eMedicine Specialties > Ophthalmology > Intraocular Pressure

Glaucoma, Primary Open Angle: Treatment & Medication

Author: Jerald A Bell, MD, Staff Physician, Department of Ophthalmology, Billings Clinic; Glaucoma Director, Leadership Council Member, Physician Advocate for Personal Service Excellence Committee
Contributor Information and Disclosures

Updated: Nov 10, 2008

Treatment

Medical Care

• Major drug classes for medical treatment of POAG include the following:
  • Alpha-agonists
  • Beta-blockers
  • Carbonic anhydrase inhibitors
  • Miotic agents
  • Prostaglandin analogs
• Basic science research continues on other possible pharmacologic sites of action, including nitric oxide and cannabinoid pathways, although no topical product has been evaluated in US FDA trials of yet.
• Medical marijuana is not indicated for glaucoma treatment, as marijuana lowers IOP minimally and its duration of action is very short.  In the future, topical derivatives that affect cannabinoid M receptors governing aqueous dynamics may be effective, but this is still under early investigation.
  • The other drug classes mentioned above have much more documented duration of action and efficacy without the systemic cannabinoid adverse effects.  Furthermore, other options to treat ocular pain from end-stage glaucoma have arisen (eg, trans-scleral or endoscopic cyclophotocoagulation, absolute alcohol [ethanol] or chlorpromazine retrobulbar injections), which directly and more effectively alleviate the problem than in the past when marijuana was used for eye pain from end-stage glaucoma.⁹    
  • Legal justification of glaucoma as an indication for systemic medical marijuana use is scientifically and medically improper, as well as unethical; education of the public and legislators is needed on this subject. 
• Some physicians incorrectly treat all elevated IOPs over 21 mm Hg with the above topical medications. Other physicians do not treat unless evidence of optic nerve damage exists, although nerve fiber layer loss of up to 40% may occur before visual field defects occur, so do not treat based on visual field testing alone. Most physicians select and treat those patients thought to be at greatest risk for POAG damage and/or progression (most common approach). See History for a list of risk factors for glaucomatous field loss.
• In any case, the goal of treatment is reduction of the pressure before it causes progressive loss of vision. Considering the high average monthly cost of glaucoma medication, along with the possible risks of adverse effects or toxic reactions from drugs, inconvenience of use, and incidence of noncompliance, a strong reason not to treat indiscriminately exists.
• Several questions should be asked when considering treatment, to include the following: Is the elevated pressure significant? Will this patient develop visual loss if left untreated? Is the treatment worth the risk of adverse effects of the medications?
• One should consider treatment more strongly if the patient reliability or the consequences of missing field loss is an issue (eg, poor reliability on visual field examination, 1-eyed patient, poor availability for follow-up care, younger patient, patient whose optic nerve is difficult to visualize, history of vascular occlusion).
• Treatment is highly recommended if signs of damage consistent with glaucomatous optic neuropathy (eg, disc hemorrhage; visible nerve fiber layer defects; notching or vertical ovalization of the cup; asymmetric cupping, especially if >0.7) are observed.
• Progressive cupping, even in the absence of visual field loss, can be glaucoma and should be treated as such, although systemic and neurologic workup/correlation for other disorders, including possible neuroimaging studies, should be considered, particularly if there are other nonophthalmologic symptoms.
• Otherwise, it depends on the assessment of risk factors and benefit of therapy to the patient, as to whether therapy should be initiated.
• Discussion with the patient about the pros and cons of treatment versus observation should be completed. Individualization of therapy is the key; an ideal pressure in one patient may cause glaucomatous damage in another patient. Risk factors, systemic conditions, life expectancy of the patient, quality of life issues, and the patient's desire for therapy should be weighed when considering treatment.
• Due to the high risk of optic nerve damage, most ophthalmologists treat if pressures are consistently above 28-30 mm Hg. If treatment is based on a high IOP only, then it should be ensured that the risks of treatment do not exceed the risk of the disease.
• Other reasons to treat include such symptoms as halos, blurred vision, or pain, or recent elevation of IOP, with continuing elevation on successive visits.
• Initiation of a monocular trial (see Medication) may be useful in helping to decide whether or not to treat (ie, if the medication is effective in achieving good pressure reduction without adverse effects, which may argue in favor of treatment, instead of just observation).
