Brinzolamide: Pharmacodynamics, Pharmacokinetics, and Clinical Considerations

Overview:

Open-angle glaucoma is a persistent ocular condition distinguished by elevated pressure within the eye, which, if not addressed, may result in harm to the optic nerve and subsequent loss of vision. Brinzolamide has emerged as an effective therapeutic option for managing open-angle glaucoma. Brinzolamide was approved by Food and Drug Administration (FDA) in the year 2013. This article reviews the pharmacological properties, mechanism of action, clinical efficacy, and safety profile of Brinzolamide in the treatment of open-angle glaucoma. Numerous clinical trials and real-world studies have demonstrated the ability of Brinzolamide to reduce intraocular pressure and preserve visual function. Moreover, Brinzolamide's convenient dosing regimen and tolerability profile make it a valuable adjunct or monotherapy option for patients with open-angle glaucoma. However, caution should be exercised in patients with known hypersensitivity to sulfa drugs or those at risk for electrolyte disturbances. Overall, Brinzolamide holds promise as an effective and well-tolerated therapeutic agent for managing open-angle glaucoma, highlighting its importance in the armamentarium of glaucoma treatment options.

Drug Group:

Brinzolamide belongs to the drug group known as carbonic anhydrase inhibitors. Brinzolamide is a chemical compound with the following chemical description: (R)-(+)-4-Ethylamino-2-(3-methoxy propyl)-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide. Its empirical formula is C12H21N3O5S3.

Available Doses and Dosage Forms:

Brinzolamide is available in the following doses and forms:

• Ophthalmic Suspension: Brinzolamide is commonly formulated as an ophthalmic suspension for topical use in the eyes. It is available in different concentrations, with the most common strength being one percent (10 mg/mL) of Brinzolamide. The ophthalmic suspension is typically supplied in multi-dose bottles or single-use vials.

For Patients:

What Is Open-Angle Glaucoma?

• Open-angle glaucoma represents the prevailing type of glaucoma, which is a gradual ocular disorder marked by optic nerve impairment, potentially causing visual impairment or complete blindness if not attended to. In this form, the drainage angle of the eye remains open, but the trabecular meshwork is responsible for eliminating aqueous humor from the eye and gradually becomes less effective over time.

• The precise cause of open-angle glaucoma remains partially elusive, yet it is thought to arise from a combination of factors such as heightened intraocular pressure (IOP), genetic predisposition, and other underlying risk elements. Elevated IOP is a significant factor that contributes to the onset and advancement of glaucoma, although certain individuals with open-angle glaucoma may exhibit normal or even low IOP levels.

• Open-angle glaucoma typically develops gradually and is often asymptomatic in the early stages. As the disease progresses, peripheral vision gradually deteriorates, resulting in the formation of blind spots in the visual field. If left untreated, open-angle glaucoma can eventually lead to tunnel vision and complete loss of vision.

• Regular eye examinations, including measurement of IOP and evaluation of the optic nerve, are crucial for early detection and diagnosis of open-angle glaucoma. Treatment options for open-angle glaucoma aim to lower IOP to prevent or slow down further optic nerve damage. This may include the use of medications (oral medications or eye drops), laser therapies (such as trabeculoplasty), or surgery (such as trabeculectomy or drainage implants).

• It is crucial to emphasize that open-angle glaucoma is a chronic condition necessitating continuous monitoring and management to safeguard vision and impede its progression. Early detection, timely treatment, and regular follow-up care are essential in managing open-angle glaucoma effectively.

How Does Brinzolamide Work?

The mechanism of action of Brinzolamide involves its inhibition of carbonic anhydrase (CA) enzymes, specifically CA II, present in the ciliary processes of the eye. By inhibiting CA II, Brinzolamide reduces the production of bicarbonate ions from the reversible reaction of water and carbon dioxide. The objective of this intervention is to reduce the production of aqueous humor, which is the fluid that fills the front part of the eye known as the anterior chamber, consequently decreasing its overall volume. By reducing the production of aqueous humor, Brinzolamide helps to lower intraocular pressure (IOP), which is a key factor in the development and progression of glaucoma. Elevated IOP is known to cause damage to the optic nerve, leading to blindness and vision loss. By regulating intraocular pressure (IOP), Brinzolamide aids in averting additional harm to the optic nerve and safeguarding visual function.

