Review Questions on Analgesic-Antipyretics and Anti-Inflammatory Agents The prototypic drug of this class is acetylsalicylic acid, otherwise known as aspirin. Aspirin possesses analgesic, antipyretic, and anti-inflammatory properties. Indomethacin and naproxen are two other agents whose actions are similar to those of aspirin. Another group of agents is the para-aminophenols, which includes acetaminophen and phenacetin (phenacetin is not available in the USA because of its toxicity). In contrast to aspirin, these drugs have analgesic and antipyretic activity but very weak anti-inflammatory action. Acetaminophen is often used as a substitute for aspirin. Cyclooxygenase 2 (Cox-2) inhibitors are now avaialble which have selectivity for the inducible form of cyclooxygenase. GI and antiplatelet adverse effects are associated with cyclooxygenase 1 (Cox-1), thus eliminating adverse effects at these sites with the Cox-2 inhibitors. The Cox-2 inhibitors include celecoxib, rofecoxib, and valdecoxib. Drugs such as colchicine, probenecid, sulfinpyrazone, and allopurinol are also discussed in this section. These are used to lower the levels of uric acid in the body (except colchicine) and are employed in the treatment of gout. THIS PROGRAM HAS 27 QUESTIONS Analgesic, antipyretic, and antiinflammatory agents A. Non-Steroidal Antiinflammatory Agents (NSAIDs) 1. Salicylates <.> aspirin <.> salicylic acid 2. Other NSAIDs <.> ibuprofen <.> indomethacin <.> naproxen <.> oxaprozin <.> piroxicam <.> sulindac <.> ketorolac 3. Analgesic/antipyretic only <.> acetaminophen 4. Cox-2 Inhibitors <.> celecoxib <.> rofecoxib <.> valdecoxib Analgesic, antipyretic, and antiinflammatory agents B. Antiarthritic agents 1. NSAIDs 2. Corticosteroids 3. Disease Modifying Antirheumatic Drugs (DMARDs) a. Immunosuppressive agents <.> methotrexate <.> cyclophosphamide <.> azathioprine b. Antimalarials <.> hydroxychloroquine c. Gold Compounds <.> aurothioglucose <.> auranofin d. Others <.> penicillamine <.> sulfasalazine <.> leflunomide e. Anti-TNFalpha drugs <.> adalimumab <.> infliximab <.> etanercept f. IL-1 antagonist <.> anakinra Analgesic, antipyretic and antiinflammatory agents C. Agents used in gout 1. Colchicine 2. NSAIDs <.> indomethacin <.> naproxen <.> sulindac 3. Corticosteroids 4. Uricosuric agents <.> sulfinpyrazone <.> probenecid 5. Xanthine oxidase inhibitor <.> allopurinol 1. Which of the following are effects of aspirin? anti-inflammatory effect in rheumatic fever and rheumatoid arthritis analgesic effects that seem to relate to actions on the CNS as well as the periphery antipyretic effects that seem to relate to actions on the CNS respiratory depressant effects inhibition of platelet aggregation Correct. No, all except the 4th foil are correct. Salicylates stimulate respiration by directly stimulating respiratory centers in the medulla. The metabolic acidosis which follows the respiraory alkalosis also stimulates respiration. The effects on respiration are usually only seen when high doses of aspirin are ingested. 2. Aspirin will lower the body temperature of: non-febrile patients patients with pyrogenic fever patients with heatstroke fever Correct. No, only the second foil is correct. The antipyretic effects of aspirin are due to the resetting of the hypothalamic temperature control center. This effect occurs only in the presence of fever. The salicylates lower the temperature in fever by increasing heat loss through the promotion of peripheral vasodilation and sweating. 3. An example of a type of pain for which aspirin is not very suitable, is pain due to: rheumatism a superficial cut headache early cancer toothache Correct. No. The answer is B. Salicylates are effective analgesics in low-intensity aches and pains (e.g. headache, myalgia, arthralgia). The mechanism of this analgesic effect is depended on the inhibition of prostanoids but still is not fully understood, however. 4. The adverse effects of acetylsalicylic acid include: gastric irritation metabolic acidosis hyperventilation hypersensitivity reactions Correct. No. All foils are correct. Salicylism is a syndrome brought on when large amounts of salicylates are used. It is characterized by tinnitus, dizziness, headache, deafness (reversible), and mental confusion. Salicylate Hyersensitivity Anaphylactoid reactions such as angioedema, laryngeal edema, and acute bronchospasm, may occur with aspirin and other NSAIDs. Allergic responses often occur within minutes. Aspirin hypersensitivity often presents as a respiratory reaction including rhinitis and/or asthma or with urticaria and angioedema. The mechanism is believed to be due to shuttling of a significant amount of arachidonic acid via the lipooxygense pathway leading to an excess formation of leukotriene D4. Aspirin hypersensitivity is uncommon: -- 0.3% of the general population -- individuals with chronic urticaria have the highest incidence (20%) -- individuals with asthma (4%) -- individuals with chronic rhinitis (1.5%) Sensitivity results in bronchospasm in asthmatic patients and is most commonly associated with nasal polyps. The aspirin triad: is aspirin hypersensitivity, asthma, and nasal polyps. Hypersensitivity reactions are more common with aspirin than other NSAIDs. Patients sensitive to aspirin have cross-sensitivity to other analgesics, NSAIDs, and azo dyes, such as tartrazine. Acetaminophen is not cross-sensitive and may be used cautiously in patients with aspirin-induced asthma. 