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Drug Detailed Description (Generic name) - Brinzolamide


Brinzolamide

Pharmacology

CAIs inhibit the carbonic anhydrase II isoenzyme in the ciliary epithelium, thereby blocking the formation of bicarbonate. This causes a decrease in sodium and water outflow from the ciliary body. More than 99% of carbonic anhydrase must be inhibited to be effective. The result is a decrease of about 40% in aqueous humor production and a decrease in IOP of up to 30–35%.341,364 Orally administered CAIs also inhibit carbonic anhydrase in the kidney, red blood cells, and other tissues, causing diuresis and often acidosis and other serious adverse effects that limit their use.341,364,365 Administration and Adult Dosage. Ophth for primary open-angle glaucoma (brinzolamide) 1 drop tid; (dorzolamide) 1 drop tid. When used adjunctively, dorzolamide is administered bid.PO for primary open-angle glaucoma (acetazo-lamide) SR cap 500 mg bid has been better tolerated than tablets; Tab 125 mg q 4 hr to 250 mg qid. Dosages >1 g/day are no more effective. (Dichlorphena-mide) 100–200 mg priming dose, followed by 100 mg q 12 hr until desired re-sponse is obtained, then 25–50 mg daily to tid. (Methazolamide) 50–100 mg bid-tid. PO for prevention of altitude sickness (acetazolamide) 750 mg/day.

Special Populations

Pediatric Dosage

Safety and efficacy not established. How-ever, dorzolamide 2% ophthalmic solution is used in infantile glaucoma, and ac-etazolamide 5–10 mg/kg qid has been used when an oral CAI was neces- 341,364,368

Geriatric Dosage

Same as adult dosage.

Dosage Forms

(Acetazolamide) Tab 125, 250 mg; SR Cap 500 mg; Inj 500 mg. (Brinzolamide) Ophth Susp 1%. (Dichlorphenamide) Tab 50 mg. (Dorzolamide) Ophth Soln 2%. (Methazolamide) Tab 25, 50 mg. Patient Instructions. Dorzolamide Tell your doctor if you experience itching, redness, swelling, or other sign of eye or eyelid irritation. This medication can cause you to have blurred vision for a short period. Make sure you know how to react to this medication before you drive, use a machine, or do anything else that might be dangerous if you cannot see properly. Dorzolamide can cause your eyes to become more sensitive to light. Wearing sunglasses and avoiding exposure to bright light can lessen the discomfort.338

Pharmacokinetics

Onset and Duration. (Acetazolamide) Tab peak IOP reduction 2–6 hr, duration 4–12 hr;341,364 SR cap onset 2–4 hr, peak 4–8 hr, duration 12–24 hr.341,364 (Brinzolamide) onset <2 hr, peak 2 hr, duration >12 hr.369 (Dichlorphenamide) onset 30 min, peak 2 hr, duration 6 hr. (Dorzolamide) onset <2 hr, peak 2–4 hr, duration 6–8 hr.341,370,371 (Methazolamide) onset 1–2 hr, peak 4–6 hr, duration 12–24 hr.341

Fate

For all oral CAIs there is a linear relationship between plasma concentration and dose. (Acetazolamide) virtually completely absorbed with a peak serum level of 30 mg/L occurring at 1 hr after a 500 mg dose of tablet; with SR Cap, serum levels remain >10 mg/L for 10 hr. 90% bound to plasma proteins; elimination is by active renal tubular secretion.364 (Methazolamide) well absorbed and distributed in plasma, CSF, aqueous humor, red blood cells, bile, and extracellular fluid. Peak serum concentrations after 50 and 100 mg bid dosages are 5.1 and 10.7 mg/L, respectively. Vdss is 17–23 L. Renal clearance accounts for 20–25% of the total clearance, with about 25% of the drug eliminated in the urine unchanged. Brinzo-lamide and dorzolamide are systemically absorbed and bind to carbonic anhy-drase in erythrocytes with terminal half-lives of 111 and 147 days, respectively; however, there is only a 21% decrease in baseline carbonic anhydrase activity, far below the 99% inhibition level necessary to induce systemic effects.368 Laboratory values of patients receiving dorzolamide did not indicate metabolic acidosis or electrolyte imbalances such as those with long-term systemic CAIs.370 t¹/2. (Acetazolamide) 4 hr; (dichlorphenamide) 2 hr; (methazolamide) 14–15 hr.341

Adverse Reactions

Topical ophthalmic solutions frequently cause ocular burn-ing, stinging, or allergic ocular reactions.372 However, fewer patients discontinue dorzolamide than pilocarpine.366,370,373 Frequent systemic effects of topical oph-thalmic solutions consist of bitter taste, occasional headache, nausea, fatigue, and, rarely, urolithiasis and iridocyclitis. Oral administration frequently cause paresthe-sias, GI disturbances, anorexia, drowsiness, and confusion. Occasionally, meta-bolic acidosis, hypokalemia, or urolithiasis occurs. Attempt to treat acidosis with sodium acetate 90 mEq/day.341 Rare, but possibly fatal, reactions include aplastic anemia, agranulocytosis, and thrombocytopenia.

Contraindications

(Oral) hypokalemia; hyponatremia; hyperchloremic acidosis; adrenocortical insufficiency; marked renal or hepatic impairment; severe COPD. Long-term use of oral CAIs is contraindicated in angle-closure glaucoma.

Precautions

Because all CAIs are sulfonamides, avoid their use in patients with histories of sulfonamide allergy. Japanese and Korean patients might be at greater risk for developing Stevens–Johnson syndrome.374 Neither topical nor oral CAIs are recommended in patients with severe renal impairment. Caution in patients with hepatic impairment. Acidosis can cause sickling of RBC in patients with sickle cell anemia.

Drug Interactions

Do not use topical CAIs with oral CAIs because the combina-tion is no more effective and adverse effects are additive, particularly in causing corneal endothelial dysfunction.375 Oral CAIs can cause salicylate toxicity in patients taking high doses of aspirin, and salicylates can displace acetazolamide from plasma binding sites, causing acetazolamide toxicity and non–anion-gap hyperchloremic metabolic acidosis.376 Diflunisal displaces acetazolamide from plasma binding sites. In one study, this resulted in a 5.6-fold increase in acetazolamide plasma levels.377 Parameters to Monitor. Malaise or fatigue, Crs, serum potassium, serum carbon dioxide. The value of monitoring CBC is controversial because the hematologic adverse effects can be immune mediated and idiosyncratic rather than dose re-lated.341,364,378 However, manufacturers recommend obtaining a baseline CBC and platelet count, with monitoring at regular intervals.

Notes

Because of their severe adverse effects and poor tolerability, use oral CAIs in primary open-angle glaucoma only as a last resort. Some clinicians consider laser surgery before using oral CAIs long term.364 Use topical CAIs only if a topical -blocker, prostaglandin analogue, or 2-adrenergic agonist cannot be used or has failed to reach target IOP. If target IOP is not achieved with monotherapy, a topical CAI can be added to another topical treatment. Dorzolamide 2% tid as monotherapy lowers IOP 23% compared with 25% for timolol and 21% for betaxolol.370 Added to timolol, dorzolamide 2% bid provides another 13–22% decrease in IOP, similar to that from adding acetazolamide.368,379 Topical dorzolamide is as effective as oral acetazolamide.371 For prophylaxis of acute altitude sickness, acetazolamide 500 mg/day is ineffective, but 750 mg/day is about as effective as dexamethasone 8–16 mg/day.367
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