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Greg Heath BSc (Hons), MCOptom, DipClinOptom 

Ocular therapeutic case studies 

Medical management of glaucoma 

The sine qua non of glaucoma management is to arrest optic nerve damage and, as 

such, prevent further losses to the patient’s visual field. It is noteworthy that the 

American Academy of Ophthalmology’s definition of open angle glaucoma – as a 

progressive neuropathy characterised by loss of ganglion cells – makes no 

reference to intraocular pressure (IOP). Notwithstanding, it is axiomatic that the 

successful management of glaucomatous patients, whether medical or surgical, lies 

in the ability of the practitioner to lower the patient’s IOP. 

Topical anti-glaucoma agents are reserved for 

those patients who have glaucoma or ocular 

hypertension. The reasons for treating the latter 

group are twofold – first, to reduce the risk of 

acquiring central retinal vein occlusion, and 

second, topical hypotensive therapy may delay or 

even prevent the onset of primary open angle 

glaucoma (POAG) in these individuals. Evidence 

supporting the benefits to hypertensives came 

from the Ocular Hypertensive Treatment Study 1 , 

conducted in the Washington School of Medicine. 

Of the 1,636 ocular hypertensives randomised to 

either the treatment group or observation group, 

the cumulative probability of developing POAG in 

the treatment cohort was 4.4%, compared with 

9.5% in the observation cohort. 

Over the past decade, there have been 

numerous additions to the ophthalmologist’s 

ocular hypotensive drugs cabinet. Indeed, the 

addition of these new agents to the treatment 

regimen has had a dramatic impact on the 

overall management of glaucomatous patients. 

In their retrospective analysis of National Health 

stations in Scotland, Bateman et al 2 revealed a 

45.9% reduction in operation rates between 

1994 and 1999. By contrast, the number of 

patients treated via their topical counterparts 

had increased dramatically. The authors 

attributed this management swing to the 

effectiveness of the new ocular hypotensive 

agents, namely the carbonic anhydrase inhibitors 

(CAIs), prostaglandin analogues and alpha2 

agonists. 

In keeping with the previous article in this 

CPD module (“Ocular therapeutic case studies: 

glaucoma – when to operate?” OT 28/06/02), 

this article will focus on the most prevalent type 

of glaucoma – POAG. The medical therapies 

currently available to combat this chronic 

malady, together with their associated side 

effects, will be discussed. 

Therapeutic trials 

Since IOP varies diurnally, assessing the 

patient’s control of their glaucoma through a 

single measurement is futile. It is for this reason 

that many practitioners (especially in the US) 

advocate a monocular therapeutic trial prior to 

prescribing the drug in question. The usefulness 

of such a trial is illustrated in the following 

example. 

Patient GH presents to the glaucoma clinic 

with IOPs of 32mmHg in each eye. The 

practitioner prescribes his/her preferred topical 

hypotensive agent to the right eye only and 

re-examines the patient three weeks later. If, on 

the subsequent visit, the patient’s IOPs are now 

R 20mmHg and L 20mmHg, then one can 

conclude that the drug has been ineffective 

(assuming that the patient adhered to the 

prescriber’s instruction of instilling in the right 

eye only). However, if the readings are 

R 20mmHg and L 28mmHg on repeat 

examination, the effect of the drug is clear. One 

important caveat is that some drugs, such as 

beta-blockers, may lower the IOP in both eyes 

despite unilateral administration. That said, 

these effects are usually asymmetric with the 

administered eye exhibiting the greatest 

hypotensive effect. 

Therapeutic trials are also useful in 

evaluating the benefits of adding another drug 

to the patient’s treatment regimen. They allow 

the practitioner to decide whether the 

additional expense and potential for side effects 

is justified in each case. 

Table 1 

Main classes of ocular hypotensive drugs and their mechanisms 

DRUG 

Beta-blockers 

Miotics 

Adrenergics: Adrenaline and Dipivefrin 

alpha2 agonists 

Carbonic anhydrase inhibitors (CAIs) 

Prostaglandin analogues 

Hyperosmotic agents 

ACTION 

Decrease aqueous production 

Increase trabecular outflow by constricting longitudinal ciliary body 

muscle and opening trabecular meshwork 

Decrease aqueous production and increase outflow facility 



Increase uveoscleral outflow 

Increase osmolality of blood thus drawing aqueous from vitreous 

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mark of 60%. 

Despite the effectiveness of such trials, the 

major drawback is the time and number of 

hospital appointments required before a final 

treatment plan is established. In the UK, where 

the NHS doctors are beleaguered, such 

methodology may be impractical. 

Patient suitability 

Although medical therapy is currently the 

mainstay of treatment for glaucoma, 

practitioners should be aware that such 

stratagems are fraught with problems. The 

disadvantages of medical therapy include: 

• IOP lowering effects less effective 

than surgery 

• Potential for serious side effects 

• Topical medications frequently overlooked as 

a cause of systemic side effects 

• Nuisance factor may interfere with the 

patient’s quality of life 

• Costs of care are high in the long term 

• Compliance 

Poor compliance is an extremely important 

negative effect. Defaulting from medical therapy 

can be a major factor in the progression of this 

insidious disease. Furthermore, poor compliance 

may occur for various reasons including age of 

patient, patient’s systemic status, occupation, 

lifestyle and their social situation. Thus, the 

busier the patient’s lifestyle is, the less 

structured the environment and the more likely 

she/he is to disregard their treatment. Similarly, 

a patient with a co-existing chronic disease, e.g. 

rheumatoid arthritis, would lack the manual 

dexterity to instil the drugs. All of these factors 

should be taken into account before a decision is 

made as to the best form of treatment for each 

individual. 

