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Everything You Need to Know about Prostaglandin Analogs & Beta-Blockers

Posted by Talin Amadian on September 12, 2020 at 8:54 AM
Talin Amadian
Dr. Talin Amadian is a practicing optometrist, writer and content contributor for Optoprep. She graduated from Western University of Health Sciences College of Optometry and continues to practice in Southern California. Her clinical training includes Neuro-Ophthalmology, Cornea and Refractive Surgery, Glaucoma and Ocular Disease. Dr. Amadian takes pride in educating patients and providing specialized care and education based on each patient’s needs. She is passionate about dry eye treatment and management. During her spare time, she enjoys mentoring and helping prospective optometry students succeed.

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So you’ve completed your entire Glaucoma workup, what’s next? The hardest part about prescribing glaucoma medications is figuring out where to start. With so many drugs available on the market, it can become very overwhelming, especially when you are in a time crunch in between patients.

Though each patient has a different clinical presentation, overall knowledge of the various Glaucoma drug categories and their mechanism-of-action will guide you through this process. 

Here’s a refresher of the two most common first-line glaucoma drugs!

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Prostaglandin Analogs

Prostaglandin Analogs (PGAs) are usually the first-line treatment and “go-to” for many practitioners when it comes to open-angle glaucoma or ocular hypertension. They deliver the convenience of once-daily dosage with 24 hour IOP control! PGA’s are safe and work great long term!

Mechanism of action:

Xalatan® (latanoprost), Travatan® (travoprost), and Xelpros ® both increase aqueous humor outflow exclusively through the uveoscleral route

Lumigan® (bimatoprost) and Vyzulta ® (latanoprostene bunod ophthalmic solution) promote the outflow of aqueous through both the uveoscleral and trabecular meshwork routes

Rescula® (unoprostone isopropyl) appears to increase aqueous outflow solely through the trabecular meshwork 

Dosage: 

PGAs are dosed once daily at night time (QHS). 

Side effects:

  • Conjunctival hyperemia
  • Foreign body sensation
  • Thickening, lengthening & hyperpigmentation of eyelashes (reversible)
  • Hyperpigmentation of the iris (irreversible); the highest incidence in green-brown irides
  • Hyperpigmentation of skin around the periorbital area
  • Cystoid macular edema in eyes with risk factors (i.e. capsular rupture, vitreous loss associated with cataract surgery)
  • Anterior uveitis; caution in patients with uveitic glaucoma
  • Increased risk for herpetic keratitis 
  • Systemic side effects of PGAs are rare, but include headache, skin rashes, and mild upper respiratory tract problems. 
  • Prostaglandins should not be used in pregnancy due to possible teratogenic effects. 

Preparations:

  • Xalatan® (latanoprost): Xalatan® has been shown to be at least as (if not more) effective than timolol (beta-blocker) in reducing IOP. The ocular hypotensive effect for Xalatan® is expected to be about 27-30% (whereas timolol is approximately 20%). The hypotensive effect of Xalatan® appears to be independent of race, gender, iris color, age, type of glaucoma, or previous glaucoma therapy. 
  • Travatan® (travoprost): The early formulations of Travatan® were preserved with BAK which demonstrated an increase in the potential for corneal epithelial toxicity and subsequent ocular surface disease. Travatan-Z® was later introduced with a unique ionic buffering compound which decreased its associated toxic effects and eliminated the need for a preservative. IOP-lowering effects of Travatan® are similar to Xalatan® except in African Americans, where Travatan® appears to be more effective. 
  • Lumigan® (bimatoprost): Lumigan® is considered to be part of the prostaglandin family but has been shown to differ sufficiently from the other prostaglandins and is sometimes referred to as a prostamide. As with the other prostaglandin analogs, studies have proven that Lumigan® used once daily is more effective than timolol twice daily. The mean IOP reduction from baseline is approximately 33% (this is slightly greater than Xalatan® and Travatan®). 
  • Rescula® (unoprostone isopropyl): Rescula® is the only prostaglandin that has a twice-daily (BID) dosage. It has also not been shown to be as effective as the other prostaglandins and is arguably not suited as a first-line monotherapy. 
  • Xelpros (latanoprost ophthalmic emulsion 0.005%): Xelpros is the first BAK-free latanoprost delivered with Lipixelle™ technology, which encapsulates latanoprost with polymer/castor oil micelles and allows for BAK-free delivery and improved solubility of latanoprost. Xelpros has been shown to have similar IOP-lowering power compared to Xalatan ®. 
  • Vyzulta ® (latanoprostene bunod ophthalmic solution): Vyzulta releases latanoprost acid and nitric oxide to reduce IOP. Once metabolized, Vyzulta ® increases outflow through both the uveoscleral pathway and the trabecular meshwork.

