Fig. 50.1 The route of drainage of aqueous humour from the eye and the sites of action of drugs used in the treatment of glaucoma.
The mechanisms by which some drugs benefit glaucoma are still uncertain but are thought to include the following:
in angle-closure glaucoma, muscarinic agonists, e.g. pilocarpine, facilitate aqueous humour drainage (1, 2) by constricting the iris circular constrictor pupillae (5), which widens the anterior angle,
beta-adrenoceptor antagonists, e.g. timolol, reduce aqueous humour production (4) and increase outflow (1),
Pupil size
This is determined by the relative tone in the two smooth muscle layers of the iris. The circular (constrictor) muscle is the more powerful and receives parasympathetic nervous innervation, producing muscle contraction that is mediated by acetylcholine acting on muscarinic receptors. The radial (dilator) muscle is sympathetically innervated, and contraction of the muscle is mediated by noradrenaline acting on α1-adrenoceptors.
The light reflex is the primary determinant of pupil size with increased light causing the pupil to constrict and reduce the amount of light that reaches the retina. Pupillary constriction is known as miosis and also accompanies accommodation for near vision, a response mediated by the parasympathetic nervous system. Miosis can be produced by drugs that stimulate muscarinic receptors and contract the circular muscle of the iris. Dilation of the pupil is called mydriasis and is caused by contraction of the radial muscle. Mydriasis can be produced by drugs that are antagonists at muscarinic receptors in the circular muscle (leaving unopposed action of the radial muscle) or by drugs that stimulate α1-adrenoceptors in the radial muscle.
Dilation of the pupil also has the effect of moving the iris towards the cornea and narrowing the anterior angle between the iris and the cornea. This can reduce aqueous humour outflow through the canal of Schlemm.
Drainage of aqueous humour
The space between the cornea, at the front of the eye (Fig. 50.1), and the iris is the anterior chamber and is filled with a clear liquid known as aqueous humour. Aqueous humour is constantly secreted by the ciliary body. Most aqueous humour flows through the pupil to the anterior chamber, and leaves the eye via the trabecular meshwork that drains to the episcleral veins through the canal of Schlemm (Fig. 50.1). Some aqueous humour drains through the sclera (uveoscleral outflow). Production of aqueous humour is influenced by innervation from the autonomic nervous system. Alpha2-adrenoceptor stimulation of the ciliary body reduces the production of aqueous humour, while β1-adrenoceptor stimulation increases its production. Outflow of aqueous humour is also influenced by innervation from the autonomic nervous system, and by prostaglandins. Contraction of the ciliary muscle aids drainage of aqueous humour through the trabecular meshwork into the episcleral veins. Pressure in the eye is maintained by a balance between the production of aqueous humour and its drainage. The intraocular pressure rises if drainage of the aqueous humour is impaired. High intraocular pressure can damage retinal ganglion cells, and is one of the factors that leads to progressive loss of vision in the disease known as glaucoma. If the anterior chamber of the eye is abnormally shallow, there will be a narrow anterior-chamber angle between the iris and cornea (iridocorneal angle) (Fig. 50.1).
Dilation of the pupil can narrow the angle further to an extent where it impedes drainage of aqueous humour through the trabecular meshwork. This can produce an acute rise in pressure in the eye (Fig. 50.1). Conversely, constriction of the circular muscle of the iris makes the pupil smaller and moves the iris away from the trabecular meshwork, widening the anterior angle and facilitating aqueous humour drainage through the canal of Schlemm.
Topical application of drugs to the eye
Drugs applied in solution to the anterior surface of the eye can penetrate to the anterior chamber and the ciliary muscle, principally via the cornea. The high water content of the cornea makes lipid solubility less important for adequate penetration of a drug than is the case for transdermal drug delivery, but formulation of the carrier is important to avoid irritation of the conjunctiva. There is little diffusion to the more posterior structures of the eye.