• Considering all of the above, no consensus exists on what is the appropriate medical treatment for preventing or delaying the damage due to POAG when a patient has only elevated IOP and no other signs of POAG. To date, no one has been able to define conclusively which subgroups will develop damage if left untreated, as opposed to those who will not sustain damage even if not treated.
• The question of medical therapy versus observation in patients with solely elevated IOP is being addressed in the OHTS, an ongoing multicenter randomized clinical trial.
  • The OHTS is a multicenter, prospective, randomized, controlled, clinical trial studying over 1600 subjects to evaluate the safety and efficacy of medical treatment in preventing or delaying onset of visual field loss and/or optic nerve damage in patients with OHT who are at moderate risk for developing POAG.
  • Their medical therapy goal for the treated group is stepped therapy to reduce IOP by at least 20% from the average baseline IOP with its treated absolute value of 24 mm Hg or less.
  • So far, their results show a 10% risk over 5 years of developing glaucoma in those patients with baseline IOP of 24-31 mm Hg. This risk was reduced to 5% with medical therapy.
  • The OHTS has also revealed the importance of pachymetry as a diagnostic tool as well as in the workup.
• Several sources agree on this initial goal of 20-25% reduction, while some specialists feel that more absolute numbers of less than 15 should be the goal of treatment. Keep in mind that the IOP goal must be set independently for each patient, depending on the risk factors, as an IOP level for one person with minimal risk factors may be far too high for a patient with multiple risk factors for sustaining glaucomatous damage.
• Other regimens have been suggested, as follows: for minimal risk factors, consider lowering IOP by 20-30%; if moderate number of risk factors are present, lower by 30-40%; and in cases of numerous risk factors with markedly elevated pressures, reduction in the 40-60% range may need to be achieved to prevent neuronal loss.
• If the patient is older than 65 years, consider treatment to keep IOP 25 mm Hg or less, secondary to 3% risk of vascular occlusion in OHT patients.
• In any case, the target IOP should be reevaluated periodically, and regular review of IOP trends should be performed to determine whether the patient is consistently maintaining that goal.
• Below is a suggested time guideline for therapy and follow-up based on initial IOP level. Adjust frequency of follow-up testing as needed based on the number of risk factors and clinical picture.
  • IOP 28 mm Hg or greater: Patients should be treated (see Medication), with follow-up care in 1 month to assess if treatment is effective and no adverse effects are present. If the goal is reached, then follow-up care should be performed every 3-4 months.
  • IOP 26-27 mm Hg: Follow-up care should be performed in 2-3 weeks to recheck pressure. If IOP is still within 3 mm Hg of the initial reading, then follow-up should be continued every 3-4 months with visual field and dilated optic nerve evaluation at least once a year. If IOP is lower, then a longer time should be considered between the pressure checks, making sure to recheck IOP at different times of the day on subsequent appointments.
  • IOP 22-25 mm Hg: Follow-up care should be performed 2-3 months later for recheck of IOP at different times of the day (ie, 8 am, 11 am, 1 pm, 4 pm). If it is still within 3 mm Hg of the initial reading at the second visit, then follow-up at 6 months with Humphrey visual field testing and dilated optic nerve evaluation, repeating it at least yearly.
• Other caveats concerning follow-up care are as follows:
  • If a new visual field defect becomes apparent on testing, confirmation with repeat (possibly multiple) examinations during future office visits should be performed, before using it as a basis for the treatment of presumed progression of POAG.
  • Gonioscopy should be performed at least once every 1-2 years if a significant increase in IOP occurs, or if miotic therapy is instituted.
  • Optic disc photos should be repeated after the initial examination if a change in disc appearance is noted (or every 1-2 years if available). 
    • Technologic and financial barriers, as well as increasing lack of trained ophthalmic staff, are making optic disc photos more difficult to obtain in many practices.
    • Whether nerve fiber layer imaging technologies (instead of recurring, serial optic disc photos) are sufficient for mainstream nontertiary ophthalmology practices is still under debate.
• Retinal tomography, ocular coherence tomography, and/or laser polarimetry should be measured at baseline and then every 1-2 years. Results should be correlated with visual field results, IOP measurements, and examination findings.
• See related CME at Glaucoma: Goals and Treatment Options.

