Orzolol

Uses

This Eye Drops is used for the treatment of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta blockers.

Orzolol 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 Orzolol works

Elevated intraocular pressure is a characteristic manifestation of ocular hypertension or open-angle glaucoma. The level of intraocular pressure (IOP) is governed by the balance between the production of aqueous humour (by ocular ciliary processes) and its outflow from the anterior segment of the eye via trabecular (conventional) or uveoscleral (unconventional) pathways. When there is an increase in the resistance to the trabecular outflow of aqueous humour, the intraocular pressure is elevated. Subsequently, optic nerve damage can occur from blood flow restrictions and mechanical distortion of ocular structures. Optic nerve damage can further result in optic disc cupping and progressive visual field loss (and blindness in some cases).

Carbonic anhydrase (CA) is a ubiquitous enzyme that catalyzes the reversible hydration of carbon dioxide to bicarbonate ions and dehydration of carbonic acid. In the ocular ciliary processes, the local production of bicarbonate by CAs promotes sodium and fluid transport. CA-II is a key isoenzyme found primarily in red blood cells (RBCs) that regulates aqueous humour production. Dorzolamide is a highly specific CA-II inhibitor, where it displays a 4000-fold higher affinity for carbonic anhydrase II than carbonic anhydrase I. The inhibition of CA-II in the ciliary process disrupts the formation of bicarbonate ions and reduces sodium and fluid transport, which leads to decreased aqueous humour secretion and reduced intraocular pressure.

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

Orzolol dosage

Instill one drop in the conjunctival sac of the affected eye(s) twice daily.

Side Effects

Mild burning, ocular hyperemia, blurred vision may occur.

Toxicity

The oral LD₅₀ of dorzolamide is 1927 mg/kg in rats and 1320 mg/kg in mice. The subcutaneous LD₅₀ is >2 g/kg in both rats and mice.

Overdose may result in electrolyte imbalance, acidosis, and possibly central nervous system effects; these symptoms should be responded with appropriate supportive treatment. It is advised that the patient's serum electrolyte (particularly potassium) levels and blood pH levels are monitored in the case of a suspected overdose.

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

For ophthalmic use only. Patients should remove their contact lenses prior to instilling this preparation and should not insert their lenses until 15 minutes after instillation of the preparation.

Interaction

Additive hypotension and bradycardia with oral calcium channel blockers, catecholamine-depleting drugs or β-blockers, antiarrhythmics (e.g. amiodarone), digitalis glycosides, parasympathomimetics, narcotics and MAOIs. Additive systemic side effects with oral carbonic anhydrase or β-blockers; avoid concurrent use. Additive systemic β-blockade with CYP2D6 inhibitors (e.g. quinidine, SSRIs) and timolol.

Volume of Distribution

There is limited information on the volume of distribution of dorzolamide; however, the plasma concentrations of dorzolamide and its main metabolite are generally below the assay limit of quantitation, which is 15nM. Dorzolamide accumulates in red blood cells following chronic administration as a result of binding to CA-II, which is contained in peripheral red blood cells (RBCs).

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

Dorzolamide readily penetrated into the eye in animal studies. Upon ophthalmic administration, dorzolamide is absorbed via the cornea and stroma. Dorzolamide is reported to be absorbed systematically following topical administration. The systemic exposure of dorzolamide following long-term administration was assessed in healthy subjects receiving an oral dose of 2 mg dorzolamide twice daily, which equates to the ophthalmic dose of 2% dorzolamide three times daily. In these subjects receiving the treatment for 20 weeks, the steady-state was reached within 8 weeks.

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

As the drug administration is stopped, dorzolamide stored in RBCs is washed out of RBCs in a non-linear fashion, with the terminal elimination half-life of ≥120 days in RBCs. This initial rapid decline in drug concentrations is followed by the slow elimination phase, where the elimination half-life of the drug is about >4 months.

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

Clearance

There is limited information on the clearance rate of dorzolamide.

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

Dorzolamide is primarily excreted unchanged in the urine; however, N-desethyldorzolamide is also detected in the urine.

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

Pregnancy & Breastfeeding use

Use in pregnancy: There are no adequate and well-controlled studies in pregnant women. This Eye Drops should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in lactation: Caution should be exercised when This Eye Drops is administered to a nursing mother.

Contraindication

Contraindicated in patients who are hypersensitive to any of the components of Orzolol.

Special Warning

Use in children: Safety and effectiveness in children below the age of 2 years have not been established.

Use in elderly patients: No overall differences in safety and effectiveness have been observed between elderly and other adult patients.

Acute Overdose

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 between 15-30°C. Protect from light.

Innovators Monograph

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