Anatomical and Physiological Basis of Ocular PharmacotherapyCHAPTER 1

The principles of therapeutics in the treatment of ophthalmic diseases require a comprehensive knowledge of ocular anatomy and physiology. The understanding of drug interactions at molecular, cellular and tissue level leading to pharmacological responses require special consideration due to the unique anatomical and physiological characteristics of eye. This chapter provides a basic account of the ocular anatomy and physiology as a basis of ocular pharmacotherapy.

The eyelids or palpebrae cover the anterior surface of the eye protecting it from injury and exposure. The space between the upper and lower lids is called the palpebral fissure, the angle between the lids are called the medial and lateral canthi (Fig. 1.1).

Anastomoses of the medial and lateral palpebral arteries supply the eyelids. Venous drainage is into the facial veins or to the ophthalmic veins. Lymphatics drain into the submandibular, superficial and deep parotid lymph nodes. Sensory innervation is by the ophthalmic and maxillary divisions of the trigeminal nerves.

Movements of the eyelids are brought about by 2 muscles, the orbicularis oculi, for closure of the lids and the levator palpebrae superioris for opening of the eyelids. Firm closure of the eyelid is achieved by the action of the orbicularis oculi muscle, supplied by the facial nerve. Closure of the eyelid for example in the instance of a blink occurs by inhibition of the levator palpebrae superioris muscle, supplied by the oculomotor nerve and the elastic recoil of the supporting connective tissues.³ The levator palpebrae superioris is responsible for the opening of the eyelid. Maximal eyelid opening is achieved by the added action of the frontalis muscle. Muller's muscle or the superior tarsal muscle arises from the distal part of the levator palpebrae superioris and inserts into the upper margin of the tarsus.³ It is composed of smooth muscle fibers and connective tissue. It is supplied by sympathetic nerves. It is mainly responsible for the width of the palpebral fissure. The motor supply is through the oculomotor nerve, while the motor neurons arise from a single central caudal nucleus of the oculomotor nerve. Thus lesions affecting the nucleus often affect both eyelids.³

Mucous membranes that cover the sclera up to the limbus and the palpebral portions of the eyelids are called conjunctiva. Their main function is protection of the anterior surface of the eye by secreting the mucous layer of the tear film, antibacterial and antiviral substances and providing immune defense. The three main regions of the 3conjunctiva include the palpebral portions covering the inner side of the eyelids, fornicial conjunctiva located at the fornices and the bulbar conjunctiva covering the white of the eyeball up to the limbus.

The lacrimal gland and accessory lacrimal glands are the main tear-producing structures. The lacrimal gland consists of an orbital part located within the orbital margin in the lacrimal fossa of the zygomatic process of the frontal bone. The palpebral part is located below the palpebral conjunctiva. Numerous accessory glands are located in the upper eyelid and the fornices and probably account for lacrimal secretions after removal of the lacrimal gland. Accessory glands of Krause are located in the superior and inferior fornix, while accessory glands of Wolfring are located on the margin of the superior tarsal plate of the upper eyelid.⁵ The lacrimal gland is supplied by the lacrimal branch of the ophthalmic artery and drains into the superior ophthalmic vein. It is supplied by parasympathetic fibers from the pterygopalatine ganglion, which are secretomotor to the gland. Acini of the gland are surrounded by myoepithelial cells, which contract to help glandular secretions exit the acini and ductules.

The tear film is composed of three layers (Fig. 1.4). The outermost layer consists of lipids from the secretions of tarsal glands. It floats on a middle aqueous layer, contributed by the main and accessory lacrimal glands. An inner mucous layer secreted by goblet cells is in contact with the surface of the conjunctiva and cornea.

The mucous layer is hydrophilic and traps particulate matter. The aqueous layer makes up more than 97% of the volume of secretions, and contains most of the proteins, immunoglobulins, lactoferrin and enzymes.

The orbit or the “sockets” of the eye are bony cavities that protect the eye and its supporting structures. The orbit also serves as a passage to connect the eye with its blood supply and nerves and also conduct the vessels and nerves that supply other parts of the face. The bony boundaries of the orbit are described below. It is a crowded space filled with numerous vessels, nerves, connective tissue and muscles apart from the eyeball. Anesthetic agents are administered into this space by the retro- and peribulbar route.5

Superiorly, the orbital margin is formed by the orbital arch of the frontal bone. Laterally, it is formed by the zygomatic bone and the zygomatic process of the frontal bone. The zygomatic bone and the maxilla form the inferior border of the orbital margin. It is slightly raised above the floor of the orbit. Medially, it is formed by the maxilla and lacrimal bone.

