It is possible to achieve a high concentration of many drugs in the eye by applying them as eye drops. In this way, a high local concentration can be reached with minimal risk of systemic side effects. However, the systemic side effects of drops cannot be discounted, particularly in sus- ceptible individuals. For example, timolol drops can precipitate asthma and slow the pulse rate in elderly patients, and pilocarpine drops can cause sweating and nausea. The action of local medications can be prolonged by incorporating them in an ointment, but for most purposes drops are supplied in 5 ml or 10 ml containers.
After the container has been opened, it should not be kept for longer than one month. In order to avoid undue stinging, drops can be buffered to near the pH of tears and they contain a pre- servative, such as benzalconium chloride. It must be borne in mind that patients who develop an allergic reaction to drops might be reacting to the preservative. Single-application containers are also used, which do not contain a preservative but are expensive.
Eye lotions are usually prescribed in 200 ml quantities and are used to irrigate the conjunc- tival sac. Sodium chloride eye lotion is used in first aid to flush out foreign bodies or irritant chemicals. Fresh mains tap water is an adequate substitute.
One of the major drawbacks of using eye drops is that, although high local concentrations of the drug are achieved in the anterior segment of the eye, little if any drug penetrates to the posterior segment. Drops are, therefore, of little
use in treating diseases of the vitreous and retina. One way of delivering a drug to the posterior segment is to give it systemically.
An example of this is the use of systemic pred- nisolone for posterior uveitis. This treatment method has the drawback of systemic side effects. This can be reduced by delivering the drug to the posterior segment by local injection either directly into the vitreous, along the orbital floor, within the sub-Tenon’s space or in the subconjunctival space.
Treatment of Infection
Chloramphenicol is rarely used as a systemic drug nowadays, but it has been useful for many years in the form of eye drops. It remains a drug of choice in the UK for superficial eye infections.
Other broad-spectrum antibiotics in use include gentamycin, framycetin, tobramycin and neomycin, as well as ciprofloxacin and ofloxacin. When an infection of the eye is sus- pected, a culture is taken from the conjunctival sac and treatment started with a wide-spectrum antibiotic. Systemic and intravitreal administra- tion might be needed if the infection is intra- ocular. A number of antiviral drugs are now available, but acyclovir in the form of Zovirax ointment is the most widely used treatment of herpes simplex keratitis. The use of systemic acyclovir and famcyclovir for herpes zoster ophthalmicus has made a great impact on the severity of ocular complications.
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Drugs and the Eye
195
Drops That Widen the Pupil
The pupils can be dilated either by local block- ade of the parasympathetic pathway or by local stimulation of the sympathetic pathway.
Parasympathetic Antagonists
Routine mydriasis to allow examination of the fundus is best achieved by tropicamide 0.5% or 1% drops because the effect lasts for only about 3 h. Cyclopentolate 1% (0.5% in babies) can last for 24 h, but because of its cycloplegic effect (blockade of accommodation) is preferable for the examination of children’s eyes when refrac- tion is also needed. Dilating the pupil runs the risk of inducing an attack of acute narrow-angle glaucoma in a predisposed individual. Because the vision could remain blurred, driving should be avoided within the first 6–8 h after mydriasis.
Atropine in drop form is a long-acting mydri- atic, which is used when it is necessary to prevent or break down adhesions between iris and lens in acute iritis (posterior synechiae). It is also used in the treatment of amblyopia in children. Its effect lasts for about seven days.
Allergic reactions are quite common and occa- sionally systemic absorption can cause central nervous system symptoms of atropine toxicity.
Sympathetic Agonist
Phenylephrine (5 or 10% drops) is a sympath- omimetic amine. It is used with a parasym- pathetic antagonist when extremely wide pupil dilation is required (e.g., for intraocular surgery or for peripheral retinal examination). There are reports of severe acute hypertension after use of 10% drops.
Drops That Constrict the Pupil
In the past, meiotics have been widely used for the treatment of chronic open-angle glaucoma.
Pilocarpine is available in 1%, 2%, 3% or 4%
solutions. Although it is effective in reducing the intra-ocular pressure, the side effects of dimming of vision and accommodation spasm can be disabling and mean that this treatment has largely been superceded. Pilocarpine is still used in the treatment of acute glaucoma attacks
to constrict the pupil and open up the closed drainage angle. Sometimes it is necessary to constrict the pupil rapidly during the course of intraocular surgery and this is achieved by instilling acetylcholine directly into the anter- ior chamber. Strong meiotics run the risk of causing retinal detachment in susceptible indiv- iduals. Meiotics have been used to reverse the effect of mydriatic drops used for fundus examination, but this practice is no longer recommended as a routine because it is unnecessary and the symptoms of meiosis may make matters worse.
