Management of Glaucoma: Focus on Pharmacological Therapy

Transcription

1 THERAPY IN PRACTICE Drugs Aging 2005; 22 (1): X/05/ /$34.95/ Adis Data Information BV. All rights reserved. Management of Glaucoma: Focus on Pharmacological Therapy Robert E. Marquis and Jess T. Whitson Department of Ophthalmology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA Contents Abstract Physiology of Aqueous Humour and Intraocular Pressure Medical Treatment of Glaucoma Cholinergics (Acetylcholine Receptor Agonists) Direct-Acting Cholinergics Adverse Effects Indirect-Acting Cholinergics Dual-Mechanism Cholinergics Adrenoceptor Agonists Nonselective Adrenoceptor Agonists Adverse Effects Selective α 2-Adrenoceptor Agonists Adverse Effects Carbonic Anhydrase Inhibitors (CAIs) Systemic CAIs Adverse Effects Topical CAIs Adverse Effects β-adrenoceptor Antagonists Nonselective β-adrenoceptor Antagonists Adverse Effects Selective β-adrenoceptor Antagonists Adverse Effects Prostaglandin Analogues Combination Therapy Other Treatment Options Laser Therapy Surgical Therapy Conclusion...17 Abstract Glaucoma represents a major cause of vision loss throughout the world. Primary open-angle glaucoma, the most common form of glaucoma, is a chronic, progressive disease often, though not always, accompanied by elevated intraocular pressure (IOP). In this disorder, retinal ganglion cell loss and excavation of the optic nerve head produce characteristic peripheral visual field deficits. Patients with normal-tension glaucoma present with typical visual field and optic nerve head changes, without a documented history of elevated IOP. A variety of secondary causes, such as pigment dispersion syndrome and ocular trauma, can result in glaucoma as well. Treatment of all forms of glaucoma consists of

2 2 Marquis & Whitson reducing IOP. With proper treatment, progression of this disease can often be delayed or prevented. Treatment options for glaucoma include medications, laser therapy and incisional surgery. Laser techniques for the reduction of IOP include argon laser trabeculoplasty and selective laser trabeculoplasty. Both techniques work by increasing outflow of aqueous humour through the trabecular meshwork. Surgical options for glaucoma treatment include trabeculectomy, glaucoma drainage tube implantation and ciliary body cyclodestruction. While each of these types of procedures is effective at lowering IOP, therapy usually begins with medications. Medications lower IOP either by reducing the production or by increasing the rate of outflow of aqueous humour within the eye. Currently, there are five major classes of drugs used for the treatment of glaucoma: (i) cholinergics (acetylcholine receptor agonists); (ii) adrenoceptor agonists; (iii) carbonic anhydrase inhibitors (CAIs); (iv) β-adrenoceptor antagonists; and (v) prostaglandin analogues (PGAs). Treatment typically begins with the selection of an agent for IOP reduction. Although β-adrenoceptor antagonists are still commonly used by many clinicians, the PGAs are playing an increasingly important role in the first-line therapy of glaucoma. Adjunctive agents, such as α-adrenoceptor agonists and CAIs are often effective at providing additional reduction in IOP for patients not controlled on monotherapy. As with any chronic disease, effective treatment depends on minimising the adverse effects of therapy and maximising patient compliance. The introduction of a variety of well tolerated and potent medications over the past few years now allows the clinician to choose a treatment regimen on an individual patient basis and thereby treat this disorder more effectively. Glaucoma is a heterogeneous family of ocular which there is a characteristic acquired loss of retidisorders that share common characteristics includ- nal ganglion cells and atrophy of the optic nerve. [6] ing excavation of the optic nerve head and peripher- Risk factors for the development of POAG include al visual field loss. Retinal ganglion cell death, elevated intraocular pressure (IOP), family history which is thought to occur through apoptosis, [1] re- of the disease, advanced age and African heritage sults in progressive optic nerve dysfunction and (table I). While elevated IOP is considered an imvisual impairment. According to the WHO, portant risk factor for POAG, it is not essential for glaucoma accounts for 13.5% of global blindness (behind cataracts and trachoma that account for Table I. Risk factors for the development and progression of 41.8% and 15.5% of global blindness, respectively [2] ). In the US, glaucoma is the second leading Elevated IOP glaucoma cause of blindness overall and the leading cause Diurnal fluctuation of IOP among African-Americans and Hispanics. [3,4] Typically, glaucoma is asymptomatic until late in its Race (African heritage, Hispanics) Family history of glaucoma course, making early detection difficult. It is estimated that as many as one-half of those with Other Advanced age glaucoma in developed countries may be unaware increased optic nerve cup-to-disc ratio that they have the disease. [5] compromised ocular blood flow Primary open-angle glaucoma (POAG) is the diabetes mellitus most common form of glaucoma throughout the myopia world accounting for about two-thirds of cases. [2] It corneal thickness (thin corneas greater risk) IOP = intraocular pressure. is defined as a multifactorial optic neuropathy in