What Is the Dosage of Brinzolamide?

The standard recommended dosage for Brinzolamide ophthalmic suspension (one percent) in the treatment of glaucoma or ocular hypertension is typically one drop to be applied to the affected eye(s) three times a day. The dispensers are made of plastic and feature a controlled dispensing tip. The packaging options and corresponding National Drug Codes (NDC) for different volumes are as follows:

• 2.5 ml (milliliter).

• 5 ml.

• 10 ml.

• 15 ml.

How Effective Is Brinzolamide?

Brinzolamide has been shown to be effective in reducing intraocular pressure (IOP), which is a primary goal in the treatment of glaucoma and ocular hypertension. Numerous clinical studies have provided evidence of the effectiveness of Brinzolamide in reducing intraocular pressure (IOP). In clinical trials, Brinzolamide ophthalmic suspension one percent has been compared to placebo (an inactive substance) and other antiglaucoma medications. These studies have shown that Brinzolamide is effective in reducing IOP when used as monotherapy or in combination with other medications. The effectiveness of Brinzolamide can vary between individuals, and the response to the medication may depend on factors such as the severity of the condition, the patient's baseline IOP, and the presence of other medical conditions. It is important to note that Brinzolamide is not a cure for glaucoma but helps in managing the condition by reducing IOP and slowing down the progression of the disease.

What Are the Things to Inform the Doctor Before Taking the Brinzolamide?

The following things need to be informed before taking Brinzolamide:

1. Medical Conditions: Inform the doctor about any existing medical conditions an individual has, such as kidney disease, liver disease, respiratory disorders, or electrolyte imbalances. These conditions may affect the use or dosage of Brinzolamide.

2. Allergies: Let the doctor know if an individual has any known allergies or sensitivities to Brinzolamide or any other medications, including sulfonamides or other carbonic anhydrase inhibitors.

3. Current Medications: Provide a complete list of all medications that are currently being taken, including prescription drugs, over-the-counter medications, vitamins, and herbal supplements. Certain medications may interact with Brinzolamide and affect its efficacy or increase the risk of side effects.

4. Pregnancy and Breastfeeding: If an individual is presently pregnant, planning to conceive, or breastfeeding, discuss this with the doctor. The use of Brinzolamide during pregnancy or breastfeeding should be evaluated based on the potential risks and benefits.

5. Previous Eye Surgeries or Eye Conditions: Inform the doctor if an individual has undergone any eye surgeries in the past or if an individual has any pre-existing eye conditions, such as corneal diseases or eye infections. These factors may influence the use and effectiveness of Brinzolamide.

6. Other Health Concerns: If an individual has any other health concerns or is currently undergoing treatment for any other medical conditions, inform the doctor. This information can help the doctor assess the suitability and safety of using Brinzolamide in their specific case.

How Is Brinzolamide Administered?

Brinzolamide is typically administered as an ophthalmic suspension, which means it is applied directly to the eye. Here are the general steps for administering Brinzolamide:

• Wash hands thoroughly with soap and water before handling the medication or touching the eyes.

• Shake the bottle of Brinzolamide ophthalmic suspension well to ensure proper mixing of the medication.

• Tilt the head back or lie down comfortably, whichever is more convenient.

• To create a small pocket, carefully and gently pull down the lower eyelid.

• Hold the bottle of Brinzolamide ophthalmic suspension upside down (with the tip pointing towards the eye) and squeeze the bottle to instill one drop into the lower eyelid pocket. To maintain cleanliness, ensure that the tip of the bottle remains clear of contact with the eye or eyelid to prevent any potential contamination.

• Release the lower eyelid and close the eyes gently. Do not blink or rub the eyes.

• If an individual is using Brinzolamide in both eyes, repeat the same steps for the other eye.

• To ensure proper absorption of medication, it is advisable to wait at least ten minutes before using any other eye drops or ointments. This interval allows sufficient time for the initial medication to be absorbed effectively.

• Recap the bottle tightly to prevent leakage and contamination.