Surgical Care

Surgery is indicated when glaucomatous optic neuropathy worsens (or is expected to worsen) at any given level of IOP and the patient is on maximum tolerated medical therapy (MTMT).

MTMT varies considerably between individuals, and it may consist of medicines from 1 or several classes (including a beta-adrenergic antagonist, a prostaglandin agent, an alpha-agonist, and a topical carbonic anhydrase inhibitor). Some patients are observed to progress simply because compliance with the medical regimen becomes too difficult because of the following: high drug costs, inability to remember the schedule of multiple medications, inability to instill them in the eyes properly secondary to arthritis or other incapacitation (especially common among elderly patients or those with other chronic systemic conditions), or intolerable ocular and systemic adverse effects.

A brief mention of surgical options is listed below. Detailed information on surgical procedures, indications, and postoperative care is beyond the scope of this chapter.

• Argon laser trabeculoplasty
  • Argon laser trabeculoplasty (ALT) uses a laser beam focused through a goniolens to treat at the border between anterior and posterior trabecular meshwork. A full treatment consists of 100 spots placed over the entire 360 degrees of the trabecular meshwork. This may be divided between 2 sessions consisting of 50 spots over 180 degrees.
  • Aqueous outflow improves after the procedure.
  • The specific mechanism of this improved outflow is unknown, but one hypothesis is up-regulation of trabecular endothelial cells.
  • IOP reduction obtained is usually in the 7-10 mm Hg range, and it may last up to 3-5 years following ALT.
  • Unfortunately, the decrease in IOP is not usually permanent. Approximately 10% of treated patients will return to pretreatment IOP for each year following treatment.
  • Complications include a brief, but potentially significant, increase in IOP after the procedure (therefore, alpha-agonists often are used either preoperatively or postoperatively for prophylaxis of this occurrence); transient iritis or corneal opacities; peripheral anterior synechiae; and hyphema.
  • ALT usually is pursued after MTMT has been reached, but it may be performed sooner in the treatment algorithm if pseudoexfoliation or pigmentary glaucoma is present, or if the patient is of black ethnicity, because laser therapy may be most effective in these individuals.
• Selective laser trabeculoplasty
  • Selective laser trabeculoplasty (SLT) uses a Q-switched 532 Nd:YAG laser to selectively target pigmented cells of the trabecular meshwork in a nonthermal manner, increasing fluid outflow and thereby lowering IOP.
  • The 3-nanosecond high-energy specific wavelength of light used induces the same cell replacement mechanism as traditional ALT but without the destructive burning and obliteration of structural support tissue in the meshwork. The short pulse of the laser does not allow time for heat to spread to other cells. SLT delivers just enough energy to the trabecular meshwork to target specific melanin-rich cells, without incurring collateral thermal damage and scarring to adjacent nonpigmented trabecular meshwork cells and underlying trabecular beams. When treated with SLT, a primarily biologic response is induced in the trabecular meshwork that involves the release of cytokines that trigger macrophage recruitment as well as other changes leading to IOP reduction.
  • The laser beam bypasses surrounding tissue leaving it undamaged by light. Unlike ALT, SLT can be repeated several times. Whereas patients treated with ALT can receive only 2 treatments in their lifetime, patients treated with SLT can receive 2 treatments a year.
  • SLT requires a specially designed laser, as follows:
    • A short pulse to allow for thermal relaxation
    • Precise wavelength for optimal melanin absorption
    • Sufficient energy to heat melanin to the point that it releases cytokines
    • Sufficient spot size to ensure full coverage at the trabecular meshwork
• Trabeculectomy
  • Trabeculectomy surgery usually is performed after MTMT and ALT have failed to control IOP adequately. If IOP is so high that ALT and SLT are likely to be ineffective in reaching target IOP, then proceeding from MTMT to penetrating surgery may be indicated.
  • A superficial flap of sclera is dissected anteriorly to the trabecular meshwork, and a section of trabecular meshwork is removed underneath the flap.
  • This alternate outflow pathway is created to increase passage of aqueous from the anterior chamber to the subconjunctival space, creating a filtering bleb and, thereby, lowering IOP.
  • Either releasable sutures or laser suture-lysis may be used to control aqueous drainage and corresponding IOP postoperative. Alternatively, to maximize surgical success, antimetabolites (eg, 5-fluorouracil, mitomycin C) may be applied during or after surgery to decrease fibroblast proliferation and scar formation.
  • Risks and complications of filtering surgery include the following: hypotony, blebitis/endophthalmitis, hyphema, suprachoroidal hemorrhage or effusions, encapsulation of the bleb with resultant transient IOP elevation, loss of 1 or more lines of visual acuity, and increased risk of cataract formation.
  • With the risk of severe complications from trabeculectomy and the need for frequent postoperative follow-up care (ie, usually weekly for 2 months, initially), some patients with transportation, financial, or long-distance issues concerning postoperative follow-up care may be better served by tube shunt surgery instead. See the Tube versus Trabeculectomy Study below.  
• Drainage implant (ie, seton/tube/shunt) surgery
  • Generally, this procedure is performed after multiple attempts at successful trabeculectomy have failed.
  • A tube is placed in the anterior chamber to shunt aqueous to an equatorial reservoir, and then posteriorly to be absorbed in the subconjunctival space.
  • Types of implants include Molteno, Baerveldt, Ahmed, and Krupin.
    • Most shunts function by allowing passive drainage of aqueous from the anterior chamber.
    • The Molteno implant consists of a silicone drainage tube, which is connected to 1 or 2 acrylic plates that are sutured to the sclera.
    • The Baerveldt implant is available with larger plates with increased reservoir size. The seton (tube) connected to the reservoir usually is tied off with an absorbable suture, allowing flow to initiate 4-6 weeks postoperative once some conjunctival wound remodeling has taken place, thereby reducing the risk of immediate postoperative hypotony.
    • The Ahmed and Krupin implants have 1-way valves, which are designed to maintain pressure above 8 mm Hg. These implants may reduce the risk of hypotony, a complication of nonvalved shunts in the early postoperative period.
  • Because of less numerous postoperative visits, tube shunts may be indicated as primary surgery when patients are unable to come as frequently for follow-up care (because of transportation, financial, or long-distance issues). This can be a particular concern in rural areas that cover large distances.
  • A valved shunt may also be indicated as primary surgery if a patient has a strenuous job or other activities that require strenuous exertion. Severe exertion may cause a significant Valsalva maneuver, significantly increasing venous pressure postoperatively, which could result in a delayed suprachoroidal hemorrhage and possible severe loss of vision.
  • The Tube versus Trabeculectomy Study has been undertaken to see if glaucoma tube shunt surgery may actually be a viable first-line alternative to (or even surpass) trabeculectomy surgery.^10,11  Some training programs have removed trabeculectomy training from their residency program curricula, with only fellows performing trabeculectomy (not a general trend).
  • One-year data have shown nonvalved tube shunt surgery was more likely to maintain IOP control and to avoid persistent hypotony or reoperation for glaucoma than trabeculectomy at 1 year, although both procedures produced similar IOP reduction.
  • Less supplemental medical therapy has been needed so far in the trabeculectomy group.
  • The incidence of postoperative complications at 1 year was higher in the trabeculectomy group.
  • Serious complications resulting in reoperation and/or vision loss occurred with similar frequency in both groups at 1 year.
• Ciliary body ablation
  • Postoperative pain and inflammation are common complaints. Loss of 1 or more lines of visual acuity has been reported. Phthisis is a concern after this procedure, although it has not been reported as of yet after the diode laser method of cycloablation.
  • This procedure is indicated as a last resort for patients who have failed medical management and other surgeries or for those patients who have limited visual potential (often 20/200 or less).
  • By destroying a portion of the nonpigmented ciliary epithelium, aqueous humor production is limited.
  • The ciliary body epithelium can be destroyed by cyclocryotherapy, diathermy, ultrasound, transscleral Nd:YAG or diode laser (known as cyclophotocoagulation), or a newer endoscopic laser (EndoOptiks, Inc).¹²   

