Ординатура / Офтальмология / Английские материалы / Ophthalmic Drugs Diagnostic and Therapeutic Uses 5th edition_Hopkins, Pearson_2007

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NATAMYCIN

This fungicidal compound is very effective against a whole range of fungi but not bacteria. Like many other antifungals it penetrates the eye very poorly and was found to be inferior to amphotericin in the treatment of candidal keratitis in rabbits (O’Day et al 1991). It is used as eye drops (5–10%) or eye ointment (1%).

FLUCYTOSINE

Flucytosine, which has a narrow spectrum of activity and is active only against yeast, is used as eye drops (1.5%). It is a synthetic compound that is well absorbed by the gut. Being distributed to all parts of the body, including the CSF, after oral administration, flucytosine is used to treat systemic infections of Candida albicans and Aspergillus spp. In susceptible organisms it is converted flururacil, which inhibits RNA function and inhibits DNA synthesis. The converting enzyme (cyosine deaminase) is not present in mammalian cells and thus flucytosine has a good therapeutic index. Serious side-effects occur occasionally; these affect the blood, causing anaemia and thrombocytopenia. Fungal cells that lack the converting enzyme will be resistant to flucytosine and it is sometimes used in combination with amphotericin, with which it is synergistic.

CLOTRIMAZOLE

A whole group of modern antifungals is referred to as the imidazoles, probably the most widely used of which is clotrimazole. Depending on the concentration, imidazoles are either fungistatic or fungicidal, producing their effect by inhibiting the incorporation of ergosterol into the cell membrane and interfering with cell respiration. Clotrimazole is poorly absorbed and is used only topically. It is, therefore, most commonly used for fungal infections of the skin (e.g. athlete’s foot and ringworm) and vagina (e.g. thrush). In the eye, a 1% solution was shown to penetrate the corneas of rabbits experimentally infected with Candida albicans (Behrens-Baumann et al 1990). The drug significantly reduced the effects of the infection.

MICONAZOLE

Another imidazole, miconazole is a broad-spectrum antifungal agent that produces its effects by acting on the cell membrane, by blocking the production of ergosterol. It rivals clotrimazole in its use in skin and genital fungal infections.

Absorption takes place across the intact cornea but if the epithelium is removed much greater absorption takes place.

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FLUCONAZOLE

Unlike the previous two compounds, fluconazole is active by mouth, being rapidly absorbed after oral administration, and is well distributed throughout the body fluids. It has recently become available as an over- the-counter preparation for the treatment of vaginal thrush. Its action is the same as the other imidazoles but, being used systemically, it is more likely to cause side-effects, which can range from the unpleasant nausea and vomiting to the very serious liver damage that can occur with longterm use. This condition can lead to jaundice and death.

TERBINAFINE

This compound is an allylamine antifungal and is active against certain filamentous and dimorphic fungi. It is used in the oral treatment of surface fungal infections. Terbinafine produces its effect by inhibiting an enzyme present in the cell membrane.

References

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Chapter 13

Anti-inflammatory agents

Inflammation is the response of the body to a variety of stimuli, e.g. infection, allergy and trauma. Many processes are involved in inflammation and they result in a characteristic reaction that is typified by a reddening of the area (as a result of vasodilation), oedema, loss of function and pain. The process is brought into play to combat and destroy invading organisms, but sometimes the body’s own cells are attacked and destroyed and damage to tissues occurs. This is particularly true for the eye, where the delicate, transparent structures are susceptible to damage by scar formation. Ocular inflammation can result in permanent loss of vision and immediate steps to limit the extent of the inflammatory process might be needed to preserve sight. The inflammatory response involves the following features:

•The increased production of prostaglandins and leukotrienes: arachidonic acid is produced by the action of phospholipase. In turn, this is converted by the enzyme cyclooxygenase into one of the variety of prostaglandins that have effects on smooth muscle and mediate some of the inflammatory reactions. For example, a mixture of prostaglandins called irin can induce the atropine-resistant miosis that occurs in uveitis. Lipoxygenase converts arachidonic acid to leukotrienes, which bring about an increase in permeability and oedema. There are two types of cyclooxygenase: COX I and COX II. The former is found to some extent in all cells whereas COX II is induced in those that are inflamed.

•The liberation of histamine from mast cells: this is caused by the allergen–antigen reaction causing an increase in the influx of calcium ions into the mast cells. Histamine, in addition to its ability to stimulate pain and itch nerve fibres, is best known for the production of the ‘triple response’. If a small amount of histamine is injected into the skin, a small red area appears at the point of injection. This is due to a direct effect of the histamine on blood vessels, causing vasodilatation. The permeability of the capillaries is increased, causing loss of cells and proteins. The effect of the protein is to raise the osmotic pressure of the fluid, causing increased loss of water into the tissues and consequent oedema. The third component is a diffuse vasodilation, causing a more diffuse red area (flare) around the site of injection.

•Vascular effects: in addition to the action of histamine, other locally active agents can induce vasodilation and increase capillary permeability. In the eye, the permeability of the blood/aqueous barrier is

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INDOMETACIN

There are many inhibitors of prostaglandin formation. The oldest, best known and cheapest is aspirin (acetylsalicylic acid). It has been tested for the prevention of cystoid macular oedema following cataract extraction.