3 Pharmacological Therapy of Glaucoma 3 often difficult clinically to distinguish corticoste- roid-induced glaucoma from inflammatory glauco- ma. its diagnosis. Visual loss and progressive optic neuropathy can occur in patients who do not demonstrate elevations in IOP. [7] Patients who develop typical optic nerve head and visual field changes in the absence of documented high IOP are said to have normal-tension glaucoma (NTG). NTG is believed to account for about 30% of glaucoma cases in Western countries [8] and over two-thirds of cases in Japan. [9] Some investigators believe that NTG may represent a variant of POAG, [10,11] whereas others feel that the mechanisms of the two disorders are different. [12,13] Ocular hypertensive subjects are those who demonstrate consistently elevated IOP without any obvious cause and have normal visual fields and optic discs. This condition is frequently encountered by clinicians and may occur as much as ten times more often than POAG. [14] Patients with ocular hypertension are at risk for developing POAG as a result of their elevated IOP. Recently, the OHTS (Ocular Hypertension Treatment Study) has demonstrated that lowering IOP with medical therapy in patients with ocular hypertension can significantly reduce the risk of developing POAG. [15] While POAG accounts for a majority of cases of glaucoma in the US, several other prevalent forms of the disease exist as well (table II). Secondary causes of open-angle glaucoma (OAG) result from either an increased resistance to aqueous humour flow at the trabecular meshwork (TM) or from elevated episcleral venous pressure. Pigmentary glaucoma is associated with pigment dispersion syndrome which occurs when iris pigment accumulates in the anterior chamber and deposits on the TM and in some cases the corneal endothelium. The pigment is liberated from the posterior iris surface as it makes contact with the zonular fibres that support the lens. [16] Another form of secondary OAG is seen in pseudoexfoliation syndrome. Deposition of a fibrillar material on anterior segment structures, including the TM, may result in increased IOP and glaucoma. A third form of secondary OAG occurs in some patients receiving corticosteroid therapy either topically or (less frequently) systemically. Patients with intraocular inflammation are typically treated with corticosteroids. Because intraocular inflammation (uveitis) itself may cause elevated IOP, either through blockage or inflammation of the TM, it is Ocular trauma may lead to glaucoma by a variety of mechanisms. In the acute post-traumatic period, markedly elevated IOP may result from hyphaema (anterior chamber haemorrhage), inflammation and cellular debris that clog the TM. Normal red blood cells (RBCs) may filter through the TM readily in most cases; however, if RBCs denature and swell, they may become lodged in the TM and cause an elevation in IOP. Blunt anterior segment trauma may also directly damage the TM and result in angle-recession glaucoma. Finally, inflammation af- ter trauma may cause scar-like adhesions between Table II. The secondary glaucomas Open-angle Pigmentary (associated with pigment dispersion syndrome) Pseudoexfoliation Corticosteroid-induced Uveitic (e.g. HLA-B27+, arthritic, sarcoidosis, idiopathic) Haemolytic/ghost cell (after vitreous haemorrhage) Elevated episcleral venous pressure (e.g. carotid-cavernous fistula, Sturge-Weber syndrome) Post-traumatic Acute hyphaema Lens dislocation into anterior chamber Haemolytic/ghost cell Angle recession Lens-associated Phacolytic (leakage of protein from hypermature cataract) Lens particle (after cataract surgery or penetrating trauma) Phacoantigenic (formerly phacoanaphylatic) Other OAG associated with uveitis Posner-Schlossman syndrome (glaucomatocyclitic crisis) Fuchs heterochromic iridocyclitis Postsurgical (e.g. after corneal transplant) Closed-angle Plateau iris syndrome Phacomorphic (swollen or large lens pushing iris forward) Uveal effusion or ciliary body anterior rotation Posterior segment tumour Neovascularisation of the angle (e.g. with retinal ischaemia) Peripheral anterior synechiae (e.g. with chronic uveitis) ICE syndromes (essential iris atrophy, Chandler syndrome and Cogan-Reese syndrome) HLA = human leukocyte antigen; ICE = iridocorneal endothelial; OAG = open-angle glaucoma.

4 4 Marquis & Whitson the peripheral iris and cornea, which can impede egress of aqueous humour by blocking outflow through the TM. If these adhesions, termed peripheral anterior synechiae (PAS), are extensive, angleclosure glaucoma may result. The angle-closure glaucomas are a group of con- ditions caused by several mechanisms with the common anatomical result of peripheral iridocorneal apposition and TM blockage (table II). Hyperopic (far-sighted) eyes with short axial length, shallow anterior chamber depth and narrow anatomical angles are predisposed to angle-closure glaucoma. An acute attack of angle-closure glaucoma may cause markedly elevated IOP and symptoms, such as headache, nausea, emesis and blurred vision from corneal oedema. If the anatomical blockade of the TM is not relieved by peripheral iridectomy (either by laser peripheral iridectomy or incisional surgery), extensive visual loss may result. Chronic angleclosure glaucoma is much less common in Cauca- sians than POAG, [17] but is a significant cause of glaucoma-related blindness among Asians and Eskimos. [18] Neovascularisation of the iris (rubeosis iridis) and iridocorneal angle (NVA) can lead to chronic angle-closure (neovascular) glaucoma if the aetiolo- gy of the neovascularisation is left untreated. Chronic uveitis and retinal ischaemia, often seen with proliferative diabetic retinopathy and retinal vascular occlusion, are common causes of rubeosis iridis and NVA that can result in neovascular glaucoma. The main goal of treatment for all forms of glaucoma is the preservation of visual function. The cornerstone of therapy to achieve this goal is the reduction of IOP. This report discusses the efficacy, safety and basic pharmacology of currently available agents that can be used as monotherapy or in combination for the medical treatment of glaucoma. The physiology of aqueous humour and IOP is reviewed in order to understand better the mechanism of action of drugs used in the treatment of this disorder. Finally, a brief description of other treatment modalities for glaucoma, including laser therapy and surgery, are provided. 1. Physiology of Aqueous Humour and Intraocular Pressure IOP is determined by the balance that exists between the rate of aqueous humour production (inflow) and the rate of fluid exit from the eye (outflow). Aqueous humour is produced by the ciliary body and leaves the eye through either the TM (conventional) or uveoscleral (unconventional) pathway. The uveoscleral pathway is poorly under- stood. In glaucoma, elevated IOP is typically caused by decreased facility of outflow through the TM pathway. Episcleral venous pressure can also influ- ence IOP through its effect on TM outflow. The relationship of IOP, aqueous humour production, outflow and episcleral venous pressure can be de- scribed as follows: IOP = F U C + P v where F is the aqueous humour formation (µl/min), U is the uveoscleral outflow (µl/min), C is the trabecular meshwork outflow facility (µl/min/ mm Hg) and Pv is the episcleral venous pressure (mm Hg). Aqueous humour is thought to be derived from plasma within the capillary network of the ciliary body (figure 1). Following ultrafiltration of plasma into the extracellular space or stroma of the ciliary processes, active transport and secretion of this fluid into the posterior chamber of the eye by the nonpig- mented epithelium of the ciliary body occurs at a rate of µl/min. [19] Aqueous humour produc- tion decreases with age. [20] Patients with diabetes mellitus [21] and inflammation of the eye (iridocyclitis) [22] also experience decreased rates of aqueous humour formation. A large fluid intake (1000mL of water) has been shown to significantly increase aqueous humour production after 90 min- utes. [23] Carbonic anhydrase, adenosine triphosphatases and adrenoceptors located in the nonpig- mented ciliary epithelium are thought to play an important role in aqueous humour formation. Pharmacological modulation of these enzymes and re- ceptors can reduce aqueous humour formation and lower IOP. Following transport of aqueous humour into the posterior chamber, it flows through the pupil into the anterior chamber (figure 1). Once there, it maintains

