Материал: 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Section VI λ Drugs for Inflammatory and Related Disorders

Chapter Summary

Eicosanoid Pharmacology

λEicosanoids are synthesized and released on demand to interact with specific G-protein–coupled receptors. They include the leukotrienes (LTs), prostaglandins (PGs), and thromboxanes (TxAs).

λFigure VI-4-1 presents the pathways for the synthesis of PGI2, PGE2, PGF2α, TXA2, and the leukotrienes from the membrane phospholipids. It also shows the sites of action of the glucocorticoids, NSAIDs, COX 2 inhibitors, zileuton, and zafirlukast.

λThe physiologic functions of relevant eicosanoids interacting with specific receptor types and the clinical aspects of the drugs affecting these actions are considered.

Nonsteroidal Antiinflammatory Drugs

λThere are more than 20 nonsteroidal antiinflammatory drugs (NSAIDs) in use. Acetylsalicylic acid (ASA), the prototype, like most other NSAIDs, is a nonselective inhibitor of the cyclooxygenases; however, it binds in an irreversible fashion, whereas the others do so in a reversible manner.

λProgressively higher doses of ASA cause antiplatelet aggregation, analgesia, antipyresis, and antiinflammation. The mechanisms responsible for each of these responses, modes of excretion, effects on the acid-base balance, and side effects are discussed.

λAspirin overdoses can cause vasomotor collapse and renal failure. The management of such toxic overdose cases is considered, as are the doses required to elicit such dangerous effects in adults and children.

λOther NSAIDs, including ibuprofen, naproxen, indomethacin, ketorolac, and sulindac, also have analgesic, antipyretic, and antiinflammatory properties. The properties of these NSAIDs are compared with those of ASA.

λCelecoxib is a selective inhibitor of cyclooxygenase 2 (COX 2), providing less gastrointestinal and antiplatelet activity than are imparted by the nonselective COX inhibitors.

λAcetaminophen is not an NSAID but an analgesic and antipyretic. Its properties are compared with those of ASA. It has the potential for creating severe liver damage.

234

Learning Objectives

Describe drug therapy for rheumatoid arthritis that potentially slows disease progression and avoids side effects of NSAIDs

Table VI-5-1. Disease-Modifying Antirheumatic Drugs (DMARDs)

235

Section VI λ Drugs for Inflammatory and Related Disorders

λNSAIDs are commonly used for initial management of rheumatoid arthritis (RA), but the doses required generally result in marked adverse effects.

λNSAIDs decrease pain and swelling but have no beneficial effects on the course of the disease or on bone deterioration.

λDMARDs are thought to slow disease progression.

λDMARDs may be started with NSAIDs at the time of initial diagnosis if symptoms are severe because DMARDs take 2 weeks to 6 months to work.

λHydroxychloroquine is often recommended for mild arthritis and methotrexate (MTX) for moderate to severe RA.

λOther DMARDs are used less frequently, sometimes in combination regimens for refractory cases.

Chapter Summary

λNSAIDs are commonly used to help alleviate the pain and inflammation associated with rheumatoid arthritis. However, they have no effect on the progress of the disease. Disease-modifying antirheumatic drugs (DMARDs) are used with the hope of slowing the disease progress. Table

VI-5-1 summarizes the mechanisms of action and the adverse effects of the DMARDs.

236

Section VI λ Drugs for Inflammatory and Related Disorders

Figure VI-6-2. Drug Interaction between Allopurinol and 6-Mercaptopurine

λPegloticase

–Mechanism: recombinant urate-oxidase enzyme for refractory gout; metabolizes uric acid to allantoin →↓ plasma uric acid

–Side effects: anaphylaxis, urticaria

λProbenecid

–Mechanism: inhibits proximal tubular reabsorption of urate, but ineffective if GFR < 50 mL/min

–Drug interactions: inhibits the secretion of weak acid drugs such as penicillins, cephalosporins, and fluoroquinolones

Chapter Summary

λAcute inflammatory episodes are treated with colchicine, NSAIDs, and intraarticular steroids. The mode of colchicine’s action and its adverse effects are considered.

λChronic gout is treated with allopurinol, a suicide inhibitor of xanthine oxidase. The goal is to reduce the uric acid pool by inhibiting its formation from purines. The adverse effects of allopurinol are considered.

λProbenecid decreases the uric acid pool by inhibiting the proximal tubular reabsorption of urate. Its use and side effects are also discussed.

238