Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

Table 2

Mechanism of Action of Drugs Used to Treat Glaucoma

Increased aqueous humor outflow-Adrenoceptor agonists Cholinergics

Prostaglandin analogues Decreased aqueous humor production

-Adrenoceptor agonists-Adrenoceptor antagonists Carbonic anhydrase inhibitors

humor outflow through either the trabecular meshwork or the uveoscleral pathway, and the episcleral venous pressure. This complex relationship can be described as

IOP = F − U/C + Pv

where F is aqueous humor production in μL/min, U is uveoscleral outflow in μL/min, C is outflow facility of the trabecular meshwork in μL/min/mmHg, and Pv is episcleral venous pressure in mmHg. In glaucoma, decreased facility of outflow through the trabecular meshwork pathway is thought to result in elevated IOP. Aqueous humor production occurs at a rate of 1.4–4.3 mmHg/min (1) and typically decreases with age (2). Pharmacological modulation of adrenoceptors, adenosine triphosphatases, and carbonic anhydrase located in the nonpigmented ciliary epithelium can decrease production of aqueous humor and result in a reduction of IOP. Most of the aqueous humor (about 80%) exits the eye through the trabecular meshwork pathway while the remainder passes directly through the interstitial spaces of the ciliary muscle into the choroidal space, although these relative amounts may change with age or inflammation (2,3). Increased outflow of aqueous humor and reduction of IOP can occur through pharmacologic modulation of adrenoceptors and prostanoid receptors located along the outflow pathways.

BIOAVAILABILITY OF TOPICAL DRUGS

The bioavailability of topical drugs used for the treatment of glaucoma is influenced by the properties of the conjunctival cul de sac, the tear film, ocular penetration, drug formulation, and drug elimination. The conjunctival cul de sac has an average volume of about 7–10 μL, although this can temporarily expand to 30 μL following instillation of an eyedrop (4). Because the drop size of commercially available glaucoma medications ranges from about 30 to 60 μL (5), much of the drug will spill out onto the cheek or into the lacrimal drainage system following instillation. Tear turnover rate is about 15% per minute under normal conditions. Following instillation of an eyedrop, reflex tearing increases this rate to 30% per minute. Thus, dilution and loss of the drug in the tear film is rapid, typically occurring within a few minutes after instillation. Punctal occlusion and eyelid closure can increase drug–cornea contact time and reduce systemic absorption through the nasolacrimal canal (6).

To reach its therapeutic target, the drug must then penetrate the cornea and anterior sclera (7). The cornea can be thought of as a “lipid–water–lipid” sandwich in which the lipid content of the epithelium and endothelium is about 100 times greater than the stroma (8). Because of its dual nature, only drugs that have both water and lipid soluble properties—typically weak acids or bases—can penetrate the intact cornea. Drugs tend to accumulate in various layers of the cornea, which can then serve as a temporary reservoir (9).

The formulation of a drug can affect its bioavailability. Most glaucoma medications have a molecular weight less than 500 g/mol and exist predominantly in the nonionized form at physiologic pH of 7.4. Each of these properties enhances corneal penetration (9,10). Increasing drug concentration can also enhance penetration up to a point, beyond which further increases only lead to greater dilution of drug in the tear film and loss through the nasolacrimal system (11). Ointments increase drug bioavailability by decreasing dilution in the tears and increasing drug–cornea contact time (12). Their usage is limited, however, because of difficulty of instillation and interference with vision. Aqueous suspensions and soluble gels have also been used to increase drug–cornea contact time and enhance bioavailability. Finally, preservatives such as benzalkonium chloride can enhance ocular penetration of certain drugs (13), although they may also damage the corneal epithelium and conjunctiva (14,15) and contribute to symptoms of ocular discomfort (16).

Once inside the eye, a portion of the drug is eliminated by passage through the aqueous outflow pathways (17) or by diffusion into the vascular system. Some drugs bind to melanin (18,19) within the anterior uveal tract, or to proteins in the tears, cornea, or aqueous humor, resulting in decreased bioavailability (20). A variety of enzyme systems within the eye also contribute to drug metabolism and elimination (21).