Systemic absorption of drug following topical application to the surface of the eye can occur either via conjunctival vessels or from the nasal mucosa after drainage of excess drug through the tear ducts. Topical administration of drugs to the eye can therefore produce systemic effects. Drainage can be reduced by shutting the eyes for at least 1 min after putting in the drops and by compressing the nasolacrimal duct at the medial corner of the eye with a finger. Both eye drops and ointments are usually administered into the pocket that can be formed by gently pulling the lower eyelid downwards (the lower fornix).
Microbial contamination is a potential problem once eye preparations have been opened. Multiple-application containers have preservative added to reduce the risk, but it is not advisable to use any eye preparation more than a month after it has been opened.
Glaucoma
Glaucoma is a group of disorders characterised by loss of retinal ganglion cells and is a form of optic neuropathy. In some cases the intraocular pressure is raised, and ischaemia of the optic nerve head may be the cause. In many cases, however, the pressure in the anterior chamber of the eye is normal and a genetic susceptibility to retinal ganglion cell apoptosis is responsible. The diagnosis requires both structural and functional changes in the eye. There is evidence of optic disc damage with deepening and widening of the depression or cup of the optic disc. Progressive visual defects occur, initially as scotomas (blind spots) in the peripheral visual field. These scotomas enlarge, resulting in tunnel vision and finally total blindness. Glaucoma is the second most common cause of blindness in the UK.
Open-angle glaucoma is caused by obstruction to outflow through the trabecular meshwork, caused by injury or death of cells. It can be associated with raised intraocular pressure, but in other cases the pressure in the eye is normal and retinal cell loss is related to the ability of the optic nerve head to withstand stress imposed by the pressure in the eye.
Angle-closure glaucoma is less common, and results from the iris blocking the drainage angle and preventing drainage through the trabecular meshwork. This usually arises when there is a shallow anterior chamber, such as occurs in long-sighted individuals. The condition is usually chronic and asymptomatic, with a risk of acute attacks of high intraocular pressure with pain and sudden visual loss.
Drugs for glaucoma
Beta-adrenoceptor antagonists reduce the formation of aqueous humour by the ciliary body. They have no effect on accommodation or pupil size. Systemic absorption can produce the typical unwanted effects associated with these compounds, particularly bronchospasm, bradycardia and worsening of uncontrolled heart failure (Ch. 5). The contraindications for topical use in the eye are the same as those for oral use. Timolol is a non-selective β-adrenoceptor antagonist whereas betaxolol is ‘cardioselective’, but they have similar efficacy in the eye.
Sympathomimetics
Brimonidine is a selective α2-adrenoceptor agonist that reduces aqueous humour production. It can cause dry mouth, gastrointestinal disturbances, taste disturbances and headache.
Carbonic anhydrase inhibitors
The intracellular mechanism of action of carbonic anhydrase inhibitors is discussed in Ch. 14. Carbonic anhydrase in the eye plays a key role in controlling aqueous humour production. It is responsible for secreting about 70% of the Na+ that enters the anterior chamber, which is accompanied by water to maintain isotonicity. Therefore, inhibition of the enzyme reduces aqueous humour production.
Acetazolamide is taken orally. Dorzolamide and brinzolamide are topical preparations for the eye, with fewer systemic unwanted effects; their duration of action in the eye is 6–12 h, but they have extremely long plasma half-lives (≥2 weeks) due to retention within erythrocytes.
Prostaglandin analogues
These drugs are analogues of prostaglandin F2α. Their precise mechanism of action in glaucoma remains uncertain, but they increase uveoscleral outflow of aqueous humour. This may result in part from an increase in extracellular matrix metalloproteinases in ciliary smooth muscle cells, and from remodelling of the uveal meshwork. Prostaglandin analogues also increase blood flow to the optic nerve, and this may contribute to neuroprotection in the retina. The reduction in intraocular pressure is greater than that achieved by β-adrenoceptor antagonists. The major disadvantage of prostaglandin analogues is an increase in brown pigmentation of the iris and growth of eyelashes. A rare complication in people who have no lens in the eye (aphakia) is the development of cystoid macular oedema, which responds to treatment with non-steroidal anti-inflammatory drugs. The prostaglandin analogues have a long duration of action of 1–2 days that is not a reflection of their half-lives.
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