Continuing Education Activity

Latanoprost is an eye drop formulation for the treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma. It is a prostaglandin F2 alpha analog. It reduces IOP by increasing the outflow of aqueous humor by improving the uveoscleral outflow. This activity covers the mechanism of action, pharmacology, adverse event profiles, and indications for latanoprost, and highlights the role of the interprofessional team in the management of conditions where latanoprost holds therapeutic value.

Objectives:

• Describe the different proposed mechanisms of action of latanoprost in the ocular tissue.
• Summarize the recommended dosing technique for latanoprost therapy.
• Review the contraindications and adverse event profile for latanoprost therapy.
• Outline the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with latanoprost.

Indications

Latanoprost is a United States Food and Drug Administration (FDA) approved eye drop formulation for the treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma. It is a prostaglandin F2 alpha analog. It reduces IOP by increasing the outflow of aqueous humor by improving the uveoscleral outflow. Dosing is once daily.

Prostaglandins are most commonly used as the first line of treatment in glaucoma due to their efficacy in the reduction of the IOP, convenient once-daily dosing, and acceptable safety profile. Latanoprost is the first prostaglandin analog to be approved by the United States Food and Drug Administration (FDA). The drug was FDA approved for ocular use in 1996.

Mechanism of Action

Prostaglandin synthesis occurs in the cell from arachidonic acid. Arachidonic acid, a 20-carbon molecule, gets metabolized to leukotrienes (LT) by lipoxygenases or converted to cyclic endoperoxides by cyclooxygenases. The cyclic endoperoxides are metabolized to prostaglandin (PG) F2 alpha by prostaglandin synthase and reductase, and to thromboxanes by thromboxane synthase.

Prostaglandin, thromboxane, and leukotriene are called eicosanoids. Various receptors exist for eicosanoids, including DP (prostaglandin D), EP (prostaglandin E), FP (prostaglandin F), IP (prostaglandin I or prostacyclin receptor) and TP (prostaglandin T). FP receptor has 2 variants- type A (full-length variant) and type B (spliced variant). Both FP receptors act as G-protein coupled receptors. FP receptors express in multiple ocular tissues, including ciliary smooth muscles.  

Latanoprost is a prostaglandin F2-alpha analog (FP receptor agonist) that increases the uveoscleral outflow of the aqueous. The proposed mechanisms include[1][2]:

• Relaxation of ciliary smooth muscles
• Cytoskeletal alteration leading to change of the shape of cells
• Remodeling of the extracellular matrix of the uveoscleral pathway by increased matrix metalloproteinases
  • PG F 2alpha and latanoprost were noted to reduce collagen I, III, and 4, hyaluronans, fibronectin, and laminin; and increase matrix metalloproteinases 2 and 3, and plasmin in cultured ciliary smooth muscles
  • In the animal model, topical PG F 2 alpha was noted to reduce the expression of TIGR (trabecular meshwork inducible glucocorticoid response gene) or MYOC (myocilin)

The drug starts reducing IOP after 3 to 4 hours of administration, and the maximum IOP lowering effect is seen 8 to 12 hours after use. The IOP lowering effect lasts for more than 24 hours, allowing once-daily dosage. 

The isopropyl ester of latanoprost gets hydrolyzed by the cornea to the acid, which is the active form. The maximum concentration of the drug in the aqueous humor is achieved 2 hours after topical use of the drop. The acid form is mainly metabolized in the liver by fatty acid oxidation, after which it is eliminated from the body by the kidney. The acid form of latanoprost (topical or intravenous) gets eliminated from the human plasma with a half-life of 17 minutes. The solubility of latanoprost, travoprost, and unoprostone improves by the addition of isopropyl ester to carboxyl-terminal of PG F 2 alpha. The addition of a phenyl ring to the omega chain of PG F 2 alpha in the prostaglandin analogs (latanoprost, travoprost, bimatoprost) improves selectivity for the FP receptor.

In animal studies, topical PG in high doses showed an initial IOP rise with a subsequent prolonged period (15 to 20 hours) of IOP reduction.[3] A high dose may also disrupt the blood-aqueous barrier and cause conjunctival hyperemia. Low dose topical PG, on the other hand, causes prolonged IOP reduction only.[3]

Other prostaglandin F2 alpha analogs with the same mechanism of action are travoprost and tafluprost.

Administration

Latanoprost may be administered with other antiglaucoma agents to reduce intraocular pressure. If using more than one topical ophthalmic drug, there should be a minimum gap of 5 minutes between two drops. Contact lenses require removal before administering the medication, and the patient should not reinsert them within 15 minutes of the topical application of the drop. Latanoprost administration is topical, one drop once daily in the evening in the affected eye/s.

Latanoprost is available as a colorless, isotonic ophthalmic solution at a strength of 0.005%. According to the manufacturer, unopened bottles should be stored 'under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). During shipping, the container may remain at temperatures up to 40 degrees C (104 degrees F) for a period not to exceed 8 days. Upon opening the bottle, it may be stored at room temperature up to 25 degrees C (77°F) for 6 weeks.

