Pathogenic mechanisms of α2-adrenergic agonists’ hypotensive action

PURPOSE: To determine pathogenic mechanism of alfaadrenergic agonists’ hypotensive action by brimonidine 0.2% administration in patients with open-angle glaucoma.

METHODS: 88 patients (age 69.1±7.25) diagnosed with mild open-angle glaucoma and with disease history of less than 1 year were included in the study. Patients were divided into two groups according to their drug regimen. Group 1 consisted of 12 patients (24 eyes) with brimonidine 0.2% instillations. Group 2 consisted of 76 patients (133 eyes) and was further divided into four subgroups. The 1st subgroup included 36 patients (66 eyes) with brimonidine 0.2% monotherapy; the 2nd subgroup included 18 patients (29 eyes) with a combined treatment with brimonidine 0.2% and prostaglandin analogues; the 3rd subgroup included 13 patients (20 eyes) with brimonidine 0.2% added to timololum 0.5%; the 4th subgroup included 9 patients (18 eyes) with brimonidine 0.2% added to dorzolamidum 2%. Patients of Group 1 underwent uveoscleral outflow examination and had the following coefficients calculated: general outflow facility coefficient (Cgen), uveoscleral outflow facility coefficient (Cuveo), aqueous humor minute volume (F). Hypotensive regimen efficiency action in Group 2 was measured by means of dynamic contour tonometry (Pascal tonometer, «SMT Swiss Microtechnology AG»).

RESULTS: In Group 1 intraocular pressure (Po) decreased to 17.5±4.01 mmHg (р=0.04) (by 28% from the initial level), Cgen increased up to 0.23±0.06 mm3 /min/mmHg (р=0.01) (by 35% from the initial level), Cuveo increased up to 0.12±0.02 mm3 /min/mmHg (р=0.01) (by 71% from the initial level), F decreased to 1.5±0.6 mm3 /min (р=0.04) (by 48% from the initial level). Only one patient on the group had intolerance to the drug. In Group 2 after 3 months of follow-up Po decreased from 23.2±4.92 to 16.3±4.64 mmHg in the 1st subgroup (by 29.7% from the initial level); from 23.4±3.84 to 18.2±4.83 mmHg (р=0.04) in the 2nd subgroup (by 22.2% from the initial level); from 23.3±3.19 to 17.2±4.53 mmHg in the 3rd subgroup (by 26.2% from the initial level); from 22.0±2.85 to 17.4±2.82 mmHg in the 4th subgroup (by 21.9% from the initial level). Brimonidine 0.2% was discontinued in 14 patients (15.9% of the total number of patients) due to various reasons (intolerance to the drug or insufficient hypotensive action).

CONCLUSION: Pathogenesis of α2-adrenergic agonists’ hypotensive action involves aqueous humor outflow increase by uveoscleral pathway and significant aqueous humor minute volume reduction. Hypotensive efficiency with IOP decrease by 24.6% was revealed in case of brimonidine 0.2% monotherapy. Additional reduction of intraocular pressure by 21.1% from the initial level was revealed in case of brimonidine 0.2% prescription in combination with other drugs. A more prominent hypotensive effect was revealed after 3 months of treatment compared to a 1 month treatment course. In most cases patients showed a high tolerability to brimonidine 0.2%. 

1. Глаукома. Национальное руководство. Под ред. Е.А. Егорова. М.: ГЭОТАР-Медиа, 2013; 824 с. [Glaukoma. Natsional’noe rukovodstvo [Glaucoma. National gudance]. Ed. by E.A. Egorov. Moscow, GEOTAR Media Publ., 2013; 824 p. (In Russ.)].

2. Национальное руководство по глаукоме для практикующих врачей. 3-е изд. Под ред. Е.А. Егорова, Ю.С. Астахова, В.П. Еричева. М.: ГЭОТАР-Медиа, 2015; 456 c. [Natsiomal’noe rukovodstvo po glaukome dlya praktikuyushchikh vrachei. 3-e izd. [Glaucoma for medical practitioners: national guidance. 3rd ed]. Ed. by E.A. Egorov, Yu.S. Astakhov, V.P. Erichev / Moscow, GEOTAR-Media Publ., 2015; 456 p. (In Russ.)].

3. McMonnies C.W. Intraocular pressure spikes in keratectasia, axial myopia, and glaucoma. Optom Vis Sci 2008; 85: 1018-1026. doi: 10.1097/opx.0b013e3181890e91.