The orbit has a superior, medial and lateral wall and a floor composed of a number of different bones. They are briefly summarized in the Figures 1.5 to 1.7 and Table 1.2.⁹

It runs forward and passes below the surface as the infraorbital canal to open below the orbital margin as the infraorbital foramen.

The pyramidal structure of the orbit is incomplete due to the presence of a number of apertures (Fig. 1.8).¹² These limited spaces are crowed with a number of blood vessels and nerves passing through. Thus lesions often present as a syndrome called “orbital apex syndrome” (Tables 1.3 and 1.4). ¹⁰

The globe is located within the bony orbit. It is roughly spherical in shape, being composed of the transparent cornea anteriorly and the opaque sclera posteriorly. It is 2.5 cm in diameter and has a volume of approximately 25 mL. The cornea has a greater curvature as compared to the sclera, and has a radius of about 7.8 mm. The sclera is the larger of the two components and is part of a sphere of radius about 11.5 cm.

The cornea is an avascular 50–60 micron- thick structure composed of 5 layers—corneal epithelium, anterior limiting lamina, substantia propria, posterior limiting lamina and endothelium (Fig. 1.9). Since it is an avascular structure it obtains nutrition by diffusion from neighboring aqueous humor. It is transparent, strong and relatively resistant to abrasions. A tear film covers the surface of the cornea. Corneal epithelial layer is composed of a basal columnar germinal layer, intermediate wing cells and an outer layer of squamous, non-nucleated cells. These cells form a continuous layer over the cornea due to the zona occludens type of tight junctions that they form. Interstices present between these cells communicate directly with the aqueous humor. Adhesion of the basal layer to the anterior limiting membrane or Bowman's membrane is facilitated by network of anchoring fibrils and plaques. Cells from the basal layer are able to regenerate and replace other cells. The rate of corneal epithelial turnover is approximately 5–7 days.¹¹

Aquaporins (AQP1) have also been identified in the endothelium and thought to play a role in maintaining corneal thickness.

A fascial membrane called Tenon's capsule surrounds the globe of the eye, separating it from the orbital fat (Fig. 1.10). It extends from the point where optic nerve exits the globe to the corneoscleral junction where it fuses with the conjunctiva. It is pierced by tendons of the extraocular muscles and it becomes continuous with their fascial coverings. It is divided into an anterior and posterior space by the tendons of the extraocular muscles and their fascia. A number of fascial septa arise from the eyeball and are fixed to the periosteum, separating the orbital fat into various compartments. They help in maintaining the position of the eye and the position of the orbital fat and hence assist in binocular vision.

The sclera is a tough, opaque fibrous structure, protecting the contents of the globe. It is continuous with the cornea at a junction known as the limbus. It permits a limited amount of drug absorption, due to its vascularity. It is covered by the conjuctival epithelium reflecting onto it from the inner surface of the eyelids. Posteriorly it is pierced by the optic nerve passing through a sieve like perforated plate. Anteriorly at the limbus, an endothelial canal called the canal of Schlemm is present. Externally, the sclera is covered by Tenon's capsule. Within this layer is present the episclera, followed by scleral stroma. The innermost layer is called lamina fusca, which is closely applied to the choroid. Sclera is composed of Type I and III collagen fibril with small amounts of type V and VI. These fibrils are surrounded by a matrix composed of decorin and biglycan. They are proteoglycans. Collagen fibers are interwoven and are also mixed with fibers from the insertions of the extraocular muscles. This particular arrangement of fibers gives the sclera its physical and mechanical properties. It is able to maintain shape while being subjected to the pull of extraocular muscles as well as accommodate minor changes in shape due to changing intraocular pressure. Interspersed between the collagen fibrils are scleral fibrocytes. They have long cytoplasmic processes that form gap junctions with other fibrocytes and are responsible for secretion and turn over of the extracellular matrix material. They are activated by injury.¹³

