Lecture 5-Drugs Used in Glaucoma Treatment PDF

Drugs used for the treatment of Glaucoma Heba Abdelazeem, PhD Lecturer of Pharmacology Faculty of Pharmacy, Alexandria University Eye structure  Eye structure The outer coat of the eye is made up of the sclera, conjuncti...

Drugs used for the treatment of Glaucoma Heba Abdelazeem, PhD Lecturer of Pharmacology Faculty of Pharmacy, Alexandria University Eye structure  Eye structure The outer coat of the eye is made up of the sclera, conjunctiva, and cornea. The sclera is the white, dense, fibrous protective coating. The conjunctiva is a mucous membrane that covers the anterior portion of the eye and lines the eyelids. The cornea is the transparent, avascular tissue that functions as a refractive and protective window membrane through which light rays pass en route to the retina. The iris controls the amount of light that enters the eye.  Eye structure The ciliary body contains the ciliary muscle and ciliary processes. The ciliary muscle contracts and relaxes the zonular fibers, which hold the crystalline lens in place (accommodation). The ciliary processes are responsible for the secretion of aqueous humor, a clear liquid that occupies the anterior chamber. The anterior chamber is bounded anteriorly by the cornea and posteriorly by the iris. The posterior chamber lies between the iris and the crystalline lens.  Eye structure The retina, the light-sensitive tissue at the back of the eye, contains all of the sensory receptors for light transmission. The optic nerve, a bundle of more than a million nerve fibers, transmits visual impulses from the retina to the brain. The lens, located behind the iris, functions to focus light onto the retina by changing its shape to accommodate near or distant vision. The aqueous humor, the thin watery fluid that fills the anterior chamber (i.e., the space between the cornea and the iris) and posterior chamber of the eye, functions to provide nourishment to the cornea and lens. The primary function of the vitreous humor (i.e., the jellylike substance between the lens and the retina) is to maintain the shape of the eye and allow the transmission of light to the retina.  Eye structure The eye is innervated by both the sympathetic and parasympathetic nervous systems. Parasympathetic fibers innervate the ciliary muscle (M3 receptors) and sphincter pupillae (M3 receptors) muscle that constrict the pupil. As a result, parasympathomimetic (cholinergic) medications generally are associated with miosis (pupillary contraction), and parasympatholytic (anticholinergic) agents with mydriasis (pupillary dilation) and cycloplegia. Tear secretion by the lacrimal glands also is a parasympathetic function. Sympathetic innervate the dilator pupillae muscle (α1 receptors), the blood vessels of the ciliary body and the extraocular muscles. Sympathomimetics cause mydriasis without affecting accommodation. The term cycloplegia refers to a paralysis of the ciliary muscle and zonules (fibrous strands connecting the ciliary body to the lens) that results in decreased accommodation (adjustment of the lens curvature for various distances) and blurred vision.  Glaucoma Glaucoma is a nonspecific term used for a group of diseases that can irreversibly damage the optic nerve, resulting in visual field loss. Increased intraocular pressure (IOP) is the most common risk factor for the development of glaucoma; however, even people with “normal” IOPs can experience vision loss from glaucoma.  Glaucoma Intraocular Pressure The inner pressure of the eye (i.e., IOP) is influenced by the production of aqueous humor by the ciliary processes and the outflow of aqueous humor through the trabecular meshwork and Uveoscleral pathway. The tonometry test is used to measure the IOP. Generally, an IOP of 10 to 20 mm Hg is considered normal. An IOP of 22 mm Hg or greater should arouse suspicion of glaucoma, although a more rare form of glaucoma is associated with a low IOP.  Glaucoma Production of aqueous humor Carbonic anhydrase (primarily isoenzyme type II), α- and β-adrenergic receptors, and sodium- and potassium-activated adenosine triphosphatases are found on the ciliary epithelium and appear to be involved in this secretion of the solutes sodium and bicarbonate. Aqueous humor is formed as an active secretion by the epithelium of the ciliary processes. Secretion begins with active transport of sodium ions by Na+/K+ ATPase. CA (In the eye, carbonic anhydrase catalyzes the conversion of H2O and CO2 to HCO3− and H+) forms HCO3 - that is subsequently released into the aqueous humor. The Osmotic gradients produced by active secretion of sodium and bicarbonate and possibly by other solutes such as ascorbate from the ciliary body epithelial cells into the aqueous humor result in movement of water into the posterior chamber, forming aqueous humor.  