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Glaucoma 1: Pharmacology

2 CPD in Australia | 0.5G in New Zealand | 7 June 2018
Figure 8: RhoKinase has several actin cytoskeletal-related targets that directly affect the contractile properties of TM outflow tissue.


Few areas in eye heath are changing as fast as glaucoma treatment and management. For optometrists there are a variety of options available to treat your patients’ glaucoma starting with eye drops and progressing to laser procedures and surgery. With a number of options available to treat glaucoma there is more to glaucoma than raised intraocular pressure.


1. Understand the indications, contraindications, dosing, and adverse effects associated with prostaglandin analogues.
2. Understand how the sympathetic and parasympathetic nervous system is used to develop medications to treat glaucoma.
3. Understand the indications, contraindications, dosing, and adverse effects associated with cholinergic agonists, alpha adrenergic agonists, beta-blockers, carbonic anhydrase inhibitors and RhoKinase inhibitors.
4. Understand the role of nitric oxide and nitric oxide-donating prostaglandin analogues in reducing intraocular pressure.
5. Understand the novel actions of RhoKinase inhibitors in reducing intraocular pressure.
6. Understand the true contraindications for beta-blockers and discern which adverse effects are not due to
beta blockade.

Despite all of the new knowledge in glaucoma pathophysiology and all of the new therapies under study, our only therapeutic option currently available is intraocular pressure (IOP) reduction. While laser trabeculoplasty and incisional ocular surgery always remain options, medical therapy is typically employed first. Safety and efficacy are chief among the reasons that medications are the mainstay of glaucoma therapy. This module addresses the medications available to manage patients with glaucoma.


Prostaglandin analogs (PGAs) are chemical mediators of inflammation that have the ability to reduce IOP by increasing uveoscleral outflow (the unconventional pathway as opposed to trabecular meshwork which is the conventional pathway). There possibly is a small component of increased trabecular meshwork (TM) outflow as well, though this is controversial. This class of medications is so effective at lowering IOP and so well tolerated and widely used that it has been argued that PGAs have caused reduction in glaucoma surgeries performed.1,2

The available PGAs include latanoprost 0.005 per cent, travoprost 0.004 per cent, bimatoprost 0.01 per cent, and tafluprost 0.0015 per cent. All are dosed once daily at bedtime (QD HS). There is no clinical necessity to dose these medications at bedtime. Based upon clinical studies, they were approved for bedtime usage in order to reduce the impact of hyperemia that a patient may notice while using these medications.3 The most important aspect of dosing is the once daily administration. Use more than once daily is theorised to lead to a PGA receptor super saturation and a reduction of clinical efficacy.

Prostaglandin analogs have been shown to have excellent IOP reduction at night while patients are sleeping supine. In fact, PGAs are one of the few meds that have been shown to reduce IOP at night when IOP is typically highest.4 PGAs work independent of episcleral venous pressure and as such are drugs of choice in glaucoma secondary to elevated episcleral venous pressure, such as in Sturge-Weber syndrome (which has elevated episcleral venous pressure due to AV malformations), and carotid cavernous fistula and dural arteriovenous shunt/malformation within the cavernous sinus.

Ocular adverse and side effects associated with PGAs include hyperemia, punctate keratopathy, increased eyelash and nose hair growth, blurred vision, dry eye, increased iris colouration, anterior chamber cell and flare reaction, as well as anecdotal evidence of cystoid macular oedema (CME) in aphakes and pseudophakes (with open or broken posterior capsule).1 PGAs have also been associated with pseudodendritic keratopathy as well as inducing recurrence of herpes simplex dendritic ulcers, but again this is from anecdotal reports. The main adverse effect is hyperemia, which may be transient and tolerable and is reversible with medication cessation.

Periorbitopathy, which includes periorbital skin darkening (similar to increased iris colouration), and deepening of ocular sulcus due to periorbital fat atrophy, have also been noted with PGAs. This can give a pseudo-enophthalmos appearance.5 About 10 per cent of the population does not respond to PGAs, but for those that do respond, IOP reduction can be dramatic. Any patient not responding at all to PGAs should immediately be suspected of being non-compliant.