Medications 

Table 1 summarises the main classes of ocular 

hypotensive agents together with their proposed 

mechanisms of action. 

Beta-blockers 

Since the introduction of Timolol in the late 

1970s, topical beta-blockers have remained the 

quintessential drug in the management of 

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July 26, 2002 OT 

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Module 4 Part 8 

glaucoma. Their popularity arose as a result of 

their potent hypotensive effects in most types of 

glaucoma, in addition to a relative dearth of 

associated ocular side effects exhibited by their 

topical counterparts (e.g. miosis, conjunctival 

hyperaemia). Notwithstanding their advantages, 

such agents have gained notoriety through their 

ability to induce potentially grave systemic side 

effects. 

Mechanism of action 

Beta-blockers reduce IOP by decreasing aqueous 

production. Their effects on uveoscleral outflow 

and episcleral venous pressure are negligible. In 

humans, there are two main alpha-adrenoceptors 

– alpha1 and alpha2. While the former 

predominate in heart muscle, the latter reside in 

the bronchial musculature. Consequently, 

stimulation of alpha1 receptors would result in 

tachycardia (increased heart rate), whereas 

stimulation of alpha2 would result in bronchial 

dilatation. 

Most of the topical beta-blockers available 

are non-selective. In other words, they block 

both types of receptor. The exception to this rule 

is Betaxolol, which is a relative cardioselective 

beta-blocker. However, it may still bind to its 

bronchial counterpart although the degree of 

potency is two orders of magnitude less than 

Timolol 3 . 

Drugs 

The various types of beta-blockers currently used 

in the treatment of glaucoma are listed in 

Table 2. 

Non-selective beta-blockers 

As mentioned earlier, Timolol has been the 

anti-glaucoma drug par excellence for decades 

and, as such, has been considered the reference 

standard for IOP lowering efficacy. Probably the 

major key to its success is its ability to lower IOP 

in up to 90% of prospective patients. It is 

available in two concentrations – 0.25% and 

0.5%. The lower concentration is suitable for 

patients possessing lightly pigmented irides, 

whereas the 0.5% is ideally suited for those with 

dark irides 4,5,6 . 

Despite boasting considerable reductions in 

IOP of up to 40% from baseline, Timolol’s 

efficacy diminishes over subsequent months in 

up to 20% of those individuals initially treated. 

Such a relative decline in efficiency has been 

coined ‘long-term drift’ by Steinert and 

co-workers 7 and these effects should be borne in 

the practitioner’s mind when initiating betablocker 

monotherapy. 

All topical beta-blockers share the same 

properties as Timolol with the exception of 

Carteolol, a non-selective beta-blocker exhibiting 

concomitant intrinsic sympathomimetic activity, 

and Betaxolol, a relatively selective beta-blocker. 

Owing to its intrinsic sympathomimetic 

activity, Carteolol may be more selective to the 

eye and, as a consequence, the likelihood of 

inducing cardiopulmonary adverse effects would 

be considerably less than its non-selective 

counterparts 8 . 

www.optometry.co.uk 

DRUG 

Timolol 

Timoptic-Xe gel 

Levobunolol 

Carteolol 

Metipranolol 

Betaxolol 

Table 2 

Topical beta-blockers 

CONCENTRATION 

0.25%, 0.50% 

0.25%, 0.50% 

0.50% 

1%, 2% 

0.1%, 0.3% 

0.5% 

Betaxolol 

In keeping with most of the topical beta-blocker 

family, Betaxolol lacks intrinsic sympathomimetic 

activity. However, in contradistinction, it is more 

cardioselective. The corollary of this therapeutic 

feature is that the drug is a better choice for 

patients with restrictive airways disease. 

However, there is an important caveat since 

Betaxolol’s cardioselectivity is only relative and it 

may exacerbate pulmonary adverse effects in 

susceptible individuals. 

Although the IOP reductions achieved with 

twice daily administrations of Betaxolol are 

somewhat modest in comparison to Timolol, the 

drug appears to be superior in retarding the 

progression of visual field defects. Moreover, 

several investigators utilising doppler colour 

imaging of retinal blood vessels have shown an 

increase in retinal blood flow following topical 

administration of Betaxolol 9 . Such 

‘neuroprotective’ effects may explain, in part, 

the efficacious nature of Betaxolol in the 

treatment of glaucoma despite relatively modest 

reductions in IOP. 

Side effects 

As illustrated in Table 3, beta-blockers have the 

potential to produce a plethora of systemic side 

effects. The cardiovascular and bronchial adverse 

effects are the result of blockading the alpha1 

and alpha2 adrenoceptors respectively. Blockade 

of the former results in bradycardia and 

hypotension and, consequently, they should not 

be given to patients suffering from heart block, 

sinus bradycardia or cardiac failure. Blockade of 

the alpha2 adrenoceptors can result in 

bronchospasm, which may prove fatal in patients 

suffering from asthma or chronic obstructive 

pulmonary disease. 

