Iris circular and radial muscles are innervated by postganglionic parasympathetic and sympathetic nerves respectively. Upon the activation of sympathetic nerves, norepinephrine is released from the postganglionic nerve ending, causing radial muscles of the iris to get contracted, causing mydriasis, whereas parasympathetic activation releases acetylcholine (ACh) from postganglionic nerve terminals causing miosis. The mechanism of them causing mydriasis and miosis are shown in Fig. 6.2. The dynamic equilibrium between both of the nervous systems determines pupillary diameter based upon the amount of light reaching the retina. The normal human eye can dilate the pupil from 1.5 to 8 mm in diameter and this change is expected to modulate the depth of focus, optical aberration, retinal illumination, and diffraction. Coordinated performance of the iris aperture along with focal length adjustment rendered by ciliary muscles by autonomic control is required for the optimum performance of visual system at different conditions. When the dynamic equilibrium exists between the sympathetic and parasympathetic system, pharmacological agents are used to achieve mydriasis or miosis by stimulating the appropriate autonomic receptors. Phenylephrine is an alpha-1 agonist capable of stimulating the contraction of iris radial muscle and cause mydriasis but atropine which is a muscarinic blocker is capable of removing the influence of cholinergic stimuli-induced contraction on iris circular muscle (sphincter muscle), thereby causing the domination of existing tone of sympathetic system leading to mydriasis. Dapiprazole is a selective α(1)-adrenoreceptor antagonist approved to reverse the mydriasis induced by atropine.

Similarly, miosis can be induced by the stimulation circular muscles of the iris (sphincter muscle) using cholinomimetic-like pilocarpine or cholinesterase inhibitors and α(1)-adrenoreceptor blocker dapiprazole. Dapiprazole causes miosis by removing the action of sympathetic tone on radial muscles of the iris, leading to the shift of equilibrium to cholinergic tone (Bartlett and Classe 1992).

Apart from the presence of acetylcholine (neurotransmitter of cholinergic nerves) and norepinephrine (neurotransmitter of sympathetic nerves), other neurotransmitters and neuropeptides such as VIP, neuropeptide Y, nitric oxide synthase (for nitric oxide), and ATP were identified in the postganglionic neurons; they are not exploited so far by any pharmacological means for diagnostic or therapeutic potential. However, they are reported to be involved in the intrinsic pathways in controlling blood supply, aqueous humor dynamics, and other functions (Neuhuber and Schrodl 2011). The list of adrenergic and cholinergic receptors identified in various ocular structures and their functional importance are shown in Table 6.1. Apart from the classical autonomic pathway, morphine is known to stimulate parasympathetic pathway through the Edinger-Westphal nucleus, causing miosis in the iris.

Anisocoria is a condition commonly manifested by the unequal sizes of pupils. This could vary from simple to life-threatening conditions. Pupillary inequality is usually identified by their reaction in both dim and bright illuminations before initiating further clinical proceedings. Once the dysfunctioning of pupils is confirmed, differential diagnostic procedure is opted in neuro-ophthalmology in defining the underlying condition. It is aided by a handful of drugs like pilocarpine, hydroxyl-amphetamine, cocaine, phenylephrine, and morphine.

Accommodation in the eye is primarily due to the strong influence of the parasympathetic system. The lens in the anterior segment is enclosed in a lens capsule and suspended by the specialized fibers called zonules from the ciliary body. Ciliary muscles are clarified into outer longitudinal, middle radial, and inner circular layers. In normal conditions influence of the parasympathetic system makes the ciliary circular muscles to contract, causing zonules to relax and thereby causing the lens to become convex and move a little toward the anterior segment. This action fixes the lens toward for near vision, called accommodation. When the radial muscle is pulled by sympathetic stimulation, stretched zonules cause reduction in curvature, leading to the lens adjustment for far vision. Antimuscarinic drugs like atropine abolish the effect of accommodation, causing the lens to fix for far vision. One of the mechanisms put forward for sympathomimetic agents is that their action on ciliary radial muscle puts traction on scleral spur, causing a decreased resistance in trabecular meshwork in reducing intraocular pressure.

Contribution of lacrimal gland secretion plays an important role in the formation of precorneal tear fluid. Parasympathetic innervation through M3 receptors plays a major role in the lacrimation and it is modulated by the sympathetic system. The lacrimal gland is reported to have transcellular Cl⁻ secretion in the acinus which involves Cl⁻-selective channels in the apical plasma membrane (Mircheff 1989). Muscarnic agonist carbachol increases transepithelial Cl⁻ fluxes that attribute to lacrimal fluid production (Selvam et al. 2013). Interestingly, some degree of cross-talk between purinergicP2 receptors and M3 and α1D-adrenergic receptors are reported to influence tear secretion (Murakami et al. 2000). Purinergic receptor subtypes are known to play divergent physiological functions in various structures like in corneal wound repair, modulating trabecular remodeling, visual processing in the retina, etc. (Sanderson et al. 2014). Pilocarpine is known to stimulate lacrimation through muscarinic receptors of the lacrimal gland and atropine is known to block lacrimal secretion and causes dry eye. Antihistaminics are known to have antimuscarinic side effects which are mediated through M3 receptor responsible for glandular secretion. Therefore, the lacrimal, P2Y(2), receptor subtype gains pharmacological importance due to its involvement in sharing the tear secretion pathway like carbachol. Topical instillation of P2Y(2) receptor agonist (diquafosol) has been reported to increase in net Cl⁻, fluid transport, and glycoprotein release onto the ocular surface (Fujihara et al. 2001; Mundasad et al. 2001).