Systemic side effects are minimal and anecdotally have included flu-like illness. Systemic contraindications are also minimal and include pregnancy (because PGAs are involved in cervical ripening and labour induction and being a child as PGAs seem to have poor efficacy though are safe).

PGAs have been lesser choices in secondary inflammatory glaucoma or any clinical entity that has anterior segment inflammation as a primary component, mostly due the fear of a potential to increase inflammation. In reality, PGAs have not been shown to worsen inflammation and do lower IOP in eyes with inflammatory glaucoma. Thus, PGAs can be used in cases of inflammation, but perhaps as a lesser choice or used cautiously.6 The onset of action is generally considered too slow to use in acute situations such as acute angle closure glaucoma. Again, not likely to harm a patient but also not likely to be significantly beneficial.

Among the available PGAs (see Figure 2) is latanoprost 0.005 per cent, going by the trade name Xalatan. This medication, like all other PGAs, is very oculoselective. The half-life is approximately 17 minutes, thus there is rapid local absorption and very low degree of systemic effects. The initial short term response to latanoprost is likely due to PF-2 receptor stimulation. Later responses may be due to latanoprost actually changing the ground substance in the cellular matrix of the ciliary meshwork. The peak action occurs eight to 12 hours after instillation with a long duration of IOP reduction, thus long term IOP control is excellent with latanoprost and is an excellent choice if patients miss dosages.

Another available PGA is travoprost 0.004 per cent, either preserved with BAK (trade name Travatan) or preserved with SofZia (Travatan Z)(see Figure 2). This medication has a profile similar to that of latanoprost with similar efficacy, dosing, and adverse effects. It is a full FP prostaglandin agonist with a sustained 30 per cent IOP reduction at all times tested. Travatan Z (preserved with SofZia) is thought to be gentler to the ocular surface than iterations preserved with BAK.7 Bimatoprost 0.01 per cent, going by the trade name Lumigan is technically a hypotensive lipid (synthetic prostamide) acting on different receptors; however, it is still considered in the PGA class. Prostamides occur naturally in ocular tissues and regulates aqueous flow and IOP. Lumigan 0.01 per cent has replaced original 0.03 per cent concentration (which is still used and marketed as Latisse for eyelash growth). The lower concentration of bimatoprost has a greater amount of BAK as a preservative and this may be a consideration in patients with sensitivity to BAK or pre-existing ocular surface disease and dry eye syndrome.8

A preservative-free PGA exists in tafluprost 0.0015 per cent (trade name: Zioptan). It is supplied in unit dose vials like preservative-free artificial tears. This is considered a favoured PGA in patients with ocular surface disease and preservative sensitivity.9

Newly approved in the US is latanoprostene bunod ophthalmic solution, 0.024 per cent, going by the trade name Vyzulta. This is the first prostaglandin analog with one of its metabolites being nitric oxide (NO) and is considered a “nitric oxide donating PGA”. Nitric oxide was first discovered as a signalling mediator involved the cardiovascular system. Nitric-oxide synthase (iNOS, NOS-2) is present in astrocytes of optic nerve heads from glaucomatous eyes of humans and is increased in the TM with elevated perfusion pressure in vitro.

NO induction increases outflow facility with additional cellular targets in the TM and Schlemm’s canal. This alters the cytoskeletal network and cell adhesion system of the cells of the conventional outflow pathway. This leads to relaxation of the TM and the inner wall of Schlemm canal.10

Vyzulta appears to have a dual mechanism of action. Upon instillation in the eye, it metabolises into two moieties, latanoprost acid, which primarily works within the uveoscleral pathway to increase aqueous humour outflow, and butanediol mononitrate, which releases NO to increase outflow through the TM and Schlemm’s canal. Clinical trials have shown Vyzulta to have greater IOP reduction than latanoprost with similar side effect profile. Like latanoprost, Vyzulta is dosed once daily at bedtime.11


  • Prostaglandins are important in that they flatten the diurnal IOP curve as well as giving lingering IOP reduction even as much as 60 hours after dosing. Thus, they are more forgiving of patients that miss dosages.

  • The most commonly encountered adverse effects from prostaglandin usage are hyperemia, eyelash growth, deepening of the ocular sulcus, and periorbital skin darkening. Hyperemia is reversible with medication cessation. Iris colour changes appear to be irreversible. Periorbitopathy may be reversible if the medication is stopped soon enough, but may indeed be permanent. Everything else likely is reversible.