What Are the Side Effects of Brinzolamide?

Here are some common side effects of Brinzolamide:

• Eye Irritation: This includes a burning or stinging sensation in the eyes and redness, itching, or discomfort after using the medication.

• Blurred Vision: Some individuals may experience temporary blurred vision or other changes in vision after instilling Brinzolamide. If one’s vision is impaired, it is advisable to refrain from driving or operating machinery to ensure one’s safety and the safety of others.

• Taste Alterations: Brinzolamide can cause a bitter or unusual taste in the mouth, which is generally temporary and resolves on its own.

• Dry Eyes: Some people may experience dryness or discomfort in the eyes while using Brinzolamide.

• Headache: Headaches can occur as a side effect of Brinzolamide treatment.

• Allergic Reactions: Although rare, allergic reactions to Brinzolamide can occur. Signs of an allergic reaction may manifest as a rash, skin itchiness, swelling, severe dizziness, or breathing difficulties.

Dietary Considerations:

There are no specific diet modifications that are typically recommended when using Brinzolamide.

Missed Dose:

The dose of Brinzolamide should not be missed. But if it is missed any day, apply it as soon as one remembers. If any problem is encountered, kindly contact the healthcare provider.

Overdose:

While there is no available clinical data, it is possible that an overdose of Brinzolamide taken orally could lead to electrolyte imbalance, an acidotic state, and potential effects on the nervous system. Monitoring of serum electrolyte levels, particularly potassium and blood pH levels, is recommended in such cases.

Storage:

Keep Brinzolamide ophthalmic suspension one percent stored within the temperature range of four to 30°C (39 to 86°F). Prior to use, ensure to shake the medication well.

For Doctors:

Indication:

Brinzolamide ophthalmic suspension, available as one percent, is a type of medication known as a carbonic anhydrase inhibitor. It is prescribed for the treatment of elevated intraocular pressure in patients diagnosed with ocular hypertension or open-angle glaucoma.

Dose:

The recommended dosage of Brinzolamide ophthalmic suspension one percent is to instill one drop into the affected eye(s) three times daily. It is possible to use Brinzolamide ophthalmic suspension alongside other topical ophthalmic medications to reduce intraocular pressure. If multiple ophthalmic drugs are being used, they should be administered at least ten minutes apart. Brinzolamide ophthalmic suspension one percent is available as a solution containing 10 mg/mL of Brinzolamide.

Dosing Considerations:

When using Brinzolamide:

1. The recommended dose is typically one drop of one percent ophthalmic suspension three times daily.

2. Administer the medication topically to the affected eye(s) using the provided dropper.

3. Consider potential drug interactions if using other eye drops and allow at least ten minutes between administrations.

4. Adjustments may be needed for pediatric and geriatric patients.

5. Follow the prescribed dosage and instructions given by the healthcare professional.

What Are the Pharmacological Aspects of Brinzolamide?

1. Pharmacodynamics: The pharmacodynamics of Brinzolamide involve its inhibition of carbonic anhydrase II, leading to a reduction in aqueous humor formation and subsequent lowering of intraocular pressure.

2. Mechanism: Carbonic anhydrase (CA) is an enzyme present in various tissues of the body, including the eye. The main purpose of it is to assist in converting carbon dioxide into carbonic acid and vice versa. In humans, there are different types of carbonic anhydrase, with carbonic anhydrase II (CA-II) being the most active form, primarily found in red blood cells and other tissues. By inhibiting carbonic anhydrase in the ciliary processes of the eye, the production of aqueous humor is reduced. This occurs by slowing down the formation of bicarbonate ions, which in turn decreases sodium and fluid transport. The end result is a reduction in intraocular pressure (IOP). Brinzolamide ophthalmic suspension contains Brinzolamide, which is an inhibitor of carbonic anhydrase II (CA-II). When applied topically to the eye, Brinzolamide effectively inhibits the formation of aqueous humor, leading to a decrease in elevated intraocular pressure. Increased intraocular pressure is a prominent risk factor for optic nerve damage and loss of visual field in conditions such as glaucoma.