The uveal tract is the pigmented middle layer of the eye. It is continuous with the pia-arachnoid coverings of the optic nerve. The iris and its muscles form the anterior part of the uveal tract. The iris acts as a diaphragm surrounding the pupil. It is composed of fibroblasts, melanocytes and loose collagenous material that contain its nerves and blood vessels. It lies between the cornea and lens, splitting the anterior segment of the eye into an anterior chamber between the cornea and iris and a posterior chamber between the iris and the lens. The main function of the iris is to control the aperture of the pupil. The larger the pupillary aperture is, the more the amount of light entering the eye and vice versa. The aperture is controlled by the sphincter pupillae and dilator pupillae. The sphincter pupillae is formed at the rim of the pupillary margin of the iris by a concentration of circularly arranged smooth muscle fibers. The pupillary aperture decreases upon contraction of these fibers. The dilator pupillae muscle fibers increase pupillary aperture when they contract as their fibers are arranged radially. The anterior surface of the iris has no epithelial covering. The epithelium of the posterior surface is bilayered, its deeper anterior layer being pigmented to absorb light. The more superficial posterior layer is non-pigmented and is in continuity with the unpigmented layer of the retina. The free surface of the iris contains numerous grooves, which allow movement of fluid from the posterior to the anterior chambers.¹⁵ The iris is pigmented and hence absorbs and retains lipophilic drugs. The stored drugs are then released slowly.

The muscles of the iris are supplied by autonomic nerves. The constrictor pupillae muscle is innervated by parasympathetic fibers arising from the ciliary ganglia. When stimulated the pupil constricts, reducing its diameter and causing a five-fold decrease in the amount of light entering the eye. The dilator pupillae muscle is supplied by sympathetic autonomic fibers that originate in the T1 segment of the spinal cord. Preganglionic fibers pass to the superior sympathetic cervical ganglion. Postganglionic fibers pass along with blood vessels and supply the muscle fibers. When stimulated, the radial fibers of the dilator pupillae constrict and the pupillary diameter increases.

The ciliary body is continuous with the choroid layer of the eye. Its main function is the suspension of the crystalline lens and the secretion of aqueous humor. It is attached to the scleral spur and passes around the eyeball in the irdiocorneal angle. Hence, anteriorly it is continuous with the tissues of the iris, while posteriorly it forms the ora serrata and continues as the choroid. It is brown in color due to the pigment contained in its epithelial layers. It has the following parts (Fig. 1.11)—pars plicata, present anteriorly, which is ruffled and pars plana present more posteriorly, which is smooth and continues with the ora serrata. Suspensory ligaments of the lens pass into the pars plana, anchoring the lens firmly. The ciliary body is covered by a bilayer of epithelial cells, a superficial unpigmented layer and an inner pigmented layer.

Ciliary body stroma is composed of loose collagen bundles and the ciliary muscle. The ciliary muscle is a ring of muscle tissue. It contains circular, radial and meridional fibers. Nerve supply to the ciliary body and muscle is predominantly parasympathetic from the ciliary ganglion. Upon stimulation, it contracts towards the optical axis, relaxing the suspensory ligaments causing the lens to bulge and accommodate.¹⁶

It is a fluid formed by the ciliary body and occupies the anterior and posterior chambers. It is secreted in the posterior chamber and flows through the pupil into the anterior chamber (Fig. 1.12). It drains through the canal of Schlemm into the episcleral veins. Some fluid may also leave the anterior segment through the surface of the iris. It provides nutrition to the avascular cornea, vitreous and lens. It also plays a major role in the regulation of intraocular pressure and the general shape of the eyeball. Any alteration to its drainage and/or secretion causes raised intraocular pressure.

Secretion of Aqueous Humor: It is secreted continuously by the epithelium of the ciliary processes of the pars plicata. They have a large surface area due to the presence of a number of folds, as well as an extensive capillary network. Fluid secretion is a result of active as well as passive processes. Fluid is essentially filtered out of the ciliary capillaries into the stroma and is then secreted by the pigmented and unpigmented epithelium of the ciliary processes into the posterior chamber of the eye. Here, the unpigmented epithelium actively secretes Na⁺ ions into the lateral intracellular spaces. Cl⁻ and HCO₃⁻ ions follow the positively charged Na⁺ ions. Water is drawn out due to the osmolar forces developed by these ions.

Outflow of Aqueous Humor: Fluid exits the anterior chamber through outflow tracts in the iridiocorneal angle (Fig. 1.12). It passes through the trabecular meshwork and then enters the canal of Schlemm. From here, it drains into the extraocular veins.

Though it is not a primary route, aqeuous also drains through uveoscleral outflow, which involves aqueous reabsorption by the ciliary body and iris and ultimately drains into the veins of the ciliary body, choroid and sclera.

Trabecular meshwork: It is the main site of resistance to the flow of aqueous and has a unique system to maintain its patency and prevent occlusion by debris. A population of phagocytic cells is found on the trabecular meshwork and also within the canal of Schlemm that removes debris and other molecules and keeps the drainage pathway clear.

