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An '''ocular hypotensive agent''' is a medicine that lowers the intraocular pressure. The category is, by membership, almost identical to that of the [[:Category:Glaucoma_medications|glaucoma medications]], because lowering the intraocular pressure is the principal pharmacologic strategy for the treatment of glaucoma; the two category names exist as parallel listings, one organised by mechanism and one by indication, because the underlying pharmacology can be described coherently from either direction. This page describes the mechanism side: how the intraocular pressure is generated, why it has to be lowered, and how each pharmacological class lowers it. The clinical-and-historical side (the disease called glaucoma, its surgical and laser treatments, the trial evidence that defines current practice) lives at [[:Category:Glaucoma_medications|glaucoma medications]].

The intraocular pressure is set by the balance between the rate at which aqueous humour is produced by the non-pigmented ciliary epithelium of the [[wikipedia:Ciliary body|ciliary body]] and the rate at which it leaves the eye by two outflow pathways: the trabecular (conventional) outflow through the trabecular meshwork into Schlemm's canal and the episcleral veins, and the uveoscleral (unconventional) outflow through the ciliary muscle and into the suprachoroidal space. Aqueous production proceeds at approximately 2.5 microlitres per minute in the resting adult eye and is the work of the membrane-bound transporters of the ciliary epithelium, principally the Na+/K+-ATPase, the carbonic anhydrase, and the chloride and bicarbonate transporters. Trabecular outflow accounts for about 80 percent of the aqueous drainage and is pressure-dependent; uveoscleral outflow accounts for the remaining 20 percent and is largely pressure-independent.

This three-element scheme (production, trabecular outflow, uveoscleral outflow) sets the targets of every clinically used ocular hypotensive class. The earliest agents acted on outflow: the cholinergic miotics [[wikipedia:Pilocarpine|pilocarpine]] and [[wikipedia:Physostigmine|physostigmine]], introduced in the 1860s and 1870s, lower the intraocular pressure by contracting the longitudinal fibres of the ciliary muscle and pulling the trabecular meshwork open, increasing conventional outflow.<ref name="fraser1863">Fraser TR. On the characters, actions, and therapeutic uses of the bean of Calabar (Physostigma venenosum, Balfour). ''Edinburgh Medical Journal''. 1863;9:36-56.</ref> The miotics have, since the 1990s, given way to medicines without their pupillary side effect, but the mechanistic precedent stands.

The 1953 introduction of [[wikipedia:Acetazolamide|acetazolamide]] opened the production side. Carbonic anhydrase in the ciliary epithelium catalyses the hydration of carbon dioxide to bicarbonate, and the bicarbonate transport across the basal membrane drives the net secretion of aqueous; inhibiting the enzyme reduces secretion by roughly half.<ref name="becker1954ohp">Becker B. Decrease in intraocular pressure in man by a carbonic anhydrase inhibitor, Diamox. A preliminary report. ''American Journal of Ophthalmology''. 1954 Jan;37(1):13-15. PMID 13114212.</ref> The systemic acetazolamide of 1953 was followed by the topical [[Dorzolamide|dorzolamide]] in 1995 and brinzolamide in 1998; the topical agents avoid the systemic adverse effects of paraesthesia, metallic taste, anorexia, fatigue, and a small but real risk of Stevens-Johnson syndrome.

The 1978 introduction of topical [[wikipedia:Timolol|timolol]] added a second production-side mechanism. The beta-adrenergic receptors of the ciliary epithelium, when stimulated by endogenous catecholamines, drive cyclic-AMP-mediated aqueous secretion; a beta-blocker on the ciliary epithelium reduces production by approximately 25 to 30 percent. The selective alpha-2 agonists [[wikipedia:Apraclonidine|apraclonidine]] and [[Brimonidine|brimonidine]] reduce production by a separate mechanism (inhibition of adenylyl cyclase via the inhibitory G-protein) and, at the same time, enhance uveoscleral outflow; the dual mechanism gives the class an additive effect with both the prostaglandins and the beta-blockers.