3. Pharmacokinetics:

• Absorption: Upon topical ocular administration, Brinzolamide is absorbed into the systemic circulation. It enters the bloodstream through the blood vessels present in the conjunctiva and other tissues of the eye. From there, it can be distributed to various parts of the body, including red blood cells (RBCs) and other tissues.

• Distribution: The distribution of Brinzolamide within RBCs allows for prolonged drug retention, as it exhibits a long half-life in whole blood, approximately 111 days. Additionally, the metabolite N-desethyl Brinzolamide, formed through the metabolism of Brinzolamide, also binds to carbonic anhydrase and accumulates in RBCs. In plasma, both Brinzolamide and N-desethyl Brinzolamide concentrations are generally low and often below the quantitation limits of the assay used (<10 ng/mL). However, approximately 60 percent of the drug is bound to plasma proteins.

• Metabolism: Brinzolamide undergoes hepatic metabolism, primarily leading to the formation of N-desethyl Brinzolamide, which, along with other minor metabolites, can accumulate in RBCs. The concentrations of these metabolites in plasma are typically low.

• Elimination: The elimination of Brinzolamide primarily occurs through the urine, where it is excreted as an unchanged drug. Metabolites such as N-desethyl Brinzolamide, N-desmethyl propyl, and O-desmethyl metabolites can also be found in the urine, albeit at lower concentrations.

Toxicity:

1. Developmental toxicity studies conducted with Brinzolamide in rabbits and rats have provided valuable insights. In rabbits, administration of a high oral dose resulted in maternal toxicity, while both low and high oral doses led to a slight increase in fetal variations. In rats, reduced body weights of fetuses were observed at a high oral dose, but there were no significant effects on organ or tissue development. Although radioactivity effects from Brinzolamide were found in fetal tissues and blood in rats, no treatment-related malformations were observed.

2. Likewise, studies on developmental toxicity conducted with Brimonidine in rats revealed no indications of harm to the fetus, even when administered at an oral dose that resulted in significantly higher plasma drug concentrations compared to those observed in humans. Brimonidine was also found to cross the placenta to a limited extent in animal studies.

3. It is important to note that there are no sufficient studies available for pregnant women, and the use of Brinzolamide during pregnancy should be carefully evaluated based on the potential benefits and risks.

4. In animal studies, Brinzolamide has been associated with urinary bladder tumors in mice and rats at high oral doses. However, these levels of exposure cannot be achieved with topical ophthalmic use in humans.

5. Regarding mutagenic potential, tests conducted on Brinzolamide showed negative results in various assays, except for a mouse lymphoma forward mutation assay where a consistent dose-response relationship was not observed. However, the overall evidence suggests that Brinzolamide is consistent with other carbonic anhydrase inhibitors in terms of mutagenicity.

6. In reproductive studies of Brinzolamide in rats, no adverse effects on fertility or reproductive capacity were observed at high oral doses.

7. Similarly, Brimonidine tartrate, another medication, did not show evidence of carcinogenicity or mutagenicity in animal studies. It did not impair fertility in rats.

Clinical Studies:

In two separate three-month clinical studies, Brinzolamide one percent was administered three times per day to patients with elevated intraocular pressure (IOP). The results showed significant reductions in IOP ranging from four to five mmHg (millimeters of mercury). These reductions were comparable to the reductions observed with a Dorzolamide hydrochloride ophthalmic solution of two percent when dosed three times per day in the same studies. Furthermore, in two clinical studies involving patients with elevated intraocular pressure, Brinzolamide ophthalmic suspension one percent demonstrated a lower incidence of stinging and burning upon instillation compared to other treatments.

What Are the Contraindications of Brinzolamide?

Patients with a known hypersensitivity to any component of Brinzolamide ophthalmic suspension, one percent, should not use this product as it is contraindicated in such individuals.