• Newer techniques
  • Deep sclerectomy/viscocanalostomy/with or without collagen implant – This is probably not as effective as trabeculectomy and is technically more difficult, but it is associated with less complications.
  • 360-degree suture canaloplasty (iScience) – This is a useful alternative in infants (with congenital glaucoma or juvenile glaucoma) to trabeculotomy. In adults, suture under tension left in the Schlemm canal to further open the trabecular meshwork (similar mechanism to miotics).
• New devices
  • ExPress shunt (Optonol)
    • Erosion problems if used without scleral flap
    • Now mainly used underneath trabeculectomy flap to better regulate flow through sclerostomy
    • Easy to learn, appears effective, and otherwise has low complication rate
    • Awaiting long-term trials
    • May be especially useful for the ophthalmologist who only occasionally does glaucoma surgery
  • iStent (Glaukos)
    • Shunt device from the anterior chamber into the Schlemm canal
    • Internal placement approach
    • May need multiple devices placed
    • Still undergoing continuing research
  • Eyepass
    • Shunt device from the anterior chamber into the Schlemm canal
    • External placement approach
    • Inactive technology
    • Poor long-term IOP control
  • Solx gold suprachoroidal space microshunt (OccuLogix)
    • Shunts fluid from the anterior chamber into the suprachoroidal space via gold microchannels
    • External placement approach
    • Possibly titratable effect with titanium-sapphire laser to modify microchannel size
    • Needs further published series data
  • Trabectome (NeoMedix)
    • FDA approved
    • Ablates all of the trabecular meshwork for 90 degrees to 180 degrees via electrocautery and aspiration of the internal wall of the Schlemm canal
    • Similar idea to goniotomy but prevents rescarring of the Schlemm canal edges, as all tissue is removed
    • May have a place between trabeculoplasty and anterior filtering operations
    • Safer than trabeculectomy or tube shunt but may be less effective
    • Needs more long-term data on complication rate and persistence of effect

Consultations

Neuro-ophthalmology consultation may have a role in those patients who are experiencing progressive visual loss that does not appear to follow a typical glaucomatous pattern or if there are systemic symptoms or complaints.

