Side Effects Associated with Prostaglandin Analog Therapy
Section snippets
Conjunctival Hyperemia
Prostaglandins are a family of autacoids in which some members have powerful effects on the vasculature, including vasoconstriction, vasodilation, or increased vascular permeability. Consequently, the effect on conjuctival vessels was carefully studied during the development of PGAs for topical application as ocular hypotensive agents. In the first study on the human eye, in 1985, Giuffrè found that the tromethamine salt of prostaglandin F2α (PGF2α) caused marked conjunctival hyperemia.48 The
Eyelash Changes
Darker and longer eyelashes are interesting and well-documented side effects associated with use of PGAs. The first report of a case with darker eyelashes was in the Scandinavian phase III study where it was observed in one patient.25 However, the prevalence of this side effect was undoubtedly underestimated in the phase III studies. It was a very unexpected effect and the examination protocols were more focused on evaluation of iris color and conjunctival injection than on eyelashes. An early
A Future Role in Hair Disorders?
There have also been some well-documented cases in which topical treatment with latanoprost was associated with growth of eyelashes in patients with alopecia areata.81, 83 This observation led Ross et al to conduct a small, prospective, randomized, and investigator-masked study on 11 patients with alopecia areata involving the eyebrows.99 No increased hair growth could be demonstrated, but as pointed out by the authors, the negative result does not rule out the possibility that different
Induced Iris Darkening
Induced iris darkening is a common side effect of topical PGA treatment18, 21, 139 that is not specific to latanoprost. It seems to be associated with all the prostaglandin antiglaucoma medications based on PGF2α, although the other PGAs may have iris darkening to a somewhat lesser extent.27, 82, 92, 108 Indeed the darkening is likely to be a class effect. There is evidence that naturally occurring prostaglandins, given topically to monkeys, produce the eye color change.106 This side effect was
Iris Cysts
A rare event, that may or may not have a direct association with PGA therapy, is the development of iris cysts. This association with latanoprost treatment was suggested by Krohn and Hove in a case report70 and was followed by additional reports implicating latanoprost as the possible cause of pigmented epithelial cyst formation.20, 72 In each case, there was decrease in the size of the cyst after stopping latanoprost medication with complete reversal in a matter of months.20, 70, 72
Periocular Skin Pigmentation
Darkening of the skin of the lids or other sites around the eye has been reported as an occasional side effect associated with topical latanoprost therapy,55, 69, 133 as well as the use of other PGAs,23, 35, 40, 43, 62, 133 although a cause-and-effect relationship has been questioned by some104 because the evidence base depends predominantly on case reports. As a result, there is no reliable figure at the present time for the incidence of skin pigmentation in association with PGA therapy. An
Cystoid Macular Edema
Cystoid macular edema (CME) was first recognized by Irvine in 1953 as a vitreal and macular abnormality following intracapsular cataract extraction.60 In 1966, Gass and Norton described the typical petaloid pattern of macular leakage by fluroescein angiography,45 and the condition became known as the Irvine-Gass syndrome. The angiographic findings may be documented without associated visual symptoms (angiographic CME) or less commonly with associated loss of visual acuity (clinical CME).
Anterior Uveitis
Prostaglandins at high levels are well-known mediators of ocular inflammation, inducing breakdown of the blood–aqueous barrier and elevation of the IOP. The development of PGAs as IOP-lowering drugs for treatment in glaucoma not only involved the use of very low concentrations, but of altering compounds to achieve an acceptable side effect profile, while retaining good IOP-lowering efficacy. With regard to latanoprost, as previously noted, this involved a phenyl substitution of PGF2α
Reactivation of Herpes Simplex Keratitis
In 1999, Wand and associates reported three patients in which herpes simplex keratitis (HSK) developed after initiation of latanoprost therapy.132 Two of these patients had a history of prior HSK, and the third developed HSK within 8 days of starting latanoprost. In one patient, the condition cleared with discontinuation of latanoprost, but recurred when rechallenged with the drug. In another patient with bilateral recurrence, the HSK could not be eradicated with antiviral therapy until the
Conclusion
Ocular side effects with a well–established cause-and-effect relationship to topical PGA therapy include conjunctival hyperemia, eyelash changes, induced iris darkening, and periocular skin pigmentation. Current evidence indicates that these represent only cosmetic concerns, with no serious ocular or systemic consequences. Other potential side effects are significantly less common and lack definitive proof of a causal relationship to PGA therapy, but have more serious sight-threatening
Method of Literature Search
Databases used included Pub Med, Web of Knowledge, International Glaucoma Review, and key review articles. Search words included prostaglandin, latanoprost, conjunctiva, hyperemia, hair growth, eyelash growth, iris pigmentation, cystoid macular edema, uveitis, and herpetic keratitits. Years covered were from 1990 to 2007. Additional sources included the authors’ personal databases. Criteria for inclusion and exclusion of articles were those which pertained to side effects associated with
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The supplement in which this article is published was funded by Pfizer. The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Dr Grierson holds unrestricted research grants from Pfizer and Alcon.