Experimental Eye Research 93 (2011) 271e283 Contents lists available at ScienceDirect Experimental Eye Research journal homepage: www.elsevier.com/locate/yexer Update on the role of alpha-agonists in glaucoma management Stella Arthur, Louis B. Cantor* Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, USA article info abstract Article history: Glaucoma is the second most common cause of world blindness (following cataract) with estimated Received 30 November 2010 cases reaching 79.6 million by 2020. Although the etiology of glaucoma is multi-factorial, intraocular Accepted in revised form 4 April 2011 pressure (IOP) is the only modifiable factor in glaucoma management proven to alter the natural course Available online 20 April 2011 of the disease. Among various classes of IOP-lowering medications currently available, alpha-adrenergic receptor agonists are used either as monotherapy, as second-line therapy, or in fixed combination with Keywords: beta-blockers. Non-selective adrenergic agonists such as epinephrine and dipivefrin are infrequently glaucoma used today for the treatment of glaucoma or ocular hypertension, and have been replaced by the alpha-2- alpha-agonists monotherapy selective agonists. The use of apraclonidine for IOP reduction in glaucoma or OHT is limited due to a high fixed combinations rate of follicular conjunctivitis. The alpha-2-selective agonist in use today is brimonidine. The brimo- neuroprotection nidineepurite formulations are preferred to brimonidineebenzalkonium chloride (BAC) formulations ocular blood flow due better tolerability while maintaining similar efficacy. Brimonidine is also effective when used in safety and efficacy combination with a beta-blocker. Using brimonidineetimolol fixed combination (BTFC) as first-line compliance and cost of alpha-agonists therapy has an added potential for neuroprotection. This would be a valuable strategy for glaucoma treatment, for patients who are intolerant of prostaglandin analogs, or for patients where prostaglandin analogues are contraindicated as first-line therapy, such as in patients with inflammatory glaucoma. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction parasympathomimetics, and alpha-adrenergic receptor agonists (Greenfield et al., 1997; Carroll et al., 2006; Costagliola et al., 2009; Glaucoma is a multi-factorial, neurodegenerative, heterogeneous Crassous et al., 2007; Lee and Higginbotham, 2005; McKinnon group of disorders associated with a characteristic, progressive, optic et al., 2008; Robin, 1997, 1995; Serle et al., 2002). neuropathy and corresponding visual field loss. It is the second most common cause of world blindness (following cataract) with esti- 2. Classification of alpha-adrenergic receptors and mated cases reaching 79.6 million by 2020 (Quigley and Broman, mechanism of action of alpha-agonists used 2006). Annual incidence of primary open angle glaucoma (POAG) for glaucoma treatment in the USA is estimated to be 2.2 million cases (Leske, 2007). Although the etiology of glaucoma is multi-factorial, intraocular pressure (IOP) Adrenergic receptors are cell membrane receptors, which belong is the only modifiable factor in glaucoma management proven to to the G-protein-linked superfamily of receptors. Adrenergic recep- alter the natural course of the disease. Numerous studies have shown tors mediate functions of the sympathetic nervous system, and that IOP reduction prevents glaucoma or delays progression of produce the “fight or flight” reaction. Two classes of adrenergic established glaucoma (Friedman et al., 2004; AGIS Investigators, receptors have been identified: excitatory alpha-receptor and 2002; Lichter et al., 2001; Leske et al., 2003; Collaborative NTG inhibitory beta-receptors (Ahlquist, 1948). Two groups of alpha- study group, 1998; Heijl et al., 2009; Kass et al., 2002, 2010; Hoyng adrenergic receptors, with associated subtypes, have been identi- and Kitazawa, 2002). Several groups of IOP-lowering medications fied: alpha-1 (A, B, D) and alpha-2 (A, B, C) (Gilsbach et al., 2009; are currently available. These include prostaglandin analogs, beta- Docherty, 2010; Piascik et al., 1995; Piascik and Perez, 2001). One adrenergic receptor antagonists, carbonic anhydrase inhibitors, of the primary actions of alpha-1 receptors is induction of smooth þ muscle contraction, which is achieved by activating Ca2 channels or þ by releasing intracellular Ca2 (Docherty, 2010). One of the main * Correspondence to: Louis B. Cantor, Eugene and Marilyn Glick Eye Institute, actions of pre-junctional alpha-2 receptors is inhibition of neuro- Indiana University School of Medicine, Department of Ophthalmology, 702 Rotary Circle, Indianapolis, IN 46202, USA. transmitters (Reitsamer et al., 2006; Starke et al.,1975; Gilsbach et al., E-mail address: [email protected] (L.B. Cantor). 