5 Pharmacological Therapy of Glaucoma 5 a physiological IOP and also nourishes the avascular Safety and tolerability are important consideracornea and lens. It may aid in the metabolism of the tions when selecting glaucoma therapy as well. vitreous and retina as well. [24] As mentioned earlier, Glaucoma drops can produce a variety of local adaqueous humour exits the eye through one of two verse effects ranging from induced miosis by pathways. Most of the aqueous humour (about 80%) cholinergics (acetylcholine receptor agonists) to leaves the eye through the TM pathway. This path- lash growth by PGAs (see section 7). Topical drugs way consists of TM, a sieve-like structure which can also produce important systemic adverse effects. consists of a connective tissue core surrounded by Once a glaucoma medication is instilled into the eye, endothelium, and Schlemm s canal, a 360 collector much of it (about 80%) passes through the nasochannel for aqueous humour that leads to the epis- lacrimal canal and is absorbed into the systemic cleral venous system. A small amount of aqueous circulation. Such absorption avoids hepatic firsthumour (about 20%) flows directly through the iris pass metabolism, so with some agents, systemic root and interstitial spaces of the ciliary muscle into adverse effects can be significant. [29] Eyelid closure the suprachoroidal space (uveoscleral pathway). The and punctal occlusion following drop instillation relative percentages of aqueous humour which exit have been shown to significantly decrease the systhe anterior chamber through these two pathways is temic absorption of topical medications. [30] variable and can change with age and presence of disease. [20,25,26] Pharmacological modulation of ad- 3. Cholinergics (Acetylcholine renoceptors and prostanoid receptors located in the Receptor Agonists) TM or ciliary body can increase aqueous humour The cholinergics, also known as parasympathoutflow through one or both pathways and lead to a omimetics or miotics, were the first class of agents reduction in IOP. used for the treatment of glaucoma, introduced over 2. Medical Treatment of Glaucoma 100 years ago. [31] They can be divided into two categories: the direct-acting agents work directly on The cornerstone of glaucoma therapy is the re- the parasympathetic receptors in the eye, whereas duction of IOP to a level which safely halts progres- the indirect-acting agents inhibit acetylcholinestersive visual loss. For most patients, initial treatment begins with medication. Currently, there are five main categories of medication for the treatment of glaucoma (table III). Typically, treatment begins with the selection of an agent as monotherapy. β- Adrenoceptor antagonists have been a mainstay of the medical treatment of glaucoma for many years and are still often used as first-line therapy, particularly Schemm's canal Trabecular meshwork Cornea Ciliary body in Europe and Latin America. Recently, the Lens prostaglandin analogues (PGAs) have emerged as a popular choice for the first-line treatment of Iris glaucoma. [27] Following a therapeutic trial, the medication is either continued or switched to a different Anterior chamber class of medication based on its effect. If expected reduction in IOP is achieved, but additional pressure Posterior reduction is required, another agent can be added to chamber the regimen. The past few years have seen an enormous increase of new available medications for cross section. The dotted line indicates the flow of aqueous humour Fig. 1. Schematic diagram of the anterior segment of an eye in glaucoma therapy (table III). A recent review estimated from its source in the posterior chamber (the ciliary body), through that there are now over possible com- the pupil, into the anterior chamber and toward the trabecular meshwork. A majority of aqueous humour traverses the trabacular binations of medications for the treatment of meshwork, collects in Schlemm s canal, then drains into the venous glaucoma. [28] system (not shown).

6 6 Marquis & Whitson Table III. Drugs used for the treatment of glaucoma Drug class/drug Strength/dose Usual dosage Cholinergics (acetylcholine receptor agonists) Pilocarpine ophthalmic solution (%) 0.5, 1, 2, 4, 6, 8 qid Pilocarpine ophthalmic gel (%) 4 hs Carbachol (%) 0.75, 1.5, 3 tid Ecothiophate iodide (%) 0.25 bid Adrenoceptor agonists Nonselective epinephrine (adrenaline) [%] 0.5, 1, 2 bid dipivefrine (%) 0.1 bid Selective α2 apraclonidine (%) 0.5, 1.0 tid brimonidine (%) 0.2 tid brimonidine P (%) 0.15 tid Carbonic anhydrase inhibitors Systemic acetazolamide (mg) 125, 250 qid acetazolamide sustained release (mg) 500 bid methazolamide (mg) 25, 50 bid to tid Topical brinzolamide suspension (%) 1 tid dorzolamide solution (%) 2 tid β-adrenoceptor antagonists Nonselective carteolol (%) 1 bid levobunolol (%) 0.25, 0.5 bid metipranolol (%) 0.3 bid timolol (%) 0.25, 0.5 bid timolol GFS (%) 0.25, 0.5 qd Selective betaxolol suspension (%) 0.25 bid betaxolol solution (%) 0.5 bid Prostaglandin analogues Bimatoprost (%) 0.03 qd Latanoprost (%) qd Travoprost (%) qd Unoprostone (%) 0.15 bid Combination agents Dorzolamide/timolol (%) 2.0/0.5 bid Hyperosmotic agents IV mannitol IV urea PO glycerin g/kg g/kg g/kg bid = twice daily; GFS = gel-forming solution; hs = at bedtime; IV = intravenous; PO = oral; qd = every day; qid = four times daily; tid = three times daily.