4. Grant W.M. Experimental aqueous perfusion in enucleated human eyes. Arch Ophthalmol 1963; 69: 783-801. doi: 10.1001/archopht.1963.00960040789022.

5. Coleman A.L., Miglior S. Risk factors for glaucoma onset and progression. Surv Ophthalmol 2008; 53(6):S3-S10. doi: 10.1016/j.survophthal.2008.08.006.

6. Heijl A., Leske M.C., Bengtsson B. et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002; 120: 1268-1279. doi: 10.1001/archopht.120.10.1268.

7. Leske M.C., Heijl A., Hyman L., Bengtsson B., Dong L., Yang Z. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology 2007; 114: 1965-1972. doi: 10.1016/j.ophtha.2007.03.016.

8. Gordon M.O., Beiser J.A., Brandt J.D. et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120: 714-720. doi: 10.1001/archopht.120.6.714.

9. Kass M.A., Heuer D.K., Higginbotham E.J. et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120: 701-713. doi: 10.1001/archopht.120.6.701.

10. Лебедев О.И. Регуляция репаративных процессов при антиглаукоматозной хирургии с помощью коллализина. Вестник офтальмологии 1989; 3:4-6. [Lebedev O.I. Regulation of reparative processes at antiglaucomatous surgery using collalysin. Vestn Oftalmol 1989; 3:4-6. (In Russ.)].

11. Лебедев О.И., Яворский А.Е., Столяров Г.М., Молчанова Е.В., Ковалевский В.В. Профилактика избыточного рубцевания при непроникающей глубокой склерэктомии. Национальный журнал глаукома 2011; 1:32-36. [Lebedev O.I., Yavorskiy A.E., Stolyarov G.M., Molchanova E.V., Kovalevskiy V.V. Prevention of excessive scarring in nonpenetrating deep sclerectomy. Natsional’nyi zhurnal glaucoma 2011; 1:32-36. (In Russ.)].

12. Нестеров А.П. Глаукома. М.: Медицина, 1995; 256 c. [Nesterov A.P. Glaukoma [Glaucoma]. Moscow, Meditsina Publ., 1995; 256 p. (In Russ.)].

13. Schmidl D., Schmetterer L., Gar er G., Popa-Cherecheanu A. Pharmacotherapy of Glaucoma. J Ocul Pharmacol Ther 2015; 31(2):63-77. doi: 10.1089/jop.2014.0067.

14. Косых Н.В., Соколова Т.Ф. Иммунологическое состояние организма и увеосклеральный отток внутриглазной жидкости при глаукоме. Офтальмологический журнал 1982; 1:28-31. [Kosykh N.V., Sokolova T.F. Immunological status of the organism and uveoscleral outflow of intraocular fluid in glaucoma. Ophthalmological J 1982; 1:28-31. (In Russ.)].

15. Лебедев О.И., Столяров Г.М., Золотарев А.В., Карлова Е.В. Метод количественной клинической оценки увеосклерального пути оттока у человека. Практическая медицина 2012; 4-1(59):215-217. [Lebedev O.I., Stolyarov G.M., Zolotarev A.V., Karlova E.V. A method of quantative clinical measurement of uveascleral outflow in human. Practical medicine 2012; 4-1(59): 215-217. (In Russ.)].

16. Карлова Е.В. Возможность использования динамической контурной тонометрии для исследования увеосклерального оттока у пациентов с первичной открытоугольной глаукомой. Вестник ОГУ 2013; 4(153):123-126. [Karlova E.V. Using of dynamic contour tonometry in uveoscleral outflow measurements in glaucoma patients. Vestnic OGU 2013; 4(153):123-126. (In Russ.)].

17. Карлова Е.В. Хирургическая активация увеосклерального оттока в лечении больных первичной открытоугольной глаукомой. Офтальмохирургия 2014; 2:52-56. [Karlova E.V. Surgical activation os uveoscleral outflow in treatment of patients with primary open-angle glaucoma. Ophthalmosurgery 2014; 2:52-56. (In Russ.)].

18. World Glaucoma Association. Consensus Meeting. R.N. Weinreb, J. Liebmann. Medical Treatment of Glaucoma: The 7th Consensus Report of the World Glaucoma Association. Amsterdam: Kugler Publications, 2010.