  • It takes about 2 weeks to see the full IOP lowering effect of travoprost. IOP lowering effects of bimatoprost are appreciated very fast, usually within a few days. It takes about 3-5 weeks to appreciate the full pressure lowering effects of latanoprost. Do not check IOP too early after starting therapy.

  • Don’t be confused about PGAs, their half-life is very short, but their duration of action is very long.

  • Every prostaglandin analog and prostaglandin-like drug have the same potential adverse effects and contraindications.

  • Use prostaglandins cautiously in patients with known previous outbreaks of herpes simplex dendritic keratitis.Exercise care when using prostaglandins in cases of uveitis.

  • Hyperemia from prostaglandin use is not an allergic reaction, but a response to the prostaglandin, which mitigates inflammation.

  • Due to chemical differences, each prostaglandin behaves differently. If a prostaglandin reduces IOP, but causes unacceptable hyperemia, try another prostaglandin. Further, if the desired IOP reduction is not optimal with one prostaglandin, try another. Caveat; do not expect dramatic pressure reductions from switching prostaglandins. For example, if IOP is reduced to 18mmHg with a one prostaglandin and your target is 15mmHg, then switching prostaglandins may work. Do not expect much more.

  • While uveitis and cystoid macular oedema (CME) have occurred from prostaglandins usage (notably in patients who have had previous bouts of uveitis and CME), these side effects are unlikely to occur in a previously normal patient. PGAs are often temporarily stopped prior to and subsequent to cataract surgery to reduce risk of CME.

  • PGAs are considered the medication class that best reduces IOP during the diurnal sleep cycle when patients are supine.



Several medications exert their IOP lower effects by mimicking or inhibiting neurotransmitters from the autonomic nervous system. Effects are based upon actions on alpha and beta-receptors in select tissues. There are both sympathetic agents and parasympathetic agents.

Parasympathetic agents are known synonymously as parasympathomimetics, miotics, and cholinergic agonists. These are medications that mimic acetylcholine, the neurotransmitter in the parasympathetic nervous system. Ocular parasympathetic receptors are in the iris and stimulation causes miosis. Receptors on the ciliary body increase accommodation and TM pore opening (leading to IOP outflow through the TM). This increase in aqueous outflow through the TM is the main mechanism of action. Receptors on the ciliary meshwork (uveal meshwork-uveoscleral pathway) cause an aqueous outflow decrease through this pathway when stimulated.12

Pilocarpine in 1 per cent, 2 per cent, and 4 per cent concentrations is the most commonly available parasympathomimetic (see Figure 3). It is a direct acting cholinergic agonist that causes miosis, ciliary body contraction, alteration of TM pores, and enhances aqueous outflow through the TM. Pilocarpine has a short effect, on the average of 4-8 hours, thus necessitating QID dosing. Local adverse effects include brow ache, globe and orbital pain, allergic reactions, possibly increased myopia due to accommodative spasm, and vision reduction if cataracts are additionally present. These effects combined with QID dosing makes pilocarpine an uncommon medication in modern therapy. The main use appears to be in breaking attacks of acute primary angle closure.13 Miotics should not be used in cases where there is significant inflammation as the ciliary body and iris mobility induced by the medication can lead to increased breakdown of the blood-aqueous barrier and potentially worsen inflammation. Another available direct-acting miotic is Carbachol, which has more potency than pilocarpine and is dosed TID.


  • Never use miotics in any eye with primary inflammation such as uveitis.Miotics are losing popularity asglaucoma treatment, due mostly to localside effects and the advent of newermedications. Miotics are rarely usedtoday in modern glaucoma therapy.
  • However, any patient with primary angle closure glaucoma should be onthis medication prior to laser surgery. It actually may be a good choice when surgery is not an option in advanced,end stage cases.
  • Due to miosis, pilocarpine canreduce vision, visual field, andpatient quality of life.

Sympathetic agents are sometimes referred to as sympathomimetic agents as they mimic or block the main sympathetic neurotransmitter, norepinephrine. These agents are adrenergic agonists (both beta and alpha agonists) or adrenergic antagonist (such as beta-blockers). One sympathomimetic agent is dipivefrin 0.1 per cent, a pro-drug of epinephrine. Its action is vasoconstriction of the ciliary body vessels, reducing sympathetic tome and reducing aqueous production.

