Glaucoma medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Rohan Bir Singh, M.B.B.S.[2]

Overview

Medical Management of Glaucoma

1. Two decisions arise in choosing an appropriate glaucoma therapy:

   • when to treat
   • how to treat

2. Primary angle-closure and infantile glaucoma are treated as soon as the diagnosis is made.
3. Open-angle glaucoma is treated:

   • when damage to the optic nerve has been demonstrated in the form of progressive pathologic cupping and/or characteristic visual field defects
   • when IOP is elevated to an extent that it is likely to cause damage to the optic nerve.

4. The goal of currently available glaucoma therapy

   • To preserve visual function by lowering IOP below a level that is likely to produce further damage to the nerve.
   • The treatment regimen should have lowest risk, fewest side effects, and least disruption of the patient’s life

5. Target pressure goal

   • Should actually be a range with an upper IOP limit that is unlikely to lead to further damage of the nerve in a given patient
   • The more advanced the glaucomatous process on initial presentation, the lower the target pressure generally needs to be prevent further progression.
   • An initial reduction in the IOP of 20%-30% from baseline is suggested, but those patients who have progressive NTG may require a decrease of at least 30% from baseline.
   • The target pressure range needs to be reassessed or changed as comparisons of IOP fluctuations, optic nerve changes, and/or visual field progression dictate.

6. The anticipated benefits of any therapeutic regimen should justify the risks, and regimens associated with substantial side effects should be reserved for patients with a high probability of eventual severe visual dysfunction.

Drugs

• Ocular hypotensive agents are divided into several group based on chemical structure & pharmacologic action:

1. Beta-adrenergic antagonists (nonselective and selective)
2. Parasympathomimetic(miotic)agents,including cholinergic and anticholinesterase agents
3. Carbonic anhydrase inhibitors (oral, topical)
4. Adrenergic agonists (nonselective and selective alpha2 agonists)
5. Prostaglandin analogues
6. Combination medications
7. Hyperosmotic agents

1. Beta Adrenergic Agonists (Beta Blockers)

   • Mechanism of action of topical beta blockers
     • Inhibition of cAMP production in ciliary epithelium → reduction of aqueous humor secretion 20%-50% (2.5 ml/min to 1.9 ml/min) → IOP reduction of 20%-30%.
   • The effect of beta blockers on aqueous production occurs within 1 hour of instillation and can be present for up to 4 weeks after discontinuation.
   • As systemic absorption occurs, a contralateral effect with lowering of the IOP in the unilateral eye can also be observed.
   • Beta blockers are additive in combination with miotics, adrenergic agonists, CAIs (oral, topical) and prostaglandin analogues.
   • Approximately 10%-20% of the patients treated with topical beta blockers fail to respond with significant lowering of the IOP.
   • If a patient is on systemic beta-blocker therapy, the addition of topical beta blockers may be significantly less effective.
   • Use of beta blockers for more than months to years may reduce their effectiveness, as the response of beta receptors is affected by constant exposure to an agonist (long-term drift, tachyphylaxis). Similarly, receptor saturation (drug-induced upregulation of beta receptors) may occur within a few weeks, with loss of effectiveness (short-term escape)
   • Six topical beta blockers are approved for use for the treatment of glaucoma in the US. All except betaxolol are non cardioselective beta1 and beta2 antagonists. Beta1 activity is largely cardiac and beta2 activity largely pulmonary.
     • Betaxolol (0.25%, bid)
     • Carteolol hydrochloride (1.0%, qd, bid)
     • Levobunolol ( 0.25%, 0.5%, qd, bid)
     • Metipranolol (0.3%, bid)
     • Timolol maleate → 0.25%, 0.5%. qd, bid
     • Timolol hemihydrate → 5.12 mg/ml, qd, bid
   • Since betaxolol is a selective beta1 antagonist, it is significantly safer than the nonselective beta blockers when pulmonary, CNS, or other systemic conditions are considered. Betaxolol may be useful in patients with a history of bronchospastic disorders, although other therapies should be tried in lieu of betaxolol, as beta selectivity is only relative and not absolute, and some beta2 effect can therefore remain. In general, the IOP-lowering effect of betaxolol is less than the nonselective beta blockers.
   • Carteolol demonstrates intrinsic sympathomimetic activity, which means that, while acting as a competitive antagonist, it also causes a slight to moderate activation of receptors. Thus, even though carteolol produces beta-blocking effects, these may be tempered, reducing the effect on cardiovascular and respiratory systems. Carteolol may also be less likely to adversely affect the systemic lipid profile when compared with other beta blockers.
   • Ocular and systemic side effects
     • bronchospasm
     • bradycardia
     • increased heart block
     • lowered blood pressure
     • reduced exercise tolerance
     • CNS depression
     • Diabetic patients may experience reduced glucose tolerance and masking of hypoglycemic signs and symptoms.
     • Abrupt withdrawal of ocular beta blockers can exacerbate symptoms of hyperthyroidism.
     • Other side effects include lethargy, mood changes, depression, altered mentation, light-headedness, syncope, visual disturbance, corneal anesthesia, punctate keratitis, impotence, reduced libido, allergy and alteration of serum lipids.