Glaucoma Types: 1.Open-angle glaucoma (wide-angle): It’s the most common type. 2.Angle-closure (narrow- angle) glaucoma  Glaucoma Open-Angle Glaucoma (Primary open-angle glaucoma (POAG)) In patients with POAG, aqueous humor outflow from the anterior chamber is continuously subnormal primarily because of a degenerative process in the trabecular meshwork (i.e., the trabecular meshwork and Schlemm canal) and tends to worsen with the passage of time. In rare cases, the outflow is normal even during a phase of elevated IOP, and the elevation appears to be to the result of hypersecretion of aqueous humor. The onset of POAG usually is gradual and asymptomatic. A defect in the visual field examination may be present in early glaucoma, but loss of peripheral vision usually is not seen until late in the course of the disease.  Glaucoma Angle-closure Glaucoma The sole cause of the elevated IOP in angle-closure glaucoma is closure of the anterior chamber angle. Angle-closure glaucoma, which is a medical emergency, usually presents as an acute attack with a rapid increase in IOP, blurring or sudden loss of vision, appearance of haloes around lights, and pain that is often severe. Acute attacks can terminate without treatment, but if the IOP remains high, the optic nerve can be irreparably damaged. Patients with chronic angle closure generally experience a gradual closure of aqueous humor outflow channels, and patients can be asymptomatic until the glaucoma is in an advanced stage. Permanent medical management of acute or chronic angle-closure glaucoma is difficult: Surgical procedures (e.g., peripheral iridectomies) often are needed. Glaucoma Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma Goals Reduce intraocular pressure to reduce risk of development and progression of visual field defects Minimize adverse effects of treatment and impact on vision, health, and quality of life Medications: β-Adrenergic Blockers Prostaglandin Analogs α2-Adrenergic Agonists Carbonic Anhydrase Inhibitors Parasympathomimetic agents Rho Kinase Inhibitors Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma β-Adrenergic Blockers Mechanism of action: Production of aqueous humor seems to be activated by β-receptors. Ophthalmic β-adrenergic antagonists block the β-adrenergic receptors in the ciliary body of the eye and lower IOP primarily by decreasing aqueous humor production. On average, β-blockers decrease IOP by 20% to 30% commonly one of the agents of first choice—along with prostaglandin analogs—in treating POAG if no contraindications exist Timolol (first ocular β-adrenergic blocker marketed), levobunolol, metipranolol, carteolol, and betaxolol. Timolol, levobunolol, and metipranolol are nonspecific β-blocking agents Betaxolol is a relatively β1-selective Carteolol is a nonspecific blocker with intrinsic sympathomimetic activity. theoretically should minimize the bronchospastic, bradycardic, and hypotensive effects associated with other ocular β-adrenergic blockers. However, no clinical differences were seen when the cardiovascular and pulmonary function effects of carteolol Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma β-Adrenergic Blockers Side effects: Local: stinging on application, Corneal anesthesia (After chronic administration), Uveitis Systemic: Decreased heart rate, reduced blood pressure, bronchospasm, block the symptoms of hypoglycemia. Therefore, Should be used with caution in patients with: sinus bradycardia, heart failure, pulmonary disease or diabetes. The use of timolol as a gel-forming liquid or betaxolol as a suspension allows for administration of fewer drugs per day and, therefore, reduces the chance for systemic adverse effects compared with the aqueous solutions. Use of the nasolacrimal occlusion technique during administration reduces the risk or severity of systemic adverse effects, as well as optimizes response.  