2009). Activation of vascular post-junctional alpha-2 receptors 0014-4835/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.exer.2011.04.002 272 S. Arthur, L.B. Cantor / Experimental Eye Research 93 (2011) 271e283 causes vasoconstriction (Reitsamer et al., 2006) and activation of extracellular matrix (ECM) degradation. ECM within the trabecular post-junctional epithelial alpha-2 receptors inhibits adenylate meshwork plays an important role in increasing outflow resistance, cyclase (Kaufman and Gabelt,1995). The functions of alpha-receptors and within conjunctiva it promotes wound healing. Hence, its and their subtypes are summarized in Table 1. degradation would increase aqueous outflow and promote post- In the eye, alpha-agonists activate alpha-1 receptors that stim- operative survival of a trabeculectomy bleb (Ito et al., 2006). ulate contraction of the iris dilator and Muller muscles, leading to mydriasis and lid retraction. Furthermore, alpha-1 stimulation also 3. Formulations and pharmacokinetics of alpha-agonist leads to vasoconstriction resulting in restricted blood flow to ciliary glaucoma medications muscle and reduced production of aqueous (Docherty, 2010). Similarly, stimulation of vascular post-junctional alpha-2 receptors 3.1. Non-selective alpha-agonists causes ciliary body and episcleral vasoconstriction (Reitsamer et al., 2006). By stimulating post-junctional epithelial alpha-2 receptors, Epinephrine is available in 0.25%, 0.5%, 1.0%, and 2.0% concen- alpha-agonists decrease intracellular cAMP (Mittag and Tormay, trations and is used twice daily. Dipivalyl epinephrine (dipivefrin) is 1985) resulting in decreased production of aqueous and increased available in a 0.1% concentration and is also used twice daily. uveoscleral outflow (Gilsbach et al., 2009; Costagliola et al., 2009; Dipivefrin is a prodrug of epinephrine, and therefore a lower David, 2001; Robin and Burnstein, 1998; Liu and Gallar, 1996; concentration is required topically (Kass et al., 1979). Due to its Mittag and Tormay, 1985, Toris et al., 1995a). Furthermore, by increased lipophilicity, dipivefrin has better corneal penetration stimulating alpha-2 receptors, alpha-agonists oppose the effects of than epinephrine and is cleaved to its active form by corneal beta-receptors on aqueous outflow and mitotic activity of cultured esterases, leading to intraocular concentrations that are similar to human trabecular meshwork endothelial cells (Stamer et al., 1996). topically applied epinephrine. In addition, alpha-agonists have been shown to modulate expres- Numerous studies conducted to elucidate the effect of epineph- sion and enzymatic activity of matrix metalloproteinases (MMPs) rine on aqueous dynamics revealed conflicting results. Some inves- and tissue inhibitors of metalloproteinase (TIMPs), which stimulate tigators found that a single dose of epinephrine (Townsend and Brubaker, 1980; Higgins and Brubaker, 1980), twice daily dose given over 1 week (Schenker et al., 1981), or intravenously administered Table 1 epinephrine (Kacere et al., 1992) may increase aqueous production. Summary of alpha-receptors and their subtypes with mechanism of actions. This effect is thought to be mediated by the beta-adrenergic prop- Receptors Action erties of epinephrine. Other studies found the epinephrine has no effect on aqueous production (Bill, 1969; Schneider and Brubaker, Alpha1A 1. Vasoconstriction of ciliary muscle resulting in reduced production of aqueous and decrease in intraocular 1991). Yet, other studies found that shortly following instillation, pressure (Docherty, 2010) both epinephrine and dipivefrin induce vasoconstriction in the iris 2. Contraction of smooth muscle cells and ciliary body, which leads to decreased aqueous production. This (Docherty, 2010; Piascik and Perez, 2001) 3. Vasoconstriction and regulation of arterial transient effect is initially replaced by an early (within hours) blood pressure (Docherty, 2010; Piascik and Perez, 2001) increase in trabecular outflow facility, and later is sustained by 4. Temperature control (Docherty, 2010; increase in uveoscleral outflow (Garner et al.,1959; Wang et al.,1999; Bexis and Docherty, 2008) Schenker et al., 1981; Townsend and Brubaker, 1980; Bill, 1969; 5. Mediation of hypertrophic growth of myocardial Ballintine and Garner, 1961). cells (Varma and Deng, 2000) Alpha1B 1. Regulation of arterial blood pressure (Piascik and Perez, 2001). 3.2. Selective alpha-2 agonists 2. Increase of the p38 kinase activity, a mediator of cell growth, proliferation, differentiation, and survival (Waldrop et al., 2002) 3.2.1. Apraclonidine