The lens is a transparent biconvex structure, with a slightly flattened anterior surface and a more curved posterior surface that is in contact with the vitreous. It is devoid of any blood vessels or nerve fibers that may impede its transparency. Its refractive or diopteric power is less than that of the cornea and tears film. The importance of the lens is its ability to alter its shape and hence diopteric power. The lens is encircled by zonular fibers that attach to the ciliary processes of the ciliary body (Fig. 1.11). Changes in tension in this tissue are transferred to the lens, and result in the change in its shape and accommodative power.

The vitreous accounts for about 80% of the mass of the eyeball and fills the vitreous chamber. It is composed of hyaluronan; that is long chains of glucosaminoglycan and a few type II collagen fibers. The fibers are anchored to the basal lamina of the ciliary body. It forms the suspensory ligaments of the lens. At the periphery, it is in a gel like state and towards the center it is in a more fluid state. Hyalocytes are found within the vitreous and they produce substance of the vitreous. The hyaloid canal occupies a central position in the vitreous and is the remnant of the hyaloids artery. It runs from the posterior surface of the lens to the optic disc. Rupture of the hyaloids artery may sometimes form structures called “floaters” that may interfere with vision.

The retina is the sensory layer of the eyeball. It lies between the choroid and the vitreous. It is continuous with the optic nerve at the optic disc and continues anteriorly to cover the iris and ciliary body. It is composed of the pigment layer in opposition to the choroid, followed by the rods and cones, external limiting membrane, outer nuclear layer, outer plexiform layer, inner nuclear layer, inner plexiform layer, ganglion cell layer, 15nerve fiber layer and an inner limiting membrane, in contact with the vitreous.

The blood retinal barrier: Cells of the pigment layer form zona occludens type tight junction with each other and prevent movement of a number of particles between the vitreous and the choroid. This function is somewhat in continuation of the function of the blood–brain barrier as the retina may be considered to be part of the brain. The blood retinal barrier properties are also determined by the endothelial cells of its capillaries. They are of the continuous type and provide a barrier to the transport of metabolites and toxins in the blood. It is a barrier to hydrophilic drugs but lipophilic drugs cross easily. Therefore, orally administered drugs and other systemic agents may be present in the eye and sometimes cause retinal toxicity, e.g. digitalis, phenothiazines, methyl alcohol, quinoline derivaties, sildenafil.

There are 7 extraocular muscles in total (Fig. 1.13). There are 4 rectii (superior, inferior, medial and lateral), and 2 obliques (superior and inferior) that attach to the globe and allow its movements, while the seventh is the levator palpebrae superioris that attaches to the upper eyelid. Individual muscles and their actions are described below.

They arise from a common tendinous ring around the margins of the optic canal called the annulus of Zinn. Each muscle passes anteriorly in positions corresponding to their names and attach onto the sclera behind the corneoscleral junction. They receive their blood supply from the ophthalmic artery and its branches. The lateral rectus is supplied by the abducent nerve, while the oculomotor nerve supplies the others.

Its origin is superomedial to the optic canal on the body of the sphenoid. It passes forward through the trochlea on the superior orbital margin. It passes posterior and laterally and inserts into the sclera between the insertions of the superior and lateral rectii. It is supplied by the trochlear nerve and ophthalmic artery and the maxillary artery.

It arises from the orbital surface of the maxilla, lateral to the nasolacrimal groove.

It passes posteriorly, laterally and upwards to insert between insertions of the inferior and lateral rectii.

It arises above the optic canal, passes anteriorly and inserts into the skin and the tarsal plate of the upper eyelid. It has a component of smooth muscles, which receive sympathetic innervation (Muller's muscle). Its other fibers are supplied by the oculomotor nerve. It receives its blood supply from the ophthalmic artery.

Together, the rectii and obliques are responsible for elevation, depression, adduction and abduction of the eyeball. Individual muscles may require to be tested to ensure that a particular nerve has been blocked by application of an anesthetic agent.

The ophthalmic artery, a branch of the internal carotid artery, and its branches supply blood to the orbit and its structures, along with branches of the maxillary artery. The important branches of the ophthalmic artery include the central retinal artery, branches to the muscles, the ciliary arteries (anterior and long and short posterior branches), the lacrimal artery, supraorbital branch, the anterior and posterior ethmoidal arteries, the meningeal, medial palpebral, supratrochlear and dorsal nasal artery.

Superior and inferior ophthalmic veins and the infraorbital vein are the main veins of the orbit. The superior ophthalmic vein is formed by the facial and the supraorbital vein. It also receives the central retinal vein and drains into the cavernous sinus. The inferior ophthalmic vein is formed on the floor of the orbit, anteriorly and receives tributaries from the inferior rectus and oblique, the nasolacrimal sac and eyelids, and also from the eyeball. It drains into the cavernous sinus, sometimes joining the superior ophthalmic vein. It also communicates with the pterygoid plexus and the facial vein.