An early adrenergic agonist is apraclonidine 1 per cent & 0.5 per cent, going by the trade name Iopidine. The mechanism of action is to act presynaptically to inhibit release of norepinephrine and reduce adrenergic receptor stimulation. The reduced sympathetic activity in the ciliary body reduces aqueous production. Thus, apraclonidine is an aqueous suppressant. There is also a small component of increased uveoscleral outflow. The original one per cent is available in single use containers designed for blunting IOP spikes associated with ophthalmic laser procedures.14 A 0.5 per cent concentration was designed for chronic use at TID dosing. Unfortunately, the medication effect wears off over several months and has a high rate of allergic reactions; thus it is rarely used.15

An adrenergic agonist far more effective and more commonly used than apraclonidine is brimonidine tartrate, going by a trade name of Alphagan. It is available in 0.2 per cent, 0.15 per cent, and 0.1 per cent concentrations. Like apraclonidine, it is an aqueous suppressant. Brimonidine is a selective alpha-2 agonist with a 30-fold greater affinity for receptors than apraclonidine (see Figure 4). Clinically, it commonly gives IOP reduction of approximately 4-6 mmHg (25-30 per cent).16 Brimonidine is labelled for TID dosing, but many clinicians prefer to dose the drug BID. This is likely acceptable if the patient is using other medications as well. However, brimonidine monotherapy dosed twice daily likely will leave patients with diurnal periods of uncontrolled IOP. Additionally, sleep studies seem to indicate that alpha adrenergic agonists such as brimonidine do not have a significant IOP lowering effect while patients are sleeping supine.17

Approximately 7 per cent of patients have toxic allergic responses that require discontinuation of brimonidine (see Figure 4). Allergic response can come after weeks, months or years after initiation of the drug. A late-onset brimonidine allergy is a common cause for discontinuation. The most significant side effects are drowsiness and fatigue, headache, and dry mouth. Because brimonidine crosses the blood-brain barrier, these effects can be significant in smaller patients and children. This medication has induced fatigue, drowsiness and even coma in children and thus should not be used in children under the age of eight years.17-19


  • Apraclonidine is virtually never used in modern glaucoma chronic therapy, but has use in acute situations and testing for Horner’s syndrome.
  • Do not use Alphagan in children (under age eight) as it is unsafe.
  • Patients can have a late-onset Alphagan allergy months or years after starting therapy.

Another class of medications affecting the sympathetic nervous system is the beta antagonists, also known as betablockers. There are beta-1 receptors on the heart and stimulation increases cardiac activity. There are beta-2 receptors on the lungs and stimulation leads to bronchiole relaxation and increased breathing ease. There are also beta-1 and 2 receptors on the ciliary body. Stimulation of these receptors increases aqueous production while blocking beta-1 and 2 receptors reduces aqueous production. This constitutes the main action of beta-blockers.20,21

Topical beta-blockers for glaucoma treatment may be selective or nonselective. Beta-1 specific blocks only beta-1 receptors. Betaxolol is the only beta-1 specific beta-blocker clinically available. While there may be crossover cardiac effects with beta-1 blockers such as betaxolol, this type will have less pulmonary effect. However, most are nonspecific and block both beta-1 and beta-2. Topical beta-blockers, due to their systemic absorption, are the class of glaucoma medication most likely to have systemic adverse effects. In fact, there may be bilateral IOP effects when using in only one eye due to systemic absorption.

Topical beta-blockers do not appear to have IOP lowering effects at night while patients are sleeping supine. Common problems with topical beta-blockers are both short term escape and long term drift. Short term escape implies that after an initial decrease in IOP from several days to weeks, a rise in IOP will occur. After an additional 2-4 weeks, the IOP will stabilise, often below pre-treatment levels, but above the initial pressure reduction. Long term drift is a slow steady rise in IOP after months to years of treatment where these medications become ineffective.

