книга / 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology
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COX2
Hydroperoxides
Section VI λ Drugs for Inflammatory and Related Disorders
ºIn adults, this can be a stable condition; in children →↑ toxicity.
ºToxic doses: inhibits respiratory center →↓ respiration →↑ pCO2 → respiratory acidosis (↓ pH, ↓ HCO3–, normalization of pCO2) plus inhibition of Krebs cycle and severe uncoupling of oxidative phosphorylation (↓ ATP) → metabolic acidosis, hyperthermia, and hypokalemia (↓ K+).
λSide effects:
–Gastrointestinal irritation: gastritis, ulcers, bleeding
–Salicylism: tinnitus, vertigo, ↓ hearing—often first signs of toxicity
–Bronchoconstriction: exacerbation of asthma
–Hypersensitivity, especially the “triad” of asthma, nasal polyps, rhinitis
–Reye syndrome: encephalopathy
–↑ bleeding time (antiplatelet)
–Chronic use: associated with renal dysfunction
–Drug interactions: ethanol (↑ gastrointestinal bleeding), OSUs and warfarin (↑ effects), and uricosurics (↓ effects)
λAspirin overdose and management:
–Extensions of the toxic actions described above, plus at high doses vasomotor collapse occurs, with both respiratory and renal failure.
–No specific antidote. Management includes gastric lavage (+/– activated charcoal) plus ventilatory support and symptomatic management of
acid-base and electrolyte imbalance, and the hyperthermia and resulting dehydration. ↑ urine volume and its alkalinization facilitate salicylate renal elimination. (Note: ASA follows zero-order elimination kinetics at toxic doses.)
Other NSAIDs
Types
λReversible inhibitors of COX 1 and COX 2, with analgesic, antipyretic, and antiinflammatory actions, include:
–Ibuprofen
–Naproxen
–Indomethacin
–Ketorolac
–Sulindac
λComparisons with ASA:
–Analgesia: ketorolac > ibuprofen/naproxen > ASA
–Gastrointestinal irritation: < ASA, but still occurs (consider misoprostol)
–Minimal effects on acid-base balance; no effects on uric acid elimination
–Allergy: common, possible cross-hypersensitivity with ASA
–Renal: chronic use may cause nephritis, nephritic syndrome, acute
failure (via ↓ formation of PGE2 and PGI2, which normally maintain GFR and RBF)—does not occur with sulindac
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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.
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Drugs Used for Treatment of |
5 |
Rheumatoid Arthritis |
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)
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Hydroxychloroquine |
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GI distress and visual |
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↓ chemotaxis |
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dysfunction (cinchonism), |
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hemolysis in G6PD |
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deficiency |
Methotrexate |
Cytotoxic to lymphocytes |
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Hematotoxicity, |
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hepatotoxicity |
Sulfasalazine |
Sulfapyridine →↓ B-cell |
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Hemolysis in G6PD |
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functions; 5-ASA possibly |
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deficiency |
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inhibits COX |
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Glucocorticoids |
↓ LTs, ILs, and platelet- |
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ACTH suppression, |
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activating factor (PAF) |
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cushingoid state, |
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osteoporosis, GI distress, |
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glaucoma |
Leflunomide |
Inhibits dihydro-orotic acid |
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Alopecia, rash, diarrhea, |
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dehydrogenase (DHOD) |
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hepatotoxicity |
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→↓ UMP →↓ |
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ribonucleotides → arrests |
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lymphocytes in G1 |
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Etanercept |
Binds tumor necrosis |
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Infections |
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factor (TNF); is a |
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recombinant form of TNF |
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receptor |
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Infliximab, |
Monoclonal antibody to |
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Infections |
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adalimumab |
TNF |
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Anakinra |
IL-1 receptor antagonist |
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Infections |
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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.
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Section VI λ Drugs for Inflammatory and Related Disorders
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Figure VI-6-1. Mechanism of Action of Allopurinol |
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Allopurinol |
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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.
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