7 Pharmacological Therapy of Glaucoma 7 ase, the enzyme responsible for the degradation of paralysis can occur in patients treated with indirectacetylcholine. The cholinergics lower IOP by in- acting cholinergics during general anaesthesia if creasing outflow of aqueous humour through the suxamethonium chloride is used as a muscle relax- TM. ant. [35] A cataractogenic effect has also been described with chronic use of ecothiophate iodide for 3.1 Direct-Acting Cholinergics the treatment of glaucoma. [36] The indirect agents are still often used for the treatment of glaucomas in Pilocarpine is the most commonly prescribed aphakia or pseudophakia across much of Europe and cholinergic compound. It works by directly stimu- Latin America. lating the muscarinic receptors of the ciliary muscle that widens the anterior chamber angle, resulting in increased outflow of aqueous humour through the 3.3 Dual-Mechanism Cholinergics TM. Pilocarpine is available in multiple concentrarinic Carbachol works by directly stimulating muscations ranging from 0.5% to 8%. It is a short-acting receptors within the eye as well as indirectly by agent and must be applied four times daily. It is also inhibiting acetylcholinesterase. [37] It is available in available as a 4% gel, which is usually applied at concentrations ranging from 0.75% to 3.0% and is bedtime. Pilocarpine typically reduces IOP by about typically applied three times daily. Carbachol re %. [32] It has been shown to decrease uveosto quires an adjuvant, such as benzalkonium chloride cleral outflow, [33] which may have a significant effectively penetrate the cornea and achieve ef- clinical effect in eyes with compromised TM outpotent fective levels in aqueous humour. Carbachol is more flow. than pilocarpine, [38] but is also more likely to produce browache and accommodative spasm. [38] It Adverse Effects is no longer commonly used in current medical Ocular adverse effects of pilocarpine are related practice. to its effect on the ciliary and pupillary sphincter muscle. Visual acuity is often diminished as a result of pupillary constriction and accommodative spasm. 4. Adrenoceptor Agonists Other local adverse events include browache and, rarely, retinal detachment. Systemic adverse effects 4.1 Nonselective Adrenoceptor Agonists from pilocarpine are not common but can include Epinephrine (adrenaline) stimulates both α- and increased salivation and sweating, diarrhoea, vomit- β-adrenoceptors within the eye. IOP reduction is ing and tachycardia. While pilocarpine is an inex- achieved primarily by increased aqueous humour pensive and effective IOP-lowering agent, it is not outflow through both the TM and uveoscleral pathas commonly used today as in previous years be- ways. [39] An acute decrease in aqueous humour procause of its local adverse effects and multiple daily duction from vasoconstriction following instillation dosage requirements. has been described, [40] but is not thought to be important clinically. Epinephrine is available in con- 3.2 Indirect-Acting Cholinergics centrations ranging from 0.5% to 2.0% and is applied twice daily, although it is rarely used in mod- The indirect-acting cholinergics include ecothioern clinical practice. Reductions in IOP ranging phate iodide and demecarium bromide. These agents work by inhibiting acetylcholinesterase, the enzyme from 15% to 25% have been reported. [41] responsible for the degradation of acetylcholine Adverse Effects Like pilocarpine, the indirect-acting miotics are Local adverse effects of epinephrine include puavailable in multiple concentrations. They are typi- pillary dilation, conjunctival hyperaemia and ocular cally used twice daily. The reduction in IOP is irritation. [42] Cystoid macular oedema (CMO) has comparable to that seen with pilocarpine. [34] In addi- been described in patients treated with topical epition to the potential adverse effects seen with pilo- nephrine following cataract surgery. [43] Long-term carpine, these agents deplete systemic cholinester- administration of epinephrine can result in adrease and pseudocholinesterase. Prolonged respiratory nochrome deposits in the conjunctiva [44] and cor-