Topically administered drugs may undergo systemic distribution primarily by nasal mucosal absorption and possibly via local ocular distribution by transcorneal/transconjunctival absorption. Nasolacrimal drainage contributes to systemic absorption of topically administered ophthalmic medications. Absorption from the nasal mucosa avoids first-pass metabolism by the liver; thus, topical ophthalmic medications can cause significant systemic side effects, especially when used frequently or chronically Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma Prostaglandin Analogs Mechanism of action: The prostaglandin analogs increase uveoscleral outflow of aqueous humor and, thereby, decrease IOP. Latanoprost and travoprost, and tafluprost are analogs of prostaglandin F2α, and they lower IOP by serving as selective prostaglandin F2α-receptor agonists (FP receptors). Bimatoprost is a synthetic prostamide analog. Due to their once-daily dosing, low incidence of systemic side effects, and potent IOP- lowering effect, PG analogues have largely replaced β adrenergic receptor antagonists as first-line medical therapy for glaucoma. PGAs have additive effects (due to their unique mechanism) when administered with β- blockers (e.g., timolol), carbonic anhydrase inhibitors (e.g., dorzolamide), and α2-adrenergic agonists (e.g., brimonidine, apraclonidine). Latanoprostene bunod is a newer PG analogue with a nitric oxide donating moiety that enhances traditional outflow through the trabecular meshwork by inducing relaxation of cytoskeleton in addition to the effect of the latanoprost backbone on the uveoscleral Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma Prostaglandin Analogs Side effects: Local: iris pigmentation; eyelid skin darkening; eyelash lengthening, thickening, pigmentation, and misdirected growth; conjunctival hyperemia; ocular irritation; superficial punctate keratitis) gradually increase the amount of brown pigment in the iris by increasing the melanin content in the melanocytes of the iris. This pigment change occurs in 7% to 22% of patients The onset of increased iris pigmentation usually is noticeable within the first year of treatment and can be permanent. The FDA approved the cosmetic use of bimatoprost solution to be applied with an applicator to the base of the upper eyelashes for the treatment of hypotrichosis (inadequate eyelashes). Loss of periorbital fat which may lead to apparent enophthalmos and sunken eye, especially when used unilaterally Systemic side effects are minimal Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma α2-Adrenergic Agonists Mechanism of action: lower IOP by decreasing the production of aqueous humor and by increasing uveoscleral outflow. Apraclonidine and brimonidine are selective α2-adrenergic agonists similar to clonidine Brimonidine is more highly selective for α2-adrenergic receptors than clonidine or apraclonidine Brimonidine is an alternative first-line agent Local side effects (More common with apraclonidine than with brimonidine): An allergic-type reaction characterized by lid edema, eye discomfort, foreign-object sensation, itching, and hyperemia. This reaction commonly necessitates drug discontinuation. Systemic side effects (e.g., dry nose and mouth, mild hypotension, decreased pulse, and lethargy) are more common with brimonidine. α2-Adrenergic agonists should be used with caution in patients with cardiovascular disease, orthostatic hypotension, depression, and renal or hepatic dysfunction Long-term IOP control should be monitored closely in patients taking α2-adrenergic agonists because tachyphylaxis can occur. Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma Carbonic Anhydrase Inhibitors Mechanism of action: Carbonic anhydrase (in the ciliary body) inhibitors (CAIs) lower IOP by decreasing bicarbonate production and, therefore, the flow of bicarbonate, sodium, and water into the posterior chamber of the eye, resulting in a 40% to 60% decrease in aqueous humor secretion. Dorzolamide and brinzolamide Topical CAIs are considered second line (after prostaglandins and beta blockers) and are effective as adjunctive agents. Local Side effects: are ocular burning, stinging, discomfort and allergic reactions, bitter taste, and superficial punctate keratitis. Systemic side effects: CAIs should be used with some caution in patients with sulfa allergies (all CAIs, topical or systemic, contain sulfonamide moieties) Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma Systemic CAIs (Acetazolamide, Methazolamide) are indicated for patients failing