Brinzolamide

Pharmacological properties

Brinzolamide ((r) - (+) - 4-ethylamino-2- (3-methoxypropyl) -3,4-dihydro-2n-thieno [3,2-e] -1,2-thiazine-6-sulfonamide-1 , 1-dioxide) - antiglaucoma agent, carbonic anhydrase inhibitor. selectively inhibits the activity of carbonic anhydrase ii (ka ii). carbonic anhydrase (ka) is an enzyme involved in the process of hydration of carbon dioxide and dehydration of carbonic acid. in the human body, this enzyme is represented by various isoenzyme forms, the most active of which is ka ii, originally found in red blood cells, and then in cells of other tissues, including eye tissue. inhibition of the ciliary body of the eye leads to a decrease in the secretion of intraocular fluid (mainly due to a decrease in the formation of bicarbonate ions with a subsequent decrease in sodium and fluid transport) and a decrease in intraocular pressure, an increase in which is the main factor in the pathogenesis of ocular nerve damage and glaucomatous narrowing of the visual field.

For brinzolamide in vitro, the activity and selectivity of inhibition relative to CA II are: IR₅₀ = 3.2 nM, K_and = 0.13 nM.

After instillation into the eye, brinzolamide is absorbed into the blood. Due to its high affinity for CA II, brinzolamide quickly and easily penetrates red blood cells and has a long half-life from the blood - approximately 111 days. In the human body, a metabolite (N-desethyl-brinzolamide) is formed, which also accumulates in red blood cells and, in the presence of brinzolamide, is active mainly against CA I. In plasma, brinzolamide and its metabolite are determined in minimal concentrations, which in most cases are below the limit of sensitivity of the quantitative method determination (less than 7.5 ng / ml). It binds to plasma proteins by approximately 60%. Brinzolamide is excreted mainly in the urine unchanged (about 60%). About 20% is excreted as a metabolite. N-desethyl-brinzolamide and small amounts of N-desmethoxypropyl and O-desmethylated metabolite are also found in urine.

When conducting pharmacokinetic studies of healthy volunteers, brinzolamide was administered orally by 1 mg in capsules 2 times a day for 32 weeks. To assess the level of systemic inhibition of CA, the activity of CA in erythrocytes was measured. Saturation of erythrocytes with brinzolamide KA-II was achieved after 4 weeks (the concentration in erythrocytes was approximately 20 μm). N-deethylbrinzolamide accumulated in red blood cells until a stable concentration was reached, which was in the range of 6–30 μmol for 20–28 weeks. The inhibition of the total activity of erythrocyte CA-II in the equilibrium state was approximately 70–75%.

Patients with moderate renal failure (creatinine clearance of 30-60 ml / min) were prescribed orally 1 mg of brinzolamide 2 times a day for 54 weeks. The concentration of brinzolamide in erythrocytes after 4 weeks was in the range of 20–40 μm. In the equilibrium state, the concentration of brinzolamide and its metabolite in erythrocytes was in the range of 22–46.1 and 17.1–88.6 μm, respectively. With a decrease in creatinine clearance, the concentration of N-deethylbrinzolamide in erythrocytes increased, and the total activity of CA in erythrocytes decreased, however, the concentration of brinzolamide in erythrocytes and the activity of KA-II remained unchanged. In patients with significant renal failure, the degree of inhibition of the total activity of the CA was higher, although it was less than 90% in equilibrium.

In a study with topical administration to the eyes, the concentration of brinzolamide in red blood cells in equilibrium was the same as the concentration established by oral administration, but the concentration of N-deethylbrinzolamide was lower. CA activity was approximately 40–70% of its initial level.

Indications

Elevated intraocular pressure or open-angle glaucoma (as monotherapy in patients insensitive to therapy with β-adrenergic receptor blockers, or in patients for whom β-adrenergic receptor blockers are contraindicated, or as an additional tool for therapy with β-adrenergic receptor blockers).

Application

When using azopt as monotherapy or additional therapy, 1 drop of the drug is instilled into the sore eye (eyes) 2 times a day. in some patients, the best result is achieved with the appointment of 1 drop 3 times a day.

After instillation, it is recommended to press the mouth of the nasolacrimal canal or close the eyelids tightly to reduce the systemic absorption of the drug and reduce the likelihood of developing systemic side effects.

In the case of replacing another antiglaucoma drug with Azopt, you should stop using another drug and switch to Azopt in a day. If several drugs are prescribed, they must be injected into the eye with an interval of at least 5 minutes. Shake well before use.

Contraindications

Hypersensitivity to the drug.

Side effects

In clinical trials involving more than 1,500 patients using azopt as monotherapy or in combination with 0.5% r-rum timolol maleate, the most common side effects were: taste changes (bitter or unusual taste) (5.3%), temporary blurred vision after instillation, lasting from several seconds to several minutes (4.8%). It was also reported about the following side effects, which were rated as undeniably, probably or possibly related to the use of the drug. they occurred frequently (10%) or rarely (1%).

Ophthalmic effects

Frequent: blurred vision, discomfort in the eyes (transient burning in eyes or tingling sensation after instillation of the drug), a foreign body sensation in the eye, hyperemia.

Rare: dry eyes, eye pain, discharge from the eyes, itching, keratitis, blepharitis, conjunctivitis, crusting of the eyelids, stickiness, lacrimation, eye fatigue, keratopathy, conjunctival follicles and visual impairment.

The following ophthalmic side effects were observed only in studies using Azopt in combination with timolol.