GUIDELINES FOR THE MEDICAL THERAPY OF GLAUCOMA

Initiate Treatment

Treatment typically begins with the selection of an agent as monotherapy. This medication should provide maximal reduction of IOP with minimal potential for adverse reactions. Beta-blockers have been used extensively as first-line agents for many years; although recently, the PGAs have emerged as a popular first-line choice (22). Ideally, initiation of therapy should begin with a one-eyed therapeutic trial, although this rationale has been questioned by recent authors (23). If the therapeutic trial demonstrates lack of efficacy of a certain drug, a different class of medication should be tried before adding additional agents. The chosen regimen should be simplified as much as possible to enhance compliance (24), decrease cost, and reduce potential for adverse effects.

Educate the Patient

Patient education is vital for successful glaucoma therapy. Patients must be educated about the chronic nature of glaucoma and the need for life-long treatment and monitoring. They must also be warned about the possibility of the most common and potentially dangerous side effects of the prescribed medications. Proper technique

for instillation of drops should also be demonstrated. The following method of drug instillation has been described by Fraunfelder (25):

1)Gently grasp the lower lid below the lashes and pull it forward, creating a pocket.

2)Place one drop of the medication into the pocket without touching the eye or periocular structures with the bottle tip.

3)Hold the lid forward for a few seconds while the drop settles into the lower cul de sac.

4)Look down and bring the lower lid up until it touches the eye.

5)Place gentle pressure over the puncta for 2 min.

When multiple drop regimens are required, patients must be instructed to wait 5–10 min between consecutive drops to prevent washout of the first medication (26). Written directions, including the name(s) of the drug(s) and the time(s) and/or frequency of administration, should also be provided to the patient to help decrease confusion and enhance compliance. It may also be important in some patients with glaucoma to maintain contact with the patient’s primary care provider to gain a better understanding of the patient’s general health and to help prevent drug-induced side effects and potential drug interactions with concurrent medications for systemic conditions.

Consider Compliance

Because glaucoma is a chronic, slowly progressive disease, and is often asymptomatic until late in its course, noncompliance with medical therapy is common. Studies have shown that many patients default on therapy a significant percentage of time (27–29) and are more likely to be noncompliant with complex drug regimens (24). Moreover, physicians are typically unable to predict or identify patients who are noncompliant with therapy (30). Methods to improve compliance include simplifying the drug regimen, patient education, tailoring therapy to an individual patient’s lifestyle or activities, reducing side effects of therapy, and improving the doctor–patient relationship (31).

Control Costs

It is important to remember that many patients with glaucoma are elderly people living on fixed incomes and may require medications for other conditions. Great variability in drug prices often exists between pharmacies within the same neighborhood or general area (32). Patients should be encouraged to shop for the lowest medication prices available. Prescribing generic equivalents or larger quantities of medication can help reduce cost as well.

Monitor the Patient

Once an acceptable reduction in IOP has been achieved, a patient is typically reevaluated about every 3–6 months. Because diurnal pressure can fluctuate greatly in patients with glaucoma, it is important to schedule follow-up visits at different times of the day to help avoid missing daytime spikes in IOP. This is especially important when changing therapy or when evaluating a patient with progressive disease despite apparent adequate IOP control. Over years of follow-up, it can be helpful to discontinue a medication in one eye for a short period to ensure continued efficacy.

ADRENERGIC AGONISTS

Nonselective Adrenergic Agonists

The nonselective adrenergic agonists include epinephrine and dipivefrin, a prodrug of epinephrine. Each agent stimulates both the -adrenergic and the -adrenergic receptors within the eye. Shortly after instillation, a transient decrease in aqueous humor production occurs, most likely through an -adrenergic mediated vasoconstriction in the ciliary processes (33). With chronic use, however, the IOP-lowering effect of epinephrine is thought to be due to increased aqueous humor outflow through both the trabecular meshwork and the uveoscleral pathways (34). Epinephrine was used for many years for the treatment of glaucoma in concentrations of 0.5–2.0% achieving pressure reductions ranging from 15 to 25% (35). It is rarely used today throughout most of the world.

