The initial treatment of COAG is usually medical. Topical administration is the preferred type of therapy, and there is a wide range of preparations available (Table 55.1). The chosen drug should be administered at its lowest concentration and as infrequently as possible to obtain the desired effect over the whole 24-h period as a high level of diurnal variation in IOP has been shown to be a more important factor in visual field development than the average IOP. A drug with few potential side effects should be chosen, with oral therapy retained as the final option. The prostaglandin analogues latanoprost and travoprost and the prostamide bimatoprost are indicated for first-line use, as are the β-blockers as these produce the greatest fall in IOP (Table 55.2). Carbonic anhydrase inhibitors and sympathomimetics, which result in a smaller fall in IOP, are reserved for patients unresponsive to first-line drugs, in patients in whom the first-line agents are contraindicated or as adjunctive therapy.

Table 55.1 Drugs used in the treatment of chronic open-angle glaucoma

Therapeutic category	Primary mechanism
Topical prostaglandins	Increase aqueous outflow
Topical prostamides	Increase aqueous outflow
Topical β-blocking agents	Decrease aqueous formation
Topical miotics	Increase aqueous outflow
Topical adrenergic agonists	Increase aqueous outflow and decrease aqueous formation
Topical carbonic anhydrase inhibitors	Decrease aqueous formation
Oral carbonic anhydrase inhibitors	Decrease aqueous formation

Table 55.2 Comparison of reduction in intraocular pressure (IOP) with a range of ocular hypotensive drugs (adapted from van der Valk et al., 2009)

Drug	Relative IOP change from baseline at trough (%) (95% CI)	Relative IOP change from baseline at peak (%) (95% CI)
Bimatoprost	−28 (−29 to −27)	−33 (−35 to −31)
Travoprost	−29 (−32 to −25)	−31 (−32 to −29)
Latanoprost	−28 (−30 to −26)	−31 (−33 to −29)
Timolol	−26 (−28 to −25)	−27 (−29 to −25)
Betaxolol	−20 (−23 to −17)	−23 (−25 to −22)
Dorzolamide	−17 (−19 to −15)	−22 (−24 to −20)
Brinzolamide	−17 (−19 to −15)	−17 (−19 to −15)
Brimonidine	−18 (−21 to −14)	−25 (−28 to −22)
Placebo	−5 (−9 to −1)	−5 (−10 to 0)

In most cases, the initial topical treatment is with a prostaglandin analogue or prostamide. If this is ineffective, another prostaglandin or prostamide may be substituted or a β-blocker used instead. Patients not reaching their target pressure on one first-line agent may be prescribed another concomitantly. Alternatively, a carbonic anhydrase inhibitor or a sympathomimetic may be added to one of the first-line drugs. Guidance on the treatment of people with OHT or suspected COAG has been published (National Institute for Health and Clinical Excellence, 2009). The treatment options (Table 55.3) take into account central corneal thickness and age, although age thresholds are only appropriate where vision is normal (OHT with or without suspected COAG) and the treatment is purely preventative. Pilocarpine is no longer recommended by NICE but is recommended as a second-line agent in European guidelines (European Glaucoma Society, 2008). Oral therapy with carbonic anhydrase inhibitors is usually reserved for use as the final stage of treatment in those complex glaucomas awaiting surgery (Fig. 55.2).

Table 55.3 Treatment of people with ocular hypertension or suspected COAG (National Institute for Health and Clinical Excellence, 2009)

Fig. 55.2 Topical therapy for chronic open-angle glaucoma (COAG) based on recommendations of European Glaucoma Society (2008).

It has been proposed that the improved control of IOP with newer therapies has led to a reduction in surgery for glaucoma (Kenigsberg, 2007). However, some patients still require surgical intervention to reach their target pressure.

The most frequently performed surgical procedures create a fistula to act as a new route for aqueous outflow and the most frequently performed surgery of this type, trabeculectomy, appears more effective in controlling IOP than laser trabeculoplasty, in which a series of laser burns is applied to the trabecular meshwork to improve the outflow of aqueous humour. (Rolim de Moura et al., 2007).

Primary angle-closure glaucoma

The medical management of acute PACG is essentially to prepare the eye for surgical treatment. The aim of treatment is to decrease the IOP and associated inflammation. Analgesics and antiemetics are sometimes needed, dependent on symptom severity, to make the patient comfortable. It is usual to treat the unaffected eye prophylactically with miotics (Fig. 55.3).

Fig. 55.3 Algorithm for the treatment of primary angle-closure glaucoma (PACG). YAG, yttrium aluminium garnet.

Paralysis of the iris sphincter usually occurs at an IOP of more than 60 mmHg, due to ischaemia. Therefore, intensive miotic therapy, previously the treatment of choice in many cases of PACG, is usually ineffective and the IOP needs to be lowered by drugs that reduce aqueous humour production rather than by trying to pull the peripheral iris away from the angle with miotics. An intravenous loading dose of mannitol is usually the first drug of choice with intravenous acetazolamide a possible alternative. This is followed by oral treatment, sometimes in combination with corneal indentation, to physically force aqueous humour into the peripheral anterior chamber and artificially open the angle. This should allow the IOP to drop sufficiently to relieve iris ischaemia and allow the sphincter to respond to pilocarpine therapy.

Once the IOP has been reduced medically, the condition is treated surgically, by either surgical peripheral iridectomy or laser iridotomy, to remove an area of the peripheral iris to allow flow of aqueous humour through an alternative pathway (see Fig. 55.1). Filtration surgery is indicated if a large proportion of the angle has been permanently closed by adhesions between the iris and the cornea.

