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

228 OPHTHALMIC DRUGS

Brimonidine Brimonidine is a highly selective alpha-2 adrenoceptor stimulant that is 1000 times more effective on the alpha-2 receptor than the alpha-1 receptor (alpha-1 receptors are found in close apposition to nerve endings whereas alpha-2 are remote to nerve terminals and are affected by circulating hormones). Brimonidine produces no mydriasis or vasoconstriction and has little effect on the cardiovascular system. It produces its ocular hypotensive effect by a reduction in secretion and enhances uveoscleral outflow (Toris et al 1995). It is rapid in onset and the peak effect is seen at 2 hours. Brimonidine has proved to be safe in long-term treatment and appears to have neuroprotective properties. It is useful as an adjunctive agent.

In some countries, brimonidine in a concentration of 0.15% is available preserved with purite and has proved to be as effective as the original formulation, which has a concentration of 0.2% and is preserved with benzalkonium chloride. The former product has a pH of 6.6–7.4 whereas the latter has a range of 6.3–6.5. The fact that both formulations appear to be equally effective might be due to the fact that the more neutral pH enhances bioavailability. The use of purite as preservative appears to have reduced the number of allergic responses (Walters et al 2001).

Preparations

Apraclonidine Apraclonidine is a derivative of clonidine, a central alpha-2 adrenergic agonist that reduces blood pressure and heart rate by reducing sympathetic tone. It is used systemically in the treatment of hypertension and, in lower doses, for the prophylaxis of migraine.

Apraclonidine, having selective alpha-2 agonist activity, has been found to produce a significant fall in intraocular pressure in patients following cataract surgery (Prata et al 1992, Wiles et al 1991). When applied topically to normal healthy volunteers it had no cardiovascular effects, unlike timolol (Coleman et al 1990). It has also been trialled as adjunctive therapy with timolol and was found to be superior to dipivefrin in producing an additive effect (Morrison & Robin 1989). However, when used together with timolol, no additive effect was seen (Koskela & Brubaker 1991). This suggests that apraclonidine shares in part timolol’s mode of action of reducing aqueous humour production. Apraclonidine is well tolerated in the eye with conjunctival hyperaemia or conjunctival blanching. Lid retraction and mydriasis have been noted in a small percentage of patients.

Apraclonidine is marketed under the trade name Iopidine (apraclonidine 1.0% and 0.5%). It is available in single-use units (1.0%) for the

230 OPHTHALMIC DRUGS

BETA-BLOCKERS

Beta-blockers were originally developed for the treatment of cardiovascular disorders and this is still the major use for this type of agent. Since it was found that propranolol reduced intraocular pressure, many other beta-blockers have been tried for the treatment of glaucoma. These include atenolol, betaxolol, bupranolol, carteolol, labetalol, levobunolol, metipranolol, metoprolol, nadolol, pindolol, sotalol and timolol. Betablockers for the treatment of glaucoma were introduced in 1978.

Beta-blockers reduce intraocular pressure by reducing secretion (Liu et al 1980). This reduction is probably due to the blocking of the betareceptors, the stimulation of which causes an increased secretion of chloride ions. Beta-blockers have no effect on outflow resistance (Reiss & Brubaker 1983). The reduction in intraocular pressure is maintained in the absence of circulating adrenaline (Maus et al 1994), ruling out the importance of the natural hormone in the normal circadian rhythm.

Beta-blockers are normally prescribed as a twice-a-day therapy, being applied morning and night. However, there is some evidence to suggest that a once-a-day therapy would produce a satisfactory reduction in intraocular pressure. Rakofsky et al (1989) compared the use of levobunolol once a day and twice a day in patients with open-angle glaucoma and found no significant difference between regimens in the reduction in intraocular pressure.

Of course, the reduction of intraocular pressure is not the only parameter that might have a bearing on the course of the condition. Retinal blood flow and its modification by drugs must also be important. Harris et al (1995) studied perimacular blood flow in normal subjects after treatment with betaxolol, carteolol and levobunolol and found no significant alteration.