Activity

Some studies show that a moderate amount of exercise can decrease IOP in both POAG patients and normal individuals. Whether it results in actual long-term IOP control and prevention of visual loss has yet to be determined.

Medication

Current medical therapy is limited toward lowering IOP. A rational approach to choosing antiglaucoma medications should minimize the number of medications and the probability of significant adverse effects. The ideal drug for treatment of POAG should have the following characteristics: (1) effectively lower IOP, (2) no adverse effects or systemic exacerbation of disease, and (3) inexpensive with once-a-day dosing. However, because no medicine possesses all of the above, these qualities must be prioritized based on the patient's individual needs and risks; then, therapy should be chosen accordingly.

Once a medicine has been initiated, close follow-up care should be performed to assess its effect. Initial follow-up care should be performed 3-4 weeks after the beginning of therapy. IOP should be rechecked at the drug's peak and trough times to see if the target IOP has been reached and is maintained throughout the day. Look for signs of allergy (eg, hyperemia, skin rash, follicular reaction). Inform the patient of systemic adverse effects and symptoms that may occur. Treatment should be continued if a therapeutic trial has shown effective lowering of IOP without adverse effects. Reevaluation should be performed 2-4 months later depending on the clinical picture.

A monocular therapeutic trial should be considered when first initiating the medical therapy, as the other eye's IOP can be used as a baseline control to gauge effect of a medication (particularly useful in patients with a widely fluctuating diurnal curve). A difference of more than 4 mm Hg between the 2 eyes posttreatment is strongly suggestive of a clinical effect. However, some agents (especially beta-blockers) may have crossover effects on the other eye even with monocular treatment, so clinical correlation must be kept in mind. If monocular therapy is found to be effective, then initiation of binocular therapy may be considered.

Some medications (eg, latanoprost, brimonidine) may have an effect that plateaus at 6-8 weeks in certain patients; keep this effect in mind when scheduling further follow-up examinations. Other patients will be nonresponders to some therapies. If this occurs, the medication should be discontinued and a new drug initiated. While discontinuing or changing therapies, keep in mind that many drugs have a wash-out period of up to 2-4 weeks (especially beta-blockers), during which they may still have some IOP-lowering effect or residual systemic response.

If one medication is not adequate in reaching the target pressure, a second medication should be chosen that has a different mechanism of action, so that the 2 drug therapies will have an additive effect. (Usually, no additive effect is seen if 2 medications from the same drug class are used.)

A specific plan of pharmacotherapy should be administered only after the possible effects of the systemic medications that a patient is taking (eg, beta-blockers, calcium channel blockers, ACE inhibitors) have been taken into consideration.

Before mention of particular medications currently used in most practices, note that as the mechanisms of axonal death by apoptosis are becoming better understood, therapies are being developed to protect nerve fibers from undergoing injury and death by several possible theoretical mechanisms. This halting of processes that is believed to contribute to ganglion cell death in glaucoma has been termed neuroprotection, and several new pharmaceuticals are being developed that hopefully will work in this manner. Agents currently under investigation as neuroprotective include glutamate receptor blockers, calcium channel blockers, inhibitors of nitric oxide synthase, free radical scavengers, and drugs to increase blood flow to the optic nerve.

See Ocular Hypertension and AAO monograph #13 for further in-depth descriptions of particular drugs.

Beta-adrenergic blockers

Topical beta-adrenergic receptor antagonists decrease aqueous humor production by the ciliary body. Adverse effects are due to systemic absorption of the drug, decreased cardiac output, and bronchoconstriction. In susceptible patients, this may cause bronchospasm, bradycardia, heart block, or hypotension. The patient's pulse rate and blood pressure also should be monitored if symptoms emerge after initiation of treatment. Patients may be instructed to perform punctal occlusion after administering the drops to reduce systemic absorption. Depression or anxiety may be experienced in some patients, and sexual dysfunction may be initiated or exacerbated. Ocular adverse effects may include blurred vision, eye ache, and corneal anesthesia.