Drug treatment

Ocular prostanoids: prostaglandin analogues and prostamides

The National Institute for Health and Clinical Excellence (2009) guideline does not differentiate between the prostaglandin analogues and the prostamide bimatoprost, but recommends one of this class for the treatment of COAG, certain patients with OHT and certain COAG suspects (see Table 55.4)

Table 55.4 Ocular prostanoids

The prostaglandin analogues, latanoprost, travoprost and tafluprost, are ester compounds thought to achieve a fall in IOP primarily by increasing the uveoscleral outflow with no significant effect on other parameters of aqueous humour dynamics, while the prostamide bimatoprost is thought to increase outflow through both trabecular and uveoscleral outflow pathways. However, there is still debate about the precise mechanisms of action of this group (Lim et al., 2008; Toris et al., 2008).

All the drugs in this class are licensed for the reduction of elevated IOP in open-angle glaucoma and OHT, and are administered once daily in the evening.

In a meta-analysis, these drugs have been shown to have a greater effect on both peak and trough readings of IOP than timolol, betaxolol, dorzolamide, brinzolamide or brimonidine, producing falls in IOP of 28–29% at trough and 31–33% at peak as shown in Table 55.2 (van der Valk et al., 2009).

Randomised head-to-head evaluations of prostaglandin therapy demonstrate similar efficacy, but differing hyperemia effects with bimatoprost and travoprost causing more hyperaemia than latanoprost (Eyawo et al., 2009; Honrubia et al., 2009). However, these studies were conducted before the introduction of the new formulations of bimatoprost 0.01% and the benzalkonium chloride–free travoprost.

The prostanoids have some interesting local side effects (Table 55.5). Pigmentation of the iris occurs in patients with mixed colour (green-brown or blue-brown) irides after 3–6 months of use and is a result of increased deposition of melanin in the melanocytes. An increase in the length and thickness of the eyelashes and pigmentation of the palpebral skin are also known side effects. Use of these drugs may lead to disruption of the blood–aqueous barrier in patients with aphakia and pseudophakia (no or false lens, respectively) and increase the risk of developing cystoid macular oedema; they should be used with caution in such patients. Reactivation of herpes simplex infection has been reported with bimatoprost, travoprost and latanoprost.

Table 55.5 Side effects of prostanoids

Ocular	Systemic
Asthenopia	Abdominal cramp
Allergic conjunctivitis	Asthenia
Blepharitis	Asthma
Blepharospasm	Bradycardia
Browache	Dizziness
Cataract	Dyspnoea
Conjunctival follicles, papillae	Elevated liver function
Conjunctival hyperaemia	Headache
Cystoid macular oedema	Hirsutism
Corneal erosion	Hypertension
Conjunctival oedema	Hypotension
Deepening of lid sulcus	Infection (primarily URTIs)
Distichiasis	Peripheral oedema
Eye discharge	Skin rash
Eye pain
Eyelash changes – increased number, length, thickness, pigmentation, misdirection, poliosis
Eyelid oedema, eyelid retraction
Eyelid and periocular skin darkening
Foreign body sensation
Increase in vellus hair on eyelids
Increased iris pigmentation
Iritis
Lid margin crusting
Localised skin reactions on the eyelids
Ocular burning, dryness, irritation pruritus, fatigue
Photophobia
Punctate epithelial erosions
Retinal haemorrhage
Tearing
Uveitis
Visual disturbance

URTIs, upper respiratory tract infection

Latanoprost

Latanoprost, which is converted to its active free acid on entering the eye, was the first of the prostanoids to be launched and is the market leader. Like timolol amongst the β-blockers, latanoprost is the drug in this class against which new drugs or combinations are assessed. It must be administered in the evening for maximum effect (Stewart et al., 2008). Latanoprost is generally very well tolerated. Serious adverse drug reactions were reported in only 17/3936 (0.43%) patients using latanoprost over a 5-year period (Goldberg et al., 2008), and patient persistence with latanoprost therapy is better than that with all other frequently used monotherapies (Rahman et al., 2009). Latanoprost is not heat stable and requires refrigeration; however, it is stable enough to be stored at room temperature for the 4-week in-use period applied in the UK. The concentration of the preservative benzalkonium chloride in latanoprost eye drops and bimatoprost 0.01% may prevent their use in certain patients. The benzalkonium chloride concentration in these formulations is 0.02%, which is four times that in bimatoprost 0.03% eye drops. The current formulation of travoprost, launched in January 2011, contains polyquaternium-1 rather than benzalkonium chloride.

Bimatoprost lowers the IOP to a greater extent than any other topical ocular hypotensive (van der Valk et al., 2009), an effect (see Table 55.2) which is sustained for at least 4 years (Williams et al., 2008). It is superior to latanoprost in terms of response rate, fall in IOP and the percentage of patients reaching their target IOP. In some studies, bimatoprost is reported to be as effective as the fixed combination of latanoprost and timolol. Many patients are non-responsive to latanoprost as they do not achieve a fall in IOP greater than 10%, although a large proportion of patients show a 20% or more fall in IOP with bimatoprost. Patients not reaching their target on latanoprost achieved lower IOPs when switched to bimatoprost (Sonty et al., 2008). Such patients achieve better diurnal control with bimatoprost than with a fixed combination of dorzolamide and timolol (Sharpe et al., 2008).

