Derivatives of arachidonic acid, a 20-carbon essential fatty acid, mediate a wide variety of biological functions, including regulation of smooth muscle tone (in the blood vessels, bronchi, uterus, and gut), platelet aggregation, hormone release (growth hormone, ACTH, insulin, renin, and progesterone), and inflammation. The synthetic cascade that produces a wide variety of derivatives (depending on the stimulus and tissue) begins with stimulation of phospholipase A2. Phospholipase A2 liberates arachidonic acid from phospholipids of the cell membrane and is a target of steroid therapy (Fig 16-6).
Figure 16-6 An outline of the synthesis of prostaglandins (PGs) and leukotrienes from arachidonic acid. In response to stimulation of a target cell with a relevant stimulus (eg, a cytokine, a neurotransmitter, various pharmacologic agents), phospholipase A2 (PLA2) is activated, and arachidonic acid is released from the sn-2 position of membrane phospholipids. Arachidonic acid is then converted by cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2) to prostaglandin H2 (PGH2), and then PGH2 is isomerized to biologically active prostanoid products. Arachidonic acid can also be metabolized through the 5-lipoxygenase and cytochrome P-450 pathways to generate leukotrienes and epoxides, respectively. PLA2 can be inhibited by corticosteroids such as dexamethasone; COX-1, by nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and aspirin; COX-2, by DUP697, SC58125, L-745-337, and NS398; and the 5-lipoxygenase pathway, by nordihydroguaiaretic acid (NDGA). IOP = intraocular pressure; PGD2 = prostaglandin D2; PGE2 = prostaglandin E2; PGF1α = prostaglandin F1α; PGF2α = prostaglandin F2α; PGG2 = prostaglandin G2; PGI2 = prostaglandin I2; TXA2 = thromboxane A2; TXB2 = thromboxane B2.
(Courtesy of Ata Abdel-Latif, PhD.)
Arachidonic acid is then converted either into hydroperoxides by lipoxygenase or into cyclic endoperoxides by cyclooxygenase (COX, also called prostaglandin-endoperoxide synthase). The hydroperoxides form a chemotactic agent and the leukotrienes C4, D4, and E4, previously known as the slow-reacting substance of anaphylaxis. Like oral antihistamines, oral leukotriene inhibitors are used in the management of seasonal allergies.
Subsequent products of endoperoxides include the PGs, which mediate inflammation and other responses; prostacyclin, a vasodilator and platelet antiaggregant; and thromboxane, a vasoconstrictor and platelet aggregant. PGs have profound effects on inflammation in the eye, aqueous humor dynamics, and blood–ocular barrier functions. When administered intracamerally or topically at high concentrations, arachidonic acid and PGs of the E and F subtypes cause miosis, an elevation of IOP, an increase in aqueous protein content, and the entry of white cells into the aqueous and tear fluid.
COX has 2 isoforms (ie, COX-2 and COX-1):
COX-2 is the relevant enzyme in inflammation (it is expressed at low levels under normal physiologic conditions and is regulated only in response to pro-inflammatory signals).
Constitutively expressed COX-1 (but not COX-2) is present in various tissues (including the inner lining of the stomach).
Previously developed NSAIDs (eg, ibuprofen, naproxen) inhibit both COX-1 and COX-2 and compete with arachidonate in binding to the COX-active site. Although these compounds are effective anti-inflammatory drugs, all of them can produce gastric ulcers when administered systemically. In contrast, COX-2 inhibitors are anti-inflammatory and analgesic, and they lack gastrointestinal toxicity. Moreover, they provide time-dependent, reversible inhibition of the COX-2 enzyme. However, oral COX-2 inhibitors, including rofecoxib, celecoxib, and valdecoxib, increase risks of cardiovascular toxicity and complications (eg, myocardial infarction).
