV, pp.3747–87).
• Glaucoma is a progressive optic neuropathy characterised by visual-field changes and cupping of the optic disc; elevated IOP is an important (but not the only) risk factor (SK Gupta Ch.17, p.278).
• The rise in IOP results from ⟶ increased aqueous formation, reduced outflow rate, or raised episcleral venous pressure; obstruction to aqueous circulation at the pupil or to drainage at the anterior-chamber angle causes glaucoma (SK Gupta Ch.17, p.278).
• Pathophysiology of visual loss — optic-nerve axons are compressed at the optic disc by elevated IOP, blocking axonal cytoplasmic flow from retinal neuronal cell bodies to the optic-nerve fibres; the resulting loss of fibre nutrition kills neurons. Compression of the retinal artery adds ischaemic neuronal damage (SK Gupta Ch.17, p.278).
• Normal IOP ranges 10–20 mmHg; in glaucoma it can rise to ~60 mmHg — pressures of this magnitude cause vision loss (SK Gupta Ch.17, p.278).
  • Vogel's clinical-consensus figures: normal IOP 10–20 mmHg; mean ≈ 15.5 mmHg with ~2.75 mmHg fluctuation; population range 10–21 mmHg (mean ~15–16 ± 3.5 mmHg over a 24-h cycle) (Vogel V4 p.3750).
  • Ocular hypertension (OHT) = IOP above normal without optic-nerve damage or visual-field loss — the single most important risk factor for glaucoma (Vogel V4 p.3750).
  • Ocular hypotony = IOP ≤ 5 mmHg (Vogel V4 p.3750).
• Disease burden framing (screening rationale) — WHO 2005: glaucoma ≈ 12% of world blindness; global prevalence (40–80 y) 64.3 million (2013) → projected 76.0 million (2020) → 111.8 million (2040); India carries 13% of global glaucoma blindness and ~50% of cases remain undetected (SK Gupta Ch.17, p.278).
• Goal of screening — identify agents that lower IOP below ~20 mmHg (mild disc changes) or below ~15 mmHg (severe disc changes), or that are neuroprotective/anti-inflammatory/anti-cataract, using models that mimic the human disease and permit tonometric monitoring (SK Gupta Ch.17, pp.279, 289).
• The quantitative driver of IOP used across assays: IOP = F/C + P_V, where F = aqueous fluid formation rate, C = outflow facility, P_V = episcleral venous pressure — every antiglaucoma target manipulates one of these three terms (Vogel V4 p.3749).

Criteria for an ideal screening model (SK Gupta Ch.17, p.279):

• Animal eye structure closely resembling the human eye (surface area, anterior segment, outflow pathway).
• The IOP-raising method should be easy to perform, produce a reliable/reproducible IOP rise, permit tonometric monitoring in the live animal, and minimise secondary ocular changes (e.g. inflammation).
• Economical, easily housed/handled animals — the rabbit is the most common and feasible model under current animal-welfare constraints; rodents (rat/mouse) are increasingly preferred for laser models on grounds of availability and cost (SK Gupta Ch.17, pp.279, 289).