Generally, bimatoprost causes similar ocular side effects to latanoprost and travoprost, but while all the ocular prostanoids cause subclinical ocular inflammation, bimatoprost and travoprost cause this to a lesser degree than latanoprost. However, bimatoprost causes hyperaemia more frequently than latanoprost, although this is described as mild. This may contribute to the higher discontinuation rate seen with bimatoprost therapy (Rahman et al., 2009). To address this issue, the manufacturers of bimatoprost have introduced a lower strength (0.01%) version containing a higher concentration of benzalkonium chloride to aid penetration of the drug. In a 12-month study, the bimatoprost 0.01% was equivalent to bimatoprost 0.03% in lowering IOP and demonstrated improved tolerability, including less frequent and severe conjunctival hyperemia (Katz et al., 2010).

β-Adrenoceptor antagonists

The exact mechanism of action of β-adrenoceptor antagonists (β-blockers) in lowering IOP has not been fully established but is thought to result from the blockade of ciliary β-receptors, preventing the cyclic AMP-induced rise in aqueous secretion, as they have been shown to reduce aqueous humour formation rather than increase outflow. Although there are both β₁– and β₂-receptors in the eye, the latter predominate and even cardioselective β-blockers are thought to work by blockade of β₂-receptors. Genetic factors have been shown to be important in patients’ response to this group of drugs (Nieminen et al., 2007, Sidjanin et al., 2008).

Four drugs are available in the UK for topical administration: betaxolol, carteolol, levobunolol and timolol (Table 55.6). β-Blockers have a number of important properties in addition to β-adrenoceptor blockade. These include intrinsic sympathomimetic activity (ISA), cardioselectivity and membrane-stabilising activity, which are all of importance when considering the side effects seen with these agents (Table 55.7). The property of membrane stabilisation is relevant to the incidence of ocular side effects. The absence of anaesthetic properties reduces the number and severity of foreign body and dryness sensations, anaesthesia of the cornea and dry eye syndrome.

Table 55.6 Ophthalmic β-blockers

Table 55.7 Pharmacological profile of ophthalmic β-blockers

Ocular side effects of topically administered β-blockers are shown in Table 55.8.

Table 55.8 Ocular and systemic side effects of topical β-blockers

Ocular	Systemic
Allergic blepharoconjunctivitis	Central nervous system
Burning and itching	Anxiety
Blurred vision	Depression
Conjunctival hyperaemia	Fatigue
Corneal anaesthesia	Hallucinations
Dryness	Irritability
Foreign body sensation	Sleep disturbances
Macular oedema	Endocrine
Nasolacrimal duct obstruction	Hypoglycaemia (insulin induced)
Pain	Gastro-intestinal
Punctate keratitis	Nausea
Uveitis	Diarrhoea
	Vascular
	Arrhythmias
	Bradycardia
	Hypotension
	Peripheral vasoconstriction
	Reduced stroke volume
	Respiratory
	Bronchoconstriction
	Dyspnoea

It has been suggested that those β-blockers that show ISA are less likely to produce bronchospasm and peripheral vascular side effects. Carteolol is the only commercially available drug that shows ISA. The selectivity of cardioselective β-blockers diminishes with increasing dosage, even within the therapeutic range. Betaxolol is the only commercially available topical β-blocker that demonstrates cardioselectivity.

A degree of bradycardia is commonly seen with all β-blockers, and β-blocker eye drops have been identified as the cause of episodes of orthostatic hypotension and syncope in elderly patients (Müller et al., 2006). The use of topical β-blockers in patients on verapamil, diltiazem, disopyramide, quinidine or amiodarone could potentiate bradycardia and should be avoided. Topical β-blockers are generally avoided in patients with normal-tension glaucoma because the nocturnal fall in arterial pressure causes a potentially dangerous reduction in ocular perfusion.

The precipitation of bronchospasm in susceptible patients can occur with the administration of as little as one drop of timolol. Those β-blockers that show cardioselectivity or ISA are less likely to cause bronchoconstriction, and it has been demonstrated that respiratory function improved in patients whose treatment was changed from timolol to betaxolol or an adrenergic agonist, these same patients having previously been asymptomatic.

All topical β-blockers have been reported to cause bronchospasm; hence, ‘at-risk’ patients with a tendency to airway disease who require therapy for glaucoma should be treated with extreme caution. Prescribers are advised that β-blockers, even those with apparent cardioselectivity, should not be used in patients with asthma or a history of obstructive airways disease unless no alternative treatment is available. In such cases, the risk of inducing bronchospasm should be appreciated and appropriate precautions taken. Lacrimal occlusion with intracanalicular plugs has been shown to almost completely prevent the bronchoconstriction caused by topical timolol in asthmatics by inhibiting or decreasing systemic absorption of the medication.

Ocular β-blockers are generally not contraindicated in diabetes, although a cardioselective agent may be preferable. However, they are best avoided in patients who suffer frequent hypoglycaemic attacks as they may mask the signs and symptoms of acute hypoglycaemia.

Systemic side effects of topically administered β-blockers are shown in Table 55.8.

The long-term benefits of β-blockers on visual function preservation have been shown to be less than would be expected. This may be due to adverse effects on the ocular microcirculation whereby the β-blockers interfere with endogenous vasodilation and cause optic nerve head arteriolar vasoconstriction. The various β-blockers demonstrate marked differences in their vasoconstrictive effect, with betaxolol possibly demonstrating the least vasoconstriction.