Drugs in the Treatment of Open-angle Glaucoma
There has been a small revolution involving the type of eye drops used for the treatment of glau- coma in recent times. For years, the mainstay of treatment was pilocarpine and the topical beta- blockers, for example timolol, but the potential systemic side effects of these drugs have led to the introduction of other novel types of ocular hypotensive agents. In general, these new agents can be divided into alpha2-adrenergic agonists, carbonic anhydrase inhibitors and prostaglandin analogues.
The production of aqueous humour can be reduced by either blockade of the beta-receptors on the ciliary body epithelial cells (i.e., with a beta-blocker) or by agonism of the alpha2- receptors. Brimonidine and apraclonidine are both alpha2-receptor agonists and show good efficacy compared with timolol. A significant number of patients, however, do develop an allergy to these agents and this has limited their widespread use. Acetazolamide was introduced as a diuretic many years ago; although not a very good diuretic, it has proved to be a potent ocular hypotensive when given orally. Again because of side effects its use has been restricted to short- term treatment. In 1995, dorzolamide was introduced and more recently, brinzolamide has become available. These are also carbonic anhydrase inhibitors but they are available in drop form and are able to penetrate the cornea.
Their ocular hypotensive effects are generally not as great as topical beta-blockers but they are useful as adjuvant agents. It has recently been discovered that a second aqueous outflow route
exists in the eye – the uveoscleral route. It is known that certain prostaglandins increase the flow of aqueous via this route and a number of topical prostaglandin F2a analogues are now available. Latanoprost, travoprost and bimato- prost have all been shown to as effective as topical beta-blockers with minimal side effects.
All these medications have the problem of compliance. Elderly patients may forget to instill drops on a regular basis. In some cases, even instillation of three different glaucoma drops fails to control the intraocular pressure. In these instances, the only sure way of lowering the pressure is by glaucoma drainage surgery.
Drugs in the Treatment of Acute Angle-closure
Glaucoma
Angle-closure glaucoma is a surgical problem.
Once the acute attack has been aborted by the use of intensive pilocarpine drops and Diamox, a small hole is made in the iris with the Yttrium–Aluminium–Garnet (YAG) laser to allow redirection of the flow of aqueous. In many patients this provides a permanent cure.
Beta-blockers may also be used during the acute stage and more recently the alpha2- agonist apraclonidine has been shown to be a useful adjunct.
Drugs in the Treatment of Allergic Eye Disease
With the increasing incidence of atopy, the treat- ment of allergic eye disease has gained in importance in recent years. Treatments are designed to interfere with either the type 1 (immunoglobulin E [IgE]-mediated) or type 4 (delayed) hypersensitivity response, both of which are thought to be important in disease pathogenesis. For mild disease, initial treatment should involve antigen avoidance (if known) and frequent use of artificial tears (hypromel- lose) to wash away antigens from the ocular and conjunctival surface. Treatment of more severe disease involves the use of systemic or topical antihistamines (levocabastine, emedastine and azelastine), which are helpful for relief of symp-
toms, and topical mast cell stabilisers (sodium cromoglicate, nedocromil sodium and lodox- amide), which are useful in disease prevention if used regularly. The treatment of severe (sight- threatening) disease involves the use of courses of topical and occasionally oral steroids.
Local Anaesthesia in Ophthalmology
Proxymetacaine (Ophthaine) is a useful short- acting anaesthetic drop that is comfortable to instill and so is particularly useful when exam- ining children. Amethocaine and benoxinate are also widely used but are longer-acting and sting quite markedly. Local anaesthetic drops should not be used as pain relievers on a long-term basis because the anaesthetized cornea becomes ulcerated and severe infection of the eye can occur. Lignocaine (1% or 2%) with or without adrenaline is injected into the eyelids for lid surgery. Local anaesthesia for intraocular surgery is obtained by topical drops, sub- Tenon’s injection, periorbital injection (outside the cone of extraocular muscles) or sometimes retrobulbar injection (within the muscle cone) of lignocaine. For a longer effect, this is some- times combined with marcaine.
Drugs and Contact Lenses
As a rule, contact lenses should not be worn when the eye is being treated with drops. The exception is when the contact lenses themselves are being used for some therapeutic purpose.
Soft hydrophilic contact lenses can take up and store the preservative from some kinds of drop.
The preservative benzalkonium chloride is espe- cially liable to be absorbed onto a contact lens.
When it is essential that drops are administered to a patient wearing contact lenses, it is often possible to prescribe in the form of single-dose containers that do not contain a preservative.
Artificial Tears
Artificial tears provide one of a number of meas- ures that are used to treat tear deficiency. Other measures include occlusion of the lacrimal
puncta or the use of mucolytic agents. The first step is to make the diagnosis. Once a deficiency of tears has been confirmed, the mainstay of treatment is hypromellose.Adsorptive polymers of acrylic acid can also give symptomatic relief.
