Goals of Therapy

The goals of therapy for patients with glaucoma are to: Prevent or slow down the progressive visual loss without causing unwanted side effects (1). Preserve the structure and the normal function of the optic nerve (1). Eliminate any pain that is present and improve vision in the acute forms (1). A target IOP range should be established for each patient, and this will be based on a risk assessment for the individual and set at the level below which further optic nerve damage is unlikely to occur (3). The initial goal of treatment is to reduce IOP by 20-40%, but in cases where there is evidence of severe optic nerve damage, or other adverse risk factors, a reduction of >40% may be targeted (3).

Etiology and Pathophysiology of Open Angle Glaucoma

Before, it was thought that an increased in IOP was the sole cause of glaucomatous optic neuropathy, however now it is recognized that IOP is only one of the many factors that contribute to the development and progression of glaucoma (1). Other factors include increased susceptibility of the optic nerve to ischemia, a reduced or dysregulated blood flow, autoimmune reactions and other abnormal physiology responses (1). The final outcome of all these processes is believed to be the apotosis of the retinal ganglion cells (1). This results in axonal degeneration and eventually permanent loss of vision (1). The increased likelihood of vision loss at a given IOP varies patient to patient (1). Some patients that do have high IOPs do not demonstrate damage, whereas other patients have progressive visual field loss despite having an IOP that is within the normal range (10 mm Hg to 21 mm Hg) (1). IOP is seen as a poor indicator of having visual field loss (1). However, an increase in IOP increases the risk of visual field loss within any range (1). Recent studies have demonstrated that lowering IOP, for any pretreatment IOP, will reduce the risk of glaucomatous progression and it may even prevent the onset to early glaucoma in patients that have ocular hypertension (1). It seems to be that multiple mechanisms are likely to result in a spectrum of combinations to produce the death of retinal ganglion cells and their axons in glaucoma (1). Pressure-sensitive astrocytes and other cells that are in the optic disk supportive matrix may remodel the disk and produce changes which may result in axonal death (1). Another possible mechanism may be from insufficient blood flow to the retina secondary to the increased perfusion pressure required in the eye, resulting in optic nerve damage (1).

The optic nerve damage in primarily open angle glaucoma can occur at a wide range of intraocular pressures (1,3). The rate of the progression is highly variable and dependent on the individual patient (1,3). Patients may have pressures in the 20 to 30 mm Hg range for many years before disease progression is noticed in the visual fields or the optic disk (1,3). For this reason, open angle glaucoma is referred to as the sneak thief of sight (1). Under normal circumstances, the iris and ciliary body secretes aqueous humor that flows from the posterior chamber to the anterior chamber of the eye (3). The trabecular meshwork is the exit point for this aqueous humor and around 80% of the aqueous humor is drained through this trabecular outflow before reaching the venous system (1,3). The uveoscleral pathway is responsible for the drainage of the remaining 20% of the aqueous humor (1,3). The aqueous humor exists the anterior chamber through the spaces between the ciliary muscles and is drained into the suprachoriodal space (1,3). When a patient has open angle glaucoma, the trabecular and uveoscleral outflow becomes hinder and the aqueous humor cannot be drained from the eye, resulting in an increase in IOP (1,3).


Glaucoma can be classified by the anatomy of the anterior chamber angle, which could be open or closed (1).

Primary angle glaucoma

The most common form of glaucoma is primary open-angle glaucoma (1,3). This occurs when there is an increased resistance to the outflow of the aqueous humor through the trabecular meshwork (1,3). This leads to a gradual and painless elevation of IOP (1). Therefore, it is usually asymptomatic (1,3). Primary open-angle glaucoma is usually bilateral but it could be asymptomatic (1). The prolonged asymptomatic phase of primary open angle glaucoma can only be discovered by ocular evaluation, so therefore it is important to have a complete eye examination every 2 to 4 years for patients older than 40 years of age and every one to 2 years for patients that are older than 65 years of age (1,3).

Secondary open angle glaucoma

Secondary open angle glaucoma stems from ocular or systemic disorders that lead to a decreased outflow through the trabecular meshwork (1,3). An example would be chronic use of glucococorticosteroids (1,3). This can create resistant to the trabecular outflow and result in IOP elevation (1,3).