In a retrospective analysis of adverse 

reactions to topical Timolol between 1978 and 

1985, over 450 cases of serious respiratory and 

cardiovascular events were reported 10 . Tragically, 

the same study disclosed 32 deaths attributed to 

the topical administration of Timolol. This 

underscores the need for the prescribing 

practitioner to be fully conversant with these 

unwanted sequelae, and it is prudent that 

she/he monitors the patient’s pulse prior to 

administration of beta-blocker therapy even if 

the patient’s medical history appears 

unremarkable. Moreover, the practitioner should 

remain cognisant when acquiring a patient’s 

drug history since numerous oral medications 

SELECTIVITY 

Non 

Non 

Non 

Non 

Non 

Relative alpha1 

DOSAGE 

Od, bds 

Od 

Od, bds 

Od, bds 

Od, bds 

Bds 

DURATION 

Up to 24 hours 






may augment the beta-blockade. These drugs 

include Quinidine 11 , calcium channel blockers 

and Digitalis 12 . 

For those patients deemed suitable for 

topical beta-blocker therapy, the practitioner 

can modify the prescription regimen in order to 

reduce the propensity of inducing systemic side 

effects. This could be achieved by either 

prescribing the lowest effective dose possible 

and/or reducing the frequency of instillations, 

i.e. od instead of bds. Interestingly, 

beta-blockers are frequently prescribed bds. Yet, 

there are numerous studies in the ophthalmic 

literature which support the hypotensive 

efficiency of a once daily regime 13,14,15 . 

Finally, a paucity of adverse effects should 

not entice the practitioner to relax his/her 

vigilance since systemic and local complications 

may only emerge years after initial 

treatment. 

Prostaglandin analogues 

Prostaglandins (PGs) are members of a family of 

substances known as the eicosonaoids. Although 

there are several PG subtypes, low doses of PGF2α 

were found to induce significant ocular 

hypotensive effects in monkeys without altering 

their refractive status or pupil size. 

Owing to their superior safety record and 

potent hypotensive effects, the usage of PG 

analogues has become de rigeur in the medical 

management of the majority of glaucomas. The 

Table 3 

Main reported side effects 

of beta-blockers 

SYSTEMIC 

Cardiovascular: 

Bradycardia 

Hypotension 

Raynaud’s phenomenon 

Pulmonary: 

Asthma 

Bronchospasm 

Dyspnoea 

Neurological: 

Depression 

Confusion 

Impotence 

Insomnia 

Miscellaneous 

Diarrhoea and nausea, 

hypoglycaemia 

OCULAR 

Allergic 

blepharoconjunctivitis 

Dry eye 

Corneal anaesthesia 

27

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DRUG 

Pilocarpine (1%, 2%, 3%, 4%) 

Carbachol (3%) 

Ecothiopate iodide (0.03%, 0.06%, 

0.125%, 0.25%) 

Physostigmine (Eserine) (0.25% -1.0%) 

Table 4 

Cholinergic agents 

two analogues currently available are 

Latanoprost 0.005% (XALATAN) and Travoprost 

0.004% (TRAVATAN). Both drugs bind to the PF 

receptor and possess the same mechanism of 

action – namely the augmentation of uveoscleral 

outflow. 

The efficiency of Latanoprost has been 

demonstrated in several multicentre, randomised 

controlled trials in the US, UK, Japan and 

Scandinavia 16,17,18 . These studies consistently 

revealed that a single dose of Latanoprost 

achieves between a 25-35% reduction in IOP 

from baseline readings. Furthermore, the timing 

of instillation is noteworthy with the majority of 

practitioners advocating evening administration, 

since the IOP-lowering effects usurp those 

achieved by Timolol maleate bds, when compared 

to morning applications alone 16 . 

Travoprost 0.004% was approved in March, 

2001 in the US. Used once daily, a 1.0-1.3mmHg 

greater reduction in IOP, compared with Timolol 

0.5% bds, was observed in 605 patients in phase 

III studies 19 . These findings were corroborated by 

Goldberg et al 20 , who revealed a 1.0-1.7mmHg 

enhanced reduction in IOP when comparing the 

same drugs. In their randomised controlled trial 

comparing the efficiency of Travoprost, 

Latanoprost and Timolol, Netland et al 21 

disclosed the greatest reduction in IOP with the 

former agent. Based on a criterion of a 30% or 

greater reduction in IOP from diurnal baseline, 

the overall responses to treatment for 

Travoprost, Latanoprost and Timolol were 54.7%, 

49,6% and 39.0% respectively. 

It is noteworthy that the same study 

demonstrated Travoprost’s superiority in lowering 

IOP levels in patients of African descent 

(2.4mmHg lower than Latanoprost and 4.6mmHg 

lower than Timolol). However, the a priori 

assumption that Travoprost should be employed 

as first line therapy in such a population group 

requires validation from further prospective 

studies. 