5. Which agent(s) have antipyretic, analgesic, and anti-inflammatory effects similar to those of aspirin? indomethacin naproxen acetaminophen propoxyphene (darvon) colchicine Correct. No, only the first two foils are correct. Indomethacin produces numerous G.I. effects and several hematopoietic reactions. It also has several CNS manifestations. Because of these many side effects, this drug should probably be used only when safer drugs have proved ineffective. Examples of similar anti-inflammatory agents but with a better side effect profile are ibuprofen, naproxen, piroxicam, nabumetone, and oxaprozin. Ketorolac is an NSAID that is often given by injection. 6. Acetaminophen differs from aspirin in that it does not: produce analgesia have a significant anti-inflammatory effect produce antipyresis absorb from the GI tract Correct. No, only the second foil is correct. Acetaminophen does possess analgesic and antipyretic activity. Acetaminophen is often used as a substitute for aspirin because it doesn't possess the GI irritation that aspirin does ("Non aspirin" analgesic). 7. In clinically-used doses, indomethacin may produce: sodium and water retention agranulocytosis sore throat peptic ulcer Correct. No. All foils are correct. See next page. Indomethacin is an NSAID used primarily in the treatment of gout as well as in rheumatoid and osteoarthritis when other NSAIDs are not effective. Indomethacin is also used in premature neonates to accelerate closure of patent ductus arteriosus. Indomethacin is sometimes used in other non-FDA-approved conditions such as primary dysmenorrhea, juvenile arthritis, Reiter's syndrome, Paget's disease, acute pseudogout, pleuritic chest pain, and pericarditis, but when used for this condition it should be used for only short periods, and side effects should be monitored carefully. Adverse effects include: Renal dysfunction can occur during therapy with NSAIDs such as indomethacin. Gastritis, GI bleeding, and ulceration are possible serious complications of therapy with NSAIDs. Adverse hematologic effects occur in less than 1% of patients receiving indomethacin, but because of their potential severity, blood counts need to be monitored periodically. Possible manifestations include hemolysis with anemia, aplastic anemia, pancytopenia, agranulocytosis, and thrombocytopenia. 8. The effectiveness of colchicine in the treatment of acute gout is due to: its ability to decrease uric acid in plasma an increased urinary excretion of uric acid its antipyretic activity inhibition of purine degradation inhibition of phagocytosis Correct. No. The answer is E. Colchicine binds to tubulin, depolymerizing microtubules thus preventing granulocyte migration and phagocytosis of urate crystals. Adverse effects include diarrhea, nausea, and vomiting. Patients suffering from an acute attack of gout who cannot tolerate colchicine may be treated with either indomethacin or other NSAIDs except salicylates. Synoviocytes phagocytose urate crystals and then secrete inflammatory mediators. These mediators attract and activate polymorphonuclear leukocytes and macrophages (MNP). Drugs with beneficial effects in gout may not influence the urate levels but interfere with the phagocytosis of the crystals as well as the release of inflammatory mediators. 9. With regard to therapeutic effect, sulfinpyrazone has effects most similar to: probenecid allopurinol indomethacin acetaminophen aspirin Correct. No. The answer is A. Both sulfinpyrazone and probenecid are uricosuric agents. That is, they increase the urinary excretion of uric acid by blocking the active reabsorption of uric acid in the proximal tubule of the kidney. These agents are used to deplete the urate deposits in the tissues of patients with chronic gout. 10. Which of the following are used in the treatment of acute gout but may cause gastrointestinal ulcers especially when high doses are required to alleviate symptoms? indomethacin naproxen aspirin ibuprofen ketoprofen Correct. At this moment non-salicylate NSAIDs are the choice of drugs in the management of acute gouty attacks, however, colchicine also can be considered as an alternative. Their ulcerogenic activity is probably based upon inhibiting the synthesis of prostaglandins. (See misoprostol as an agent that may prevent G.I. ulcers!) No! All can be used except aspirin!. At this moment non-salicylate NSAIDs are the choice of drugs in the management of acute gouty attacks, however, colchicine also can be considered as an alternative. Their ulcerogenic activity is probably based upon inhibiting the synthesis of prostaglandins. (See misoprostol as an agent that may prevent G.I. ulcers!) 