Rare: corneal erosion.

System effects

Azopt is a sulfonamide inhibitor of CA and can be absorbed by entering the systemic circulation. In this regard, other side effects inherent in this class of drugs are possible, although during clinical trials they were not observed.

An undesirable systemic effect associated with the use of Azopt, which was most often reported in clinical trials, was a change in taste (bitter or unusual taste in the mouth after instillation of the drug). This side effect is probably caused by the penetration of eye drops into the nasopharynx through the nasolacrimal canal. Pressing the mouth of the nasolacrimal canal or tightly closing the eyelids after instillation reduces the incidence of this side effect.

Are common

Rare: chest pain and alopecia.

From the gastrointestinal tract

Frequent: taste change (bitter or unusual taste).

Rare: dry mouth, nausea, and dyspepsia.

Hypersensitivity reactions

Rare: dermatitis.

From the nervous system

Frequent: headache.

Rare: paresthesia, depression, dizziness.

From the respiratory system

Rare: rhinitis, shortness of breath, pharyngitis, bronchitis, nosebleeds, and hemoptysis.

Side effects from the gastrointestinal tract, nervous system, blood system, kidneys and metabolism, as a rule, arise with the systemic use of CA inhibitors. The same types of side effects inherent to oral ACA inhibitors may occur when applied topically.

special instructions

Azopt is a sulfonamide and undergoes systemic absorption despite the fact that it is applied topically. in this regard, when using brinzolamide in the form of eye drops, adverse reactions characteristic of sulfonamides can occur.

If serious adverse reactions or hypersensitivity occur, use should be discontinued.

The experience with Azopt in treating patients with pseudoexfoliation glaucoma and pigmented glaucoma is limited.

The use of brinzolamide in patients with angle-closure glaucoma has not been studied.

The effect of brinzolamide on the function of the corneal epithelium when it is damaged has not been studied.

Special studies on the use of the drug in patients who wear contact lenses have not been conducted, therefore, it is recommended to monitor such patients with the use of brinzolamide, since CA inhibitors can affect the hydration of the cornea, and the use of contact lenses can increase the risk of corneal damage. For other corneal injuries, such as in patients with diabetes mellitus, careful care is also recommended. It has been reported that benzalkonium chloride, which is commonly used as a preservative in ophthalmic preparations, can cause the development of acupuncture keratopathy and / or toxic ulcerative keratopathy. Since Azopt contains benzalkonium chloride, regular monitoring is necessary during prolonged treatment with the drug in patients with dry eyes or patients with corneal injuries.

Benzalkonium chloride can be absorbed by soft contact lenses, so patients should be warned that it is necessary to wait 15 minutes after instillation of Azopt and only then put on contact lenses. Azopt should not be used while wearing contact lenses.

The possibility of developing withdrawal after discontinuation of the drug has not been studied.

Oral carbonic anhydrase inhibitors may decrease the ability to perform work requiring concentration and coordination in elderly patients. Azopt is absorbed when applied topically, therefore, the development of these systemic effects is possible.

Shake well before use. To prevent contamination of the dropper tip and suspension, do not touch the tip of the dropper bottle to the eyelids and other surfaces. The bottle should be kept tightly closed.

There is no need for dose adjustment in the elderly.

The effectiveness and safety of Azopt in patients under the age of 18 years has not been established, therefore, it is not recommended to prescribe the drug to such patients.

The use of Azopt for the treatment of patients with liver failure has not been studied, therefore, it is not recommended to prescribe the drug to such patients.

The use of Azopt in patients with acute renal failure (creatinine clearance of 30 ml / min) or in patients with hyperchloremic acidosis has not been studied. Since brinzolamide (and its metabolite) is excreted mainly in the urine, its use in such patients is contraindicated.

Controlled studies of the effectiveness and safety of the drug in pregnant women have not been conducted. Experimental studies in animals have established the presence of toxic effects on reproductive function; The potential risk to humans has not been studied. In this regard, Azopt should be prescribed to pregnant women only in case of emergency, when the potential health benefits of the mother outweigh the possible risk to the fetus.

It is not known whether brinzolamide passes into breast milk, so you should either refuse to take the drug, or stop breastfeeding.

Temporary blurred vision after instillation of the drug can adversely affect the ability to drive vehicles or work with potentially dangerous mechanisms.If blurred vision occurs immediately after instillation, the patient must wait until vision is fully restored.

Interactions

In clinical trials, the use of azopt in combination with timolol showed no signs of interaction. in rare cases, oral administration of carbonic anhydrase inhibitors with high doses of salicylates revealed changes in the acid-base and electrolyte balance.

Cytochrome P450, which is responsible for the metabolism of brinzolamide, includes the isoenzymes of CYP 3A4 (basic), CYP 2A6, CYP 2C8 and CYP 2C9. It can be expected that CYP 3A4 inhibitors such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin can inhibit the metabolism of brinzolamide. Caution should be exercised while the use of CYP 3A4 inhibitors. However, the accumulation of brinzolamide in this case seems unlikely, since it is mainly excreted in the urine. Brinzolamide is not an inhibitor of cytochrome P450 isoenzymes.

Overdose

With topical use, brinzolamide is not described. when taken orally, the following symptoms may occur: electrolyte imbalance, acidosis, disorders of the nervous system. symptomatic treatment, monitoring of electrolyte levels (especially potassium) in the blood and monitoring of blood ph.

Storage conditions

At a temperature of 4-30 ° C. the bottle after opening must be used within 4 weeks.