Ophthalmology

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Chapter 22 Ophthalmology

Ophthalmic Prostaglandins

Description

Ophthalmic prostaglandins (PGs) are topically applied for treating glaucoma.

Prototype and Common Drugs

image Prototype: latanoprost (all are PGF2α)
image Others: travoprost, bimatoprost, unoprostone

MOA (Mechanism of Action)

image Glaucoma is characterized by increased intraocular pressure (IOP) and can lead to blindness if not treated. Strategies to reduce IOP include reducing the production and secretion of aqueous humor and facilitating its drainage.
image Drainage occurs via two main pathways

image 80% to 90% via Schlemm’s canal (the trabecular network)
image 10% to 20% via the uveoscleral route (Figure 22-1)

image PGs bind prostaglandin F (FP) receptors that are located on the ciliary muscle and reduce IOP by increasing outflow of aqueous humor through the uveoscleral pathway. This is thought to be accomplished through the following mechanisms:

image Relaxation of the ciliary muscle
image Vasodilatation as a contributor to early effects
image Remodeling or shrinking of the ciliary muscle, resulting in increased space for outflow as a mechanism for long-term control of glaucoma

image Administering exogenous PG-F (specifically PGF2α) stimulates the FP receptor and increases aqueous outflow through the mechanisms just described.
image

Figure 22-1

Pharmacokinetics

image These PGs are administered topically to the eye, and only a small amount reaches the systemic circulation.

Indication

image Glaucoma

Contraindications

image Previous cystoid macular edema is a contraindication and previous incisional surgery on the eye is a risk factor; ocular PGs should be used with caution in these patients because of the increased risk of cystoid macular edema.

Side Effects

image Local irritation: Conjunctival hyperemia (redness), itching, foreign body sensation, tearing, and eye pain are side effects.
image Blurred vision may occur.
image Pigmentation of the iris: This occurs in patients with mixed-color irises (green-brown or blue-brown) and is a result of increased deposition of melanin. Pigmentation of the palpebral skin (eyelids) also occurs.
image Eyelash growth occurs with unoprostone only.
image Cystoid macular edema involves accumulation of fluid in the macular area of the retina. This is a well-recognized complication of cataract surgery.
image Punctate epithelial keratopathy involves loss of superficial epithelial cells and associated defects on the cornea.

Important Notes

image Raised IOP eventually results in damage to the optic nerve and can result in blindness.
image Glaucoma is often asymptomatic in early stages of the disease, and when symptoms develop they are irreversible. Therefore patients with no special risk factors should be assessed every 2 years by an optometrist or ophthalmologist after the age of 40 for IOP changes. If present, glaucoma must be treated by an ophthalmologist.
image Other pharmacologic approaches to glaucoma include the following:

image β-Blockers (decreased aqueous production)
image α-Adrenergic agonists (increased aqueous outflow)
image α2 Agonists (decreased aqueous production)
image Parasympathomimetics (increased outflow)
image Carbonic anhydrase inhibitors (decreased aqueous production)

image Most patients with glaucoma are treated with more than one medication simultaneously.

Evidence

Prostaglandin versus Placebo

image A Cochrane review in 2007 was unable to find any evidence comparing PGs with placebo for the treatment of glaucoma.

Prostaglandin versus Other Therapy for Glaucoma

image A systematic review in 2008 (eight randomized controlled trials [RCTs], 1722 patients) did not find a significant reduction in the mean IOP in patients receiving latanoprost compared with those receiving brimonidine (α2 agonist) but did find a significant reduction in mean IOP compared with the dorzolamide (carbonic anhydrase) group (WMD = 22.64). The number of ocular adverse events (excluding hyperemia) was significantly higher in the brimonidine group compared with the latanoprost group (relative risk [RR] = 0.66). The authors concluded that latanoprost was superior to dorzolamide but not brimonidine and those ocular adverse events were significantly fewer in latanoprost users than in brimonidine users. Neither travoprost nor bimatoprost was compared with dorzolamide or brimonidine in the present literature.