to respond to or tolerate maximum topical therapy. Systemic and topical CAIs should not be used in combination because no data exist concerning improved IOP reduction, and the risk for systemic adverse effects is increased. Despite their excellent effects on elevated IOP of any etiology, the systemic CAIs frequently produce intolerable adverse effects. As a result, systemic CAIs are considered third-line agents in the treatment of POAG and often used for short-term administration to lower IOP The systemic carbonic anhydrase inhibitors are associated with significant adverse effects that include paresthesias of the hands and feet, nausea, vomiting, and weight loss. Patients can develop systemic acidosis, hypokalemia, hyponatremia, and nephrolithiasis due to the inhibition of renal carbonic anhydrase. Sulfonamide allergy, renal failure, hepatic insufficiency, COPD, and decreased serum potassium and sodium levels are all contraindications of systemic carbonic anhydrase inhibitor therapy. Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma Parasympathomimetic Agents Mechanism of action: The parasympathomimetic (cholinergic) agents reduce IOP by increasing aqueous humor trabecular outflow. The increase in outflow is a thought to be a result of physically pulling open the trabecular meshwork secondary to muscarinic-induced ciliary muscle contraction, thereby reducing resistance to outflow (They do not affect aqueous production). Pilocarpine and carbachol are cholinomimetics that stimulate muscarinic receptors and are referred to as having a direct mechanism of action. Carbachol (Isopto Carbachol) is reserved as a third-line agent in patients who are unresponsive or intolerant to initial medications. Echothiophate, an irreversible organophosphate inhibitor of acetylcholinesterase, enhances muscarinic cholinergic activity by reducing hydrolysis of neurally released acetylcholine Because of the serious ocular and systemic toxic effects of echothiophate, it is reserved primarily for patients who are either not responding to or are intolerant of other therapy.i.e Echothiophate iodide may be used if maximal doses of other agents and combination therapy are ineffective. Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma Rho Kinase Inhibitors Mechanism of action: Rho kinase (ROCK) inhibition decreases intraocular pressure by limiting adhesions within the trabecular meshwork and contraction of the ciliary muscle, facilitating aqueous humor outflow by increasing the meshwork pore size. Netarsudil is the first approved agent in a new class of antiglaucoma medications, Rho kinase inhibitors. Efficacy appears to be similar to that of beta blockers. Netarsudil may be used in combination with other antiglaucoma agents. The most common local side effects are conjunctival hyperemia, conjunctival hemorrhage, and corneal verticillate. Systemic effects are rare. A combination of netarsudil/latanoprost ophthalmic solution 0.02%/0.005% was approved in the United States. Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma COMBINATION THERAPY In general, drugs with different pharmacologic actions have at least partially additive effects in lowering IOP in the treatment of glaucoma. Drugs with similar pharmacologic actions should not be combined because dose-related adverse effects are more likely and the increase in benefits is likely to be more modest. For example, the IOP-lowering effect is greater when timolol is used in combination with pilocarpine, dorzolamide, brimonidine, and travoprost. The trend toward the development of fixed-combination products offers many advantages in the treatment of POAG: ✓ improved adherence because of a reduction in the number of dosages and bottles, ✓ eliminating the need to instill two separate drugs 5 to 10 minutes apart to prevent a washout effect from the second medication, ✓ Improving safety and tolerability by limiting the exposure to the BAK preservative ✓ a cost savings for the patient by potentially eliminating a copay for one of the medications. There are two β-adrenergic blocker combination products currently on the market, timolol/dorzolamide and brimonidine/timolol in the US. Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma PATIENT EDUCATION A large percentage of patients also fail to use topical ophthalmic drugs correctly. Patients should be taught the following procedure: 1. Wash and dry the hands; shake the bottle if it contains a suspension. 