Polyvinyl alcohol is another compound present in a number of tear substitutes. Recently, a new agent, sodium hyaluronate (0.1%) has been shown to improve symptom relief and improve the ocular surface abnormalities in cases of severe dry eye. By their nature, tear substitutes tend to adhere to the surface of the eye and in the conjunctival sac. For this reason, their pro- longed use is liable to give rise to preservative reactions. Preservative-free preparations are often preferable. Some patients with a severe dry eye problem might need to instill the drops every hour or even more frequently.
Anti-inflammatory Drugs and the Eye
Local steroids are widely used in the treatment of eye disease; systemic steroids are not used unless the sight of the eye is threatened. It must be remembered that systemic steroids give the patient a sense of well-being, which might give a false impression of the real benefit obtained.
Furthermore, systemic steroids can have serious and life-threatening side effects, such as ver- tebral collapse through osteoporosis and perfor- ated gastric ulcer (Figure 24.1).
Local steroids should also be applied with caution, and it is a good rule always to have a specific reason for giving them.That is to say,they should not be prescribed just to make red eyes turn white without a clear diagnosis. The reasons for this are two-fold: first, local steroids enhance the multiplication of viruses, especially herpes simplex; and second, they can cause glaucoma in certain predisposed individuals. In such indiv- iduals, the instillation of one drop of steroid can cause a temporary rise of intraocular pressure.
The most potent steroid in this respect is dexam- ethasone, followed by betamethasone, pred- nisolone and hydrocortisone. It has been claimed that rimexolone, clobetasone and fluorometho- lone are relatively safe in this respect.
Recently, a number of nonsteroidal anti- inflammatory drugs (NSAIDs) have been made available in topical form (diclofenac [Voltarol
Ophtha], ketorolac [Acular] and flurbiprofen [Ocufen]) to reduce our dependence on topical steroids. They have been shown to be of use in the treatment of postcataract surgery inflam- mation and in reducing the pain after excimer laser surgery and corneal abrasions.
Anti-angiogenic Drugs and the Eye
Uncontrolled angiogenesis (growth of new blood vessels) is a common finding in many potentially blinding conditions, such as prolif- erative diabetic retinopathy, central retinal vein occlusion, wet age-related macular degenera- tion (ARMD) and retinopathy of prematurity.
Inhibiting their growth offers us the hope of dramatically reducing the number of patients going blind each year. It is thought that the angiogenic response is caused by elevated levels of a cytokine called vascular endothelial growth factor (VEGF) produced by abnormal or ischaemic cells within the eye. Attempts to reduce the levels of VEGF and hence turn off the angiogenic drive have involved intravitreal
Steroids give a patient a feeling of well-being. . . .
Figure 24.1. There might be a false impression of the real benefit obtained.
injections of anti-VEGF antibodies or oligonu- cleotide aptamers, which bind VEGF, or the intravitreal/sub-Tenon’s injection of an anti- angiogenic steroid (triamcinolone). All of these treatments are showing great promise in clini- cal trials. An alternative mechanism of treat- ment is the destruction of preformed new vessels. Recently, a new type of treatment for wet ARMD has seen the use of a light-activated dye, injected intravenously, which preferentially locates in the choroidal neovascular membrane (photodynamic therapy). Activation of the dye by light of a specific wavelength causes throm- bosis and destruction of blood vessels harbour- ing the dye. Treatment of patients with one particular subtype of wet ARMD (classic with no occult blood vessels) has shown stabilisation of vision in 60–70% of cases.
Damage to the Eyes by Drugs Administered Systemically
There are a number of drugs, which if given in excessive doses, can lead to severe visual handicap and blindness. Some of these are still available on prescription. Chloroquine and hydroxychloroquine in excessive doses can lead to pigmentary degeneration of the retina and
blindness. Certain antipsychotic drugs can also cause fundus pigmentation in excessive doses;
melleril and chlorpromazine have been incrim- inated in this respect in the past. Recently, a number of cases of uveitis have been reported in patients using bisphosphonates for the treat- ment and prevention of osteoporosis. Interest- ingly, sudden visual loss has been reported in a number of patients taking the oral anti- inflammatory COX-2 inhibitors (celecoxib and rofecoxib). The vision has returned to normal upon cessation of treatment.
Apart from causing glaucoma in some patients, systemic steroids are thought to increase the rate of formation of cataracts.
Ethambutol and isoniazid can cause optic atrophy. Sometimes excessive doses of quinine are taken as an abortifacient and as the patients regain consciousness they are found to be blind from quinine toxicity. Methyl alcohol is toxic to the ganglion cells of the retina and blindness is a hazard of meths drinkers. It sometimes con- taminates crudely prepared alcoholic beverages leading to unexpected loss of vision. The list of drugs with ocular side effects is large and the reader should consult a specialised textbook for more information. Nowadays, disasters and indeed lawsuits should be avoidable if the drug literature is checked before prescribing an unfamiliar drug.