In the anterior segment of the eye, aqueous humor produced by the ciliary processes is secreted into the posterior chamber and it reaches into anterior chamber through the pupil. From the anterior chamber, majority of the aqueous humor (80–95 %) drains into the canal of Schlemm to the episcleral venular plexus and finally it drains into systemic circulation. Apart from this route, it also routes through unconventional uveoscleral pathway. The rate of production of aqueous humor and its disappearance through drainage pathways together determines intraocular pressure and finally development of glaucoma. Production of aqueous humor comes under the influence of the sympathetic system through beta-receptors which is regulated by presynaptic α2 receptors (autoreceptors) in the sympathetic nerve endings. The classical regulation of intraocular pressure is achieved by blocking β2 adrenergic receptors or by stimulating presynaptic α2 receptors. Apart from this mechanism, directly or indirectly acting sympathomimetics widen the trabecular meshwork by creating a traction in the scleral spur through ciliary muscles. Epinephrine has also been reported to increase uveoscleral flow, which is likely through stimulating beta-2-adrenergic receptors (Almand Nilsson 2009).

The sympathetic system supplies to tissues of eyes through its various receptors and thus may produce diverse effects depending on the receptor activated. It supplies the pupil dilator muscle and brings about mydriasis through α1 receptor. It also produces the contraction of Muller’s muscle through the same receptors. The sympathetic system has dual effect on aqueous production wherein it enhances the aqueous humor formation through ß2 receptors while inhibiting formation through α2 receptors. It also relaxes the ciliary body muscle through its ß2 receptors. The parasympathetic ocular effects are produced through muscarinic receptors. This includes supply to the sphincter papillae muscle, causing miosis and contraction of the ciliary body muscle, leading to accommodation and enhanced drainage of aqueous humor.

Alpha-2 adrenergic agonists, in addition to their pressure-lowering effects in the eye, may act directly upon retinal neurons, including retinal ganglion cells. Alpha-2A expression was identified in the human retina, on ganglion cells, and cells in the inner and outer nuclear layers (Kalapesi et al. 2005), whereas only a few clinical studies so far showed any benefit of neuroprotection in glaucoma (Evans et al. 2003; Sena and Lindsley 2013). Presence and involvement of β-adrenergic system in angiogenic processes has been implicated in infantile hemangiomas, retinopathy of prematurity, and cancer (Filippi et al. 2015). As the neurotransmitters of the autonomic nervous system such as acetylcholine and norepinephrine are vasoactive substances, therefore, presence of adrenergic and cholinergic receptors at the cornea, iris, ciliary body, retina, and choroid is expected to play a significant role on their vascular tone and cellular homeostasis (Mori et al. 2010; Toda et al. 1996; Casini et al. 2014). However, the current knowledge available is not enough to speculate the pharmacological utilization of these receptors in various ophthalmic conditions.

Adrenergic agonists and antagonists are the major class of drugs which have been extensively used in ophthalmology. Norepinephrine, epinephrine, and dopamine are the three major adrenergic neurotransmitters of the sympathetic division of the autonomic nervous system. These amines work by activating adrenergic receptors, namely, alpha- and beta-receptors, present in various tissues of the eye which are primarily innervated by postganglionic sympathetic nerves. The distribution of these receptors is mentioned in Table 6.1.

Adrenergic agonists can be classified into directly acting, indirectly acting, and mixed-acting agents. Drugs such as epinephrine which can directly stimulate the receptors by binding to one or more receptors are known as directly acting. Drugs which can increase the release of responsible neurotransmitter from presynaptic vesicles to augment the effect of the sympathetic innervations are known as indirectly acting such as cocaine. Drugs which can perform both the actions of direct and indirect activation are known as mixed acting (Fig. 6.1).

The eye has both alpha- and beta-adrenergic receptors. Adrenergic receptors are present in corneal epithelium, endothelium, iris radial and sphincter muscles, trabecular meshwork, ciliary epithelium, ciliary muscles, lacrimal gland, and retinal pigment epithelium (Table 6.1). The adrenergic system plays a vital role in maintaining the tonicity of this part for the physiological processes of the eye through constriction and dilation. Thus, this system has been a subject for manipulation for various diagnostic, palliative, and curative strategies in ophthalmic conditions.