19. Золотарев А.В., Карлова Е.В., Лебедев О.И., Столяров Г.М. Медикаментозная активация увеосклерального оттока внутриглазной жидкости при глаукоме: патогенетические аспекты. Вестник офтальмологии 2013; 129(4):83-87. [Zolotarev A.V., Karlova E.V., Lebedev O.I., Stoliarov G.M. Medication assisted activation of uveoscleral outflow of intraocular fluid in glaucoma: pathogenic aspects. Vestn Oftalmol 2013; 129(4):83-87. (In Russ.)].

20. Cantor L.B. Brimonidine in the treatment of glaucoma and ocular hypertension. Therapeutics and Clinical Risk Management 2006; 2(4):337-346. doi: 10.2147/tcrm.2006.2.4.337.

21. Toris C.B., Camras C.B., Yablonski M.E. Acute versus chronic effects of brimonidine on aqueous humor dynamics in ocular hypertensive patients. Am J Ophthalmol 1999; 128(1):8-14. doi: 10.1016/s0002-9394(99)00076-8.

22. Дугина А.Е. Селективные агонисты альфа2-адренорецепторов в лечении глаукомы. Национальный журнал глаукома 2014; 3:95-100. [Dugina A.E. Selective of alfa2-adrenoceptor agonists in glaucoma treatment. Natsional’nyi zhurnal glaucoma 2014; 3:95-100. (In Russ.)].

23. Fan S., Agrawal A., Gulati V., Neely D.G., Toris C.B. Daytime and nighttime effects of Brimonidine on IOP and aqueous humor dynamics in participants with ocular hypertension. J Glaucoma 2014; 23(5):276-281. doi: 10.1097/ijg.0000000000000051.

24. Toris C.B. Effects of Brimonidine on aqueous humor dynamics in human eyes. Arch Ophthalmol 1995; 113(12):1514. doi: 10.1001/archopht.1995.01100120044006.

25. Kim C.Y., Hong S., Song G.J. Brimonidine 0.2% versus brimonidine Purite 0.15% in Asian ocular hypertension. J Ocul Pharmacol Ther 2007; 23:481-486. doi: 10.1089/jop.2007.0042

26. Chang J.N., Spada L.P., Blanda W.M., Orilla W.C., Bruke J.A., Hughes P.M. Alpha-2-agonist polymeric drug delivery systems. US Patent Application 20060233860, 2006.

27. Hong S., Han S-H, Kim C.Y., Kim K.Y., Song Y.K., Seong G.J. Brimonidine reduces TGF-beta-induced extracellular matrix synthesis in human Tenon’s fibroblasts. BMC Ophthalmol 2015; 15:54. doi: 10.1186/s12886-015-0045-8.

28. Lambert W.S., Ruiz L., Crish S.D., Wheeler L.A., Calkins D.J. Brimonidine prevents axonal and somatic degeneration of retinal ganglion cell neurons. Mol Neurodegener 2011; 6(1):4. doi: 10.1186/1750-1326-6-4.

29. Galanopoulos A., Goldberg I. Clinical efficacy and neuroprotective effects of brimonidine in the management of glaucoma and ocular hypertension. Clin Ophthalmol 2009; 3:117-122. doi: 10.2147/opth.s3270.

30. Kitaoka Y., Kojima K., Munemasa Y., Sase K., Graefes H.T. Axonal protection by brimonidine with modulation of p62 expression in TNF-induced optic nerve degeneration. Arch Clin Exp Ophthalmol 2015; 253(8): 1291-1296. doi: 10.1007/s00417-015-3005-3.

31. Bhagav P., Upadhyay H., Chandran S. Brimonidine tartrate–eudragit long-acting nanoparticles: formulation, optimization, in vitro and in vivo evaluation. AAPS Pharm Sci Tech 2011; 12(4):1087-1101. doi: 10.1208/s12249-011-9675-1.

32. Столяров Г.М., Тихомирова Н.В., Тихомиров И.В. Метод количественной оценки увеосклерального оттока для оптимизации лечения глаукомы. Вестник офтальмологии 2016; 3:10-15. [Stoliarov G.M., Tikhomirova N.V., Tikhomirov I.V. Quantitative evaluation of uveoscleral outflow for optimization of glaucoma treatment. Vestn Oftalmol 2016; 3:10-15. (In Russ.)].