Table 16-18 lists several NSAIDs along with their initial adult oral dosages. Aspirin and other NSAIDs inhibit the local signs of inflammation (heat, vasodilation, edema, swelling), as well as pain and fever. However, they have complex effects on clotting. At low doses (300 mg every other day), aspirin permanently inhibits the COX in platelets, which is essential for the conversion of arachidonic acid to prostaglandin G2 and thromboxane. Inhibition of thromboxane production, in turn, prevents coagulation. Although nucleated cells can replenish their COX, anucleate platelets cannot. After aspirin is stopped, COX activity recovers by 10% per day in parallel with platelet turnover. The anticoagulant effect of aspirin therefore lasts for at least 48–72 hours despite discontinuation of aspirin therapy. Other NSAIDs inhibit clotting in a reversible fashion, and their use does not need to be discontinued so far in advance of elective surgery.
Table 16-18 Nonsteroidal Anti-inflammatory Drugs (Systemic)
When used during febrile viral infections in children, aspirin has been associated with Reye syndrome, although no causal link has been proven. The National Reye’s Syndrome Foundation, the US Surgeon General, the FDA, the Centers for Disease Control and Prevention, and the American Academy of Pediatrics recommend that aspirin and combination products containing aspirin not be taken by anyone younger than 19 years during fever-causing illnesses. The British Medicines and Healthcare Products Regulatory Agency recommends that aspirin labels state that the drug is not intended for use in children younger than 16 years unless recommended by a physician. Other NSAIDs are effective antipyretics and are not associated with the constellation of symptoms observed in Reye syndrome.
The relative risks and benefits of aspirin therapy should be assessed for each patient. Aspirin therapy for postoperative pain or for pain associated with traumatic hyphema may increase the risk of hemorrhage because of the antiaggregant effect on platelets. The same side effect may benefit patients with platelet emboli, as in some cases of amaurosis fugax. Diversion of arachidonic acid to the lipoxygenase pathway by inhibition of COX may explain why aspirin is associated with asthma attacks and hypersensitivity reactions (mediated by the leukotrienes C4, D4, and E4) in susceptible people. Systemic acidosis associated with concomitant use of CAIs may shift a higher proportion of aspirin molecules into the more lipid-soluble nonionized form, which penetrates the blood–brain barrier more readily and potentiates CNS toxicity from aspirin. Aspirin and other COX inhibitors are less effective than steroids in the treatment of scleritis and uveitis.
NSAIDs such as indomethacin can be effective for orbital inflammatory diseases. The prophylactic use of indomethacin in patients undergoing cataract surgery has reduced the incidence of angiographically detected CME, but an effect on visually significant CME has yet to be determined. Flurbiprofen sodium, 0.03% (generic available), was the first commercially available topical ocular NSAID. When applied preoperatively, it reduces PG-mediated intraoperative miosis.
In addition to treating ocular inflammation, topical NSAIDs as a class have been reported to prevent and treat CME related to cataract surgery. Topical diclofenac sodium, 0.1% (generic available), has been approved by the FDA for treatment of inflammation and pain following cataract surgery, and ketorolac tromethamine (0.4%, 0.45%, 0.5%, and generic 0.5%) has been approved to treat postoperative pain and irritation. Additional topical NSAIDs with various dosages were approved by the FDA for the treatment of inflammation and reduction of pain after cataract extraction, with dosing initiated 1 day before surgery and continued through the first 2 weeks after surgery. They include nepafenac, 0.1%, 3 times daily, and 0.3%, 1 time daily; and bromfenac sodium, 0.09%, 1 time daily or 2 times daily, and 0.07%, 1 time daily (see Table 16-14).
NSAIDs have been associated with corneal complications, including melting and corneal perforation; these complications have been observed both in postoperative patients and in cases of uveitis, usually in patients with preexisting diabetes mellitus and ocular surface disorders.
Congdon NG, Schein OD, von Kulajta P, Lubomski LH, Gilbert D, Katz J. Corneal complications associated with topical ophthalmic use of nonsteroidal anti-inflammatory drugs. J Cataract Refract Surg. 2001;27(4):622–631.
Flach AJ. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc. 2001;99:205–210.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.