8 8 Marquis & Whitson nea. [45] Systemic adverse effects associated with epi- for prevention of postoperative IOP elevations folnephrine therapy include headache, palpitations, lowing anterior segment laser surgery. The original high blood pressure and anxiety. 0.2% formulation is approved for three times daily Dipivefrine 0.1% is a pro-drug molecule of epi- administration in the US, although it is often used nephrine with two ester groups added. It was de- twice daily by most clinicians It has received formal signed to enhance corneal penetration and reduce approval for twice daily administration in other systemic and local adverse effects. Following drop countries. Brimonidine 0.2% has been shown to be instillation, corneal esterases cleave the molecule equivalent to timolol at reducing IOP at peak (hour 2 into an active metabolite, which then passes into the after administration), but is significantly less effecanterior chamber. [46] IOP reduction with dipivefrine tive at trough. [53,54] Brimonidine 0.2% is significantis comparable to that seen with epinephrine, while ly more effective at reducing IOP than the cardioseboth local and systemic adverse effects are seen less lective β-adrenoceptor antagonist, betaxolol, at peak frequently. [47] effect (5.8mm Hg vs 3.8mm Hg, p = 0.004). [55] The trough reduction in IOP; however, is comparable 4.2 Selective α 2-Adrenoceptor Agonists between the two agents (3.9mm Hg vs 3.2mm Hg). [55] Clonidine is a relatively selective α2-adrenoceptor agonist with some α1-adrenoceptor agonistic Adverse Effects activity. It lowers IOP by decreasing production of Local adverse effects associated with apracloniaqueous humour. [48] It is a very lipophilic molecule dine include allergic blepharoconjunctivitis and readily crosses the blood-brain barrier. Systemic (15 48%), tearing and foreign body sensation. [56] hypotension can be seen following topical instilla- Eyelid retraction and pupillary mydriasis, through tion of clonidine. It is still used clinically in parts of α1-adrenoceptor stimulation, can be seen as well. Europe for the treatment of glaucoma. Systemic adverse effects include dry mouth, and Apraclonidine, or para-aminoclonidine hydro- nose, headache and fatigue. [57] Unlike clonidine, chloride, is a para-amino derivative of clonidine cardiovascular adverse effects, such as systemic hywith relatively selective α2-adrenoceptor agonistic potension are rarely seen with apraclonidine. [58] activity. It is a much more hydrophilic molecule Brimonidine is devoid of many of the α than clonidine and less likely to penetrate the bloodnoceptor mediated adverse effects seen with 1 -adre- brain barrier. Apraclonidine lowers IOP by reducing aqueous humour production and increasing outflow apraclonidine, such as pupillary mydriasis, eyelid through the TM pathway. [49] It is available in 0.5% retraction and conjunctival blanching. The most and 1.0% concentrations. Mean reductions in IOP common ocular adverse event seen with brimoni- for both concentrations range from 20% to 27%. [50] dine is allergic blepharoconjunctivitis, occurring in The 0.5% concentration is typically used for shortapy. Systemic adverse effects reported with 12 15% of patients after several months of therterm adjunctive therapy (<3 months) in patients not controlled with other agents, whereas the 1.0% conbrimonidine use include dry mouth (33%), fatigue centration is indicated for the prevention of postopshould be avoided in small children because of (16%) and headache (18.7%). [53,54] Brimonidine erative IOP elevation following anterior segment laser surgery. Apraclonidine is rarely used for long- associated CNS and respiratory depression. term therapy because of its high rate of allergic A new formulation, brimonidine P, has recently blepharoconjunctivitis. [51] been introduced that contains a lower concentration Brimonidine is a highly selective α2-adrestabilised of brimonidine (0.15%) and a different vehicle with noceptor agonist. It lowers IOP by decreasing aqueplace oxychloro complex as a preservative in ous humour production and increasing uveoscleral of benzalkonium chloride. Comparable reducous outflow. [52] It is used as mono- or, more typically, tion in IOP to the original 0.2% solution has been adjunctive therapy for the long-term management of reported along with a significantly lower rate of glaucoma or ocular hypertension. It is also effective allergy (9.2% vs 15.7%, p = 0.007). [59] Lower rates

9 Pharmacological Therapy of Glaucoma 9 of fatigue, dry mouth and conjunctival hyperaemia 5.2 Topical CAIs were also found with the new formulation. [59] Dorzolamide was the first topical CAI to be used 5. Carbonic Anhydrase Inhibitors (CAIs) for glaucoma therapy, introduced into the US market in It is available as a 2.0% ophthalmic The carbonic anhydrase inhibitors (CAIs) are solution with a relatively acidic ph of 5.5 and is sulfonamide drugs that lower IOP by reducing aquethis approved for three times daily administration. At ous humour formation. In the ciliary epithelium, dosage it lowers IOP by 18 22%. [63] It has been carbonic anhydrase isoenzyme II catalyses the conacetazolamide shown to be less effective at lowering IOP than oral version of CO2 and H2O to HCO3 and H +, a or 0.5% timolol used twice daily, but process important for the production of aqueous comparable to 0.5% betaxolol used twice daily. [63] It humour. By inhibiting this conversion, aqueous hulatanoprost. is additive in hypotensive efficacy to timolol [64] and mour formation is decreased. CAIs are available as [65] Comparisons between 2% dorzo- both oral (systemic) and topical agents. lamide and 0.2% brimonidine used as monotherapy have shown similar efficacy at both peak and 5.1 Systemic CAIs trough. [66,67] Brinzolamide was introduced into the US market Acetazolamide was first used for glaucoma thersion with a more physiological ph of 7.4, roughly in It is available as a 1.0% ophthalmic suspenapy in [60] It is currently available in 125mg and 250mg tablets, and typically administered four equivalent to that of human tears. Like dorzolamide, times daily. Sustained release capsules of 500mg are brinzolamide is approved for three times daily ad- also available and are used twice daily. Acetazoas ministration. It has been shown to lower IOP equally well as dorzolamide. [68] Brinzolamide has been lamide produces reduction in IOP of about 20 30%. [61] Methazolamide, a slightly weaker CAI, reported to be better tolerated than dorzolamide by is available in 25mg and 50mg tablets. It can be most patients, presumably as a result of its more administered two or three times daily. It is slightly physiological ph. [69] less effective than acetazolamide, but is sometimes better tolerated by patients Adverse Effects When introduced in the mid 1990s, the topical Adverse Effects CAIs represented a major advance over the oral The oral CAIs are effective IOP-lowering agents agents for the medical management of glaucoma. but are limited in their clinical usefulness by their Thus far, they appear to be devoid of many of the numerous and often severe adverse effects. Paraes- significant systemic adverse effects seen with the thesias of the hands and feet, nausea, vomiting, oral CAIs. Bitter taste has been reported in about fatigue and weight loss are all common complica- 25% of patients. [70] Local adverse events seen with tions of chronic oral CAI therapy. Less commonly, dorzolamide include stinging (12%), burning (19%) renal stones may develop with long-term use. Sys- and itching (12%). [63] Irreversible corneal decomtemic acidosis, hypokalaemia, and hyponatraemia pensation has been reported in patients with marked often result from inhibition of carbonic anhydrase in endothelial compromise. [71] In a large, multicentre, the kidney. Although uncommon, bone marrow de- comparative trial, brinzolamide caused less ocular pression resulting in thrombocytopenia, agranulocy- discomfort than dorzolamide, with reported rates of tosis and aplastic anaemia has been described. [62] burning and stinging of 3.0% and 16.4%, respective- Rarely, Stevens-Johnson syndrome may result from ly. [72] Other ocular adverse events associated with oral CAI therapy. Because of their poor tolerability brinzolamide include foreign body sensation in most patients, the oral CAIs are typically reserved (1.8%), itching (1.2%) and dry eyes (1.2%). [72] Like for short-term use in patients on maximal medical the oral CAIs, dorzolamide and brinzolamide are therapy, often as a temporising measure before sur- sulfonamides and should be avoided in patients with gery. sulfonamide hypersensitivity.