Lymphatics draining the conjunctive only have been identified. Furthermore, the eye is a site of immune privilege. That is, potentially immunogenic tissues in the eye survive over prolonged intervals of time without provoking an immune reaction. It is believed that such a phenomenon occurs in order to protect an organ or tissue essential for the survival of the host, since loss of sight may have life-threatening consequences.

The structures of the orbit receive motor innervation from fibers that are somatic as well as 17autonomic. The optic nerves carry the sense of sight while other structures in the orbit are receiving somatic sensory innervation by the ophthalmic division of the trigeminal nerve. The ophthalmic nerve has three main branches; the lacrimal nerve, the frontal nerve and the nasociliary nerve. The conjunctiva and the skin covering the lateral part of the upper eyelid are supplied by the lacrimal nerve. The frontal nerve supplies the skin of the upper eyelid and conjunctiva. The skin of the lower eyelid is supplied by the infraorbital branch of the zygomatic nerve, which is a branch of the maxillary nerve. The cornea, sclera, iris and ciliary body are supplied by the nasociliary nerve.

The ciliary ganglion: The ciliary ganglion is located in the orbital fat near the apex. It has three main roots; they are the sensory, sympathetic and motor or parasympathetic. The sensory root arises as branches from the nasociliary nerve and passes through the ganglion to supply the sclera, cornea, iris and ciliary body. The sympathetic root arises from postganglionic neurons around the sympathetic plexus of the internal carotid arteries, and passes through the ganglion emerging as short ciliary nerves to supply the blood vessels of the eyeball and the dilator pupillae muscles of the iris. The parasympathetic root is derived from preganglionic fibers of the Edinger-Westphal nucleus and travels with the oculomotor nerve to the orbit. Here a branch separates and joins the ciliary ganglion. Postganglionic parasympathetic fibers arise from the ganglion and pass with the short ciliary nerves and supply the sphincter pupillae and the ciliary body.

Impulses generated by the rods and cones of the retina leave each eye via the optic nerve. Fibers carrying impulses from the nasal halves of each retina cross over to the opposite sides at the optic chiasma, while fibers from the temporal halves of each retina pass on uncrossed. Thus fibers from the right halves of both the retinae pass in the right optic tract, while the fibers of the left halves both the retinae are carried in the left optic tract (Fig. 1.14). Fibers continue on in the optic tract, and relay at the lateral geniculate body of the thalamus. Fibers from this nucleus pass on to the occipital cortex via the optic radiations (geniculocalcarine fibers) to the primary visual cortex.

Impulses also enter various other pathways: fibers from the optic chiasma; pass on to the suprachiasmatic nucleus; the pretectal nucleus to coordinate the pupillary reflexes, superior colliculus for eye movements and also to the ventral lateral geniculate body.¹⁸

Direct reflex: When light is shone in one eye, the pupil constricts. The diagram representing the pupillary light reflex pathways is shown in Figure 1.15. Impulses travel to the pretectal nucleus, and from here to the Edinger-Westphal nucleus, parasympathetic fibers arise here and pass back to the constrictor pupillae muscle with the oculomotor nerve, and through the ciliary ganglion. Alteration of the pupillary diameter grossly affects the amount of light that enters the eye by a factor of about 1 to 30 and hence aids in dark adaptation. Dilator pupillae muscle fibers are supplied by sympathetic fibers originating from the intermediolateral gray horn of T1 thoracic segment, through the superior cervical ganglion. Postganglionic fibers pass along with blood vessels and supply the muscle (Fig. 1.15).

Indirect reflex: When light is shone in one eye, a pupillary reflex is observed in the unilluminated eye as well. It is called the consensual or indirect pupillary reflex. Fibers from the pretectal nucleus supply the Edinger-Westphal nucleus of both sides, hence leading to the consensual or indirect pupillary reflex.¹⁹

A high degree of visual acuity is permitted by the accommodation mechanism. This mechanism involves the contraction or relaxation of the ciliary muscle, and adjustments in the focal length of the lens allowing the eye to maintain acuity of vision at all times.

There appears to be a feedback mechanism related to chromatic aberration, where a difference in the ability of the lens to focus red and blue light acts as a signal to correctly adjust the focal power of the lens. Also, convergence of both eyes occurs at the same time. Pupillary diameter also adjusts along with the accommodation process.