2. Parasympathomimetic agents

   • Classification
     • Direct-acting cholinergic agonists (e.g., pilocarpine)
       • Affect the motor end plates in the same way as acetylcholine, which is transmitted at postganglionic parasympathetic junctions, as well as at other autonomic, somatic, and central synapses.
     • Indirect-acting anticholinesterase agents (e.g., echothiophate iodide,demecarium bromide)
       • Inhibit the enzyme acetylcholinesterase, thereby prolonging and enhancing the action of naturally secreted acetylcholine.
   • Carbachol has both direct and indirect actions, although its primary mechanism is direct.
   • Mechanism of IOP Reduction
     • both direct- and indirect-acting agents Contraction of the ciliary muscle, which pulls the scleral spur to tighten the trabecular meshwork, increasing the outflow of aqueous humor.
   • These agents can reduce the IOP by 10%-20%.
   • The currently accepted indications for miotic therapy
     • Chronic treatment of increased IOP in patient with at least some filtering angle
     • Prophylaxis for ACG prior to iridectomy
   • Other actions of the parasympathomimetic agents
     • Reduce uveoscleral outflow. This action may actually worsen the glaucoma if miotics are used in patients with little to no trabecular outflow.
     • Cause the pupillary sphincter to contract, stimulate secretory activity in the lacrimal and salivary glands, and disrupt the blood-aqueous barrier. These actions have little bearing on the IOP-lowering effect, except in ACG, where the mechanical action of the contracting pupillary sphincter may pull the iris away from the trabecular meshwork.
   • Side effects of miotic agents
   • Retinal detachment, especially in patients with peripheral retinal disease.
   • Induced myopia, brow ache, alteration of vision in dim light and in patients with lens opacities.
   • Paradoxical angle closure (indirect-acting miotics or the stronger direct- acting agents), caused by the contraction of ciliary muscle leads to forward movement of the lens-iris diaphragm, an increase in the anteroposterior diameter of the lens, and a very miotic pupil. The concomitant administration of an alpha-adrenergic agonist such as phenylephrine may cause a larger pupil without interfering with the reduction of IOP.
   • Generalized cataract formation in addition to anterior subcapsular opacity (indirect-acting miotics). Direct-acting agents may also be weakly cataractogenic.
   • Formation of iris pigment epithelial cysts (indirect-acting miotics)
   • Ocular surface changes (pseudopemphigoid) (indirect-acting miotics)

Major Studies

• Advanced Glaucoma Intervention Study (AGIS) - large American National Eye Institute (NEI) sponsored study designed "to assess the long-range outcomes of sequences of interventions involving trabeculectomy and argon laser trabeculoplasty in eyes that have failed initial medical treatment for glaucoma." It recommends different treatments based on race.
• Early Manifest Glaucoma Trial (EMGT)-Another NEI study found that immediately treating people who have early stage glaucoma can delay progression of the disease.
• Ocular Hypertension Treatment Study (OHTS)] -NEI study findings: "...Topical ocular hypotensive medication was effective in delaying or preventing onset of Primary Open Angle Glaucoma (POAG) in individuals with elevated Intraocular Pressure (IOP). Although this does not imply that all patients with borderline or elevated IOP should receive medication, clinicians should consider initiating treatment for individuals with ocular hypertension who are at moderate or high risk for developing POAG."
• Blue Mountains Eye Study "The Blue Mountains Eye Study was the first large population-based assessment of visual impairment and common eye diseases of a representative older Australian community sample." Risk factors for glaucoma and other eye disease were determined.

Contraindicated medications

Glaucoma is considered an absolute contraindication to the use of the following medications:

• Amyl nitrite
• Clorazepate Dipotassium
• Dexmethylphenidate hydrochloride
• Dicyclomine
• Glycopyrrolate
• Hyoscyamine
• Mecamylamine
• Methscopolamine bromide
• Methylphenidate
• Phentermine
• Scopolamine
• Isometheptene mucate, dichloralphenazone and acetaminophen

Chronic non-congestive angle-closure glaucoma is considered an absolute contraindication to the use of the following medications:

• Acetazolamide
• Atomoxetine

Uncontrolled narrow-angle glaucoma is considered an absolute contraindication to the use of the following medications:

• Darifenacin
• Duloxetine
• Fesoterodine
• Solifenacin
• Tolterodine