FYI

image Iris bio-identification (photos of the iris used to identify people, analogous to a fingerprint) could be affected by pigment changes that result from the use of ocular PGs.

Aptamers

Description

Aptamers are a new approach to drug design that uses nucleotide sequences to bind to targets.

Prototype

image Prototype: pegaptanib

MOA (Mechanism of Action)

image Aptamers are nucleotide sequences that bind to biologic targets, typically proteins. Pegaptanib, the first aptamer approved for human use, targets a protein called vascular endothelial growth factor (VEGF).
image Age-related macular degeneration is characterized by an overgrowth of blood vessels in the macula of the eye. These vessels function poorly and also leak, which obscures vision and eventually leads to degeneration of the macula and blindness.
image VEGF is an angiogenic growth factor whose function is to promote new blood vessel growth; it is believed to be largely responsible for this overgrowth of leaky, dysfunctional vessels in the macula. In addition to stimulating the growth of new blood vessels, VEGF also increases vascular permeability.
image By binding to VEGF, pegaptanib prevents further growth of blood vessels and also reduces the leakage that promotes gradual loss of vision.

Pharmacokinetics

image Pegaptanib is administered via intravitreal (directly into the vitreous of the eye) injection by an ophthalmologist. After injection, the drug slowly reaches the systemic circulation, although it is not believed to be widely distributed.

Indication

image Age-related macular degeneration

Contraindications

image Ocular infection: Pegaptanib is administered via intravitreal injection; therefore the patient should be free of infection before this delicate procedure is performed.

Side Effects

image Most of the side effects are caused by the local injection into the eye.
image Increased IOP is most likely a result simply of the administration of liquid into an enclosed space.
image Vitreous floaters appear as floating objects in the patient’s field of vision. These are simply the components of the injection, typically small air bubbles, and are thus considered harmless and temporary.

Serious, Rare

image Endophthalmitis results from infection of the eye, typically because of improper injection technique.

Evidence

Aptamers versus Other Vascular Endothelial Growth Factor Inhibitors or Sham for Treatment of Macular Degeneration

image A 2008 Cochrane review (five trials, N = 2500 participants) examined the effects of anti-VEGF therapies for neovascular macular degeneration. Two of the included studies compared pegaptanib versus sham treatment. A key outcome in assessing interventions in macular degeneration is deterioration of vision, with the cutoff for deterioration being a loss of ≥15 letters of visual acuity on an eye chart. Compared with sham-treated patients, fewer pegaptanib-treated patients experienced this loss of visual acuity (numbers needed to treat [NNTs] ranged from 7 to 14, depending on dose). Endophthalmitis occurred in 1.3% of pegaptanib-treated patients.

Important Notes

image An important potential advantage of aptamers over monoclonal antibodies is that aptamers are unlikely to elicit an immune response, as they are not antibodies. Hypersensitivity reactions are an important limitation to the use of monoclonal antibodies in some patients.
image Another advantage of aptamers over monoclonal antibodies is stability. Aptamers can withstand high temperatures and have a long shelf-life, making them more convenient in everyday use.
image Another indication in which aptamers are being studied is cancer. Aptamers are smaller than monoclonal antibodies, and it is believed this may make it easier for them to penetrate tumors.

FYI

image The term aptamer comes from the Latin aptus, meaning fitting.
image Aptamers were first discovered in and continue their primary application in basic science research.
image The SELEX process is an automated technique for manufacturing aptamers. It begins with a library of nucleotide sequences of varying lengths, which are then exposed to a ligand target. The sequences that do not bind to the ligand are then washed away. The remaining sequences are then amplified and subjected to another round of binding and removal. With each successive round, the techniques that are used to remove the less tightly bound sequences are intensified, such that with the end of each round, the remaining sequences have increased affinity for the ligand over those of the previous round (Figure 22-2).
image

Figure 22-2 (Modified from Bunka DHJ, Stockley PG: Aptamers come of age—at last, Nat Rev Microb 4:588, 2006. Reprinted by permission from Macmillan Publishers.)

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