A novel anti-glaucoma agent which has 

recently been released in the UK is the 

prostamide analogue, Bimatoprost 0.03%. Unlike 

the PG analogues, which are derived from 

arachidonic acid, Bimatoprost is derived from 

anandamide by the action of the enzyme 

cyclooxygenase 2 (COX 2). It reduces IOP by 

approximately 30% and is instilled once daily 

(preferably in the evening). When compared to 

Timolol 0.5% bds, the IOP decrease achieved 

following administration of Bimatoprost od is 

unrivalled 22 . Moreover, in the same study, 

Sherwood and Brandt demonstrated that in 

those eyes in which Bimatoprost had been 

MECHANISM 

Direct 

Direct 

Indirect 

Indirect 

DOSAGE 

Qds 

Tds 

0d, bds 

Qds 

DURATION 

4-8 hours 

6-12 hours 

12-24 hours 

4-6 hours 

instilled, there was no significant diurnal 

variation in IOP reduction. 

Unlike Latanoprost and Travoprost, 

Bimatoprost does not bind to the PF receptors. 

Furthermore, the drug appears to not only 

enhance uveoscleral outflow, but promote 

outflow via the trabecular route 23 . 

Docosanoids 

Although these drugs have been used clinically 

in Japan since 1994, they only were approved in 

the US in August, 2000. Docosanoid compounds 

are derived from docosahexaenoic acid, which 

consists of a 22-carbon chemical backbone 

(cf, 20-carbon structure of arachidonic acid). 

Unlike PG analogues, the docosanoids do not 

bind to the PF receptor. The docosanoid 

prototype is Unoprostone isopropyl 0.15% 

(RESCULA). 

Even though the mechanism by which 

Unoprostone achieves its therapeutic effects is 

known – via increasing outflow – the receptor to 

which the drug binds in order to achieve its 

effects remains elusive. 

Studies have shown Unoprostone to have an 

excellent safety profile. Notwithstanding, its use 

clinically as a form of monotherapy is somewhat 

limited owing to the fact that its IOP-lowering 

effects are extremely modest. Indeed, in their 

randomised controlled trial comparing 

Latanoprost with Unoprostone, in patients with 

either open angle glaucoma or ocular 

hypertension, the percentages of patients 

achieving a 30% reduction in IOP when treated 

with the drugs were 44% and 8% respectively 24 . 

However, it appears that Unoprostone may prove 

to be an effective adjunct to Latanoprost if the 

IOPs remain greater than 22mmHg on the latter 

drug alone 25 . 

Side effects 

As mentioned earlier, the PG analogues have a 

very good safety record to date. However, one 

should execute a degree of caution since 

information is still being gathered about the 

safety of long-term treatment. 

In clinical trials, Latanoprost’s safety profile 

appeared promising with no systemic side effects 

reported 26 . Several ocular adverse effects, on the 

other hand, have been noted. The most common 

ocular manifestations include hyperaemia 27 , 

hypertrichosis 28 and an increase in both iris and 

eyelash pigmentation 26,28 . 

Although these side effects are innocuous, 

there have been some which are worthy of note, 

particularly cystoid macular oedema. 

Unfortunately, this maculopathy escaped the 

safety net of clinical trials. Nevertheless, there 

are numerous case reports suggesting that 

patients who have had a history of cataract 

surgery, cystoid macular oedema or uveitis are 

more susceptible 29-33 . In addition, a similar cohort 

is also at risk of acquiring uveitis following 

Latanoprost therapy 33 . It therefore seems 

prudent to either avoid these drugs or use them 

with extreme caution in any patient whose 

previous ocular history encompasses any of these 

conditions. 

The adverse reactions of Travoprost are 

similar to Latanoprost. 

Cholinergic drugs 

Cholinergic drugs, or parasympathomimetics, 

remain the oldest effective treatment for 

glaucoma. However, with the exception of their 

possible use in closed angle glaucoma, these 

agents have been superseded by the topical 

beta-blockers, CAIs, adrenergic agonists and PG 

analogues. This is due to their inherent, 

troublesome ocular adverse effects. 

Table 4 lists some of the various cholinergic 

agonists together with their dosages and 

duration of effects. 

Acetylcholine (ACh) is a neurotransmitter 

released from vesicles in nerve terminals and 

rapidly hydrolysed by the enzyme 

acetylcholinesterase. This allows the receptor to 

repolarise and prepare for subsequent 

stimulation. Cholinergic drugs may exert their 

actions by either stimulating the cholinergic 

receptors directly (agonists) or indirectly, by 

inhibiting the enzyme which breaks down ACh, 

acetylcholinesterase (cholinesterase inhibitors). 

Although the author has limited the 

discussion to the management of POAG, the fact 

that pilocarpine, the most frequently prescribed 

drug of its class, is more commonly utilised in 

the initial management of angle-closure 

glaucoma warrants a brief overview of such 

management. 

As long as the IOP is not so elevated as to 

render the pupillary sphincter ischaemic, 

cholinergic agents may allow aqueous humour to 

communicate freely with the outflow channels by 

pulling the peripheral iris away from the 

trabecular meshwork with a subsequent decrease 

in IOP. An important caveat to this mode of 

treatment is that pilocarpine has the capacity to 

precipitate angle-closure glaucoma, especially in 

eyes with shallow anterior chambers or 

spherophakia. The mechanisms underlying this 

unfortunate side effect are further anterior 

chamber shallowing (due to forward movement 

of the iris-lens diaphragm) and an increase in 

the anteroposterior diameter of the lens (due to 

contraction of the ciliary muscle). 

In POAG, the parasympathomimetics decrease 

IOP by increasing the facility of outflow. The 

mechanism by which this is achieved is thought 

to be due to the stimulated contraction of the 

longitudinal muscle of the ciliary body, thereby 

exerting traction on the scleral spur and 

trabecular meshwork. As a consequence, the 

trabecular sheets become separated thus 

enhancing aqueous outflow. 