Betaxolol

In theory, because of its cardioselectivity, betaxolol should have fewer adverse effects on the pulmonary system. It should also have fewer adverse cardiovascular effects because of comparatively lower systemic β-receptor occupancy after ocular administration. Maximum occupancies for β₁ and β₂ receptors after ophthalmic administration were 52% and 88% for carteolol, 62% and 82% for timolol, and 44% and 3% for betaxolol, respectively. The lack of systemic effects of betaxolol compared with timolol has been highlighted by Easton who reported the case of an 85-year-old lady who developed atrial fibrillation on having her β-blocker eye drops changed from timolol to betaxolol (Easton, 2007)

However, betaxolol is less effective than other β-blockers as an ocular hypotensive agent (van der Valk, 2009). On initiation of treatment, the fall in IOP is slower than with other topical β-blockers. The 0.25% suspension is as effective as the 0.5% solution and is better tolerated by the patient (Yalvac et al., 2007). Experimental studies showed the drug reaches the retina after topical administration and displays a voltage-dependent L-type calcium channel-blocking activity, which probably leads to improved retinal perfusion. This effect may explain the significant improvement in visual field performance seen with betaxolol in a comparison study with timolol in open-angle glaucoma. The significant improvement with betaxolol occurred despite the more effective reductions in IOP with timolol.

Carteolol

It has been suggested that because of the ISA of carteolol, attributable to its metabolite 8-hydroxycarteolol found in the plasma, smaller changes are seen in pulmonary and cardiovascular parameters than are seen with the non-cardioselective β-blockers without ISA. Carteolol appears to be neutral in its effect on serum lipid levels, whereas timolol adversely affects high-density lipoprotein cholesterol (HDL-C) and the total cholesterol/HDL-C ratio. Carteolol is generally well tolerated and has been shown to be as effective as timolol at lowering IOP in the majority of patients. It has a greater vasodilator effect on the retinal and choroidal vasculature than timolol and levobunolol but less than that of betaxolol. It is the least lipophilic of the topical β-blockers and consequently is likely to show a lower incidence of central nervous system side effects.

Levobunolol

Levobunolol is the potent l-isomer of bunolol. It is metabolised to dihydrolevobunolol in the eye, prolonging the drug’s half-life and making it one of only two topical β-blockers licensed for once-daily use. It is as effective with once-daily dosing as the usual twice-daily regimen. It is not cardioselective, showing greater affinity for the β₂-receptor, and does not possess ISA. It is reported to be as effective as timolol 0.5% and metipranolol 0.6% (now discontinued) in lowering IOP and more effective than betaxolol 0.5%. The incidence of allergic contact dermatitis is greater with levobunolol than timolol (Jappe et al., 2006), and a greater percentage of patients on levobunolol than timolol or betaxolol discontinued the drug due to adverse effects (Rahman et al., 2009). Its effect on tear volume and corneal epithelial barrier function is similar to that produced by timolol, and it has less effect on non-invasive break-up time of the precorneal tear film. This may be attributable to its formulation which includes polyvinyl alcohol. Levobunolol appears to have no effect on the retinal and choroidal vasculature.

Timolol

This non-cardioselective β-blocker without ISA was the first to be introduced, and as such is the agent against which all newer β-blockers were compared. It is effective in the long-term treatment of glaucoma, often in conjunction with other antiglaucoma therapy in terms of IOP lowering. Many patients can be placed on once-a-day therapy provided the IOP is maintained at satisfactory levels. However, the presentation of timolol in a prolonged-release formulation (a polysaccharide-based, gel-forming solution) leads to a prolonged corneal contact time and increased penetration of timolol into the eye. This is the preferred form for once-daily administration. Both timolol eye gels, 0.1% and 0.5%, have been shown to be as effective as the 0.5% solution administered twice daily. The 0.1% gel has the advantage of a much lower drug load, giving rise to plasma levels of timolol 10 times lower than achieved after twice-daily dosage of timolol 0.5% eye drops. The concentration of timolol achieved in the aqueous humour following administration of the 0.1% gel formulation, despite being approximately 40% of that following administration of the 0.5% solution is sufficient to occupy 100% of β₁– and β₂-receptors (Volotinen et al., 2009). Timolol is available in combination products with the carbonic anhydrase inhibitors brinzolamide and dorzolamide, the prostaglandin analogues latanoprost and travaprost, the prostamide bimatoprost and the sympathomimetic brimonidine (see Table 55.6).

Sympathomimetic agents

The original sympathomimetic drug used in the treatment of OHT and open-angle glaucoma, adrenaline (epinephrine) and its lipophilic pro-drug dipivefrine have been discontinued. Adrenaline (epinephrine) is an α- and β-adrenoreceptor agonist. It decreases IOP by reducing aqueous inflow via an α-mediated vasoconstriction in the ciliary body and increased outflow due to a dilation of the aqueous and episcleral veins. Adrenaline (epinephrine) is a mydriatic and therefore its use is contraindicated in PACG and in patients who show a shallow anterior chamber, because of the risk of precipitating angle closure. More selective sympathomimetics apraclonidine and brimonidine are in use today.

Apraclonidine

Apraclonidine (a derivative of clonidine) was the first of the selective adrenergic agonists to be introduced. This drug, which acts predominantly on α₂ but also on α₁-receptors, reduces the rate at which aqueous humour is produced due to ciliary vasoconstriction. Eye drops containing apraclonidine 1% are used to control or prevent postsurgical elevation of IOP following anterior segment laser surgery.

Eye drops containing a 0.5% solution are licensed for the short-term adjunctive treatment of patients on maximally tolerated medical therapy who require additional IOP reduction to delay laser treatment or glaucoma surgery, but the benefit for most patients is less than 1 month. Apraclonidine 0.5% is as effective in lowering IOP as brimonidine 0.2%, but has less effect on blood pressure and heart rate. Although an off-licence use, apraclonidine is sometimes used in children in whom brimonidine is strictly contraindicated (Wright and Freedman, 2009).