There are several contraindications to topical beta-blocker usage. One of the most notable is bradycardia. Beta blockade can result in slowing of sinus nodal discharge with resultant dose-dependent bradycardia. In most cases, the degree of bradycardia is asymptomatic and does not impact a patient’s life. Patients using topical beta-blockers who develop symptomatic bradycardia, as manifested by diminished capacity for physical activity or undiagnosed syncope, likely have coexistent pathology of the sinus AV node or conduction pathways and should be referred to a general practitioner (GP). 20,21

Beta-blocker therapy can be implemented in a patient with an implanted pacemaker following approval from the treating physician. Topical beta-blocker therapy should be avoided in patients with asymptomatic bradycardia and heart block. Patients with symptomatic bradycardia often present with syncope and dizziness, and are identified prior to ophthalmic examination. Asymptomatic patients without aerobic conditioning (such as athletes) with resting pulse rate under 55 beats per minute should be evaluated by a GP. However, patients with normal resting pulse rates and with no history of syncope or dizziness are unlikely to experience any serious bradycardia effects from topical beta-blockers.22,23

Other contraindications for topical betablocker use include asthma, emphysema, myasthenia gravis, cerebrovascular insufficiency, heart block, hypotension (BP<100/60), to name a few. Beta-blockers are bad for athletes as it prevents heart rate from exceeding 135 BPM. Athletes cannot train through this block.24

Every patient considered for a topical beta-blocker needs baseline blood pressure and resting pulse measurement in addition to review of medical history. Topical betablockers can be used even if the patient is on systemic beta-blockers for hypertension. However, systemic beta-blockers will reduce the IOP lowering effectiveness of topical beta-blockers because they have already exerted a mild IOP reduction. GP approval should be obtained before prescribing topical beta-blockers for patients on oral formulations.24

There are controversies regarding the use of topical beta-blockers in patients with congestive heart failure (CHF) and those with diabetes. CHF has long been a theoretical contraindication to the use of topical and systemic beta-blockers. Possibly, this warning came from the theoretical potential for beta-blockers to reduce cardiac contractility and therefore worsen cardiac output.

Currently, it is accepted that beta blockade benefits patients with CHF and actually reduces mortality. Reduced resistance to ejection actually improves cardiac output. Beta-blockers also function as  antiarrhythmics, likely by inhibiting cardiac sympathetic stimulation, thus reducing sudden death from arrhythmia. In contrast to early concerns, beta blockade is now a well-accepted therapy for patients with stable class II-III CHF.

There is at present no conclusive evidence based information regarding the effects of topical beta-blocker therapy on the intrinsic recovery of plasma glucose levels in patients with diabetes. It may be that patients requiring insulin in an advanced stage of diabetic disease may be at greater risk from beta-blocker induced prolongation of hypoglycemia. However, topical betablockers are quite safe for the vast majority of diabetic patients.24

There have been a myriad of other reported adverse effects from beta-blocker therapy including depression, confusion, anxiety, fatigue, malaise, irritability, somnolence, confusion, impotence, and altered lipid profiles. Important to remember that these reports are single cases or case series with no controlling for concurrent diseases that also may have impacted patients. Additionally, many of these reports involved oral and not topical beta-blockers.

There appears to be no reason to withhold topical beta-blocker therapy in patients for fear of inducing sexual dysfunction, even if they have a pre-existing history. Depression has been reported, but there is no reason to expect that topical beta-blocker therapy will induce depression in an otherwise normal individual.25,26 However, the impact of betablockers in patients that already suffer from depression is presently unknown.

The most commonly prescribed topical beta-blockers for glaucoma include timolol and betaxolol, which are non-selective beta-blockers and betaxolol, which is a selective beta-1 blocking agent (see Figure 5). All agents are dosed BID. Carteolol is a non-selective beta-blocker that maintains intrinsic sympathomimetic activity (ISA). That is, it allows for residual agonal tone and is the beta-blocker least likely to affect cardiac function.


  • Beta-blocker contraindications are somewhat controvertible. The most significant contraindications are COPD, asthma, emphysema, symptomatic bradycardia, and asymptomatic bradycardia with heart block. Beta-blockers can be considered in patients with CHF pending approval by the patient’s PCP. All other contraindications can be considered ‘relative’ and betablockers can be used in many of these situations on a case-by-case basis. However, if a ‘contraindication’ is present, it does not mean that betablockers (or any medication for that matter) cannot be used, but should be a lesser choice.
  • Beta-blockers work well and are generally safe in children.
  • Beta-blockers should not be dosed at bedtime for two reasons. Some patients have nocturnal hypotension and this may lower blood pressure further. In addition, aqueous formation decreases in the evening during sleep and topical beta-blockers have less effect. Beta-blockers appear to have no IOP lowering effect at night/during sleep.