Dipivefrin, or dipivefrin epinephrine, is a modified form of the parent epinephrine molecule to which two ester groups have been added (36). It is a much more lipophilic compound than epinephrine (37) and undergoes hydrolysis into the active epinephrine compound as it passes through the cornea (38). Dipivefrin is currently available as a 0.1% solution and is administered twice daily. Studies have shown comparable efficacy to epinephrine 1 or 2% (39) and betaxolol 0.5% (40).

Local side effects of the epinephrine compounds include burning upon instillation, conjunctival hyperemia, and mydriasis. With chronic use, oxidation and polymerization of epinephrine may occur resulting in the formation of adrenochrome, which can be deposited in several ocular tissues including the conjunctiva (41), cornea (42), nasolacrimal sac (43), and nasolacrimal duct (44). Epinephrine maculopathy, a reversible type of cystoid macular edema, has been described in aphakic eyes treated with epinephrine following cataract surgery (45). Systemic side effects from topical epinephrine use include tachycardia, high blood pressure, headaches, tremors, and anxiety. Both local and systemic side effects are less common with dipivefrin; however, development of large bulbar conjunctival follicles may occur following its prolonged use (46,47). Neither epinephrine nor dipivefrin are commonly used in modern clinical practice for glaucoma management. They may play a role in combination with miotics or topical CAIs when other agents are contraindicated or not well tolerated.

Selective 2-Adrenergic Agonists

Clonidine is an -adrenergic receptor agonist with both 1 and 2 activity. Topical administration of clonidine lowers IOP (48) by reducing production of aqueous humor (49). It is a very lipophilic molecule and readily crosses the blood–brain barrier to produce centrally mediated systemic hypotension. This has limited its clinical use as an ocular hypotensive agent, although it is still used in some parts of Europe for the treatment of glaucoma.

Apraclonidine, a para-amino derivative of clonidine, is less lipophilic than clonidine. Apraclonidine is much less likely to cross the blood–brain barrier, thereby causing fewer cardiovascular side effects (50). It is a relatively selective 2 agent with some1 activity. Studies have shown it may lower IOP by both reducing aqueous humor

production (51) and increasing outflow facility (52). It is available in 0.5 and 1.0% formulations. Efficacy studies have shown both concentrations lower IOP by 20–27% (53,54) when used twice daily. The 0.5% solution has shown similar efficacy to timolol 0.5% (53). Comparable daytime reductions in aqueous humor production when compared to timolol 0.5% have also been demonstrated (55).

Apraclonidine 0.5% can be used twice or three times daily for short-term therapy (less than 3 months) in those patients not controlled by other agents. Additivity to timolol (56) and other nonselective -blockers (57) has been demonstrated. The 1% solution has proven to be quite effective at minimizing short-term pressure elevations following anterior segment laser procedures such as iridotomy (58), trabeculoplasty (59), and capsulotomy (60), although it is less effective in those patients already being treated with the drug on a chronic basis (61).

The most common ocular side effect seen with apraclonidine is an allergic blepharoconjunctivitis, occurring in up to 48% of patients (62). This high rate of allergic reactions has significantly limited its long-term use for glaucoma management. Other local adverse events include eyelid retraction, pupillary mydriasis, tearing, and foreign body sensation (63). Systemic side effects from apraclonidine include transient dry nose and mouth, fatigue, and headache (64).

Brimonidine tartrate is a highly selective 2-adrenergic receptor agonist. Its effect on aqueous humor suppression is comparable with apraclonidine (65), but less than that of timolol (66). It has also been shown to increase uveoscleral outflow without affecting trabecular outflow or episcleral venous pressure (67). The original 0.2% formulation can be used as either monotherapy or adjunctively with other agents and is also useful for the prevention of postoperative pressure elevation after anterior segment laser surgery (68). It has been formally approved for three times a day dosing in the USA, but is approved for twice daily use in other countries. Brimonidine 0.2% is comparable in IOP-lowering efficacy to timolol 0.5% at peak, but significantly less effective at trough (69). It has also been shown to be superior to betaxolol 0.25% used twice daily (70) and comparable to dorzolamide 2% taken three times daily (71). Twice-daily brimonidine 0.2% is comparable to once-daily latanoprost at peak but less effective at trough (72).