Primary angle closure glaucoma

Primary angle closure glaucoma may result in an acute, subacute, intermittent or chronic presentation (1). When attacks of this type of glaucoma occur, these are considered to be ocular emergencies as they can lead to irreversible vision loss within hours (1,3). A major risk factor for this type of glaucoma is narrow anterior chamber angles (1,3). If the papillary margin of the iris touches the lens for 360 degrees, then the flow of the aqueous humor from the posterior to the anterior chamber may be blocked (1,3). As a result of the aqueous humor being trapped behind the iris due to the papillary block, the peripheral iris may be pushed anteriorly into apposition with the trabecular meshwork (1,3). This will obstruct the outflow and the IOP may rise rapidly to greater than 60 mm Hg (1,3).

Secondary angle closure glaucoma

Scarring and adhesions between the peripheral iris and the anterior chamber angle may result in the block of the outflow of the aqueous (1,3). In many causes, high IOP that is greater than 40 mm HG may result in optic nerve damage (1,3). Very high IOP that is greater than 60 mm Hg may result in permanent loss of visual field within a matter of hours to days (1,3)


The overall prognosis for primary open angle glaucoma is excellent when it is discovered early and treated adequately (1). Patients that have advanced visual field loss can have continued visual field loss reduced if the IOP is maintained at low pressures (Less than 10 to 12 mm Hg) (1). However, there is still progression of visual field loss in 8% to 20% of patients despite reaching standard therapy IOP goals (1). In untreated patients and those who fail to achieve target IOP reduction, up to 80% have continued visual field loss (1).

Signs and Symptoms

Primary angle glaucoma is usually asymptomatic until advanced visual field loss is noticeable (1,3). In advanced cases of the disease, visual acuity may be reduced (1,3). There may be symptomatic visual field defects in advanced disease (1). Tunnel vision may develop at the terminal stage as peripheral vision is lost (1,3). It is usually bilateral, but vision loss may initially affect on eye only (1,3). Intermittent or chronic angle glaucoma can be free of symptoms (1). The symptoms of secondary glaucoma are usually linked to the underlying cause (1). Usually, primary open angle glaucoma is typically found in patients older than 50 years of age (1). It is a slowly progressive disease (1). Disk changes and visual field loss may be present and IOP can be normal or elevated (> 21 mm Hg) (1).

Closed angle glaucoma is typically associated with symptomatic acute episodes (1). Furthermore, in closed angle glaucoma, symptoms such as blurred or hazy vision with halos around lights due to a hazy edematous cornea may be present (1). Acute episodes produce symptoms that are associated with a cloudy, edematous cornea, ocular pain or discomfort, nausea and vomiting (1). IOP is typically elevated significantly (40 to 90 mm Hg) when symptoms are present (1).

Risk Factors

Open Angle Glaucoma (1) Acquired, Primary (1) Elevated IOP Advanced age Positive family history Myopia Migraine hypertension or nocturnal hypotension

Acquired, Secondary

Blunt or penetrating trauma Previous intraocular surgery or inflammation Corticosteroid Use (Ophthalmic, systemic, nasal or inhaled) Congenital Positive family history

Non Pharmacological Treatment

There are no proven lifestyle changes that can be undertaken to improve the outcome of the disease (2). However, aerobic exercise can lower IOP in a modest amount in some patients that do have glaucoma (2).

Pharmacological Treatment

Patients that have risk factors in addition to elevated IOP may require treatment even if they do not have glaucomatous optic disc and visual field damage (1,2,3). Otherwise, all patients that have an elevated IOP and characteristic disk changes and or visual field defects that are not caused by other factors should be treated (1). Patients that have open-angle glaucoma at normal pressure should further lower their IOP as this would prove to be beneficial (1).

Pharmacological treatment of patients that have glaucomatous change with either elevated or normal IOP is initiated in a stepwise manner, beginning with lower concentrations a single well tolerated topical agent (1). The goal of this therapy is to prevent further visual loss (1). A target IOP is chosen based on a patient baseline IOP and these are specific for the patient (1,2). It is based on the amount of existing visual field loss, the extent of glaucomatous damage, and the IOP range that is believed to be associated with that damage (2,3). Typically an initial target of 30% reduction in IOP is used (3). Greater reductions may be used in patients that have a very high baseline IOP or advanced visual field loss (1). Patients that have a normal baseline IOP may have a target IOP of less than 10 to 12 mm Hg (1).