10 10 Marquis & Whitson 1 6. β-adrenoceptor Antagonists available as 0.5% preparations. Once daily 0.5% Timoptic XE lowers mean IOP as effectively as β-adrenoceptor antagonists are a commonly pretimolol 0.5% solution used twice daily. [80] Timolol scribed class of agents for the treatment of Maleate Gel-Forming Solution and 0.5% Timoptic glaucoma. Since their introduction for ophthalmic XE produce clinically equivalent reductions in use in 1979, they have been a mainstay of glaucoma IOP. [81] Timolol remains the US FDA s gold stantreatment and a frequent choice for first-line therdard drug for glaucoma therapy against which all apy. Their popularity has declined somewhat in recent years, however, with the introduction of more new medications must be compared prior to approv- effective, safer drugs, in particular, the PGAs. [27] al. Most topical ophthalmic β-adrenoceptor antagonists Levobunolol is available in 0.25% and 0.5% soused today are nonselective agents, inhibiting both lutions and is typically administered twice daily. β1- and β2-adrenoreceptors. These include timolol, Most patients can maintain adequate IOP control levobunolol, metipranolol and carteolol. A β 1 -selec- with once daily therapy as a result of its active tive agent, betaxolol, is also available for use. β- metabolite, dihydrolevobunolol, which is also effecadrenoceptor antagonists lower IOP by reducing tive at lowering IOP. [82] Like timolol, levobunolol aqueous humour formation, most likely through the lowers IOP by decreasing aqueous humour formainhibition of catecholamine-stimulated synthesis of tion. [83] Its efficacy is equivalent to that of cyclic adenosine monophosphate in the ciliary epi- timolol. [84] thelium. [73] While β-adrenoceptor antagonists are very effective IOP-reducing agents, tachyphylaxis, Carteolol is available as a 1% solution and, like or drift may occur after long-term therapy. [74] A timolol and levobunolol, it is administered twice recent study has shown that after 2 years, as many as daily. Its efficacy is comparable to timolol with 50% of patients treated initially with a β-adre- average reported IOP reductions of 20 32%. [85,86] noceptor antagonist as monotherapy will require a Carteolol demonstrates intrinsic sympathomimetic different or additional medication for IOP conadrenoceptor agonist response not seen with other activity (ISA) which produces an early, transient β- trol. [75] topical β-adrenoceptor antagonists. It was hoped 6.1 Nonselective that the ISA of carteolol might protect against some β-adrenoceptor Antagonists of the systemic adverse effects seen with other β- adrenoceptor antagonists, such as reduced pulse and Timolol was the first ophthalmic β-adrenoceptor blood pressure. While this has not proven to be the antagonist approved for the treatment of glaucoma. case, carteolol has been shown to have fewer delete- Like other β-adrenoceptor antagonists, it lowers IOP rious effects on serum lipids than timolol. In a by decreasing aqueous humour formation. [73] It is comparative study involving 58 normolipidemic most effective during waking hours, having little to no effect on aqueous humour production during adult men, topical carteolol therapy was associated sleep and producing less reduction in IOP at with a 3.3% decrease in plasma high-density lipo- night. [73,76] Timolol reduces IOP by 20 35% on avtotal cholesterol/hdl-c ratio, whereas timolol pro- protein-cholesterol (HDL-C) and a 4% increase in erage. [77,78] As a result of its binding to iris melanin, timolol is often less efficacious in patients with dark duced changes of 8% and 10%, respectively. [87] Me- irides. [79] It is available in 0.25% and 0.5% concenother tipranolol 0.3% solution is used twice daily. Like the trations, which are typically used twice daily. Once topical β-adrenoceptor antagonists, it lowers IOP by reducing aqueous humour production. [88] daily gel-forming solutions (Timoptic-XE, Merck & Co., Inc., West Point, PA, USA and Studies have shown comparable efficacy to timolol Timolol Maleate Gel-Forming Solution, Alcon and levobunolol with average IOP reductions of Laboratories, Inc., Fort Worth, TX, USA) are also 21 33%. [89,90] 1 The use of trade names is for product identification purposes only and does not imply endorsement.

