5.1
Atropine and Other Pharmacological
Approaches to Prevent Myopia
Louis M.G. Tong*,†,‡, Veluchamy A. Barathi and
Roger W. Beuerman†,§
Introduction
An earlier chapter (Chapter 1.1) in this book has mentioned the rising incidence of myopia in many countries, and that myopia may occur at a relatively young age (prior to 10 years) and then stabilizing at 16 years or younger. When myopia stabilizes at higher severities, e.g., at greater than 6 D, there is a risk of potential blinding conditions such as retinal detachment, retinal degeneration and glaucoma (Chapters 2.3, 2.4 and 2.5). Higher severity of myopia induces morbidity by increasing the aberrations and reducing quality of life (Chapter 2.1). For these reasons, it is important to attempt to arrest the progression of myopia, or even stop the onset of myopia.
Historically, many forms of treatment to arrest myopia have been attempted,1 as early as in the 19th century.2 Currently, there is no general guideline followed by eye care practitioners for interventions that may decrease myopia in children. Recently, the authors have published review articles on the common modalities that have been advocated for myopia treatment.3,4 Apart from pharmacological therapies, these modalities include optical treatment such as changing the pattern of spectacle wear,5,6 the use of bifocals, multifocals and RGP contact lenses,7,8 and the use
*Singapore National Eye Centre. E-mail: Louis.tong.h.t@snec.com.sg
†Singapore Eye Research Institute, Singapore.
‡Duke-NUS Graduate Medical School, Singapore.
§Duke–NUS, SRP Neuroscience and Behavioral Disorders, Ophthalmology, Yong Loo Lin School of Medicine, National University of Sinagapore, Singapore.
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of orthokeratology9 and visual training.10 Apart from pharmacological therapies, and studies that show the effect of progressives on a subset of myopia,11,12 no other forms of treatment have been shown in randomized controlled studies to have a beneficial effect. For this reason, this chapter will focus only on pharmacological therapies.
The aim of this chapter is to summarize the postulated mechanisms, historical aspects, and the current evidence for the efficacy and safety of various pharmacological treatments to arrest myopia progression.
Possible Mechanisms of Pharmacological Treatment
The main eyedrops that have been evaluated in the treatment of human myopia include the anti-muscarinic agents and ocular hypotensives. Common anti-muscarinic drugs that have been evaluated include atropine,13 pirenzepine,14 tropicamide15 and cyclopentolate.16 The ocular hypotensives that have been evaluated are the beta-adrenergic blockers labetalol and timolol,17 adrenaline18 and parasympathomimetic pilocarpine.2
Although atropine19,20 and pirenzepine14 have been shown to reduce myopia progression via slowing of axial elongation, the exact mechanism is still unknown.
Both atropine and pirenzepine are blocking agents that are effective against muscarinic acetylcholine receptors of which there are five types, all of which are present in ocular tissues in varying amounts.21–23 However, pharmacologically, the use of a blocking agent is contingent on identifying the agonist of the effective pathway. In the case of myopia, the actual agent has not been identified and the use of atropine is historical, based on a hypothesized role of accommodation in myopia, which has turned out not to be the case. The second issue regarding the target of atropine, is the location of the muscarinic cholinergic receptors. Many ocular tissues have these receptors (Fig. 1). As shown in Fig. 2, the goal of current research is to determine the initial site of action of atropine or other muscarinic blockers. Locating the tissue with the critical receptor population will be the first step in developing new therapies with better targeting.
The muscarinic cholinergic receptors (mAChRs) are well known members of the G-protein coupled receptor superfamily (GPCRs). The mAChRs have both a neuronal and a non-neuronal presence, and interest in non-neuronal applications has been expanding. It has been established
347 Atropine and Other Pharmacological Approaches to Prevent Myopia
Figure 1. Immunohistochemistry of muscarinic receptor subtypes in cultured mouse (a) and human scleral fibroblasts (b). Subtype selective antibodies bound demonstrated the presence of the muscarinic receptors M1–M5. No binding was observed when the primary antibody was omitted (not shown). The M1–M5 receptors were localized to the cell membrane as well as to the cytoplasm. Magnification, 200×.
Figure 2. Schematic showing the action of topical anti-muscarinic agent on myopia.
that there are five types of muscarinic receptors, M1–M5.24 Muscarinic receptors are linked to proliferation through intracellular pathways involving the mitogen activated protein kinase (MAPK). However, in addition and maybe importantly for myopia, there are also established interactions between the muscarinic receptors and the growth factor receptors such
348 L.M.G. Tong, V.A. Barathi and R.W. Beuerman
as epidermal growth factor.24 These pathways interact through the cytoplasmic components of the pathways through various mechanisms referred to as transactivation.
The ocular role of these receptors in accommodation has been well-established, which is the underlying reason for the application of atropine to prevent myopia, thought to be associated with near-work. The two tissues that are intimately linked to myopia, the retina and sclera, are both potential targets of muscarinic blockers. The function of mAChRs M1–M3 receptors appears to dominate. This has been the case for mammalian retina, retinal pigment epithelium and the lens.25–27 The chicken retina has also been explored for the effects of mAChRs. This has been motivated by the finding that pirenzepine slows myopia progression in the experimental model of myopia in the chick, suggesting a role for M1, as pirenzepine has a stronger effect on this muscarinic sub-type.28 However, after an extensive effort it was found that the M1 receptor does not exist in the chick, which puts some doubt on the role of muscarinic action in the control of sclera growth. These studies did find the presence of M2 and M4. It was found that various muscarinic antagonists, when injected into the posterior chamber of the chick eye, changes ZENK expression, a chicken analog of the early-immediate mammalian gene EGR–1.29
Recent studies have demonstrated that multiple mAChRs occur in mammals including humans associated with specific tissues.30 The M3-receptor is the main mAChR in human cornea, iris, ciliary body, and the epithelium of the crystalline lens.26–31 The M2- and M4-receptors have been found in the rat retina.32 The biology of the subtypes of mAChRs in the eye has not been explored in detail, but at both the mRNA and protein levels, all five mAChRs were detected in the human sclera,21,33 tree shrew sclera,34 guinea pig sclera,35 and mouse sclera21 (Fig. 1). However, the functional significance of cholinergic receptors in SFs remains to be studied in detail.
Anti-muscarinic agents have been known to influence sclera remodeling in tree shrew myopia.23 Chapter 4.2 describes the changes in the extracellular matrix of the sclera, which are known to be involved in scleral remodeling during myopiagenesis.
Drugs such as atropine have been known to affect the release of dopamine, which is a critical retinal neurotransmitter important for control of the growth of the eye.36 Atropine can also influence growth hormone, which may exert an effect on the growth of the eye and hence