The first of the new generation of NSAIDs was indomethacin (now called indometacin), a compound that has been tested in topical formulation for cystoid macular oedoma and for the treatment of noninfectious conjunctivitis (Kishore et al 1994). Eyedrops containing 0.1% have been used around cataract surgery to reduce surgically induced miosis and postoperative inflammatory response. Indometacin has produced comparable results to dexmethasone in the treatment of acute anterior uveitis (Sand & Krogh 1991). It is related to diclofenac, being an acetic acid derivative, and produces its effect by inhibiting the lipoxygenase pathway (which converts arachidonic acid to prostaglandins). There are no commercially available products.

OXYPHENBUTAZONE

Oxyphenbutazone is a white crystalline powder almost insoluble in water. It is a derivative of phenylbutazone, with similar anti-inflammatory, analgesic and antipyretic effects and belongs to the group of NSAIDs known as the pyrazolones. It is given in general medicine, usually by mouth, for the treatment of rheumatic and allied disorders. Oxyphenbutazone can be used in a 10% concentration in a greasy eye ointment base for non-purulent inflammatory anterior segment eye conditions. Where other conjunctival decongestants are contraindicated, a single application of this ointment provides a useful alternative for the optometric practitioner. This compound has been withdrawn from both systemic and topical use.

IBUPROFEN

Perhaps one of best known of the modern NSAIDs, ibuprofen is available as an over-the-counter preparation for producing analgesia and relieving inflammation. Although not yet available as a topical ophthalmic preparation, it has been tested in artificially induced ocular inflammation in rabbits and was found to be effective (Tilden et al 1990).

DICLOFENAC

Diclofenac is potent inhibitor of cyclooxgenase. By reducing the production of prostaglandins but not inhibiting lipoxygenase directly, diclofenac apparently reduces the amount of arachidonic acid available

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to it, thus preventing the synthesis of leukotrienes. It is used for the inhibition of intraoperative miosis (Bonomi et al 1987, Erturk et al 1991, Fabian et al 1991) and the suppression of postoperative inflammation. For the latter it has been used alone (Vickers et al 1991) or in combination with prednisolone (Struck et al 1994) or dexamethasone (Ronen et al 1985). In other studies, it has been shown to be as effective as dexamethasone for this purpose (Avci et al 1993, Ilic et al 1984). Dicolfenac has also been used in the prevention and treatment of cystoid macular oedema. Its use in the treatment of more everyday inflammations, such as vernal conjunctivitis, giant papillary conjunctivitis and seasonal allergic conjunctivitis, is less proven and currently under going study. Laibowitz et al (1995) found that 0.1% diclofenac relieved the symptoms of acute seasonal allergic conjunctivitis.

NSAIDs have analgesic properties as well as anti-inflammatory ones and they have been used to treat eye pain and reduce photophobia after radial keratotomy (Sher et al 1992, 1993) and in patients with episcleritis.

Because the mechanism of action is different from that of steroids, it is possible that given together the drugs could have additive, if not synergistic actions. Topical solutions are well tolerated.

Diclofenac has been compared with prednisolone in topical use (Hersh et al 1990) and was found to have similar effects on corneal wound healing but a superior performance in treating the accompanying iritis. Although it is principally used short term, perioperatively after refractive and strabismus surgery, diclofenac has an indication for the treatment of seasonal allergic conjunctivitis.

Preparations

BAK, benzalkonium chloride

KETOROLAC

Ketorolac is a potent cyclooxygenase inhibitor with good penetrative properties; good levels can be obtained in the aqueous humour.

Preparations

BAK, benzalkonium chloride

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The adrenal cortex produces a mixture of steroid hormones, which fall into three main groups: glucocorticoids, mineralocorticoids and sex hormones (androgens). Mineralocorticoids are necessary to maintain the electrolyte balance of the body, whereas glucocorticoids affect glucose, protein and bone metabolism and have anti-inflammatory properties. The naturally occurring glucocorticoids include corticosterone and hydrocortisone, which have sodium retention properties. To separate this latter effect from the anti-inflammatory effects, newer, synthetic and more potent steroids have been developed. Betamethasone and dexamethasone, for example, are 25 times more potent in producing antiinflammatory effects.

No other group of drugs deserves the title of a ‘two-edged sword’ as much as the corticosteroids. They are known on the one hand for their useful and sometimes sight-saving effects in the treatment of inflammation, while on the other for the very serious adverse effects that can arise from their use. For example, corticosteroids can assist in the reduction of intraocular pressure when used to treat uveitic secondary glaucoma but can cause a rise in intraocular pressure if used topically in patients who are ‘steroid responders’.

Corticosteroids inhibit the inflammatory response to noxious stimuli whether they are radiation, mechanical, chemical, infectious or immunological, affecting the inflammatory process in many ways. They reduce the vasodilatation that is responsible for the redness that accompanies inflammation and stabilize mast cells, thereby reducing the release of histamine. Their use maintains the normal permeability of blood and prevents the development of oedema. Part of their mechanism of action involves the inhibition of the production of prostaglandins, which mediate some of the effects of inflammation. Prostaglandins are produced by conversion of arachidonic acid by cyclooxygenase, and