Levobunolol 0.25%, 0.5% (Betagan)

Nonselective beta-adrenergic blocking agents that lower IOP by reducing aqueous humor production.

Timolol maleate/hemihydrate (Timoptic 0.25%, 0.5%; Timoptic XE, Betimol 0.25%, Istalol)

Nonselective agents that may reduce elevated and normal IOP, with or without glaucoma, by reducing production of aqueous humor.
The brands Timoptic XE and Istalol are both administered qd. However, Timoptic XE is a gel-forming solution, while Istalol is an aqueous solution.

Carteolol HCl 1% (Cartrol, Ocupress)

Blocks beta1- and beta2-receptors and has mild intrinsic sympathomimetic activity (ISA), with possibly fewer cardiac and lipid profile adverse effects.

Betaxolol suspension 0.25%, 0.5% (Betoptic-S)

Beta1-selective adrenergic antagonist, with possibly less pulmonary effects than nonselective agents. IOP-lowering effect is slightly less than nonselective beta-blockers.

Metipranolol hydrochloride (OptiPranolol)

Beta-adrenergic blocker that has little or no intrinsic sympathomimetic effects and membrane stabilizing activity. Has little local anesthetic activity. Reduces intraocular pressure by reducing production of aqueous humor.

Levobetaxolol (Betaxon)

Selectively blocks beta1-adrenergic receptors with little or no effect on beta2-receptors. Reduces intraocular pressure by reducing production of aqueous humor.

Adrenergic agonists

Alpha2-adrenergic agonists work by decreasing aqueous production. Systemic adverse effects include dry mouth, fatigue, and drowsiness. Ocular adverse effects include allergic (follicular) conjunctivitis and contact dermatitis.

Of this class, the alpha2-selective agonist, brimonidine, is used most commonly to treat POAG. Apraclonidine also is alpha2-selective but is believed to have more of an allergic potential; therefore, it is used less commonly as a long-term medication.

Brimonidine (Alphagan-P 0.2%, 0.15%, 0.1%)

Lowering of IOP of up to 27% reported. Bid dosing used initially, especially if in combination with other classes of agents. Tid dosing used most often in single-agent therapy that does not adequately control IOP with bid dosing. A moderate risk of allergic response to this drug exists. Caution should be used in individuals who have developed an allergy to Iopidine.
The brand Alphagan-P contains the preservative Purite and has been shown to be much better tolerated than its counterpart Alphagan or generic brimonidine.

Apraclonidine 0.5%, 1% (Iopidine)

Reduces IOP whether or not accompanied by glaucoma. Selective alpha-adrenergic agonist without significant local anesthetic activity. Has minimal cardiovascular effect.

Less-selective sympathomimetics

These less-selective adrenergic drugs increase outflow of aqueous humor through the trabecular meshwork and possibly through the uveoscleral outflow pathway, probably by a beta2-agonist action. Up to one third of patients will not respond to these drugs.

Less-selective adrenergics, such as epinephrine and dipivefrin, also can have a significantly higher allergic component and other substantial adverse effects, such as exacerbation of hypertension, angina, palpitations, or cystoid macular edema (CME). These less-selective agents are used infrequently.

Dipivefrin (AKPro, Propine)

Prodrug converted to epinephrine in eye by enzymatic hydrolysis. Appears to act by decreasing aqueous production and enhancing outflow facility. Has same therapeutic effect as epinephrine with fewer local and systemic adverse effects. May be used as an initial therapy or as an adjunct with other antiglaucoma agents for the control of IOP.

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

Lowers IOP by increasing outflow and reducing production of aqueous humor. Used as adjunct to miotic or beta-blocker therapy. Combination of miotic and sympathomimetic will have additive effects in lowering IOP.
Dipivefrin is converted to epinephrine in eye by enzymatic hydrolysis. Appears to act by decreasing aqueous production and enhancing outflow facility. Has same therapeutic effect as epinephrine with fewer local and systemic adverse effects. May be used as an initial therapy or as an adjunct with other antiglaucoma agents for the control of IOP.

Memantine (Namenda, Axura)

Indicated for moderate-to-severe Alzheimer disease; failed initial phase III trial endpoints for glaucoma indication, although subgroup analysis shows possible efficacy for patients with severe visual loss from glaucoma; possible neuroprotective systemic treatment of glaucoma, although as of now, this is a non-FDA approved off-label use of the drug. N-methyl-D-aspartate (NMDA) antagonist. NMDA receptor stimulation in the CNS by glutamate (an excitatory amino acid) is hypothesized to contribute to Alzheimer symptoms, as well as apoptosis (programmed cell death) and neuronal degeneration.