28 

July 26, 2002 OT 

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Side effects 

a) Systemic 

The systemic side effects relate mainly to 

stimulation of the patient’s parasympathetic 

system and include increased sweating and 

salivation, bradycardia, diarrhoea and 

anxiety. The most serious systemic 

complication is ‘scoline apnoea’ associated 

with ecothiopate iodide. Patients succumbing 

to this grave complication are unable to 

respire normally following termination of 

general anaesthesia. Owing to this and the 

multitude of local adverse effects, this 

cholinesterase inhibitor is seldom used. 

b) Local 

To recapitulate, the local side effects negate 

the use of these agents as first line therapy 

against glaucoma. They include: 

• Miosis 

• Accommodative spasm 

• Iris cysts 

• Anterior subcapsular lens opacities 

• Angle-closure glaucoma 

• Retinal detachment 

• Increase in the permeability 

of the blood-aqueous barrier 

• Lacrimation 

All of the above ocular side effects are more 

pronounced with cholinesterase inhibitors. Since 

the permeability of the blood aqueous barrier is 

enhanced with these drugs, they should not 

under any circumstance be instilled in eyes 

suffering from glaucoma which has an 

inflammatory or neovascular aetiology. 

Carbonic anhydrase 

inhibitors (CAIs) 

Oral CAIs have been used to treat glaucoma for 

decades. Their serious side effects, such as 

metabolic acidosis and the potentially fatal 

haematological disorders (thrombocytopenia, 

agranulocytosis and aplastic anaemia), have 

resulted in the abrogation of such therapy for 

the treatment of chronic glaucoma. 

There are many forms of the enzyme carbonic 

anhydrase (CA) distributed throughout the 

human body and the eye is no exception. Indeed, 

CA is present in the corneal endothelium, 

crystalline lens and in the non-pigmented ciliary 

epithelium. 

The mechanism by which these drugs achieve 

their hypotensive effects is to reduce the 

formation of aqueous. This is achieved via 

their direct action on the ciliary epithelial 

isoenzyme. 

The two topical CAIs available – Dorzolamide 

2% (TRUSOPT) and Brinzolamide 1% – are less 

effective than Timolol in reducing IOP and, as a 

consequence, are reserved as adjunctive, rather 

than first line therapy 34 . The recommended 

monotherapeutic dosage is tds, whereas a bds 

regimen is suggested when used concomitantly 

with other hypotensive agents. The agents which 

can be employed concurrently with the topical 

CAIs will be discussed later. 


Side effects 

Although these drugs have not been associated 

with the serious systemic adverse effects 

observed in patients administering the oral 

counterpart, CNS effects have been recorded. 

These include taste perversion (especially with 

carbonated beverages) and nephrolithiasis 35 . 

The ocular side effects of these drugs are 

numerous and may mitigate against their use in 

a significant number of patients. These include 

conjunctival hyperaemia, allergic reactions, 

blepharitis and a burning/stinging sensation 

upon instillation 36-38 . The latter complaint is the 

most frequent ocular manifestation reported. 

Owing to the fact that CA exists in the 

corneal endothelium, concerns have been 

justifiably raised as to the implications which a 

topical CAI may have on corneal metabolism. 

Konowal and co workers 39 discovered that 

Dorzolamide can cause irreversible corneal 

oedema in glaucomatous patients with 

endothelial compromise (e.g. subclinical Fuchs’ 

dystrophy, post-surgical changes). Thus, it is 

incumbent on all practitioners to examine the 

patient’s corneae carefully before a decision to 

prescribe these agents is made. 

Adrenergic agonists 

Historically, adrenergic agonists have been used 

in the treatment of glaucoma and ocular 

hypertension since the early 20th century. The 

agonists currently available are – Adrenaline 

(Epinephrine) 0.5%, 1%, 2%, Dipivefrin 

(PROPINE) 0.1%, Apraclonidine (IOPIDINE) 0.5%, 

1%, and Brimonidine (ALPHAGAN-P, ALPHAGAN) 

0.15%, 0.2%. 

The adrenergic system consists of alpha1, 

alpha2, beta1 and beta2-r receptors. A decrease in 

aqueous production is mediated by the 

beta-adrenergic system while an increase 

in outflow facility is mediated by the 

alpha-adrenergic system. Intuitively, one would 

expect that non-selective adrenergic agonists, 

such as Adrenaline, would achieve their 

hypotensive effects through a combination of the 

aforementioned mechanisms. Although the exact 

mechanism is disputed, the most widely accepted 

hypothesis is that Adrenaline achieves its ocular 

hypotensive effects by increasing both 

conventional and unconventional outflows. 

Both Apraclonidine and Brimonidine are 

alpha2-agonists and lower IOP by decreasing 

aqueous formation. Interestingly, it appears that 

Brimonidine, which exhibits a higher degree of 

selectivity for the alpha2 receptor, also enhances 

uveoscleral outflow 40 . 

Since Brimonidine and Apraclonidine have 

supplanted both Adrenaline and its pro-drug, 

Dipivefrin, as the adrenergic agonist of choice in 

the treatment of glaucoma and ocular 

hypertension, the author will limit his discussion 

to the former two drug types. 