2. With a forefinger, pull down the outer portion of the lower eyelid to form a “pocket” to receive the drop. 3. Grasp the dropper bottle between the thumb and fingers with the hand braced against the cheek or nose and the head held upward. 4. Place the dropper over the eye while looking at the tip of the bottle; then look up and place a single drop in the eye. 5. The lids should be closed (but not squeezed or rubbed) for 5 minutes after instillation. Nasolacrimal occlusion also should be used to improve ocular bioavailability and reduce systemic absorption. Occlusion of the puncta (through the application of slight pressure with the finger to the inner corner of the eye closest to the nose for 3 to 5 minutes during and after drug instillation). Nasolacrimal occlusion decreases nasolacrimal drainage of drug, thereby decreasing the amount of drug available for systemic absorption by the nasopharyngeal mucosa. Therapeutic Agents for Treatment of Primary Open-Angle Glaucoma PATIENT EDUCATION 6. Recap bottle and store as instructed. Use of more than one drop per dose increases costs, does not improve response significantly, and may increase adverse effects. When two drugs are to be administered, instillations should be separated by at least 5 minutes (preferably 10 minutes) to prevent the drug administered first from being washed out. The patient should be taught not to touch the dropper bottle tip with eye, hands, or any surface.  Primary Open-Angle Glaucoma Nonpharmacologic Therapy: Laser and Surgical Procedures When drug therapy fails, is not tolerated, or is excessively complicated, surgical procedures such as laser trabeculoplasty (argon or selective) or a surgical trabeculectomy (filtering procedure) may be performed to improve outflow.  Acute Angle-Closure Glaucoma Acute angle-closure crisis is a medical emergency and requires urgent laser or surgical intervention. The treatment of choice for PACG is peripheral laser iridotomy. Laser iridotomy uses laser energy to cut a hole into the iris to alleviate the aqueous humor buildup behind the iris, resulting in reversal of appositional angle closure. Patients currently experiencing an acute angle-closure crisis should receive medical therapy to lower IOP, reduce pain, and reverse corneal edema before the iridotomy. IOP should first be lowered with topical β-blockers, topical α-agonist, prostaglandin F2α analog, systemic carbonic anhydrase inhibitors, or hyperosmotic agents. Once the IOP has been controlled, pilocarpine can be used to break the pupillary block.  Acute Angle-Closure Glaucoma Hyperosmotic agents Mechanism of action: Glycerin (oral), isosorbide (Oral), and mannitol(IV) are hyperosmotic agents that increase the osmolality of blood. These agents create an osmotic gradient that draws water from the vitreous humor, thus decreasing IOP. The resulting dehydration of the vitreous humor may cause posterior movement of the lens, which then causes the anterior chamber to deepen, thus opening the anterior angle. For oral agents, Isosorbide is preferred in patients with diabetes because it is not metabolized into glucose.  Medications to avoid in glaucoma (Drug-induced Glaucoma) In Angle-Closure Glaucoma The classes of medications that have the potential to induce angle closure are topical anticholinergic or sympathomimetic dilating drops, Medications with anticholinergic properties include first-generation antihistamines, tricyclic antidepressants, and antipsychotics. Medications with sympathomimetic properties include phenylephrine and pseudoephedrine. Sulfa-Containing Drugs as topiramate, acetazolamide, and hydrochlorothiazide and , trimethoprim/sulfamethoxazole The pathophysiology of drug-induced angle-closure glaucoma is usually increased pupillary block (ie, increased iris-lens contact at the pupillary border) from pupillary dilation (except for Sulfa drugs). Sulfa-based drugs,, cause swelling of the ciliary body, which causes an anterior displacement of the lens, resulting in a decrease in anterior-chamber depth.  Medications to avoid in glaucoma (Drug-induced Glaucoma) In Open Angle Glaucoma Steroids are the most important open angle glaucoma medication to avoid. Glucocorticoids reduce the facility of aqueous humor outflow through the trabecular meshwork. The decreased facility of outflow appears to result from the accumulation of extracellular material blocking the trabecular channels. 29