Carbonic anhydrase inhibitors

Reduce secretion of aqueous humor by inhibiting carbonic anhydrase (CA) in the ciliary body. In acute angle-closure glaucoma, administer systemically; apply topically in patients with open-angle glaucoma. These drugs are less effective, and their duration of action is shorter than many other classes of drugs. Adverse effects are relatively rare but include superficial punctate keratitis, acidosis, paresthesias, anorexia, nausea, depression, dysgeusia, and lassitude.

Oral agents, such as acetazolamide and methazolamide, primarily are used only for the treatment of refractory POAG and secondary glaucomas because they have increased systemic adverse effects. However, oral CAIs can have a slightly greater effect than topical CAI medications and are appropriate to use in certain clinical situations. The mechanism of IOP reduction is similar to other CAIs, being accomplished by reduction of bicarbonate accumulation in the posterior chamber, with a resultant decrease in sodium and associated fluid movement linked to the bicarbonate ion. An additional IOP-lowering effect exists by the creation of a relative metabolic acidosis.

Dorzolamide HCl (Trusopt) 2%

More commonly used concomitantly with other topical ophthalmic drug products to lower IOP. If more than one ophthalmic drug is being used, administer drugs at least 10 min apart. Either drug reversibly inhibits CA, reducing hydrogen ion secretion at renal tubule, and increases renal excretion of sodium, potassium bicarbonate, and water to decrease production of aqueous humor.

Brinzolamide (Azopt)

Catalyzes reversible reaction involving hydration of carbon dioxide and dehydration of carbonic acid. May use concomitantly with other topical ophthalmic drug products to lower IOP.
May cause less ocular discomfort on instillation, secondary to a buffered pH, but can still cause foreign body sensation.
If more than one topical ophthalmic drug being used, administer drugs at least 10 min apart.

Acetazolamide (Diamox)

Reduces rate of aqueous humor formation by direct inhibition of enzyme carbonic anhydrase (CA) on secretory ciliary epithelium, causing in turn a reduction in intraocular pressure (IOP). More than 90% of CA must be inhibited before IOP reduction can occur. May reduce IOP by 40-60%. Effects are seen in about an hour, they peak in 4 h, and trough in about 12 h. Derived chemically from sulfa drugs. If one form is not well tolerated, another form may be better or lower dose of the drug may better tolerated.
Used for adjunctive treatment of chronic simple (open-angle) glaucoma and secondary glaucoma and preoperatively in acute angle-closure glaucoma when delay of surgery desired to lower IOP

Methazolamide (Neptazane)

Reduces aqueous humor formation by inhibiting enzyme carbonic anhydrase, which results in decreased IOP.

Beta-blocker/carbonic anhydrase inhibitor combination

Combination solution may further decrease aqueous humor secretion compared to each solution used as monotherapy.

Dorzolamide HCl/timolol maleate (Cosopt)

CAI that may decrease aqueous humor secretion, causing a decrease in IOP. Presumably slows bicarbonate ion formation with subsequent reduction in sodium and fluid transport.
Timolol is nonselective beta-adrenergic receptor blocker that decreases IOP by decreasing aqueous humor secretion.
Both agents administered together bid may result in additional IOP reduction compared with either component administered alone, but reduction is not as much as when dorzolamide tid and timolol bid are administered concomitantly.

Prostaglandin analogs

Increase uveoscleral outflow of aqueous. One mechanism of action may be through induction of metalloproteinases in the ciliary body, which breakdown the extracellular matrix, thereby reducing resistance to outflow through the uveoscleral pathway. Can be used in conjunction with beta-blockers, alpha-agonists, or topical CAIs. Many patients respond well to these agents; other patients do not respond at all. Adverse effects include conjunctival hyperemia, iris pigmentation, CME, and uveitis.

Latanoprost 0.005% (Xalatan)

Decreases IOP by increasing outflow of aqueous humor through uveoscleral pathways.

Bimatoprost (Lumigan)

Prostaglandin agonist that selectively mimics effects of naturally occurring substances, prostamides. Exact mechanism of action unknown but believed to reduce IOP by increasing outflow of aqueous humor through trabecular meshwork and uveoscleral routes. Used to reduce IOP in open-angle glaucoma or ocular hypertension.