Because of its high selectivity for the 2-adrenergic receptor, brimonidine does not typically produce many of the 1-mediated side effects seen with apraclonidine, such as eyelid retraction and pupillary dilation. Allergic blepharoconjunctivitis, while not as common as that seen with apraclonidine use, still occurs fairly often with reported rates ranging from 12 to 15% (69,73). Systemic side effects include oral dryness, fatigue, and headache (74). Because of the risk of pronounced central nervous system and respiratory depression, brimonidine should be avoided in small children (75).

A new formulation of brimonidine has been developed with a lower concentration of drug (0.15%) preserved in stabilized oxychloro complex (Purite®) in place of benzalkonium chloride. Comparable efficacy and lower rates of allergy, dry mouth, and fatigue when compared with the original formulation have been reported (76). A 0.1% concentration of this agent has recently become available for clinical use as well.

-ADRENERGIC ANTAGONISTS

-Adrenergic antagonists, or -blockers, were first introduced for the treatment of glaucoma in the late 1970s. Since then, they have been a mainstay for the medical management of glaucoma, although their popularity has waned somewhat in recent years with the introduction of PGAs (22). Tonographic (77) and fluorophotometric (78) studies have shown that -blockers lower IOP by reducing aqueous humor production, presumably through inhibition of catecholamine-stimulated cyclic adenosine monophosphate (cAMP) synthesis in the ciliary epithelium (79). -Blockers have no significant effect on either aqueous outflow facility (80) or the blood–aqueous barrier (81). They are available for clinical use as nonselective agents, inhibiting both1- and 2-adrenoreceptors, and 1-selective agents.

The IOP-lowering effect of topical -blockers peaks 2 h after administration (82) and lasts for at least 24 h (83). These agents are typically dosed twice daily for optimum results, although many patients can be controlled with once-daily therapy (84,85). Although they are effective at lowering IOP in chronic glaucoma management, some patients may demonstrate a loss of efficacy with continued use (86). “Long-term drift” typically begins within 3 months to 1 year after starting therapy (87) and may resolve after a brief washout period (88). Topical -blockers are often less effective in patients receiving oral -blockers for cardiovascular disease (89). Studies have revealed that up to one-half of patients treated with -blockers as initial therapy will require a different or additional medication for pressure control within 2 years (90).

Nonselective -Blockers

Timolol was the first -blocker to be used for the management of glaucoma and remains the US Food and Drug Administration’s “gold standard” for comparison of new glaucoma medications before approval. Like other topical -blockers, timolol lowers IOP by reducing aqueous humor production (78). It is available in both 0.25 and 0.5% concentrations and is typically dosed twice a day. Reported rates of reduction in IOP range from 20 to 35% (91). However, recent circadian studies have revealed that timolol is significantly less effective at night than during the day (92), presumably because of its lack of effect on nocturnal aqueous humor formation (93). It may also be less effective in patients with dark irides because of melanin binding (94). Comparison studies have shown timolol to have superior IOP-lowering efficacy than epinephrine (95) and pilocarpine (96), and slightly less efficacy than phospholine iodide in patients with aphakia (97). Additivity with timolol has been demonstrated with pilocarpine (98), brimonidine (99), both oral (100) and topical (101) CAIs, and the PGAs (102,103).

Two gel-forming solutions of timolol (Timoptic XE® and Timolol Maleate Gel Forming Solution®) are also available for clinical use. Studies have shown similar IOP-lowering efficacy between once-daily timolol gel and timolol solution used twice daily (104,105). Timoptic XE® is formulated in both 0.25 and 0.5% concentrations whereas Timolol Maleate Gel Forming Solution® is available in a 0.5% concentration. A comparison study has revealed the two timolol gel formulations to produce similar reductions in IOP (106).

Levobunolol, an analogue of propranolol, is available in both 0.25 and 0.5% concentrations. Like timolol, levobunolol reduces IOP by decreasing aqueous humor

formation (107). Comparative studies have shown twice-daily levobunolol to be equivalent to twice-daily timolol (108) and metipranolol (109), and superior to betaxolol (110). Once-daily instillation of levobunolol 0.5% provides equivalent reduction in IOP to twice-daily therapy in many patients because of its active metabolite, dihydrolevobunolol, which is also effective at reducing IOP (111).