Ocular and systemic side effects of α₂-agonists are shown in Table 55.9.

Table 55.9 Ocular and systemic side effects of topical α₂-agonists

Ocular	Systemic
Ocular pruritus	Dry mouth/nose
Discomfort	Headache
Tearing	Asthenia
Hyperaemia	Bradycardia
Conjunctival and lid oedema	Depression
Lid retraction, conjunctival blanching and mydriasis (reported after perioperative use of apraclonidine)
Miosis (reported with brimonidine)
Uveitis

Brimonidine

More α₂-selectivity is seen with brimonidine, which results in miosis rather than mydriasis. Vasoconstriction of microvessels is also not seen. It is thought to increase uveoscleral outflow as well as reducing aqueous production. Brimonidine administered twice daily is almost as effective as timolol twice a day at peak. However, bromonidine is significantly less effective at trough, and some consider it to be more efficacious when administered three times a day, the frequency used in the USA. Brimonidine may be used as monotherapy to lower IOP in patients with open-angle glaucoma or OHT who are intolerant of β-blockers or in whom β-blockers are contraindicated, as there is no effect on pulmonary function and only minimal cardiovascular effect. It may also be used as an adjunctive therapy in those patients whose IOP is not adequately controlled with a single agent as its IOP-lowering activity has been shown to be additive to that of β-blockers and prostaglandin analogues.

A database containing details of drug use in 956 glaucoma patients over 18 years shows that brimonidine had the highest proportion of discontinuations due to adverse effects (Rahman et al., 2009). It has high allergenicity and may increase the likelihood of allergy to preparations subsequently used.

A formulation of brimonidine, brimonidine-Purite 0.15%, given twice daily, has been shown to be as effective as brimonidine 0.2% twice a day. It has a more favourable safety and tolerability profile, a reduced incidence of allergic conjunctivitis and better patient satisfaction and comfort rating. In a 4-month study, co-administration of latanoprost and brimonidine 0.15% results in a greater fall in IOP than co-administration of latanoprost and brinzolamide or dorzolamide (Bournias and Lai, 2009). This product is not available in the UK.

Brimonidine is contraindicated in patients receiving monoamine oxidase inhibitors or antidepressants which affect noradrenergic transmission, and there is the possibility of brimonidine potentiating or causing an additive effect with CNS depressants. Its use is contraindicated in children in whom it causes drowsiness, ataxia, pallor, irritability, hypotension, bradycardia, miosis and respiratory depression (Lai Becker et al., 2009).

Experimental evidence in animals has demonstrated that brimonidine is a potential neuroprotective agent. However, to date, clinical trials have failed to translate into similar efficacy in humans (Saylor et al., 2009).

Commercially available preparations of sympathomimetic agents are shown in Table 55.10.

Table 55.10 Available ocular products containing sympathomimetic agents

Miotics

Miotics act to increase the outflow of aqueous humour by a stimulation of ciliary muscle and an opening of channels in the trabecular meshwork. Miotics are directly acting parasympathomimetic agents that act at muscarinic receptors. The only such drug currently available commercially in the UK is pilocarpine.

Miosis is an unwanted incidental effect and can cause considerable difficulties to patients. Reduced visual acuity, especially in the presence of central lens opacities, spasm of accommodation, accompanied by severe frontal headache (browache) and diminished night vision may cause poor adherence in many patients.

Ocular side effects of pilocarpine are shown in Box 55.1. In eyes with narrow angles, PACG may be precipitated by an aggravation of pupillary block. Systemic side effects are due to parasympathetic stimulation and include anxiety, bradycardia, diarrhoea, nausea, vomiting and sweating (Box 55.2).

Box 55.2 Systemic side effects of topical pilocarpine

The onset of action of pilocarpine is 20 min, but its short duration of action necessitates four times daily dosing. The frequency of instillation of pilocarpine eye drops is a major disadvantage, and advances have been made to reduce the inconvenience of a four-times-daily dosage regimen. A slow-release gel preparation, Pilogel (Table 55.11), has been introduced. A single daily application, administered at bedtime, allows low IOP to be maintained for 24 h, with the patient sleeping through the more troublesome ocular side effects.

Table 55.11 Commercially available forms of pilocarpine

Carbonic anhydrase inhibitors

There are many forms of the enzyme carbonic anhydrase, three of which (CA-I, CA-II and CA-IV) are present in ocular tissues. In the ciliary epithelium, the inhibition of CA-II slows the formation of bicarbonate ions and their secretion into the posterior chamber of the eye. This reduces the sodium transport into the posterior chamber and decreases aqueous humour production, resulting in lower IOP. Inhibition of other forms of the enzyme results in many side effects.

Acetazolamide

This is the only systemic carbonic anhydrase inhibitor available in the UK. Although it is amongst the most potent ocular hypotensive agents available, it has limited use in the long-term management of glaucoma due to poor patient adherence following occurrence of side effects. The systemic side effects are shown in Box 55.3.

Paraesthesia occurs in almost all patients on commencement of therapy but usually disappears on continued therapy. The malaise complex can include fatigue, depression, weight loss and decreased libido.

Acetazolamide is also available in injection form, and given either intramuscularly or, preferably, intravenously. It is useful in the preoperative/emergency treatment of closed-angle glaucoma.