11 Pharmacological Therapy of Glaucoma Adverse Effects Adverse Effects In general, topical nonselective β-adrenoceptor Except for occasional transient stinging upon inantagonists are effective and well tolerated by most stillation, betaxolol is typically well tolerated localpatients. Reported local adverse effects include connoceptors, thereby minimising the potential for pul- ly. It was designed to be specific for β 1 -adrejunctival hyperaemia, stinging, superficial punctuate keratitis and worsening dry eye symptoms. [91] Sevmonary (β2-adrenoceptor mediated) adverse effects. In most patients with restrictive airway disease, eral reports of reversible anterior granulomatous betaxolol does not exacerbate breathing uveitis following long-term use of metipranolol problems. [106] However, exceptions have been rehave been published since the early 1990s. [92,93] ported, so caution must be used when prescribing These agents can exert serious systemic adverse betaxolol for patients with respiratory aileffects from inhibition of β1-adrenoceptors of the ments. [107,108] While cardiovascular adverse effects, heart and β2-adrenoceptors of the lung. Bradycardia, such as bradycardia and congestive heart failure arrhythmia, cardiac block, congestive heart failure have been reported with betaxolol therapy, they and bronchospasm have been reported following the appear to be less common than those which are seen use of topical nonselective β-adrenoceptor antago- with the nonselective agents. [109,110] CNS adverse nists. [94,95] These agents should, therefore, be avoid- effects are also less common with betaxolol than ed in patients with severe heart disease, asthma or with nonselective β-adrenoceptor antagonists. [111] chronic obstructive pulmonary disease. They should also be used with caution in patients with diabetes, [96] due to their masking of hypoglycaemia, and 7. Prostaglandin Analogues Since their introduction into the US market in in patients with myasthenia gravis. [97] CNS adverse 1996, the PGAs have emerged as a popular choice effects, including depression, anxiety, impotence, for the first-line treatment of glaucoma. [27] The fatigue and hallucinations have also been described once-daily PGAs, latanoprost, travoprost and bifollowing the use of topical nonselective β-adre- matoprost, are typically the most potent class of noceptor antagonists. [94,95,98] IOP-reducing drugs available. They also offer excellent control of diurnal IOP fluctuation that occurs 6.2 Selective β-adrenoceptor Antagonists commonly among glaucoma patients and increases their risk of visual field progression over the long Betaxolol is a cardioselective β1-adrenoceptor term. [112,113] Finally, except for minor cosmetic issues, such as mild conjunctival hyperaemia and antagonist that lowers IOP by reducing aqueous eyelash growth, they pose few, if any, systemic humour formation. [99] It is a less effective IOPsafety concerns. A fourth PGA, unoprostone, is also lowering agent than timolol and the other nonselecavailable, although it is less effective than other tive agents with average reductions in IOP ranging members of this class and must be used twice daily. from 18% to 26%. [100,101] Despite its weaker IOP- The PGAs are all multicarbon-chain, lipophylic lowering efficacy, two reports have shown trends molecules, derived from arachidonic acid and sharfor better visual field preservation with long-term ing similar structural features to PGF2α (figure 2). betaxolol therapy than with timolol therapy. [102,103] They lower IOP by increasing outflow of aqueous Although increasing ocular perfusion has not yet humour, primarily through the uveoscleral pathbeen proven to be beneficial for the treatment of way. [114] Their exact mechanism of action is still not glaucoma, several investigators have speculated that clear, but they are thought to exert their effect by enhanced retinal and optic nerve head blood flow binding to the prostanoid FP receptors of the ciliary from the calcium channel blocking properties of body, upregulating production of various metalbetaxolol may account for this observed enhanced loproteinases. These metalloproteinases then revisual field preservation. [104,105] Betaxolol is availa- model the surrounding extracellular matrix making ble as a 0.25% suspension and a 0.5% solution that it more permeable to aqueous humour, which leads are each administered twice daily. to enhanced outflow of aqueous humour and reduc-

12 12 Marquis & Whitson HO O O HO O O HO OH HO OH O CF 3 PGF 2α isopropyl ester Travoprost HO O O HO O O HO OH HO O Latanoprost Unoprostone HO O NH HO OH Bimatoprost Fig. 2. Chemical structures of prostaglandin F2α (PGF2α) and commercially available prostaglandin analogues. Latanoprost was introduced into the US market in It has since become the most widely prescribed drug for the treatment of glaucoma in the US and in available countries around the world. Lata- noprost has been compared with timolol in several multicentre studies involving over 800 pa- tients. [ ] Once-daily latanoprost administered in the evening was significantly more effective at low- ering IOP than twice daily timolol. Mean IOP reduction was 6.7 ± 3.4mm Hg for latanoprost compared with 4.9 ± 2.9mm Hg for timolol after 6 months of tion of IOP. [115] PGAs have also been shown to relax the ciliary muscle, further facilitating uveoscleral outflow. [33] Some increased outflow may occur through the TM pathway as well. [116] Only one pub- lished report has compared the safety and efficacy of all three once-daily PGAs (latanoprost, travoprost and bimatoprost) in a single, large, prospective, multicentre trial. This study, which involved more than 400 patients with glaucoma or ocular hypertension, showed statistically equivalent reduction in IOP among the three agents after 3 months of therapy. [117] Significantly more conjunctival hyperaemia occurred with bimatoprost compared with latanoprost (p = 0.001).

13 Pharmacological Therapy of Glaucoma 13 treatment. [118] Unlike timolol, which decreases offers excellent diurnal IOP control and long duraaqueous humour production during waking hours tion of action, with significant reduction in IOP only, latanoprost has been found to be equally as (approximately 6mm Hg) remaining for at least 84 effective at reducing IOP during the evening as hours after its final dose. [131] It is a very stable during the day. [121] Other studies have shown lata- compound and does not require refrigeration or pronoprost to be significantly more effective at reduc- tection from sunlight. [132] Travoprost is available as ing IOP than dorzolamide [122] and brimonidine. [123] a 0.004% solution and, like latanoprost, is adminis- A long-term study involving over 300 patients with tered once daily in the evening. glaucoma or ocular hypertension has shown no loss Bimatoprost was also introduced into the US of efficacy after 5 years of use of latanoprost as an market in the spring of It is termed a prosadjunctive agent. [124] At this time, latanoprost is the tamide because of its unique structural presence of only PGA to have received a formal first-line usage an amide rather than an ester group at the carboxyapproval from the FDA. It requires refrigeration for terminal end of the α carbon chain (figure 2). It is long-term (>1 year) storage as well as protection still not clear whether bimatoprost is hydrolysed to a from sunlight to maintain stability. [125] It does not free acid during its passage through the cornea (as require refrigeration once opened by the patient. It is are the other members of this class of agents) enaavailable as a 0.005% solution administered once bling it to bind to the prostanoid FP receptor, or daily, typically in the evening. whether it enters the eye as an intact molecule to Travoprost was introduced into the US market in interact with a unique, as yet, unidentified, prosthe spring of Similar to the other PGAs, it tamide receptor. [133,134] It lowers IOP by increasing works by increasing outflow of aqueous humour aqueous humour outflow through both the uveosthrough the uveoscleral pathway. It differs from the cleral (pressure-insensitive) pathway as well as the other PGAs, which exhibit partial agonist activity, in TM (pressure-sensitive) pathway. [135] In a large, that it is a full agonist at the PGF2α receptor. [126] randomised, clinical trial involving over 1100 pa- Like latanoprost, travoprost is thought to reduce IOP tients with glaucoma or ocular hypertension, onceby interaction with this receptor resulting in in- daily bimatoprost was found to be significantly creased outflow of aqueous humour. [126] In a large, more effective at lowering IOP than timolol multicentre trial involving over 800 patients with (8.1mm Hg vs 5.6mm Hg, p < 0.001). [136] Bimatoglaucoma or ocular hypertension, 0.004% travoprost prost was also found to be equal or superior at was found to be equal or superior to 0.005% lata- reducing IOP compared with latanoprost after 3 noprost using pooled data, and superior to 0.5% months of therapy in 232 patients. [137] When signifitimolol at reducing IOP after 1 year with final IOP cant baseline IOP differences were accounted for in values ranging from 17.7mm Hg to 19.1mm Hg for this study, both drugs produced equivalent mean travoprost, 18.5mm Hg to 19.2mm Hg for lata- reductions in IOP. More recently, a large, randomisnoprost and 19.4mm Hg to 20.3mm Hg for timo- ed multicentre trial involving 269 patients has lol. [127] Travoprost and latanoprost produced clini- shown bimatoprost to produce significantly greater cally and statistically equivalent reductions in IOP at reduction in IOP than latanoprost at all assessment the majority of individual time points evaluated points after 6 months of treatment. [138] However, in throughout this 1 year study. Two other multicentre this study, the mean IOP lowering effect of latatrials have confirmed its greater efficacy when com- noprost at 8:00am. (24.1%) was much less than that pared with timolol. [128,129] Travoprost has also been reported in previous studies (approximately shown to be an effective adjunctive agent offering 30 35%). [ ] Bimatoprost has also been coman additional 5 7mm Hg IOP reduction in patients pared with the fixed combination 2% dorzolamide/ inadequately controlled on timolol. [130] Subgroup 0.5% timolol (Cosopt, Merck & Co., Inc., West analysis has revealed that travoprost is significantly Point, PA, USA). Bimatoprost produced significantmore effective at reducing IOP (by almost 2mm Hg) ly greater reduction in IOP than Cosopt at the early in Blacks compared with non-blacks. [127] morning timepoint at each visit throughout the 3- Postmarketing studies have shown that travoprost month study. [139] Furthermore, about twice as many