Carteolol is available as a 1% formulation and lowers IOP as effectively as timolol with less ocular irritation (112). Unlike other topical -blockers used for glaucoma management, carteolol has intrinsic sympathomimetic activity (ISA) that produces an early, transient adrenergic response. Although the ISA of carteolol has not proven to protect against systemic -adrenergic effects such as reduced pulse and blood pressure (113), it may decrease the risks associated with serum lipid abnormalities. In a comparative trial involving 58 healthy, normolipidemic adult men, topical carteolol 1% produced a 3.3% decrease in plasma high-density lipoprotein (HDL) cholesterol and a 4% increase in total cholesterol/HDL ratio, whereas timolol therapy was associated with changes of 8 and 10%, respectively (114).

Metipranolol is available in a 0.3% formulation, and like other topical -blockers, lowers IOP by reducing aqueous humor inflow (115). Studies have shown similar efficacy and safety to timolol (116) and levobunolol (109) with pressure reductions ranging from 21 to 33%.

Although local side effects are uncommon with nonselective -blockers, occasional burning, conjunctival hyperemia, superficial punctate keratopathy, worsening dry eye symptoms, and corneal anesthesia have been reported with their use (117). Several cases of reversible granulomatous anterior uveitis have been described with metipranolol therapy (118,119).

Measurable plasma levels of timolol can be found within a few minutes after dosing (120) and can be significantly reduced by nasolacrimal occlusion (121). Through systemic absorption, adverse events can occur with topical -blocker use by inhibition of 1-receptors in the heart and 2-receptors in the lung. Reported cardiovascular effects include bradycardia, arrhythmias, heart failure, and syncope (122,123). Asthmatics are especially prone to bronchospasm and airway obstruction (124). A variety of central nervous system effects have been associated with topical -blocker therapy including depression, anxiety, confusion, hallucinations, fatigue, and emotional lability (125,126). Topical -blockers may also mask the signs of hypoglycemia in diabetics (127) and have been reported to exacerbate myasthenia gravis (128).

Selective -Blockers

Betaxolol is a cardioselective 1-receptor blocker, currently available as a 0.25% ophthalmic suspension that is dosed twice daily. Like the nonselective agents, betaxolol lowers IOP by reducing aqueous humor production (129). Studies have shown slightly less efficacy when compared with timolol with reported rates of IOP reduction ranging from 18 to 26% (130,131). Despite less effective IOP control, studies have reported better visual field preservation with long-term therapy when compared with timolol (132,133). Some authors have speculated that improved retinal and optic nerve head blood flow from betaxolol’s calcium channel-blocking properties may account for this

observation (134,135). Other comparative studies have revealed similar efficacy to dipivefrin (40) and slightly less efficacy when compared with brimonidine (70).

Betaxolol is usually well tolerated locally, except for occasional transient burning and stinging upon instillation. Although it typically does not cause breathing problems in patients with reactive airway disease (136), exacerbations have been reported (137), so it should be prescribed with caution in patients with asthma or chronic obstructive pulmonary disease. Cardiovascular side effects (138) and central nervous system side effects (139) appear to be less common with betaxolol than with nonselective-blockers.

CARBONIC ANHYDRASE INHIBITORS

The CAIs are sulfonamide derivatives that lower IOP by reducing aqueous humor inflow. They are available as both oral (systemic) and topical agents. In the ciliary epithelium, CA catalyzes the hydration of CO2 into carbonic acid (H2CO3), with the resultant formation of HCO3− and H+, a process important for aqueous secretion through ion transport. Although four CA isoenzymes have been identified within the eye (140–143), the CA II isoenzyme is thought to be the main therapeutic target (144). Both topical and oral CAIs should be avoided in patients with known sulfonamide hypersensitivity.

Oral CAIs

Acetazolamide was first used as an oral agent for the reduction of IOP in 1954 (145). Fluorophotometric studies have shown that acetazolamide reduces aqueous humor inflow by 21 to 30% in the human eye (146) and lowers IOP by up to 30% from baseline (147). It is available in 125 and 250 mg tablets that are dosed four times a day and 500 mg sustained release capsules that are taken twice daily (148). Methazolamide is available in 25 and 50 mg tablets and is typically dosed two to three times a day. Methazolamide has a longer plasma half-life and a lower rate of protein binding than acetazolamide. It is less effective than acetazolamide at reducing IOP (149) but is also less likely to cause systemic side effects (150).

