View source for Topical Carbonic Anhydrase Inhibitors

{{Article
|Authors=Braden.A.Burckhard,Alexander.L.Ringeisen
|Category=Glaucoma
|Reviewer=Manishi.Desai
|Date reviewed=April 16, 2020
|Article status=Up to Date
}}
= Background  =

Primary open-angle glaucoma (POAG) is a multifactorial optic neuropathy associated visual field loss and progressive retinal ganglion cell death. The main risk factor for POAG is elevated intraocular pressure (IOP), but there are many other associated factors.  Topical carbonic anhydrase inhibitors (CAI) took many years to develop - due to the poor side-effect profile of oral CAIs - but were an important addition to the treatment of POAG.  Dorzolamide (TRUSOPT) and brinzolamide (AZOPT) both''' work by inhibiting carbonic anhydrase (isoenzyme II), which is found in the ciliary body epithelium'''. This reduces the formation of bicarbonate ions, which reduces fluid transport, reducing IOP. 

Dorzolamide and brinzolamide can be used topically because they have sufficient corneal penetration to reach the ciliary body. They may be used as monotherapy but most frequently are used in combination with other glaucoma medications, except for oral CAIs.  Commonly, these medications are combined with other topical glaucoma agents for additional effect.  Dorzolamide has been combined with the β receptor antagonist timolol into a single medication (COSOPT) and with the α2 adrenergic agonist brimonidine (COMBIGAN).  These combinations also benefit patients by making adherence to the medications more manageable; patients apply fewer drops and are responsible for fewer medications.

== Indications ==
Primary open-angle glaucoma.

== Mechanism of Action (proposed)  ==

Current pharmacological therapies for lowering the IOP in glaucoma include increasing aqueous humor outflow and suppression of aqueous humor production. '''CAIs work by suppressing aqueous humor production.'''   

Aqueous humor secretion depends on the production of bicarbonate (HCO-3) from carbonic anhydrase II, an isoenzyme found in the non-pigmented ciliary body epithelium. Chemically, carbonic anhydrase catalyzes carbon dioxide (CO2) hydration and conversion to carbonic acid (H2CO3), which freely dissociates into bicarbonate anions and protons. Bicarbonate formation influences fluid transport by affecting Na+, possibly by regulating the pH for optimal active ion transport. Blockade of carbonic anhydrase by CAIs in local tissues reduces the formation of bicarbonate ions, thus reducing fluid transport and IOP.    

It has also been proposed that CAIs cause vascular dilation and increased blood flow by increasing tissue CO2 concentrations and/or lowering tissue pH. Vascular abnormalities have been reported as contributing factors to glaucomatous optic neuropathy. Prospective clinical trials have demonstrated blood flow deficiencies of POAG patients in the retinal, choroidal, and retrobulbar circulations, and ischemia has been shown to correspond with areas of glaucomatous visual field loss. Although no studies have directly compared the ocular hemodynamic effects of systemic and topical CAI, many small prospective clinical trials suggest topical CAI therapies also increase ocular perfusion parameters.   

== Side effects  ==

The use of systemic CAIs have been associated with numerous side effects, giving patients significant problems with malaise, fatigue, depression, paresthesias, metallic taste, nausea, decreased libido, hypokalemia, aplastic anemia, metabolic acidosis, and nephrolithiasis. The development of topical CAIs minimized these relatively common side effects, although small amounts of the medication have been reported to reach systemic circulation.  A rare incidence of topical CAI induced thrombocytopenia with dorzolamide 2% was reported by Martin et al. in 2001.  

Some side effects of topical CAIs include bitter after-taste, burning and stinging from local reactions, allergic reactions of the conjunctiva, and superficial punctate keratopathy (SPK).  

== Preparations and Dosing  ==
Dorzolamide Hydrochloride (Trusopt) Preparation: Solution, 2%. 
* Dosage: 1 drop 3 times daily when used alone or twice daily if being used in combination with other topical glaucoma treatment.


Brinzolamide (Azopt) Preparation: Suspension, 1%.
* Dosage: 1 drop 3 times daily when used alone or twice daily if being used in combination with other topical glaucoma treatment.

= References  =
#Henderer JD, Rapuano CJ. Ocular Pharmacology. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. Chapter 64. New York, NY: McGraw-Hill; 2011.
#Flach AJ, Fraunfelder FW.  Ophthalmic Therapeutics. In: Riordan-Eva P, Cunningham ET, Jr. eds. Vaughan & Asbury's General Ophthalmology, 18e. Chapter 22. New York, NY: McGraw-Hill; 2011.
#Brent Siesky, PhD1, Alon Harris, MS, PhD1, , Edward Brizendine, MS2, Clarice Marques, MD1, Jennifer Loh, MD1, Joseph Mackey, MD1, Jennifer Overton, MD1, Peter Netland, MD3. Major Review: Literature Review and Meta-Analysis of Topical Carbonic Anhydrase Inhibitors and Ocular Blood Flow. Survey of Ophthalmology. Volume 54, Issue 1, January–February 2009, Pages 33–46. 
#Manik Goel, Renata G Picciani, Richard K Lee, and Sanjoy K Bhattacharya. Aqueous Humor Dynamics: A Review. Open Ophthalmology Journal. 2010; 4: 52–59. Published online 2010, Sep 3.
#Martin, Xavier D. MD; Danese, Marco MD. Dorzolamide-induced Immune Thrombocytopenia: A Case Report and Literature Review, Journal of Glaucoma: April 2001;  Volume 10 , Issue 2, pages 133-135.