Topical Glaucoma Medications (Alpha-2 Agonists, CAIs, Miotics & Combo)

On Monday we reviewed the most important concepts associated with prostaglandin analogs and beta-blockers.

Today we will continue on with reviewing the mechanisms of action, dosages, side effects, contraindications, and preparations of topical alpha-2 agonists, carbonic anhydrase inhibitors, miotics, and combination medications. 

Alpha-2 Agonists 

Mechanism of action: This class of IOP-lowering medication decreases intraocular pressure by reducing the amount of aqueous secretion and enhancing aqueous outflow through the uveoscleral route. 

Dosage: The recommended dosage for Iopidine® and Alphagan® is three times per day (TID)

Side Effects:

• Hyperemia, burning, stinging, blurred vision, and foreign body sensation
• Conjunctival vessel blanching and a mild miotic effect is commonly seen
• Blepharitis, blepharoconjunctivitis, and conjunctival follicles
• Systemic side effects can also occur with alpha-2 agonists which include dry mouth, headache, fatigue, and drowsiness
• Some patients have also shown a decrease in systolic and diastolic blood pressure and heart rate (but these are generally clinically insignificant)
• Alpha-2 agonists are contraindicated in patients taking monoamine oxidase inhibitors (MAOIs)
• These medications are not contraindicated in patients with cardiopulmonary disease, but caution should be exercised in those with severe cardiovascular disease
• Alpha-2 agonists should also be avoided in young children due to the fact that they cross the blood-brain barrier

Preparations: 

• Iopidine® (Apraclonidine): In addition to decreasing aqueous secretion and increasing uveoscleral outflow, Iopidine® may have additional IOP-lowering effects due to its influence on ocular blood flow. Once instilled, Iopidine® shows a significant drop in IOP that lasts about 12 hours, with a peak effect at about 3-5 hours, which can be up to a 30-40% drop in IOP. Most patients show approximately a 20% decrease in IOP on average with both 0.5% and 1.0% solutions. However, the benefits of Iopidine® in most patients are short-lived due to the development of tachyphylaxis or ocular allergies that may warrant discontinuation; therefore, Iopidine® is most commonly used after laser surgery of the anterior segment to offset potential acute IOP spikes.
• Alphagan® (Brimonidine): Alphagan® is a potent and highly selective alpha-2 adrenoreceptor agonist (about 30x more selective than apraclonidine). There is also evidence that shows that Alphagan® may provide neuroprotective properties that could potentially spare retinal ganglion cells and the optic nerve from further degeneration (this is controversial). Peak IOP-lowering with Alphagan® occurs about 2 hours after instillation of the medication and lasts about 10-12 hours; therefore as a monotherapy, Alphagan® is typically dosed three times daily (TID). Alphagan is usually not the initial drug used to treat glaucoma but is often rather used as a secondary medication for further IOP reduction.

Carbonic Anhydrase Inhibitors (CAIs)

Mechanism of action: CAIs lower IOP by inhibiting aqueous secretion. It is also important to note that these molecules are chemically related to sulfonamides. 

Dosage: CAIs are typically recommended to be used at a dosage of TID when monotherapy, or BID as an adjunctive treatment. 

Side Effects:

• Ocular irriation, stinging, burning, foreign body sensation, and blurred vision 
• Superficial punctate keratitis, conjunctivitis, and headaches
• A bitter taste tends to occur in about 25% of patients
• Even though CAIs are related to sulfonamides, risk of systemic hypersensitivity reaction in those patients with sulfa allergies appears to be low (use caution)
• Use of CAIs is also cautioned in patients with severe renal and/or hepatic impairment, and because of potential additive systemic effects, topical CAIs should be avoided in patients concurrently taking oral CAIs

Preparations:

• Trusopt® (dorzolamide): Trusopt® is typically used TID as monotherapy, or BID as an adjunctive treatment. Its IOP-lowering effect has been shown to be similar to betaxolol but inferior to timolol (average decrease in IOP is approximately 23-24%, with peak effect occurring 2 hours after administration). Trusopt® should be used with caution in patients exhibiting corneal endothelial dysfunction, as some studies have shown that it may cause further decompensation.
• Azopt® (brinzolamide): The IOP-lowering effect of Azopt® has been proven to be equivalent whether dosed at BID or TID. Its hypotensive effect is similar to that of Trusopt®.

Miotics

Mechanism of action: Miotics are cholinergic agonists (parasympathomimetics) that act by stimulating the muscarinic receptors on the pupillary sphincter muscle and ciliary body. In primary open angle glaucoma, miotics are used to reduce IOP by increasing aqueous outflow through the trabecular meshwork route, which occurs secondarily to the contraction of the ciliary muscle. In angle closure glaucoma, miotics act to open the angle by contraction of the pupillary sphincter muscle, which results in miosis and subsequent pulling of the peripheral iris away from the trabeculum.

Dosage: Dosage of miotics as monotherapy is four times daily (QID), but when used in combination with other medications, twice daily (BID) is typically adequate.

Side Effects: 

• Miotics are used far less frequently than all other ocular hypotensive agents due to their side effect profile (adverse events are relatively common)
• Accommodative spasm (which can last several hours), miosis, pupillary block with subsequent angle closure in patients with narrow angles (causes forward displacement of the crystalline lens)
• There may also be a relationship between use of topical miotics and vitreoretinal traction and retinal detachment
• Systemic effects include headache, nausea, weakness, salivation, lacrimation, vomiting, diarrhea, bronchiolar spasm, and pulmonary edema (rare)

Preparations:

• Pilocarpine: This medication is available in concentrations from 0.25% to 10%. Pilocarpine gel (Pilogel®) is also available to use at nighttime.
• Carbachol and Echothiophate: These medications are very rarely used to treat IOP in patients with glaucoma due the their significant side effect profiles.

Combination Medications

• Cosopt®: Timolol and dorzolamide (beta-blocker and carbonic anhydrase inhibitor). Cosopt® is typically dosed BID. 
• Combigan®: Timolol and brimonidine (beta-blocker and alpha-2 agonist). Combigan® is usually dosed BID.
• Simbrinza®: Combination of brinzolamide and brimonidine (carbonic anhydrase inhibitor and alpha-2 agonist). Recommended dosage for Simbrinza® is TID. Simbrinza® does not contain a beta-blocker (useful in patients in which beta-blockers are contraindicated).

Now that you have brushed up on everything there is to know about the most commonly used topical glaucoma medications, you should now be extremely confident when working through treatment and management options for your complicated glaucoma patients!

-Dr. Dexter