First Line Agents

Beta blockers are first line agents for the treatment of open angle glaucoma (2). Topical timolol, levobunolol and betaxolol are ocular hypotensive agents that are highly effective and they lack significant ocular side effects (2). These decrease IOP by inhibiting the formation of the aqueous humor (2). These are contraindicated in those with pulmonary diseases (2). Betaxolol hydrochloride is relatively selective for the beta1 receptor and it could be used in caution in patients with mild obstructive pulmonary disease (2).

If the patient is contraindicated to the first line beta blockers, prostaglandins or brimonidine is used instead (2). These are alternative first line agents (2). Prostaglandin analogues like latanoprost and travoprost are used to lower IOP by increasing the outflow through the uveoscleral pathway (2). These are slightly more efficacious than the nonselective beta-blockers (2). There have not been any significant side effects from clinical experience, but there have been ocular effects that include darkening of some brown coloured irides, lengthening of eyelashes and mild conjunctivial hyperemia (2). Nonetheless, the safety profile is quite excellent (2).

Brimonidine is an alpha 2 adrenergic agonist and helps suppress the formation of the aqueous humor (2). It may also increase uveoscleral outflow (2). However, there is a significant incidence of allergy while taking this medication (2). A new formulation of brimonidine that uses purite instead of benzalkonium chloride may lower the rate of ocular allergy (2).

The patient’s response to the selected therapy should be assessed in 2-4 weeks (1). If there is inadequate response, it is important to ensure compliance (1). If possible, the concentration or the frequency of dose can be increased (1). Other possibilities include switching to an alternative first line agent, or adding a second first line agent if only partial response is achieved (1). If there is intolerance, then the concentration should be reduced if possible (1). Formulation change, or switching to a different class alternative or alternative first line agents are possibilities in dealing with intolerance (1).

The patient’s response should be assessed again in another 2 to 4 weeks (1). If there is partial response, a second or third first line agent or topical CAI (multidrug regimens containing 2-4 agents may be required) (1).

Dorzolamide and brinzolamide are the two available agents that are available in this class (2). These decrease IOP by inhibiting an enzyme that is needed for the formation of the aqueous humor. Both have limited effects when compared to the systemic effects of oral formulations, but they do not lower the IOP to the same extent (2). These drugs are often used as adjunctive therapy or for primary treatment in patients that have cardiopulmonary contraindications to beta blockers (2).

The patient should be assessed again in another 2 to 4 weeks (1). If there is inadequate response to first and second line topical combination therapy, a direct acting cholinergic agent (4th line) could be added (1). An oral carbonic anhydrase inhibitor could be added in place of the topical carbonic anhydrase inhibitor (1). Multiple topical therapies plus an oral carbonic anhydrase inhibitor may be needed (1).

Cholinergic agonists

Pilocarpine and carbachol are cholinergic agonists that are used topically to directly stimulate muscarinic receptors to contract the ciliary muscle and increase the trabecular outflow (2). These drugs have ocular side effects like miosis with reduced night vision, accommodative spam (including myopia), brow ache and very rarely, retinal detachment (2). These drugs are poorly tolerated in children and also in young adults (2).

Oral Carbonic anhydrase inhibitors

Acetazolamide and methazolamide both lower the IOP by decreasing the production of aqueous humor (2). This is used for emergencies because of significant side effects (2). About 50% of the people who are on this drug cannot use these agents long term because of GI or CNS difficulties, or renal lithiasis (2). Oral and topical carbonic anhydrase inhibitors may exhibit cross-reactivity in patients allergic to sulfonamides (2).

The patient should then be assessed for another 2-4 weeks (1). If the patient is intolerant or has exhibited inadequate response to the maximally tolerated combination drug therapy, laser or surgical procedure is required (1). Laser trabeculoplasty is used and it is used to improve outflow (1). This creates a channel through which the aqueous humor can flow from the anterior chamber to the subconjunctival space (1). This will then be reabsorbed by the vasculature (1). This procedure could fail due to inadequate healing and scarring of the site (1).


  1. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2007. p. 1551-1563.
  2. Gray J, editor. Therapeutic Choices. 5th edition. Ottawa: Canadian Pharmacists Association; 2007. p. 285-295.
  3. Bope ET, Rakel RE, Kellerman R. Conn’s Current Therapy 2010. 1st ed. Philadelphia: Saunders Elsevier; 2010 [cited 2010 Nov 21]. Available from: MDConsult


This information is presented for informational purposes only and is not meant to be a substitute for advice provided by qualified health care professionals. You should contact your qualified health care provider if you have or suspect any health problems. This article is not intended to provide medical advice for its readers

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