Warnings and Precautions:

Various warnings and precautions associated with Brinzolamide are:

1. Sulfonamide Hypersensitivity Reactions: Brinzolamide ophthalmic suspension contains a sulfonamide compound. Although it is applied topically to the eye, it can be absorbed systemically. Therefore, similar adverse reactions associated with sulfonamides may occur with the use of Brinzolamide. While rare, severe reactions such as Stevens-Johnson syndrome (a serious disorder that affects the skin and mucous membranes), toxic epidermal necrolysis (a severe form of Stevens-Johnson syndrome), fulminant hepatic necrosis (severe liver damage), agranulocytosis (a condition where the bone marrow fails to produce enough white blood cells), aplastic anemia (a rare and serious condition where the bone marrow experiences insufficient production of new blood cells), and other blood disorders have been reported with sulfonamides. Sensitization to sulfonamides can recur regardless of the route of administration. If serious reactions or hypersensitivity occur, discontinue the use of Brinzolamide.

2. Corneal Endothelium: The corneal endothelium contains carbonic anhydrase activity in its cytoplasm and around the plasma membranes. Patients with low endothelial cell counts have an increased risk of corneal edema. Caution should be exercised when prescribing Brinzolamide to these patients.

3. Severe Renal Impairment: There have been no studies conducted on the use of Brinzolamide in patients with severe renal impairment (creatinine clearance <30 mL/min). Since Brinzolamide and its metabolite are primarily excreted by the kidney, the use of Brinzolamide is not recommended in such patients.

4. Acute Angle-Closure Glaucoma: Brinzolamide has not been studied in patients with acute angle-closure glaucoma. The management of patients with this condition requires additional therapeutic interventions along with ocular hypotensive agents.

5. Contact Lens Wear: The preservative benzalkonium chloride in Brinzolamide may be absorbed by soft contact lenses. During the instillation of Brinzolamide, contact lenses should be removed, but they can be reinserted 15 minutes after instillation.

What Are the Drug Interactions of Brinzolamide?

Brinzolamide can potentially interact with other drugs, leading to changes in their effectiveness or increasing the risk of side effects. Here are some notable drug interactions associated with Brinzolamide:

1. Oral Carbonic Anhydrase Inhibitors: Concomitant use of Brinzolamide with oral carbonic anhydrase inhibitors may result in an additive effect on carbonic anhydrase inhibition. Therefore, the concurrent use of Brinzolamide and oral carbonic anhydrase inhibitors is generally not recommended.

2. Salicylate Therapy: High-dose salicylate therapy may cause acid-base and electrolyte alterations. While such alterations were not observed in clinical trials with Brinzolamide, the possibility of these interactions should be considered when administering Brinzolamide ophthalmic suspension at one percent.

3. Topical Ophthalmic Drugs: If using multiple topical ophthalmic drugs, it is recommended to administer them at least ten minutes apart to avoid potential interactions or washout effects.

Specific Considerations:

• Carcinogenicity data for Brinzolamide is not available. Various tests for mutagenic potential showed mostly negative results, except for a positive result in the presence of microsomal activation in a specific test. In reproductive studies conducted in rats, Brinzolamide did not have adverse effects on fertility or reproductive capacity at doses up to 18 mg/kg/day, which is significantly higher than the recommended human ophthalmic dose.

• Regarding pregnancy, developmental toxicity studies in rabbits and rats showed some effects at high doses, including maternal toxicity and fetal variations. However, no treatment-related malformations were observed. Brinzolamide was found to cross the placenta and be present in fetal tissues and blood in animal studies. There are no well-controlled studies in pregnant women, and the use of Brinzolamide ophthalmic suspension one percent during pregnancy should be considered only if the potential advantages outweigh the potential risks to the developing fetus.

• For nursing mothers, Brinzolamide was detected in the milk of lactating rats but at concentrations lower than in the blood and plasma. It is unknown whether Brinzolamide is excreted in human milk. When there is a possibility of serious adverse reactions in nursing infants, a careful decision should be made, weighing the importance of the drug to the mother against the potential risks to the nursing infant. It is advisable to seek guidance from a healthcare professional to assess the situation and make an informed choice regarding whether to discontinue nursing or discontinue the drug.

• In pediatric use, a clinical study conducted on pediatric patients aged four weeks to five years showed no significant IOP-lowering efficacy when Brinzolamide ophthalmic suspension one percent was dosed twice a day. However, five out of 32 patients demonstrated a one-millimeter increase in corneal diameter.

• No notable disparities in safety or efficacy have been noted between older individuals, specifically geriatric use, and younger age groups.