The dosage is one drop once daily at night, and curiously the IOP lowering effect reduces (or paradoxical IOP rise may occur) when used more than once daily.[4] The reduction in IOP lowering effect may be due to the development of subsensitivity at the FP receptors.[4]

The average IOP drop with latanoprost is in the range of 30% to 35%. At 6 months, latanoprost was noted to reduce IOP by 35% when applied in the evening and 31% when instilled in the morning compared to timolol, which caused a 27% reduction of IOP.[5] A meta-analysis found that the mean IOP reduction in mm of Hg with various antiglaucoma drugs was - bimatoprost 5.61, latanoprost 4.85, travoprost 4.83, levobunolol 4.51, tafluprost 4.37, timolol 3.70, brimonidine 3.59, carteolol 3.44, levobetaxolol 2.56, apraclonidine 2.52, dorzolamide 2.49, brinzolamide 2.42, betaxolol 2.24, and unoprostone 1.91.[6]

Once-daily latanoprost has been shown to achieve uniform round the clock reduction of IOP either alone or when combined with a twice-daily dose of timolol.[7] When using a combination drop of latanoprost and timolol, the dosage is once daily.

Other than open-angle glaucoma, latanoprost has also shown efficacy in different variants of glaucoma, including[8]:

• Pediatric glaucoma
• Chronic angle-closure glaucoma
• Normal-tension glaucoma
• Steroid-induced glaucoma
• Pigmentary glaucoma

Adverse Effects

The primary adverse effects of latanoprost include eyelid edema, blurred vision, dry eyes, itching, redness, the growth of eyelashes, change in eyelid pigmentation (may become darker), iris, and eyelash.

Conjunctival hyperemia is one of the most common side effects noted in 5% to 15% of patients, which is more than timolol treated eyes. Latanoprost with preservative (benzalkonium chloride) may reduce the goblet cell density.[9] The conjunctival redness usually appears within 2 to 3 days of initiation of the topical treatment, and reduces within one month and is typically mild with prolonged use.

The eyelashes become thicker, longer, darker, increase in number, and may become misdirected. The changes of the eyelashes are usually reversible after discontinuation of the drug; this is due to the stimulation of the growth phase of the hair cycle.

The pigmentation is due to increased melanin in the melanocytes, but the number of melanocytes does not increase. There is an upregulation of the tyrosinase activity in the melanocytes.[10]

The pigmentation may increase as for the duration of drug use. The brownish color change of the iris after latanoprost use is permanent, but the pigmentation of the eyelid, periorbital tissue, and eyelash may be reversible. The pigmentation of iris usually starts around the pupillary margin and then spreads towards the peripheral iris. Iris nevi and freckles are not affected by latanoprost. The pigmentation of iris usually begins within one year of therapy and continues to increase with the use of the drug. Patients should receive counsel regarding the possible change in iris color, which may be more evident if using the medicine in only one eye. The iris pigmentation is more common in light-colored rides, but may also occur in dark or brown rides. Darkening of the iris may occur in up to 10% of cases. Pigmentation of periocular tissue is reducible by removing the excess latanoprost drop from around the eye. 

Latanoprost may worsen intraocular inflammation (uveitis) and should be avoided in the actively inflamed eye. 

Latanoprost may induce or aggravate macular edema, including cystoid macular edema. Aphakic patients and pseudophakic patients with open posterior capsule are at higher risk of developing cystoid macular edema. 

Reactivation of herpetic keratitis may occur with the use of latanoprost, and patients with active herpetic keratitis should avoid latanoprost.

Contaminated multidose vial of latanoprost may cause bacterial keratitis in patients with a corneal epithelial defect or other corneal diseases. 

Damage to the ocular surface, including reduced tear break up time, superficial punctate keratopathy may occur due to the preservative in latanoprost (benzalkonium), and the ocular surface toxicity has been noted to be less with preservative-free tafluprost.[11]

Latanoprost is classified as FDA pregnancy risk category C. There are no adequate studies in pregnant women.[12][13] It was found to cause no carcinogenesis, no mutagenesis, and did not affect fertility in animal studies. However, latanoprost was noted to cause a chromosomal aberration in treated human lymphocytes.

Other side effects of latanoprost include contact dermatitis/allergic conjunctivitis, and iris cyst.[14]

Contraindications

Latanoprost is contraindicated in patients with documented hypersensitivity to the drug or components of the formulation. The components of the drop include latanoprost (the active ingredient). Inactive ingredients include benzalkonium chloride (preservative), water, sodium chloride, monobasic sodium phosphate, and dibasic sodium phosphate.

Monitoring

Monitor intraocular pressure every 2 to 4 weeks until target intraocular pressure is attained. Subsequently, every 6 months is sufficient.

Enhancing Healthcare Team Outcomes

Latanoprost is one of the prostaglandin analogs, which are considered the first-line management of open-angle glaucoma. Multiple randomized control trials have proven its efficacy in lowering IOP in primary open-angle glaucoma, which is similar to travoprost, and bimatoprost, but the tolerability of latanoprost may be better (Level I).[15][16] Retinal examination for cystoid macular edema, and ruling out active inflammation before starting therapy is vital. Also, the IOP should be monitored by the ophthalmologist and the ophthalmic specialty-trained nurse regularly to ensure that the medication is working. The pharmacist should educate the patient about the adverse effects of the drug that may include darkening of the color of iris, eyelids, periocular area, and eyelashes.[15]

An interprofessional team approach is needed to provide comprehensive and collaborative care for the patient. The ophthalmology trained nurse and the pharmacist play a crucial role in assisting the clinician to achieve this goal. The nurse can assist the clinician in educating the patient about the indication and expected outcomes of latanoprost therapy as well as the need for following up IOP testing. The pharmacist can help the team by educating the patient about proper dosing, administration, storage as well as adverse side effects of the drug to ensure its efficacy. Collaboration and communication across these various disciplines in an interprofessional team approach can achieve the best outcomes in latanoprost therapy. [Level V]