QuizWise 8

1. Which of the following preservative used in eye drops is most frequently associated with adverse reactions
   a. Benzalkonium chloride
   b. Parabens
   c. Chloro-butanol
   d. Sodium chlorite

2. BAC toxicity is caused due to
   a. Detergent effect causing loss of tear film stability
   b. Direct damage to the corneal/conjunctival epithelium 
   c. Immune allergic reaction
   d. All of the above

3. What are the changes seen in ocular tissue after long term use of anti-glaucoma medication.
   a. Alteration in sub-basal nerve plexus.
   b. Decreased expression of HLA-DR on conjunctival epithelial cells
   c. Increase in Pro-inflammatory cytokine secretion by conjunctival cells
   d. All of the above
   e. a and b
   f. a and c

4. Which of the following side effect is more common with bimatoprost than with latanoprost ?
   a. Iris pigmentation
   b. Lengthening of eye lash
   c. Conjunctival hyperemia
   d. Eyelid pigmentation
   e. Both a, b and c
   f. B ,c and d

5. What is “short term escape” due to beta blocker.
   a. IOP lowering capacity decreases over short term due to up regulation of beta receptor and increase in the number of receptor in ciliary process.
   b. Decline in efficacy attributed to some alteration at the receptor site 
   c. Decline in efficacy due to time dependent decrease in cellular sensitivity to adrenergic antagonist.
   d. None of the above 

QuizWise 8 Responses
1. Answer a : Benzalkonium chloride
The prevalence of ocular surface disease of 59% has been reported in glaucoma cases with higher prevalence in patients using BAC containing antiglaucoma medications.
Reference: Leung EA, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma 2008;17(5):350-355 DOI: 10.1097/IJG.0b013e31815c5f4f

2. Answer d : all of the above
Benzalkonium chloride, the most commonly used preservative in topical antiglaucoma preparations has a slow turnover and the quaternary ammonium molecules may be retained in the ocular tissues for as long as 168h after application.
Reference: Champeau EJ, Edelhauser HF. Effect of ophthalmic preservatives on the ocular surface: conjunctival and corneal uptake and distribution of benzalkonium chloride and chlorhexidine digluconate. The preocular tear film in health, disease and contact lens wear. Lubbock, TX: Dry eye Institute, Inc. 1986
BAC promotes the activation of lipooxygenases, synthesis and secretion of eicosanoids, inflammatory mediators and many cytokines such as interleukin (IL)-1a, tumor necrosis factor, IL-8, IL-10, resulting in irritation, delayed hypersensitivity and allergic reactions.  
Reference: De Saint Jean M, Debbasch C, Brignole F, Rat P, Warnet JM, Baudouin C. Toxicity of preserved and unpreserved     antiglaucoma topical drugs in an in vitro model of conjunctival cells. Curr Eye Res 2000;20(2):85-94. DOI: 10.1076/0271-3683(200002)20:2;1-d;ft085
 Delayed and prolonged effect of BAC is because of incorporation and persistence of BAC molecules in cell membranes.¹ This   affects the lipid layer of the tear film causing it’s instability² thereby predisposing to inflammation of the ocular surface and conjunctival metaplasia. In addition, preservatives have direct destructive effects on the mucous gland, reducing the number of goblet cells and production of the protective mucus layer.³

Reference:
1. Yee RW. The effect of drop vehicle on the efficacy and side effects of topical glaucoma therapy: a review. Curr Opin Ophthalmol  2007;18(2): 134-139. DOI: 10.1097/ICU.0b013e328089f1c8
2. Detry-Morel M. Side effects of glaucoma medications. Bull Soc Belge Ophtalmol.2006;299:27-40. PMID: 16681086https://www.ncbi.nlm.nih.gov/pubmed/16681086
3. Herreras JM, Pastor JC, Calonge M, Asensio VM. Ocular surface alteration after long-term treatment with an anti-glaucomatous drug. Ophthalmology  1992;99(7):1082-108. DOI:10.1016/S0161-6420(92)31847-0