Carbonic anhydrase inhibitors (CAIs) are sulfonamide non-antibiotic drugs. The enzyme, carbonic anhydrase, catalyses the hydration of carbon dioxide to carbonic acid that then dissociates into bicarbonate ions and hydrogen. Bicarbonate then diffuses into the eye, making it hypertonic in relation to plasma, and fluid flows osmotically into the eye from plasma. Blocking carbonic anhydrase blocks bicarbonate formation. This disrupts the process of ultrafiltration, which is the manner in which aqueous is formed by slowing production of bicarbonate in secretory neuroepithelial cells of ciliary body. Thus, CAIs are aqueous suppressants.27

There are numerous side effects noted with CAI use, but many occur mostly from oral use and not topical. Some noted effects include dysguisia (a metallic taste), paresthesia of the digits, malaise, bone marrow toxicity and suppression of formed blood elements, and kidney stone formation from metabolic acidosis. Oral formulations should be used cautiously in sickle positive patients as the metabolic acidosis can promote red blood cell sickling. Dysguisia, ocular irritation, and blurred vision are the most common adverse events associated with topical use.28,29

Patients with compromised corneal endothelium and a predisposition to corneal oedema should avoid  topical CAI use. There has been long conjecture that patients who are sulfa allergic should not use any form of CAI. Allergies with sulfonamide antibiotics implies cross reactivity with other sulfonamide antibiotics, but not necessarily with sulfonamide non-antibiotics (such as CAIs), due to structural differences. Non-antibiotic sulfonamides lack the same structural configuration as sulfonamide antibiotics and are less likely to result in a severe allergic reaction. Cross reactivity between sulfonamide antibiotics and sulfonamide non-antibiotics is extremely rare. Thus, it is important to determine of a patient who has ‘sulfa allergies’ is sensitive to sulfonamide antibiotics or sulfonamide non-antibiotics. CAIs, which are sulfonamide non-antibiotics, can be used in patients who are sensitive to sulfonamide antibiotics.30 When in doubt, proceed with caution and check with the patient’s GP.

The most commonly used oral CAI is Acetazolamide (Diamox) (see Figure 6). It is supplied in 125mg, 250mg, and 500mg SR (Diamox sequels) tablets. The standard dosing is 1000mg QD PO (250mg PO QID or 500 mg PO BID). While commonly used in acute situations such as angle closure attack, chronic use is typically limited to about six weeks due to side effect intolerance. Another oral CAI is methazolamide  (Neptazane). Dosing ranges from 25mg PO BID up to 50 mg PO TID. Methazolamide side effects and contraindications are similar to acetazolamide, but is much better the same IOP lowering ability of Diamox.

A commonly used topical CAI is dorzolamide 2 per cent (trade name Trusopt). In adults, it responds with approximately a 10-26 per cent IOP reduction. It binds to melanin, so it is slightly less effective in dark irides. It has poor lipid solubility and does not penetrate cornea well. In order to get corneal penetration, dorzolamide is formulated at a relatively low pH, thus it tends to be an irritating medication to use. The standard labelled dosing is TID, though many effectively use it at BID dosing. Reported adverse effects with dorzolamide include hyperemia, bitter taste, toxic allergy, aplastic anemia, and an onset of corneal oedema in patients with compromised corneal endothelium.