Topical carbonic anhydrase inhibitors

The topical carbonic anhydrase inhibitors dorzolamide and brinzolamide are useful alternatives to acetazolamide in glaucoma management. They are licensed as monotherapy for patients with OHT or open-angle glaucoma resistant to β-blockers or those in whom use of β-blockers is contra-indicated. Dorzolamide is also licensed for the treatment of pseudo-exfoliative glaucoma, and limited clinical data in paediatric patients are available. Both drugs are licensed as adjunctive therapy to β-blockers and brinzolamide to prostaglandin analogues, although there is evidence to suggest that dorzolamide is as efficacious as brinzolamide when added to latanoprost (Nakamura et al., 2009).

Dorzolamide is used either alone three times a day or concurrently with a β-blocker or twice daily with a prostaglandin analogue. While the licence for brinzolamide states that the drug can be used twice a day as monotherapy, some patients may respond better to a three times daily dosage. Mean changes in IOP with brinzolamide administered twice daily and three times daily and dorzolamide administered three times daily are equivalent. However, the fall in IOP achieved with these agents is less than that seen with timolol 0.5% twice daily.

Side effects similar to those of systemic sulphonamides may occur and should be watched for. The most common side effects are shown in Table 55.12. Of the two topical carbonic anhydrase inhibitors, brinzolamide appears to cause less burning and stinging on instillation due to the neutral pH (7.5) of the formulation. This is reflected in a much greater discontinuation rate with dorzolamide (31%) than with brinzolamide (14%) (Rahman et al., 2009).

Table 55.12 Side effects of topical carbonic anhydrase inhibitors

Ocular	Systemic
Blurred vision	Dry mouth
Burning/stinging	Dyspnoea
Conjunctivitis	Headache
Eyelid pain/discomfort	Nausea
Fatigue	Taste perversion
Itching
Nasolacrimal duct obstruction
Ocular discharge
Tearing

Animal studies suggested that both topical carbonic anhydrase inhibitors may improve ocular blood flow independent of the IOP; however, while this has been well established for dorzolamide in humans, data for brinzolamide are limited. It remains to be established whether this effect can help reduce visual field loss in patients with glaucoma.

Combination products

A large number of patients require more than one medication to achieve target pressure. A need for the patient to use two products concomitantly may lead to confusion, with multiple instillation of one product and non-use of the other. Also, if the second drop is instilled too soon after the first, wash-out of the first product with the second drop, overflow of the precorneal tear film and a dilution of both products may occur. In addition, the patient receives a larger dose of preservative which can irritate the eye and is a common reason for non-tolerance of the regimen. The combination of two drugs in one topical ophthalmic preparation may improve adherence and result in a reduction in preservative load. Single rather than multi-drop combinations are recommended to improve adherence and maintain patients’ quality of life.

For a combination of two drugs to be an acceptable alternative to the prescriber, the fixed combination must be more effective than either of the components used alone and at least as effective as the drugs administered separately, that is not demonstrate antagonism. In addition, adverse effects of the fixed combination must not be more numerous or more frequently encountered than with the components administered separately. There are six products in which timolol is combined with a second ocular hypotensive agent. They differ slightly in their therapeutic indications.

Fixed combination of timolol and dorzolamide

A combination of timolol 0.5% and dorzolamide 2% (Cosopt®) was the first topical ocular hypotensive combination to be marketed. It is indicated in the treatment of elevated IOP in patients with open-angle glaucoma or pseudoexfoliative glaucoma when topical β-blocker monotherapy is not sufficient. The fixed combination of dorzolamide and timolol is more effective than either timolol or dorzolamide alone, and as effective as its two components administered separately. In a review of its efficacy compared with other ocular hypotensives, an 80% response rate was reported for the fixed combination of dorzolamide and timolol (Yeh et al., 2008). It has also been reported to be a useful agent when used adjunctively with latanoprost, resulting in a further fall in IOP. Although generally well tolerated, the main problem with Cosopt® is burning and stinging on instillation. Although discontinuation of the combination in trials is low, Cosopt ® has been found to be the third most frequently discontinued eye product in practice (Rahman et al., 2009).

Fixed combination of timolol and latanoprost

A combination of timolol 0.5% and latanoprost 0.005%, marketed as Xalacom®, was first launched in the UK in 2001, shortly before the launch of travoprost and bimatoprost. Xalacom® is indicated for the reduction of IOP in patients with open-angle glaucoma and OHT who are insufficiently responsive to topical beta-blockers or prostaglandin analogues. It is administered once a day and has been shown to be more effective when administered in the evening than in the morning (Takmaz et al., 2008). It is unclear whether fixed combinations of prostaglandin analogues with timolol are superior to prostaglandin analogues alone.

Fixed combination of timolol and brimonidine

A combination of timolol 0.5% with brimonidine 0.2% is marketed as Combigan® and is indicated for the reduction of IOP in patients with COAG or OHT who are insufficiently responsive to topical beta-blockers.

The fixed combination has been shown to be superior in reducing IOP than either brimonidine or timolol alone and is as safe and effective as concomitant treatment with the individual components. Use of the combination product has been shown to result in a 24% fall in IOP (Papaconstantinou et al., 2009). Use of the brimonidine/timolol combination results in a greater number of side effects than timolol alone has fewer side effects than brimonidine alone (Sherwood et al., 2006) and fewer cases of allergy than brimonidine used alone (Motolko, 2008).

Fixed combination of timolol and travoprost

A fixed combination of travoprost 0.004% and timolol 0.5% (DuoTrav®) has been shown to be more effective than either of its components and is as efficacious as the components administered concomitantly while fewer side effects are reported with the combination product (Gross et al., 2007). The fixed combination of travoprost and timolol is indicated to decrease IOP in patients with open-angle glaucoma or OHT who are insufficiently responsive to topical β-blockers or prostaglandin analogues. Although the Summary of Product Characteristics states that the dose is one drop in the affected eye(s) once daily, in the morning or evening, it has been shown that an evening dose demonstrates better 24-h pressure control (Konstas et al., 2009).