In view of the high allergy rate and 

tachyphylaxis associated with Apraclonidine, its 

use has been restricted to short-term therapy 

such as post-laser trabeculoplasty and YAG laser 

iridotomy. The rationale behind instilling the 

drug post-operatively is to reduce the risks of an 

acute rise in IOP. Brimonidine, on the other 

hand, has proved not only to be very efficacious 

as an adjunctive hypotensive agent (its effects 

are comparable to those achieved with Timolol) 

in long-term therapy, but it also possesses both 

an excellent safety profile and intrinsic 

neuroprotective properties. 

In March 2001, the FDA approved a 

reformulated Brimonidine – Alphagan-P. The 

concentration of Brimonidine in Alphagan-P is 

slightly lower than the original (0.15% 

compared to 0.2%). Furthermore, whereas the 

original formulation contains the preservative 

Benzalkonium chloride, the new formulation 

contains the proprietary preservative, Purite. 

The latter preservative is the same type used in 

the lubricant, Refresh tears. 

Both drugs appear equipotent in lowering 

IOP despite their disparate concentrations. 

Interestingly, the pH of the original lies between 

6.3 and 6.5 and is therefore relatively acidic. The 

pH range of Alphagan-P, on the other hand, is 

between 6.6 and 7.4. Thus, this solution errs 

more towards neutrality than its original 

counterpart. It is, therefore, reasonable to 

assume that the more neutral solution enhances 

bioavailability which, in turn, would allow the 

drug to exert effects comparable to its more 

concentrated cousin. 

Drugs administered at a lower concentration 

have the obvious advantage of reducing the 

likelihood of adverse effects. In addition, owing 

to the preservative used, a substantial reduction 

in the number of allergic reactions with 

Alphagan-P has been noted 41 . 

Side effects 

The side effects associated with Brimonidine are 

fairly unremarkable. The most common ocular 

manifestations include allergic conjunctivitis 

together with a low rate of burning upon 

instillation. The systemic side effects are also 

innocuous and include drowsiness, headache, 

dry mouth and high levels of fatigue. 

Concomitant and 

combination therapy 

Frequently, glaucoma patients with IOPs 

inadequately controlled with monotherapy have 

to administer more than one type of ocular 

hypotensive drug. This section describes the 

agents employed in clinical practice which work 

synergistically to provide an enhanced 

decrement in a patient’s IOP. 

The ocular hypotensive effects of the PG 

analogues may be augmented through the 

concomitant use of numerous anti-glaucoma 

agents. In their retrospective analysis of 73 eyes 

of 73 patients with glaucoma and inadequate 

IOP control on Latanoprost alone, O’Connor et 

al 42 revealed that the greatest additional 

hypotensive effects were observed when the 

patient received Dorzolamide bds (19.7%). 

Further decrements in IOP were also 

observed with the concomitant use of betablockers 

and Brimonidine (12.3% and 9.5% 

respectively). 

The PG analogues may themselves be added 

29

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to any ocular hypotensive drug with the 

exception of the cholinergic agonists, such as 

pilocarpine. Owing to the contraction of 

longitudinal muscle of the ciliary body, the 

intercellular junctions on the body’s face tighten 

with the net effect of reducing uveoscleral 

outflow. Thus, mechanistically, these agents 

antagonise the PG analogues whose therapeutic 

mode of action is to increase uveoscleral 

outflow. 

To date, numerous studies have shown 

Brimonidine to be a very effective adjunctive 

agent. Indeed, when employed concurrently to 

beta-blockers, Brimonidine demonstrated 

significant additional decrements in IOP 43 . 

Moreover, these effects appeared superior to 

those achieved when a topical CAI was 

administered concurrently to the same 

adrenergic antagonists. A recent randomised 

controlled trial comparing the efficacy of 

Brimonidine bds, and Latanoprost od, as 

adjunctive therapy in the management of poorly 

controlled glaucomatous patients on 

beta-blocker monotherapy, found no statistical 

difference in achieving the investigators’ target 

of a further 15% reduction in IOP 44 . 

Furthermore, the authors were astute to point 

out that despite such therapeutic parity, adverse 

effects associated with both types of drugs 

(watery eyes, cold hands and feet) were 

significantly higher following administration of 

Latanoprost. 

The fact that in one large scale study 45 , 

Brimonidine induced a further mean reduction 

in IOP of 20.3% when added to Latanoprost is 

testimony to its effectiveness as an adjunctive 

agent. An additional 18.9% reduction was 

observed when Brimonidine was introduced to a 

pre-existing concomitant regimen of 

Latanoprost and a non-selective 

beta-blocker. 

Interestingly, there have been conflicting 

results regarding the additional therapeutic 

efficacy when the docosanoid, Unoprostone 

isopropyl 0.12% is administered with 

Latanoprost 0.005%. The results collated by 

Stewart et al 25 seem to demonstrate a positive 

beneficial effect, whereas Aung et al 46 only 

noted such favourable results when Latanoprost 

was added to a pre-existing monotherapeutic 

regimen of Unoprostone bds. When Unoprostone 

was introduced to eyes which were hitherto 

treated with Latanoprost alone, no further IOP 

lowering was observed. However, Saito and 

co-workers 47 found no net increase in 

hypotensive potency with the same combination 

irrespective of the prior monotherapeutic 

regimen. 