An idiosyncratic, transient, induced myopia has been described with oral use of acetazolamide (151), which is thought to occur from ciliary body edema and forward displacement of the lens-iris diaphragm (152). Systemic adverse effects of the oral CAIs are very common and often limit their clinical use. Paresthesias of the hands and feet and urinary frequency are often seen following initiation of therapy. Gastrointestinal symptoms, such as nausea, diarrhea, weight loss, and metallic taste are also common. Serum electrolyte imbalances including metabolic acidosis from loss of bicarbonate and hypokalemia from urinary excretion may occur and are especially common in elderly patients (153). Kidney stone formation, through reduced excretion of urinary citrate (154) or magnesium (155), has been associated with oral CAI therapy (156). Bone marrow depression resulting in thrombocytopenia, agranulocytosis and aplastic anemia are uncommon, idiosyncratic reactions that typically occur within a few months of starting therapy. Although quite rare, Stevens–Johnson syndrome has also been associated with chronic oral CAI use (157). Because of their numerous adverse systemic

effects and poor tolerability in many patients, the oral CAIs are most commonly used in acute settings or as short-term treatment in patients on maximal topical therapy.

Topical CAIs

The topical CAIs lower IOP by decreasing aqueous humor flow through inhibition of the CA II isoenzyme in the ciliary epithelium (158). Dorzolamide was the first topical CAI to be used for the treatment of glaucoma, approved in the USA in 1994. The recommended dosage is three times daily, although it is often prescribed twice a day by clinicians to enhance patient compliance. It is formulated with a relatively acidic pH of 5.5 and is available as a 2% solution in the USA and as both a 0.5 and a 1.0% solution in other countries. Studies have shown mean IOP reduction of 18 to 22% with three times daily dorzolamide 2% (159). Efficacy is less than twice-daily timolol 0.5% but comparable to twice-daily betaxolol 0.5% (159). As monotherapy, it is comparable to brimonidine 0.2% at both peak and trough (71,160). Adjunctive studies have shown additivity to timolol 0.5% (161) and latanoprost (162).

Brinzolamide was approved for use in the USA in 1998. It is available as a 1% ophthalmic suspension and is formulated with a more neutral pH of 7.4. It lowers IOP by the same mechanism as dorzolamide (163). Comparative studies of brinzolamide 1% and dorzolamide 2% have shown similar IOP-lowering efficacy between the two agents when used as monotherapy (164) or when used adjunctively (165). When added to timolol 0.5%, further reduction in IOP of greater than 4.0 mmHg can be produced (166).

A major advantage of the topical CAIs is the significant reduction in systemic adverse effects seen with use of the oral agents (167). Transient bitter taste has been reported in about 25% of patients treated with dorzolamide (168) or brinzolamide (169). Rarely, thrombocytopenia can occur with topical CAI use (170). Increased central corneal thickness can occur following exposure to dorzolamide in patients with corneal guttata (171). In patients with marked endothelial compromise, irreversible corneal decompensation has been reported (172). Brinzolamide may be better tolerated than dorzolamide in some patients because of its more physiologic pH (173). Comparative studies have shown less ocular discomfort and lower rates of burning and stinging with brinzolamide (174).

CHOLINERGICS

The cholinergics, also known as parasympathomimetics or miotics because of their constricting effect on the pupil, work by mimicking the cholinergic effect of acetylcholine. They are among the oldest agents used for the treatment of glaucoma, having been introduced in the 1870s (175). Cholinergics can be classified as direct-acting agents that act by directly stimulating the parasympathetic receptors in the eye, and indirect-acting agents that work by inhibiting acetylcholinesterase, the enzyme responsible for the hydrolysis of acetylcholine. These agents lower IOP by increasing trabecular outflow of aqueous humor. Although the cholinergics have been largely supplanted by newer classes of glaucoma medications, they may still play a role in the management of selected patients.