Fixed combination of timolol and bimatoprost

A fixed combination of bimatoprost 0.03% and timolol 0.5% (Ganfort®) is available for the reduction of IOP in patients with open-angle glaucoma or OHT who are insufficiently responsive to topical β-blockers or prostaglandin analogues. The fixed combination has been shown to be more effective than either of its components used alone and as effective as the components used in their usual dosing regimen, that is bimatoprost once daily in the evening and timolol twice daily, used concomitantly. Conjunctival hyperaemia has been reported more frequently by patients on bimatoprost (39%) than the bimatoprost/timolol fixed combination (23%) with the lowest incidence in those receiving timolol (7%) (Brandt et al., 2008).

Fixed combination of timolol and brinzolamide

A fixed combination of brinzolamide 1% and timolol 0.5% (Azarga®) is a recently launched combination topical ocular hypotensive presentation. The combination is indicated to reduce IOP in adult patients with open-angle glaucoma or OHT for whom monotherapy has produced insufficient IOP reduction. It has greater IOP-lowering efficacy than brinzolamide or timolol alone (Kaback et al, 2008). Brinzolamide/timolol administration leads to a 30–33% fall in IOP at trough and 34–35% at peak and is better tolerated than, and preferred to, the dorzolamide/timolol combination, probably because of the neutral pH (7.2) of the suspension (Manni et al., 2009; Mundorf et al., 2008).

Hyperosmotic agents

Hyperosmotic agents are of great value during PACG emergencies due to their speed of action and effectiveness. The most commonly used agents are oral glycerol and intravenous mannitol, although both isosorbide and urea have been used in the past. Hyperosmotic agents act by drawing water out of the eye and therefore lower IOP. The maximal effect of glycerol is seen within 1 h and lasts for about 3 h, while mannitol acts within 30 min with effects lasting for 4–6 h.

Glycerol

Glycerol is given orally, usually as a 50% solution in water, the dose being 1–1.5 g/kg body weight given as a single dose. It is not a strong diuretic but may cause headaches, nausea and vomiting. Although it is metabolised to glucose in the body, it may be given to diabetics who are well controlled. All practitioners should be aware of the difference in dose in mL required for a 50% solution of glycerol formulated as a 50% w/v solution and one formulated as a 50% v/v solution (Table 55.13).

Table 55.13 Doses of hyperosmotic agents used in the treatment of POAG

Mannitol

Mannitol is given as a 20% solution in water for intravenous administration. The dose is 1–2 g/kg body weight up to a maximum of 500 mL given over 30–40 min at a rate not exceeding 60 drops/min. It is a strong diuretic and as large volumes are required, it may cause problems due to cardiovascular overload, pulmonary oedema and stroke. Cerebral dehydration leads to headache and the patient may experience chills and chest pain. Mannitol is now generally preferred over acetazolamide as an initial treatment for PACG.

Patient care

Chronic open-angle glaucoma

When the condition is first diagnosed, patients should be told that the disorder cannot be cured but only controlled by the regular use of the prescribed treatment. As patients may not be aware of progression of the disease, the result of non-adherence with treatment should be made clear and the importance of regular attendance at clinics stressed.

The existence of a patient self-help group, the International Glaucoma Association (http://www.glaucoma-association.com), should be brought to the patient’s attention. They will be able to put the patient in contact with their nearest support group.

The patient’s technique for instillation of eye drops should be checked and corrected if necessary. Emphasis should be on the dose (one drop), the position of instillation, into the temporal side of the lower conjunctival sac, and the importance of punctal occlusion to minimise systemic side effects.

The preferred times for administration of topical medication should be discussed with the patient. Prostaglandins, prostamides and the gel form of pilocarpine are best administered at bedtime; a 12-hourly regimen should be employed for twice-daily drugs; 8-hourly for drugs given three times a day; and as near a 6-hourly regimen as practical for the aqueous formulation of pilocarpine. β-Blockers given once daily should be administered in the morning. The importance of allowing a reasonable interval between drops should be emphasised. Sometimes, the order of instillation of different types of eye drop is important for pharmacological or practical reasons. For example, the instillation of pilocarpine should always precede that of a sympathomimetic to prevent pain in the eye resulting from a strong miosis following a weak mydriasis. The instillation of aqueous eye drops, which remain in the conjunctival sac for a maximum of 10 min, should precede that of viscous eye drops, for example hypromellose eye drops, or suspensions (e.g. dexamethasone 0.1% eye drops) where the contact time is prolonged.

Eye drops containing benzalkonium chloride should not be instilled if soft contact lenses are in situ. The patient should be instructed to remove the lens immediately before instillation and replace it approximately 30 min later.

As there is a hereditary component to COAG, patients should be told to advise first-degree relatives to be screened. Such people over the age of 40 years are entitled to free eye tests by their optometrist.

Primary angle-closure glaucoma

Patients found to have shallow anterior chambers and narrow angles are normally promptly listed for peripheral iridectomies. However, if the procedure is delayed, they should be advised of the symptoms of an attack of acute PACG and details of the factors that are likely to precipitate an attack so that they can be avoided. They should be advised that there are a number of prescription and non-prescription drugs that they should not take (Lachkar and Bouassida, 2007). When visiting the doctor and purchasing medicines from a pharmacy, the patient should always remember to mention their condition, and the prescriber should ensure that the drug is appropriate for a patient prone to angle closure. Examples of drugs contraindicated in this condition are listed in Table 55.14. Note that the absence of a drug from this list does not imply safety.