Topical beta-blockers are an effective adjunct 

to the other hypotensive agents with the 

exception of the sympathomimetics. However, as 

mentioned previously, their ability to sustain 

their IOP lowering effects may diminish with 

time in a significant proportion of patients. 

Thus, together with the introduction of newer 

drugs with their superior safety profile, their 

future use as an adjunct may be somewhat 

limited. 

Combination drugs 

Combining two therapeutic agents into one 

preparation has, potentially, many advantages. 

An enhanced ameliorative effect with a reduced 

dosage not only would reduce the risk of side 

effects but should also improve patient 

compliance. 

The Dorzolamide 2%/Timolol 0.5% 

(CAI/beta-blocker) combination (COSOPT) 

instilled bds appears to be similar in efficacy to 

the concomitant administration of the 

components bds 48 . Another study seemed to 

show the combination to be superior in lowering 

IOP compared with its individual components 49 . 

Another combination agent containing 

Latanoprost 0.005% and Timolol 0.5% (Xalocam) 

instilled once daily has been shown to reduce 

IOP effectively in patients with either ocular 

hypertension or glaucoma, but only 

demonstrated a modest degree of superiority 

over od dosing of Latanoprost alone 

(1-1.2mmHg) and Timolol bds alone (1.9mmHg) 50 . 

Case histories 

The previous article in this CPD module 

concentrated on case histories in which patients 

were either unable to tolerate medical therapy 

or where such therapy failed to control their 

ocular malady. The following case histories, in 

general, illustrate the factors to be considered 

when deciding to initiate the appropriate 

medical therapy. 

Case 1 

Patient details 

• Male, caucasian, aged 45 years 

• Occupation – long distance HGV driver 

• General health – good, no medication being 

taken, pulse regular, 60 beats/min 

• Diagnosis – POAG. Baseline IOPs – 

R 26mmHg, L 27mmHg 

• Previous ocular history – unremarkable 

Discussion 

As the patient’s general health was good and his 

pulse was regular, most of the topical 

hypotensive agents could be considered. In view 

of their effectiveness at lowering IOPs and low 

cost, beta-blockers prescribed od might be 

considered first. The only hypotensive agents 

which would be definitely contraindicated are 

the miotics, since the miosis associated with 

such agents would severely restrict his field of 

view and, as such, would be detrimental to his 

occupation. 

Case 2 


• Female, caucasian, aged 65 years 

• Occupation – retired 

• General health – good. No medication being 

taken. Pulse regular – 70 beats/min 

• Ocular history – unilateral POAG (R eye). 

Baseline IOPs – R 27mmHg, L 15mmHg. 

Also had early central, bilateral posterior 

subcapsular lens opacities 

Discussion 

Since this patient had unilateral glaucoma, a PG 

analogue would be a relative contraindication 

due to iris colour changes (a cosmetic concern) 

and the potential to induce unilateral 

hypertrichosis (again, a cosmetic concern). 

Miotics would also be contraindicated due to her 

pre-existing lens opacities. 

As with Case 1, beta-blockers would probably 

be the first drug of choice due to their 

effectiveness and low cost. The drug would be 

initially prescribed od and the patient 

reassessed approximately six to eight weeks 

later. (Note: such reassessment time-scale 

periods represent an ideal. However, the author 

is aware that this may be impractical in many 

glaucoma clinics owing to the overwhelming 

number of patients seen. Thus, the reassessment 

period may be longer, say three months.) 

Case 3 


• Male, caucasian, aged 50 years 

• Occupation – teacher 

• General health – ankylosing spondylitis 

(diagnosed five years). Taking Diclofenac 

Sodium. Asthmatic, taking Salbutamol and 

Fluticasone propionate 

• Ocular history – POAG. Baseline IOPs 

– R 25mmHg, L 26mmHg. Since he was 

diagnosed as suffering from ankylosing 

spondylitis, he developed three bouts of 

anterior uveitis in his right eye and two 

bouts in his left eye 

Discussion 

Due to the patient’s asthma, beta-blockers were 

contraindicated. Furthermore, the fact that he 

had a previous history of anterior uveitis 

associated with ankylosing spondylitis negated 

the use of PG analogues. The optimum 

monotherapeutic drug of choice would be 

Brimonidine bds. Ideally, the lesser 

concentrated, purite form would be prescribed 

(if available) since it is associated with less local 

side effects. 

Case 4 


• Female, Asian, aged 65 years 


• General health – good. No medication being 

taken. Pulse regular – 68 beats/min 

• Ocular history – diagnosed bilateral POAG six 

months previously. Initial, baseline IOPs 

were R 32mmHg, L 30mmHg 

Discussion 

This patient was initially prescribed Timolol 

0.50% bds (due to dark irides and initial high 

IOPs). She was reassessed three months later. 

IOPs were R 24mmHg and L 23mmHg. In 

addition, visual fields were repeated and there 

appeared to be a slight deterioration in both 

fields. The ophthalmologist added Latanoprost 

0.005% od, OU in the evening. The patient was 

30 

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reviewed six weeks later and the IOPs recorded 

were R 19mmHg and L 17mmHg. Moreover, visual 

fields were repeated and there was no overt 

difference from the plots recorded at her 

previous visit. 