The uveoscleral pathway was, until 1996, the smaller of the two outflow routes and not specifically pharmacologically targeted. The Hungarian-American pharmacologist [[wikipedia:László Z. Bitó|László Bitó]] showed in the late 1970s and 1980s that low concentrations of prostaglandin F2α paradoxically lowered intraocular pressure by markedly enhancing the uveoscleral outflow, through remodelling of the extracellular matrix of the ciliary muscle and downregulation of matrix metalloproteinases; the resulting [[Latanoprost|latanoprost]] (Xalatan, Pharmacia, 1996) and [[Bimatoprost|bimatoprost]] and travoprost lowered intraocular pressure by 28 to 32 percent on once-daily evening dosing, more than any class before.<ref name="bito1989ohp">Bito LZ, Stjernschantz J, Resul B, Miranda OC, Basu S. The ocular effects of prostaglandins and the therapeutic potential of a new PGF2 alpha analog, PhXA41 (latanoprost), for glaucoma management. ''Journal of Lipid Mediators''. 1993 Jul;6(1-3):535-543. PMID 8358017.</ref> The prostaglandins displaced timolol as the standard first-line topical therapy within five years of their introduction and remain so.

The most recent mechanistic target is the trabecular meshwork itself. The Rho-associated kinase (ROCK) inhibitor [[wikipedia:Netarsudil|netarsudil]] (Aerie, 2017) acts directly on the actomyosin contractility of the trabecular meshwork cells and on Schlemm's canal endothelial cells, increasing conventional outflow facility for the first time with a pharmacological agent. Trabecular meshwork cells are now under active investigation as a target distinct from aqueous secretion or uveoscleral remodelling, and additional ROCK inhibitors, selective adenosine-A1 agonists, and other trabecular-targeted agents are in trial.

== Classes indexed ==

By the part of the aqueous-humour dynamic on which the medicine acts:

* '''Reduced aqueous production''' (ciliary-epithelium-acting agents):
** [[:Category:Carbonic_anhydrase_inhibitors|Carbonic anhydrase inhibitors]] (topical: [[Dorzolamide|dorzolamide]], brinzolamide; oral: [[wikipedia:Acetazolamide|acetazolamide]], methazolamide)
** Topical beta-blockers ([[:Category:Beta-blockers|beta-blockers]] used ophthalmically): timolol, betaxolol, levobunolol, carteolol
** Topical alpha-2 agonists: [[Brimonidine|brimonidine]], apraclonidine (which act both on production and on uveoscleral outflow)
* '''Enhanced uveoscleral outflow''':
** Prostaglandin analogues (uveoscleral outflow): [[Latanoprost|latanoprost]], [[Bimatoprost|bimatoprost]], travoprost, tafluprost
** Alpha-2 agonists (the uveoscleral component of their action)
* '''Enhanced trabecular outflow''':
** Cholinergic miotics (ciliary-muscle contraction pulling the trabecular meshwork open): pilocarpine, carbachol, echothiophate
** Rho-associated kinase inhibitors (direct relaxation of trabecular meshwork cells): [[wikipedia:Netarsudil|netarsudil]]
* '''Hyperosmotic dehydration of the vitreous''' (emergency reduction of intraocular pressure in acute angle-closure):
** Intravenous [[wikipedia:Mannitol|mannitol]], oral glycerol

== Notes on scope ==

The boundary of this category is "medicine whose principal pharmacological action is to lower the intraocular pressure." The category overlaps almost completely with [[:Category:Glaucoma_medications|glaucoma medications]], which contains the same medicines organised by clinical indication; the article at that page describes the disease and the trial evidence, the article here describes the underlying physiology. The medicines used in non-glaucomatous causes of elevated intraocular pressure (intraocular trauma, postoperative inflammation, uveitic glaucoma, neovascular glaucoma associated with retinal disease) are listed here when their indication includes IOP reduction. The medicines used for non-pressure conditions of the eye (the [[:Category:Ophthalmic_antihistamines|ophthalmic antihistamines]], the topical antibiotics, the antifungals, the cycloplegics and mydriatics, the dry-eye medicines, and the intravitreal anti-VEGF agents for macular degeneration) are not ocular hypotensive agents and belong to those categories.

== About these pages ==

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.

== References ==

<references/>

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Category:Ocular hypotensive agents - Revision history

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