  Answer 3. d. ( a and c)
 Instillation of topical antiglaucoma drops for a period of three or more months has been found to cause significant subclinical inflammation, which has been detected as increased expression of HLA-DR on conjunctival epithelial cells.¹  Pro-inflammatory cytokine secretion by conjunctival cells has been noted to occur as a result of instillation of antiglaucoma eye drops.²

Reference: 
1. Arici MK, Arici DS, Topalkara A, Guler C. Adverse effects of topical antiglaucoma drugs on the ocular surface. Clin Exp Ophthalmol 2000;28(2):113-117. DOI: 10.1046/j.1442-9071.2000.00237.x

2. Malvitte L, Montange T, Vejux A, Baudouin C, Bron AM, Creuzot Garcher C, Lizard G. Measurement of inflammatory cytokines by multi cytokine assay in tears of patients with glaucoma topically treated with chronic drugs. Br J Ophthalmol  2007;91(1):29-32. DOI: 10.1136/bjo.2006.101485

Manu Saini.et.al observed that, in vivo confocal microscopic examination showed a statistical significant decrease in central corneal SBNFL (sub-basal nerve fibre layer)  nerve number, length and density and corresponding decrease in corneal sensitivity. Density of the basal epithelial cells was significantly increased in the eyes with chronic ocular hypotensive medications as compared to that in the control group. Central corneal sensation threshold was observed to be decreased in antiglaucoma medication group with corresponding decrease in Sub basal nerve fibre layer density.
Reference: Manu Saini, Murugesan Vanathi, Tanuj Dada, Tushar Agarwal, Rebika Dhiman, Sudarshan Khokhar. Ocular surface evaluation in eyes with chronic glaucoma on long term topical antiglaucoma therapy. Int J Ophthalmol , 2017; 10(6),931-938. doi: 10.18240/ijo.2017.06.16

Answer 4. e (Iris pigmentation, conjunctival hyperemia and Lengthening of eye lash)
According to study conducted by kenji inou et al – Iris pigment changes occurred in 31.7% of latanoprost patients, 37.9% of travoprost patients, 34.5% of tafluprost patients, and 50.0% of bimatoprost patients.¹– Eyelash lengthening/number increase occurred 54%, 46%, 26%, and 46% more often in the eye treated with bimatoprost, travoprost, latanoprost, and tafluprost, respectively^.1A meta-analyses has shown that conjunctival hyperemia occurred significantly less often with latanoprost than with travoprost or with bimatoprost.²

Reference: 
1. Kenji Inoue.Managing adverse effects of glaucoma medications. Clinical Ophthalmology 2014:8 903–913 doi: 10.2147/OPTH.S447082. 
2. Honrubia, F., Garcia-Sanchez, J., Polo, V., de la Casa, J. M. M., & Soto, J. Conjunctival hyperaemia with the use of latanoprost versus other prostaglandin analogues in patients with ocular hypertension or glaucoma: a meta-analysis of randomised clinical trials. British Journal of Ophthalmology.2008. 93(3), 316–321. doi: 10.1136/bjo.2007.135111

Answer 5.  a. IOP lowering capacity decreases over short term due to up regulation of beta receptor and increase in the number of receptor in ciliary process.
Beta-blocking drugs, provide varied examples of tachyphylaxis. Beta-blockers bind to the beta-adrenergic receptors, competing with the body’s natural agonists that aim to increase aqueous secretion in the ciliary tissues of the eye. The beta-blocker timolol induce short-term “escape” and long-term “drift” in responsiveness over days, months and years of treatment. It has been shown that, in certain patients, treatment with beta-blockers can lead to a rapid increase in the density of beta-adrenergic re­ceptors on the cell surface. Extended use of beta-blockers may reduce their effectiveness, because the response of beta receptors is affected by constant exposure to an agonist (long-term drift, tachyphylaxis). Similarly, receptor saturation (drug-induced up-regulation of beta receptors) may occur within a few weeks, with loss of effectiveness (short-term escape) https://www.reviewofophthalmology.com/article/the-truth-about-tachyphylaxis