Beta-Blockers

Beta-blockers lower IOP by antagonizing the effects of catecholamines and beta-adrenergic receptor sites. There are four types of adrenergic receptors and they are found in various parts of the eye and body:

  • Alpha-1: found in arterioles, pupil dilator, and Muller’s muscle
  • Alpha-2: found in the ciliary epithelium
  • Beta-1: found in myocardium
  • Beta-2: found in bronchi and ciliary epithelium

Beta-blockers that are non-selective are equally potent at both beta-1 and beta-2 receptor sites. However, cardioselective beta-blockers are more potent at beta-1 receptor sites, in order to reduce the bronchoconstrictive effect of the beta-2 blockade.

Mechanism of action: 

Since Beta-blockers decrease the secretion of aqueous humor, they can be used in all types of glaucoma treatment to reduce intra-ocular pressure, regardless of the position of the anterior chamber angle. However, in about 10% of cases, the efficacy of these agents can decrease over time, anywhere from days to years after initiation of treatment. These phenomena are called “short-term escape” or “long-term drift”, respectively. Since aqueous production at night is usually less than half of that produced during the day, beta-blockers work best when used in the morning. 

Dosage: 

Beta-blockers are usually dosed twice-daily (BID) or once-daily in the morning (QAM) when used as adjunctive therapy with other IOP lowering medications. 

Side effects:

  • Ocular side effects
    • Ocular allergies 
    • Corneal punctate epithelial erosions
    • Reduced aqueous tear production
  • Systemic side effects
    • Bradycardia and systemic hypotension due to blockage of beta-1 receptors
    • Bronchospasm due to beta-2 receptor blockade (can be fatal in patients with COPD and Asthma)
    • Sleep disorders
    • Confusion
    • Depression
    • Fatigue
    • Headache

Preparations:

  • Timolol (Timoptic®, Timpotic® in Ocudose, Timoptic-XE®, Betimol®, Istalol®): Timolol is a non cardioselective beta-blocker. The mean decrease in IOP is approximately 25% (this is greater than pilocarpine and topical carbonic anhydrase inhibitors, but typically less than prostaglandin analogs). Timolol is usually prescribed twice-daily (BID) as it has been shown that the IOP-lowering effect lasts for at least 12 hours once instilled. However, timolol also works well as a once-daily therapy, and the IOP reduction ranges from about 17-28% with a single drop. There is limited proof that the 0.5% preparation of timolol provides a greater hypotensive effect than the 0.25% preparation. 
  • Levobunolol (Betagan®): Levobunolol is similar to timolol in that it is also a non cardioselective beta-blocker. The potency of this medication is also similar to timolol (the mean reduction of IOP given twice-daily is equivalent to the BID dosage of timolol). Levobunolol can also be used as a once-daily medication with a similar IOP-lowering effect as a twice-daily dosage. 
  • Betaxolol (Betoptic®): Betaxolol is the only cardioselective beta-blocker, exhibiting greater specificity for the beta-1 receptor, and at the ocular beta-2 receptor it shows about half the potency as timolol (and is, therefore, less effective at decreasing IOP when compared to timolol and levobunolol). Betaxolol has also been shown to block sodium and calcium channels in the microvascular tissue of the optic disc, which may increase optic disc blood flow and protect critical nerve tissue. Because of this possible added neuroprotection, studies have shown that the preservation of the visual field appears to be superior with betaxolol.
  • Metipranolol (OptiPranolol®): Metipranolol is a non cardioselective beta-blocker. Retinal perfusion pressure and blood flow appear to increase when topical metipranolol is administered; however, it has been shown to occasionally cause granulomatous anterior uveitis.
  • Carteolol (Ocupress®): Carteolol is a non cardioselective beta-blocker; however, it appears to have a more selective action on the eye than on the cardiopulmonary system (may induce less bradycardia than timolol). Carteolol shows a similar IOP-lowering effect to timolol, and also appears to cause less ocular irritation than timolol and may even produce some moderate corneal anesthesia as well. 

Though it may seem like a lot of information, knowledge about the most common first-line therapies in glaucoma will help any clinician with a starting point to tackle even the most complex Glaucoma cases. These are patients that can be presenting for their annual eye exam without knowledge of glaucomatous visual field loss or mild glaucoma suspects with multiple risk factors. 

Stay tuned for reviews on other intraocular pressure lowering medications such as alpha-agonists, carbonic anhydrase inhibitors, and combination medications!

Dr. Amadian

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Topics: Analogs, Beta-Blockers

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