Not all beta-blockers are the same; they vary in several ways:

Selectivity Beta-receptors can be divided into two groups: beta-1 and beta-2. Beta-1 are found in the heart and kidneys whereas the bronchi contain beta-2 receptors. Most beta-blockers are non-selective and have similar potency on both types of beta-receptor. However, some have a greater affinity for beta-1-receptors; these are called cardioselective agents.

One of the troublesome side-effects of the use of beta-blockers in the treatment of glaucoma is the blocking of the effect of beta-2 stimulants, used to dilate bronchi during asthma attacks, leading to aggravation of such attacks (Fraunfelder & Barker 1984). The use of beta-blockers with reduced activity on beta-2-receptors will have less effect on the bronchi and therefore have advantages in patients with obstructive airway disease (Berry et al 1984). However, they are not completely safe and all beta-blockers must be used with care in asthmatic patients. Harris et al (1986) reported respiratory difficulties in patients receiving topical betaxolol, a cardioselective beta-blocker.

DRUGS FOR THE TREATMENT OF GLAUCOMA 231

Intrinsic These drugs are partial agonists and can stimulate the receptor before sympathomimetic blocking it. Many advantages have been claimed for drugs having activity this property (e.g. less bradycardia, less bronchoconstriction) but none would appear to have been substantiated by clinical trials. For example, carteolol (a beta-blocker with intrinsic sympathomimetic activity; ISA) causes an inhibition of exercise-induced tachycardia (Brazier &

Smith 1987).

Timolol Timolol was the first beta-blocker to be introduced as a topical solution in the early 1980s. Ophthalmic solutions are well tolerated by the eye, causing less irritation than betaxolol or artificial tears (Kendall et al 1987). When applied topically it produces an effect not only in the treated eye but also in the untreated contralateral eye. Woodward et al (1987) demonstrated bilateral beta-blockade in rabbit eyes from unilateral application and concluded that this effect must be due to systemic absorption. In many trials, the contralateral eye has been used as a control; these results would seem to call this practice into doubt.

Like all topical beta-blockers timolol has a twice-a-day dose regimen. Onset of action is rapid, with maximum effect being seen at 2 hours. Some lowering of intraocular pressure can still be detected at 24 hours.

232 OPHTHALMIC DRUGS

Recently, a long-acting form – Timoptol LA – has been introduced. This requires application only once a day. The drop is formulated with a polysaccharide to produce a viscous gel, which retards drainage from the conjunctival sac.

Another interesting development of timolol is the study of the relative potencies of the two isomers of timolol L- timolol and D-timolol. L-timolol is the normal isomer which has been used up to now and has by far the most affinity for the beta-receptor. If the fall in intraocular pressure produced by timolol is entirely due to blockade of the beta-receptor, then the D form should be inactive. Chiou et al (1990) found the two isomers to be equi-effective on topical instillation in lowering intraocular pressure. Furthermore, D-timolol had a beneficial effect on retinal and choroidal blood flows whereas the L isomer had the opposite effect. This finding confirms that of Martin & Rabineau (1989), who found that timolol had a vasoconstrictor effect on retinal arteries. Chiou (1990) concludes that D-timolol could be a better agent for the treatment of glaucoma than L-timolol.

Because timolol has been on the market for such a long time, longterm studies are available to allow the real beneficial effects of treatment (i.e. protection against disc cupping and visual field loss) to be monitored. This is especially true in the treatment of ocular hypotensive patients. Epstein et al (1989) examined patients for over 4 years and found that timolol had a beneficial effect on visual fields and the optic disc compared with untreated patients. Similar findings were reported Kass et al (1989), who treated one eye of ocular hypertensive patients and found that medical treatment reduced the incidence of ocular change.

The disadvantages of timolol are that its efficacy appears to show a long-term decline (Steinert et al 1981) and that it is associated with respiratory and cardiovascular complications (Nelson et al 1986).

Preparations

* Polyvinyl alcohol and carbomer 974P ** Gellan gum

BAK, benzalkonium chloride NS, not stated

DRUGS FOR THE TREATMENT OF GLAUCOMA 233

OTHER BETA-BLOCKERS

After timolol came a series of topical beta-blockers for the treatment of open-angle glaucoma. There are many systemically used beta-blockers but only a few showed topical activity. Those that reached the market are, in alphabetical order, betaxolol, carteolol, levobunolol and metipranolol.