14 14 Marquis & Whitson patients had an IOP <16mm Hg at the final visit with from 1.1% to 23% have been reported with the oncebimatoprost (31% vs 14%). However, it is important daily PGAs. [119,127,136] The incidence with unoprosto note that Cosopt performed less well in this tone appears to be much lower. The increase in study than in earlier reports, [64,140] producing reduc- pigmentation is irreversible and is a result of intions in IOP ranging from only 4.4mm Hg to creased production of melanin within iris melano- 5.6mm Hg versus a more typical range of about cytes, not a proliferation of melanocytes. [146] Eye mm Hg. Bimatoprost is available as a 0.03% lash growth is also common with long-term use of solution and is administered once daily in the eve- these agents with reported rates ranging from 26% ning. It does not require refrigeration to maintain to 57%. [127,136] Exacerbations of anterior uveitis [147] stability. [141] and herpetic keratitis [148] have been reported with Unoprostone was introduced in Japan in 1994 latanoprost use. CMO has been reported with use of and became available in the US in the summer of latanoprost after complicated cataract surgery and in It differs structurally from the other PGAs in those with a history of CMO. [149,150] The PGAs having a 22-carbon chain backbone instead of the should probably be avoided in these patients. typical truncated 20-carbon structure found in the other agents (figure 2). When used as monotherapy, studies have shown twice daily unoprostone to be 8. Combination Therapy significantly less effective than either timolol [142] or The selection of agents for combination therapy latanoprost. [143] It has demonstrated comparable ef- in the treatment of glaucoma is a task commonly ficacy to brimonidine or dorzolamide when used as encountered by clinicians. In the OHTS, almost 50% an adjunctive agent to timolol. [144] It is available as a of patients required two or more medications to 0.15% formulation and is administered twice daily. reach the required, relatively modest, target IOP Because unoprostone is less effective at lowering reduction of 20% from baseline and a final IOP of IOP than the other PGAs and requires more frequent <24mm Hg. [15] For many years, β-adrenoceptor anadministered, its clinical use has been somewhat tagonists have been a mainstay of glaucoma therapy limited. and remain a popular choice for first-line therapy In general, the PGAs are well tolerated drugs among some ophthalmologists. Recently, however, with typically <5% of patients discontinuing regis- the once-daily PGAs have assumed a leading role in tration studies as a result of adverse events. Report- the initial medical treatment of glaucoma. [27] Once a ed systemic adverse effects have been limited to first-line agent is chosen, its efficacy is evaluated headache and upper respiratory tract symptoms. after a brief trial period. If less than expected IOP Specifically, latanoprost has been shown to have no reduction is produced, the drug is usually stopped deleterious effect on blood pressure, pulse and pul- and an alternate class of agents is tried. If the exmonary function in patients with chronic obstructive pected IOP reduction occurs but a lower IOP is pulmonary disease. [145] Local cosmetic effects, on needed for that particular patient, selection of an the other hand, are common with these agents. Con- adjunctive agent is typically performed. junctival hyperaemia has been reported in 3 15% of When selecting an adjunctive agent, its safety patients treated with latanoprost. [ ] Hyperaemia and tolerability are of paramount concern. A simple is more commonly seen with the newer agents with dosage regimen can enhance patient compliance. reported rates of 15 45% for bimatoprost [136,137] and Also, an agent s ability to work well with the initial 35 50% for travoprost. [ ] Typically, the con- drug chosen is important to consider. A drug used junctival hyperaemia seen with these agents is fairly for the treatment of glaucoma lowers IOP by one of mild in most patients. About 3% of patients in phase two ways, as mentioned earlier: reduction of aque- III studies discontinued therapy with bimatoprost ous humour production or increased outflow of and travoprost because of hyperaemia. aqueous humour (table IV). When choosing agents An increase in iris pigmentation, most often in for combination therapy, those drugs with complemulticoloured irides, can occur with long-term use mentary mechanisms of action usually work well of the PGAs. Rates of iris colour change ranging together.