Latanoprost

Article Author:
Koushik Tripathy
Article Editor:
Ragi Geetha
Updated:
8/28/2019 12:25:02 AM
PubMed Link:
Latanoprost

Indications

Latanoprost is an 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 reduction of the IOP, convenient once-daily dosing, and acceptable safety profile. Latanoprost is the first prostaglandin analog to be approved by the food and drug administration (FDA), USA. The drug was FDA approved for ocular use in 1996.

Mechanism of Action

Prostaglandins 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] 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 should not be inserted within 15 minutes of the topical application of the drop. Latanoprost is administered topically 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 development of subsensitivity of 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 other 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 1 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, and the number of melanocytes does not increase. There is 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 1 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 may be reduced 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 latanoprost should be avoided in active herpetic keratitis. 

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 attaining target intraocular pressure. 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 and 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]

After the physician decides to prescribe latanoprost, the nurse and pharmacist both need to reiterate proper administration technique and teach the patient. The pharmacist should also verify the dose and check for any drug-drug interactions, reporting back to the healthcare team with any concerns. Nursing will be instrumental in monitoring therapy and verifying patient compliance. All these various disciplines collaborating and communicating in an interprofessional team approach can achieve the best outcomes in latanoprost therapy. [Level V]


References

[1] Ocklind A, Effect of latanoprost on the extracellular matrix of the ciliary muscle. A study on cultured cells and tissue sections. Experimental eye research. 1998 Aug;     [PubMed PMID: 9733584]
[2] Lindsey JD,Gaton DD,Sagara T,Polansky JR,Kaufman PL,Weinreb RN, Reduced TIGR/myocilin protein in the monkey ciliary muscle after topical prostaglandin F(2alpha) treatment. Investigative ophthalmology     [PubMed PMID: 11431442]
[3] Camras CB,Bito LZ,Eakins KE, Reduction of intraocular pressure by prostaglandins applied topically to the eyes of conscious rabbits. Investigative ophthalmology     [PubMed PMID: 924742]
[4] Lindén C,Alm A, Latanoprost twice daily is less effective than once daily: indication of receptor subsensitivity? Current eye research. 1998 Jun     [PubMed PMID: 9663846]
[5] Alm A,Stjernschantz J, Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. A comparison with timolol. Scandinavian Latanoprost Study Group. Ophthalmology. 1995 Dec;     [PubMed PMID: 9098273]
[6] Li T,Lindsley K,Rouse B,Hong H,Shi Q,Friedman DS,Wormald R,Dickersin K, Comparative Effectiveness of First-Line Medications for Primary Open-Angle Glaucoma: A Systematic Review and Network Meta-analysis. Ophthalmology. 2016 Jan;     [PubMed PMID: 26526633]
[7] Rácz P,Ruzsonyi MR,Nagy ZT,Gaygi Z,Bito LZ, Around-the-clock intraocular pressure reduction with once-daily application of latanoprost by itself or in combination with timolol. Archives of ophthalmology (Chicago, Ill. : 1960). 1996 Mar;     [PubMed PMID: 8600885]
[8] Digiuni M,Fogagnolo P,Rossetti L, A review of the use of latanoprost for glaucoma since its launch. Expert opinion on pharmacotherapy. 2012 Apr;     [PubMed PMID: 22348427]
[9] Kahook MY,Noecker R, Quantitative analysis of conjunctival goblet cells after chronic application of topical drops. Advances in therapy. 2008 Aug;     [PubMed PMID: 18670744]
[10] Grierson I,Jonsson M,Cracknell K, Latanoprost and pigmentation. Japanese journal of ophthalmology. 2004 Nov-Dec     [PubMed PMID: 15592791]
[11] Changes in Ocular Surface Characteristics after Switching from Benzalkonium Chloride-Preserved Latanoprost to Preservative-Free Tafluprost or Benzalkonium Chloride-Preserved Tafluprost., Tokuda N,Kitaoka Y,Matsuzawa A,Tsukamoto A,Sase K,Sakae S,Takagi H,, Journal of ophthalmology, 2017     [PubMed PMID: 28831305]
[12] Salim S, Glaucoma in pregnancy. Current opinion in ophthalmology. 2014 Mar     [PubMed PMID: 24469077]
[13] De Santis M,Lucchese A,Carducci B,Cavaliere AF,De Santis L,Merola A,Straface G,Caruso A, Latanoprost exposure in pregnancy. American journal of ophthalmology. 2004 Aug     [PubMed PMID: 15289149]
[14] Lee JH,Kim TH,Kim SC, Allergic contact dermatitis caused by topical eye drops containing latanoprost. Annals of dermatology. 2014 Apr     [PubMed PMID: 24882991]
[15] Parrish RK,Palmberg P,Sheu WP, A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter study. American journal of ophthalmology. 2003 May     [PubMed PMID: 12719078]
[16] Alm A, Latanoprost in the treatment of glaucoma. Clinical ophthalmology (Auckland, N.Z.). 2014     [PubMed PMID: 25328381]