Another available topical CAI is brinzolamide ophthalmic suspension 1 per cent, going by the trade name Azopt. It is very similar to dorzolamide in IOP reduction, dosing (TID), and adverse effects. It is formulated at physiological pH, thus is significantly more comfortable and better tolerated than Trusopt with a lower incidence of allergic reactions. However, in order to formulate brinzolamide at a more comfortable pH, it had to be made into a suspension. Thus patients are more likely to complain of blurred vision with brinzolamide than dorzolamide (see Figure 7).31


  • The standard dosing of 1000mg/day is likely the reason that Diamox is so poorly tolerated and is likely an overdose, especially in smaller patients.
  • Topical CAI’s work very well in cases of uveitic glaucoma. Also, they work very well and are well tolerated in children.
  • While dosing is TID, many prescribe topical CAIs BID. This is probably acceptable as part of polytherapy, but is questionable for monotherapy.
  • Avoid using topical CAI’s in patients with compromised corneal endothelium, and cautiously in patients with true allergy to sulfa medications, and a history of renal stones.
  • Due to the safety of topical CAI’s compared to oral CAI’s, the therapeutic index indicates that oral CAI’s are no longer appropriate in the chronic care of glaucoma in most cases, though there are exceptions.
  • Topical CAIs appear to be effective in lowering IOP at night/during sleep. They are also seen to be the medication class, which is the best additive/adjunctive therapy to use with PGAs.
  • The most common adverse effects of topical CAIs are dysguisia, blurred vision, burning and stinging. The most notable contraindication is corneal endotheliopathy and reduced endothelial cell count.
  • It is not recommended to use an oral and topical carbonic anhydrase together. However, many clinicians will do so in extreme or unusual situations.



The newest class of medication recently approved in the US is the rho-kinase inhibitor/norepinephrine transported inhibitor. The Rho family consists of three small guanosine triphosphate (GTP) binding proteins (RhoA, RhoB, RhoC), which regulate aspects of cell shape, motility, proliferation, and apoptosis throughout the body. RhoKinases are Ks are serine/threonine kinases that regulate smooth muscle contraction, specifically in the TM. RhoKinase appears to have several actin cytoskeletal-related targets that directly affect the contractile properties of TM outflow tissue (see Figure 8). RhoKinase and Rho GTPase inhibitors can increase aqueous humour drainage in TM tissue, leading to a reduction in IOP. RhoKinase inhibitors exhibit a widening of the extracellular spaces and juxtacanalicular tissue morphological changes within 30 minutes of administration and lasting up to 12 hours. This class of medication acts primarily by increasing aqueous outflow through the TM.32-34

The medication recently approved is netarsudil ophthalmic solution 0.02 per cent (trade name Rhopressa).35 It has been said to be a novel “triple action” eye drop that specifically targets the TM, enhancing trabecular outflow. Preclinical results have demonstrated that netarsudil also lowers episcleral venous pressure, which reduces resistance to drainage through the conventional TM pathway. It possibly also provides an additional mechanism that reduces fluid production in the eye and therefore lowers IOP. Biochemically, netarsudil is known to inhibit both RhoKinase (ROCK) and norepinephrine transporter. Once-daily dosing is recommended. The primary adverse event is hyperemia, which was experienced by approximately 35 per cent of the Rhopressa patients, of which 80 per cent was reported as mild.36


Fixed combination (FC) agents combine two or more approved medications in one bottle. Each FC medication gives somewhat better IOP reduction than either component part with theoretically enhanced compliance. Commonly available FC agents involve topical betablocker/carbonic anhydrase inhibitor (Cosopt, Azarga), beta-blocker/alpha adrenergic agonist (Combigan), alpha adrenergic agonist/carbonic anhydrase inhibitor (Simbrinza), and beta-blocker/PGA (DuoTrav, Xalacom, Ganfort).


Approval of a RhoKinase inhibitor paves the way for future release of a FC with a PGA. Under development is netarsudil/latanoprost 0.02/0.005 per cent (trade name Roclatan). At this point, clinical trials look very promising and it appears very effective at reducing IOP.37

Dr. Joseph Sowka, OD, FAAO, Diplomate is a Professor of Optometry at Nova Southeastern University College of Optometry where he serves as Chief of The Advanced Care Service and Director of the Glaucoma Service at the College’s Eye Institute. He is also Chair of the Department of Optometric Sciences. He is the longest tenured faculty member at the College. Dr. Sowka is a founding member of both the Optometric Glaucoma Society and Optometric Retina Society. He is also the Chair of the Neuro-Ophthalmic Disorders in Optometry Special Interest Group for the American Academy of Optometry. Dr. Sowka is a Glaucoma Diplomate of the American Academy of Optometry. He is the lead author of the annual Handbook of Ocular Disease Management published by Review of Optometry. He is a partner and co-owner of Optometric Education Consultants.

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