Table 55.14 Drugs contraindicated in narrow-angle glaucoma

Therapeutic class		Examples
Antimuscarinics	Topical	Atropine, cyclopentolate, homatropine, tropicamide
	Antispasmodic	Atropine, dicycloverine, hyoscine, propantheline
	Motion sickness	Hyoscine, promethazine, cyclizine
	Bronchodilator	Ipratropium, tiotropium
	Urinary retention	Darifenacin, fesoterodine, flavoxate, oxybutynin, propiverine, solifenacin, tolterodine, trospium
Drugs used in anaesthesia		Glycopyrronium, ketamine, suxamethonium
Antidepressants		Amitriptyline, amoxapine, citalopram, clomipramine, dosulepin, doxepin,duloxetine,fluvoxamine, imipramine, lofepramine, maprotiline, mirtazapine, nortriptyline, paroxetine, phernelzine, reboxetine, sertraline, trazodone, trimipramine, venlafaxine
Antipsychotics		Chlorpromazine, clozapine, flupentixol, fluphenazine, olanzapine, pericyazine, perphenazine, pipotiazine, promazine, risperidone, sulpiride, thioridazine, trifluoperazine, zuclopentixol
Antihistamines		Alimemazine, antazoline, cetirizine, chlorphenamine, clemastine, cyproheptadine, diphenhydramine, hydroxyzine, loratidine, pizotifen
Antiarrhythmics		Disopyramide
Antiepileptics		Carbamazepine, topiramate
Sympathomimetics		Adrenaline, cocaine, dipivefrine, ephedrine, isometheptene, naphazoline, phenylephrine, pseudoephedrine, salbutamol, xylometazoline
Drugs used in the treatment of ADHD		Atomoxetine, dexamfetamine, methylphenidate, ritodrine
Drugs used in the treatment of parkinsonism		Benserazide, carbidopa, entacapone, levodopa, orphenadrine, procyclidine, selegiline, trihexyphenidyl,
Non-steroidal anti-inflammatory drugs		Mefenamic acid
Sulphonamide derived drugs		Acetazolamide, co-trimoxazole, hydrochlorothiazide, sulphasalazine
Miscellaneous		Botulinum toxin, carboprost, paracalcitol, pilocarpine

Following an attack of angle closure and surgical treatment of the disorder, the patient should be told that the drugs previously contraindicated can be safely taken provided that iridectomy/iridotomy remains patent.

Patient adherence

The patient is more likely to comply with the prescribed treatment if the drug or drugs can be administered according to a simple, infrequent dosage regimen and cause no or few, local or systemic side effects.

Thus, a patient treated with a once-daily prostaglandin analogue or prostamide or once- or twice-daily β-blocker would be expected to adhere to the regimen better than someone treated with pilocarpine, with its unfortunate side effects and inconvenient four-times-a-day dosage regimen. Common side effects of topical and systemic medication should be fully discussed with the patient so that the hyperaemia encountered with the prostanoids and the paraesthesia with acetazolamide are not unexpected, leading to premature discontinuation of therapy.

As glaucoma is predominantly a disease of elderly people, physical disability may prevent successful treatment, however conscientious the patient. For example, rheumatoid arthritis may reduce the patient’s ability to squeeze the bottle of eye drops, while the tremor of Parkinson’s disease can make correct positioning of instillation difficult. Various aids have been introduced to help with correct positioning and squeezing of eye drops, and these should be made available to patients so disabled.

Patients with poor visual acuity can be helped by colour coding of eye drop labels and supplying bottles labelled with large print. Some manufacturers have endeavoured to enhance adherence by including dose-reminder caps and facilitating instillation by supplying aids to open or position the bottle. Other manufacturers have made their eye drop containers easier to squeeze or supply aids to squeeze the bottle. A list of such devices, some of which are available on prescription, others free of charge from manufacturers of drugs used in the treatment of glaucoma is available on the International Glaucoma Association’s website (http://www.glaucoma-association.com/).

Where self-medication is impossible, a simple infrequent dosage regimen is more likely to be achieved when a relative, a neighbour or the district nursing service becomes responsible for administration of the medication. In these cases, a drug administered once daily, such as a long-acting timolol preparation or a prostaglandin analogue or bimatoprost, has an obvious advantage over one that should be administered at 12-hourly intervals. If pilocarpine is required and bedtime administration is possible, the prescribing of pilocarpine ophthalmic gel will be more practical than pilocarpine eye drops, the administration of which is totally impractical for anyone other than someone living with the patient.

Common therapeutic problems in glaucoma are listed in Table 55.15.

Table 55.15 Common therapeutic problems in glaucoma

Problem	Comments
Lack of adherence	Treatment perceived to be worse than disease
	Complex multiple drug regimens
	Frequency of dosing
	Inability to differentiate between different types of medication
	Inability to instil medication
Contraindication to therapy	Pilocarpine in uveitis
	β-Blockers in asthma, bradycardia, heart block, uncontrolled heart failure
	Prostaglandin analogues and prostamides in aphakia
	Wide range of topical and systemic drugs in shallow anterior chamber
	α₂-agonists in depression
	Carbonic anhydrase inhibitors in renal failure
Intolerance to drug	Miosis and ciliary spasm with pilocarpine
	Red eye with prostaglandin analogues, bimatoprost
	Bronchospasm with β-blockers
	Paraesthesia with acetazolamide
Use outside licensed indications	Paediatric patients
	Pregnant women
	Nursing mothers
Hypersensitivity	To active drug
Hypersensitivity	To preservative in multidose formulations