Betaxolol Betaxolol is claimed to produce less bronchoconstriction because of its cardioselectivity (i.e. it is more effective on beta-1 receptors than on beta-2). However, it is not highly selective and care must still be taken in administering this agent to patients with obstructive airway disease. It is available as a solution and a suspension. Although betaxolol achieves a relatively modest reduction in intraocular pressure, it seems to be effective in slowing the rate of deterioration of the visual fields and this effect may be the consequence of an increase in retinal blood flow (Gupta et al 1994).

Preparations

BAK, benzalkonium chloride

Carteolol Carteolol is less potent than the other drugs being used in 1% and 2% solutions. Duff & Newcombe (1988) found that the hypotensive effect of carteolol was not as well maintained with twice-a-day therapy as it was with timolol.

Preparations

BAK, benzalkonium chloride

234 OPHTHALMIC DRUGS

Levobunolol Although there are minor differences between the individual betablockers, they all produce their effect in the same manner – by reducing aqueous humour production and aqueous flow. Yablonski et al (1987) found that levobunolol produced its effect in the same way as did timolol. Freyler et al (1988) compared levobunolol and timolol and found little difference in efficacy. A similar result was reported by SavelsberghFilette & Demailly (1988).

Preparations

* With 1.4% polyvinyl alcohol BAK, benzalkonium chloride

Metipranolol Metipranolol is only available in single dose units. Krieglstein et al (1987) reported a higher incidence of stinging with metipranolol when compared with levobunolol, although both were equally effective as ocular hypotensive agents.

Preparations

TOPICAL CARBONIC ANHYDRASE INHIBITORS

Carbonic anhydrase inhibitors are useful drugs for lowering intraocular pressure which in the past have had to be administered systemically. Unfortunately, given by this route, they produce some undesirable systemic side-effects (see above) that can lead to a large proportion of patients discontinuing therapy. The traditional agents, such as acetazolamide and dichlorphenamide, were found not to be active when applied topically. Acetazolamide has poor lipid solubility and corneal penetration. In the early 1980s the development of trifluoromethazolamide generated some interest because it provided good lipid solubility as well as water solubility and potency. Unfortunately, it was unstable and did not reach clinical use. However, it encouraged further research into newer compounds such as MK-927, which showed marked activity in lowering intraocular pressure in animals (Sugrue et al 1990)

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intraocular pressure by about 25%. They have a long duration of action, allowing for once-a-day treatment, normally applied at night. They all have a peculiar side-effect of increasing pigmentation of the iris and eyelashes. This is a particular problem if the patient is receiving treatment in one eye only.

Bimatoprost Bimatoprost differs from the other agents in this group in that it belongs to the group of compounds referred to as prostamides, which mimic the effects of prostaglandin alpha-2 (PGα2) without acting on any known PG receptor. Bimatoprost reduces intraocular pressure by increasing aqueous outflow through an effect on the trabecular meshwork and increasing uveoscleral outflow (Brubaker 2001). The onset of the effect is about 4 hours after administration, reaching a maximum at 8–12 hours. This effect is maintained for at least 24 hours, permitting once daily treatment.

Bimatoprost is well absorbed by the cornea.

Preparations

Latanoprost Latanoprost is a prostaglandin analogue that produces its effect by acting on a PG receptor. It reduces intraocular pressure principally through an increase in uveoscleral outflow, although it does have some effect on the trabecular meshwork. Its time course is very similar to that of bimatoprost. Effects are seen 3–4 hours after administration, with the maximum effect being attained at 12 hours and maintained for 24 hours.

It has additive ocular hypotensive effects with miotics, sympathomimetics, beta-blockers and carbonic anhydrase inhibitors, which is to be expected because they all work by different mechanisms to that of latanoprost.

Latanoprost is a prodrug and is inactive in vitro, requiring hydrolysis to release the active form.

Preparations

BAK, benzalkonium chloride