Brinzolamide

Brinzolamide

Systematic (IUPAC) name
(5R)-5-ethylamino-3-(3-methoxypropyl)- 2,2-dioxo-2λ6,9-dithia- 3-azabicyclo[4.3.0]nona-7,10-diene- 8-sulfonamide
Clinical data
Trade names	Azopt, Befardin
AHFS/Drugs.com	monograph
MedlinePlus	a601233
Licence data	EMA:Link, US FDA:link
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Ophthalmic
Pharmacokinetic data
Bioavailability	Absorbed systemically, but below detectable levels (less than 10 ng/mL)
Protein binding	~60%
Biological half-life	111 days
Excretion	Renal (60%)
Identifiers
CAS Number	138890-62-7
ATC code	S01EC04 (WHO)
PubChem	CID: 68844
IUPHAR/BPS	6797
DrugBank	DB01194 Y
ChemSpider	62077 Y
UNII	9451Z89515 Y
KEGG	D00652 Y
ChEBI	CHEBI:3176 Y
ChEMBL	CHEMBL220491 Y
Chemical data
Formula	C12H21N3O5S3
Molecular mass	383.51 g/mol
SMILES O=S(=O)(c1sc2c(c1)[C@@H](NCC)CN(CCCOC)S2(=O)=O)N
InChI InChI=1S/C12H21N3O5S3/c1-3-14-10-8-15(5-4-6-20-2)23(18,19)12-9(10)7-11(21-12)22(13,16)17/h7,10,14H,3-6,8H2,1-2H3,(H2,13,16,17)/t10-/m0/s1 Y Key:HCRKCZRJWPKOAR-JTQLQIEISA-N Y
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Brinzolamide (trade names Azopt, Alcon Laboratories, Befardin, Fardi Medicals, ) is a carbonic anhydrase inhibitor used to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Chemistry

Brinzolamide is a carbonic anhydrase inhibitor (specifically, carbonic anhydrase II). Carbonic anhydrase is found primarily in erythrocytes (but also in other tissues including the eye). It exists as a number of isoenzymes, the most active of which is carbonic anhydrase II (CA-II).

Indications

Use for the treatment of open-angle glaucoma and raised intraocular pressure due to excess aqueous humor production.

Pharmacodynamics

Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion and thus lowers the intraocular pressure in the anterior chamber, presumably by reducing the rate of formation of bicarbonate ions with subsequent reduction in sodium and fluid transport; this alleviates the effects of open-angle glaucoma.

Pharmacokinetics

Absorption

The recommended frequency for topical application is two times per day. Following ocular instillation, the suspension is systemically absorbed to some degree; however the plasma concentrations are low and generally below the limits of detection (less than 10 ng/mL) due to extensive binding by tissues and erythrocytes. Oral administration is less-favored due to variable absorption from the stomach mucosa and an increased side-effect profile versus ophthalmic administration.

Distribution

The compound is fairly well protein-bound (60%), but adheres extensively to the carbonic anhydrase-containing erythrocytes. Due to the abundance of readily-bound erythrocytes and minimal known metabolism, Brinzolamide's whole blood half-life is very long (111 days).

Metabolism

While definitive sites of metabolism have not been firmly established, there are several metabolites worthy of note. N-Desethylbrinzolamide is an active metabolite of the parent compound, and thus exhibits carbonic anhydrase inhibitory activity (largely carbonic anhydrase-I, when in the presence of Brinzolamide) and also accumulates in the erythrocytes. However, Brinzolamide's other known metabolites (N-Desmethoxypropylbrinzolamide and O-Desmethylbrinzolamide) either have no activity or their activity is currently unknown.

Excretion

Brinzolamide is excreted primarily unchanged (60%) in the urine, although the renal clearance rate has not been definitively determined. N-Desethylbrinzolamide is also found in the urine along with lower concentrations of the inactive metabolites, N-Desmethoxypropylbrinzolamide and O-Desmethylbrinzolamide; exact levels have not been definitively determined.

Cautions

Side effects

• Common, but mild: Blurred vision; bitter, sour, or unusual taste; itching, pain, watering, or dryness of the eyes; feeling that something is in the eye; headache; runny nose

• Rare, but serious: Fast or irregular heartbeat; fainting; skin rash, hives, or itching; severe eye irritation, redness, or swelling; swelling in the face, lips, or throat; wheezing or trouble breathing

Precautions

• Hypersensitivity to other sulfonamides
• Acute angle-closure glaucoma
• Concomitant administration of oral carbonic anhydrase inhibitors
• Moderate-to-severe renal or hepatic insufficiency

Combination with timolol

The combination of brinzolamide with timolol is marketed under the trade name Azarga. Clinical studies have shown this combination to be more effective than either of the medications taken as monotherapy.

References

• Product Information: Azopt(R), brinzolamide. Alcon Laboratories, Inc, Fort Worth, TX, 1998b.
• Sall KN, Greff LJ, Johnson-Pratt LR, et al.: Dorzolamide/timolol combination versus concomitant administration of brimonidine and timolol: six-month comparison of efficacy and tolerability. Ophthalmology 2003; 110:615-624.