Travoprost ophthamic solution (Travatan)

Prostaglandin F2-alpha analog and selective FP prostanoid receptor agonist. Exact mechanism of action unknown but believed to reduce IOP by increasing uveoscleral outflow.

Unoprostone (Rescula)

Prostaglandin F2-alpha analog and selective FP prostanoid receptor agonist. Exact mechanism of action unknown but believed to reduce IOP by increasing uveoscleral outflow.

Miotic agents (parasympathomimetics)

Miotics work by contraction of the ciliary muscle, tightening the trabecular meshwork and allowing increased outflow of aqueous through traditional pathways. Miosis results from action of these drugs on the pupillary sphincter. Adverse effects include brow ache, induced myopia, and decreased vision in low light. These agents are used less commonly today since the advent of newer drugs with fewer adverse effects.

Pilocarpine is one of the more commonly used agents in this class. Less frequently used miotics include phospholine iodide (0.03%, 0.06%, 0.125%, 0.25% qd/bid) and carbachol (0.75%, 1.5%, 3% tid/qid).

Pilocarpine 1%, 2%, 4% (Pilocar, Pilagan, Pilogel, Ocusert)

A naturally occurring alkaloid, pilocarpine mimics the muscarinic effects of acetylcholine at postganglionic parasympathetic nerves. Directly stimulates cholinergic receptors in the eye, decreasing resistance to aqueous humor outflow.
Instillation frequency and concentration are determined by patient's response. Individuals with heavily pigmented irides may require higher strengths.
If other glaucoma medication also is being used, at bedtime, use gtt at least 5 min before gel.
Patients may be maintained on pilocarpine as long as IOP is controlled and no deterioration in visual fields occurs.
May use alone or in combination with other miotics, beta-adrenergic blocking agents, epinephrine, CAIs, or hyperosmotic agents to decrease IOP. Use with prostaglandin analogs can have a small additive effect.

Hyperosmotic agents

These agents are used infrequently, most commonly to reduce extremely elevated IOP in acute situations of angle-closure or certain secondary glaucomas, or selectively as a preoperative measure before intraocular surgery.

Osmotics lower IOP by increasing the osmotic gradient between the blood and ocular fluids, resulting in loss of water from the eye (especially the vitreous) into the hyperosmotic blood plasma, with concomitant lowering of IOP, but an increase in intravascular volume. Therefore, care should be used in any patient with cardiac, renal, or hepatic abnormalities.

Systemic adverse effects include nausea, vomiting, headache, increased thirst, chills, fever, confusion or disorientation, electrolyte imbalances, and urinary retention.

Isosorbide 45% w/v solution (Ismotic)

In the eyes, may create an osmotic gradient between plasma and ocular fluids and induce diuresis by elevating osmolarity of glomerular filtrate. Effects may, in turn, inhibit tubular reabsorption of water. Treatment is preferred when less risk of nausea and vomiting than that posed by other oral hyperosmotic agents desired. Palatability best if poured over ice before ingestion. May use in patients with diabetes.

Mannitol (Osmitrol, Resectisol)

Reduces elevated IOP when the pressure cannot be lowered by other means.
Initially assess for adequate renal function in adults by administering a test dose of 200 mg/kg, given IV over 3-5 min. Should produce a urine flow of at least 30-50 mL/h of urine over 2-3 h.
In children, assess for adequate renal function by administering a test dose of 200 mg/kg, given IV over 3-5 min. Should produce a urine flow of at least 1 mL/h over 1-3 h.
The 20% w/v solution most commonly is used IV. Alternatively, concentrations of 10%, 15%, or 25% may be used.

Glycerin 50% (Ophthalgan, Osmoglyn)

Used in glaucoma to interrupt acute attacks. Oral osmotic agent for reducing IOP. Able to increase tonicity of blood until finally metabolized and eliminated by the kidneys. Maximum reduction of IOP usually occurs 1 h after glycerin administration. Effect usually lasts approximately 5 h.
Used for diagnostics. Facilitates ophthalmoscopic and gonioscopic examination in acute glaucoma. Used only for topical application to cornea. By virtue of osmotic action (attraction of water through the semipermeable corneal epithelium), promptly reduces edema and causes clearing of corneal haze. Action is transient and therefore used primarily for diagnostic purposes.

Beta-blocker / alpha agonist combination

Combination solution may further decrease aqueous humor secretion compared to each solution used as monotherapy, while improving compliance.

Brimonidine/timolol (Combigan)

Selective alpha-2 adrenergic receptor agonist with a nonselective beta-adrenergic receptor inhibitor. Each of them decrease elevated IOP, whether or not associated with glaucoma. damage.

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