Although other adjunctive agents could have 

been used, it is always prudent to add an agent 

which has the least dosage regimen (i.e. od) as 

the greater dosages correlate negatively with 

compliance. Since the PG analogues fit into this 

category, they were the initial adjunct of choice 

for this patient. 

Case 5 


• Female, Afro-Caribbean, aged 70 years 


• General health – supraventricular tachycardia 

controlled with Quinidine. 

Hypercholesterolaemia controlled with 

Simvastatin 

• Ocular history – POAG OU. Initial baseline 

IOPs – R 27mmHg, L 29mmHg. Diagnosed 

with Fuchs’ dystrophy 10 years previously 

Discussion 

Due to her co-existing endothelial changes, 

topical CAIs should not be employed in the 

hypotensive regimen. In addition, topical 

beta-blockers were also contraindicated as 

Quinidine may enhance the beta-blockade. 

Since PG analogues remain the most effective 

monotherapeutic hypotensive agent with the 

simplest dosage regime, they should be 

considered as the first line therapy in this case. 

Moreover, since several studies have 

demonstrated Travoprost to possess greater 

hypotensive qualities in patients of 

Afro-Caribbean descent, it would seem 

reasonable to consider this agent first. 

Conclusion 

This article has outlined the agents which 

encompass the mainstay of glaucoma treatment 

to date. Owing to the chronicity of the disease 

and relative lack of symptoms, it is essential that 

the practitioner reinforces the importance of 

complying with the therapy initiated. Finally, the 

decision to prescribe a particular topical agent 

must not be made without prior knowledge of 

the patient’s medical status or level of 

independence. 

About the author 

Greg Heath is an optometrist working part-time 

in private practice. He is currently reading 

medicine at the Royal Free and University College 

London Medical School. 

Abbreviations 

Od – daily; bds – twice daily; tds – three times 

daily; qds – four times daily; OD – right eye; OS 

– left eye; OU – both eyes. 

References 

For a full set of references, please fax 

01252-816176 or email nicky@optometry.co.uk. 


Multiple choice questions 

Ocular therapeutic case studies 

- Medical management of glaucoma 

Please note there is only one correct answer 

1. Which one of the following agents lowers 

IOP by reducing aqueous production? 

a. Travoprost 

b. Pilocarpine 

c. Unoprostone 

d. Dorzolamide 

2. Which one of the following statements 

regarding pilocarpine is true? 

a. It is a sympathomimetic 

b. It is the mainstay of glaucoma treatment 

c. It can be used safely on all patients with 

narrow anterior chamber angles 

d. It can be employed in the treatment of both 

POAG and PCAG (closed angle glaucoma) 


concerning Betaxolol is true? 

a. It possesses intrinsic sympathomimetic 

activity 

b. It can be administered safely in all patients 

with chronic obstructive airways disease 

c. It may increase retinal blood flow 

d. It is usually prescribed od 

4. Which one of the following is ineffective 

when used as POAG monotherapy? 

a. Brimonidine 

b. Unoprostone 

c. Latanoprost 

d. Timolol 

5. Which one of the following is not a potential 

side effect of PG analogues? 

a. Uveitis 

b. Cystoid macular oedema 

c. Trichiasis 

d. Conjunctival hyperaemia 

6. Which one of the following statements is 

true of medical therapy for primary open 

angle glaucoma? 

a. It is associated with high long-term costs 

b. It is associated with no serious side effects 

c. It is the most efficacious method of 

lowering IOP 

d. It is less hassle than surgery for the patient 

7. For a patient who is a healthy 65-year old 

male with IOPs of R 15mmHg, L 25mmHg, 

which one of the following would be the 

most likely initial therapy? 

a. Timolol od, OU 

b. Latanoprost od, OD 

c. Dorzolamide tds, OU 

d. Levobunolol od, OS 

8. Which of the following are 

not suitable adjuncts? 

a. Timolol and Latanoprost 

b. Pilocarpine and Travoprost 

c. Dorzolamide and Levobunolol 

d. Brimonidine and Latanoprost 

9. A 60-year old healthy male pseudophake 

presents with IOPs of R 31mmHg, 

L 30mmHg. Which one of the following is 

the least likely to be prescribed? 

a. Timolol od 

b. Brimonidine bds 

c. Brinzolamide tds 

d. Travoprost od 

10. A patient is taking adjunctive therapy for 

her POAG. Although her IOPs are well 

controlled, she complains of a dry mouth. 

Which one of the following drugs is the 

most likely culprit? 

a. Levobunolol 

b. Pilocarpine 

c. Brimonidine 

d. Unoprostone 

11. Which of the following statements 

regarding beta-blockers is true? 

a. They are the most efficacious 

hypotensive agent 

b. They are the adjunctive agent 

of choice 

c. They can be administered safely 

in patients suffering from bradycardia 

d. They can be administered safely 

in patients with Fuchs’ dystrophy 


is true regarding POAG patients’ 

compliance to medical therapy? 

a. It is unrelated to the patient’s age 

b. It is influenced by the patient’s 

lifestyle 

c. It is unrelated to the patient’s systemic 

status 

d. It is unrelated to the patient’s 

occupation 

An answer return form is included in this issue. It should be completed and 

returned to: CPD Initiatives (c4082i), OT, Victoria House, 

178–180 Fleet Road, Fleet, Hampshire, GU51 4DA by September 4, 2002. 

31

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