Genazopt

Uses

Treatment of elevated IOP in adult patients with open-angle glaucoma or ocular HTN for whom monotherapy provides insufficient IOP reduction.

Genazopt is also used to associated treatment for these conditions: Increased Intra Ocular Pressure (IOP), Ocular HypertensionIncreased Intra Ocular Pressure (IOP), Migraine, Ocular Hypertension, Open Angle Glaucoma (OAG)

How Genazopt works

Brinzolamide is a highly specific inhibitor of CA-II, which is the main CA isoenzyme involved in the secretion of aqueous humor. Inhibition of CA in the ciliary process of the eye slows the formation of bicarbonate, and reduces sodium and fluid transport. This results in a reduction in the rate of aqueous humor secretion and the intraocular pressure. Brinzolamide is absorbed systemically following topical ocular administration. Since it has a high affinity for CA-II, brinzolamide binds extensively to red blood cells, where CA-II is primarily found. As sufficient CA-II activity remains, adverse effects resulting from the systemic inhibition of CA by brinzolamide are not observed. The metabolite N-desethyl brinzolamide is also formed. This metabolite binds to CA and accumulates in red blood cells as well. In the presence of brinzolamide, the metabolite binds mainly to carbonic anhydrase I (CA-I).

Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate. Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise, and a decrease in both systolic and diastolic blood pressure. In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure.

The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye. According to one study, the reduction of aqueous humor secretion may occur through the decreased blood supply to the ciliary body resulting from interference with the active transport system or interference with prostaglandin biosynthesis.

Dosage

Genazopt dosage

1 drop into the affected eye(s) twice daily

Side Effects

Dysgeusia, blurred vision, eye pain & irritation, foreign body sensation.

Toxicity

The oral LD50 for timolol maleate is 1028 mg/kg in the rat and 1137 mg/kg in the mouse.

Symptoms of timolol overdose may include dizziness, headache, shortness of breath, bradycardia, in addition to bronchospasm. Sometimes, an overdose may lead to cardiac arrest. An overdose of timolol can be reversed with dialysis, however, patients with renal failure may not respond as well to dialysis treatment.

Precaution

The concomitant administration of Brinzolamide 1% ophthalmic suspension and oral carbonic anhydrase inhibitor is not recommended due to no additional benefits.If hypersensitivity reaction occurs after instillation patients should be advised to discontinue the use of Brinzolamide and consult with physicians.

Patients with inadequate cardiac function, DM, myasthenia gravis, cerebrovascular insufficiency, history of atopy. Avoid abrupt withdrawal as it may exacerbate angina symptoms or precipitate MI in patients with coronary artery disease, or precipitate thyroid crisis in patients with thyrotoxicosis. Patients undergoing major surgery. May mask signs of hyperthyroidism and hypoglycaemia. Ophth soln should not be used as monotherapy for angle-closure glaucoma. Renal and hepatic impairment. Pregnancy and lactation.

Interaction

Ketoconazole, itraconazole, clotrimazole, ritonavir, troleandromycin; oral Ca-channel blockers, guanethidine, β-blockers, antiarrhythmics, digitalis glycosides, parasympathomimetics; quinidine, cimetidine.

Volume of Distribution

1.3 - 1.7 L/kg

Timolol is distributed to the following tissues: the conjunctiva, cornea, iris, sclera, aqueous humor, kidney, liver, and lung.

Elimination Route

Absorbed into systemic circulation following topical ocular application

The systemic bioavailability of the ophthalmic eyedrop in one study of healthy volunteers was 78.0 ± 24.5% , indicating that caution must be observed when this drug is administered, as it may be significantly absorbed and have various systemic effects. Another study measured the bioavailability of timolol eyedrops to be 60% in healthy volunteers.

The peak concentration of ophthalmic timolol in plasma, Cmax was about 1.14 ng/ml in most subjects within 15 minutes following the administration of timolol by the ophthalmic route. The mean area under the curve (AUC) was about 6.46 ng/ml per hour after intravenous injection and about 4.78 ng/ml per hour following eyedrop administration.

Half Life

111 days

Timolol half-life was measured at 2.9 ± 0.3 h hours in a clinical study of healthy volunteers.

Clearance

One pharmacokinetic study in healthy volunteers measured the total plasma clearance of timolol to be 557 ± 61 ml/min. Another study determined the total clearance 751.5 ± 90.6 ml/min and renal clearance to be 97.2 ± 10.1 ml/min in healthy volunteers.

Elimination Route

Timolol and its metabolites are mainly found excreted in the urine.

Pregnancy & Breastfeeding use

Control cardiac failure prior to therapy. History of severe cardiac & resp disease. Patients subject to hypoglycemia or labile insulin-dependent diabetes. May mask hyperthyroidism or worsen Prinzmetal's angina, severe peripheral & central circulatory disorders & hypotension. History of atopy or severe anaphylactic reaction to a variety of allergens. Avoid concomitant use of 2 local β-adrenergic blockers or 2 local carbonic anhydrase inhibitors. Close monitoring of IOP in patients with pseudoexfoliative or pigmentary glaucoma. Narrow-angle glaucoma. Monitor patients with compromised corneas eg, patients with DM or corneal dystrophies. Remove contact lenses prior to application; reinsert after 15 min. May impair ability to drive or operate machinery. Pregnancy. Childn <18 yr.

Contraindication

Bronchial asthma, severe COPD, sinus bradycardia, 2nd or 3rd degree AV block, overt cardiac failure, cardiogenic shock, severe allergic rhinitis, bronchial hyperreactivity, hyperchloraemic acidosis, severe renal impairment.

Acute Overdose

Although no human data are available, electrolyte imbalance, development of an acidosis state, and possible nervous system effects may occur following oral administration of an overdose. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored.

There have been reports of inadvertent overdosage with Timolol Ophthalmic Solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest.

Storage Condition

Store in cool and dry place

Innovators Monograph

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