11. Possesses both antiinflammatory and analgesic properties: acetylsalicylic acid (aspirin) piroxicam both neither Correct. No. The answer is both. 12. Ringing in the ears is a common side effect of high doses of: acetylcalicylic acid (aspirin) acetaminophen both neither Correct. Tinnitus, or ringing in the ears, has been used as an endpoint to mark the attainment of effective serum salicylate levels in the treatment of rheumatic fever. Incorrect. Salicylates (but not acetaminophen) cause ringing in the ears. This is one of the symptoms of salicylism. 13. Decreases blood levels of uric acid: allopruinol probenecid both neither Correct. Each drug can lower blood uric acid levels, but by entirely different mechanisms. By using both drugs together it is possible to reduce the uric deposits (tophi) in joints of the gout patient much more rapidly than by either drug alone. Partly correct. Allopurinol, an inhibitor of xanthine oxidase, does lower serum uric acid levels by decreasing the formation of uric acid. Partly correct. Probenecid does lower blood uric acid levels by decreasing the tubular reabsorption of uric acid. I.E., by promoting the urinary excretion of uric acid (uricosuria). No. Both drugs reduce the levels of uric acid in the blood. 14. Inhibition of prostaglandin synthesis may explain the therapeutic effects of: aspirin acetaminophen both neither Correct. This is the best answer because the antipyretic and analgesic effects that the salicylates and the aniline derivatives share seem to be closely related to the capacity of these agents to inhibit prostaglandin synthase in the CNS. Partly. C is the best answer because the antipyretic and analgesic effects that the salicylates and the aniline derivatives share seem to be closely related to the capacity of these agents to inhibit prostaglandin synthase in the CNS. No. You should recognize the importance of the action of antipyretic analgesic and anti-inflammatory drugs in inhibiting prostaglandin synthetase as the best explanation yet offered for the diverse effects of the salicylate and aniline derivatives. 15. Toxic effects include gastrointestinal irritation, hypersensitivity, and hyperventilation: Correct. Aspirin produces all three of these toxic effects. Incorrect. This is incorrect because hyperventilation is an unusual toxic reaction found only with aspirin and stands as the key reaction in causing the disturbances in acid-base balance that characterize aspirin poisoning. 16. Which of the following is the mechanism of action of allopurinol? it blocks tubular reabsorption of uric acid it inhibits phagocytosis it increases uric acid secretion in the proximal tubules it decreases uric acid synthesis Very good. No. The answer is D. Allopurinol decreases uric acid synthesis by inhibiting xanthine oxidase thus blocking the conversion of 1. hypoxanthine to xanthine and 2. xanthine to uric acid. Colchicine is not involved in uric acid synthesis but it does inhibit phagocytosis of sodium urate crystals by polymorphonuclear leukocytes in the joints, thus decreasing inflammation. 17. A uricosuric agent used to treat gout: Colchicine Probenecid Allopurinol Indomethacin Ibuprofen Correct. No. The answer is B. Probenecid blocks both the reabsorption and secretion of uric acid, but the net effect is an increase in excretion (uricosuria). 18. Considering what you have learned about mechanisms, which one of the following might you use to treat uric acid crystals in the kidney? Allopurinol Colchicine Indomethacin Probenecid Correct. No. The answer is A. Uric acid crystals in the kidney can cause serious kidney damage. This can be minimized by giving allopurinol which will decrease PRODUCTION of uric acid. It is also very important to keep the urine alkaline. 19. Inhibition of the following enzyme(s) will reduce uric acid production: PRPP-amidotransferase HGPRTase xanthine oxidase 2-3 dihydroporcelainase Right. Partly. Partly. No. The first and third foils are correct. Inhibition of amidotransferase and xanthine oxidase would reduce uric acid production. Inhibition of HGPRTase would lead to decreased recycling, decreased feedback inhibition of the first step, and increased uric acid production. The kidney, by its organic acid secretory system, is responsible for excretion of uric acid. Plasma urate is almost completely filtered at the glomerulus and then is almost completely reabsorbed. Subsequent tubular secretion is responsible for 80-85 percent of the uric acid finally excreted. The ketoacids and lactic acids are known to inhibit tubular secretion of uric acid. Many drugs also do this. Maximal solubility of urate in plasma is roughly equal to the upper limit of normal serum urate levels. The KU lab reports values are 4-8 mg percent in males, and 2-6 mg percent in females. 20. Inhibition of tubular reabsorption of uric acid would: increase urinary uric acid excretion. decrease urinary uric acid excretion. That is correct. No. The answer is A. 21. Which of the following are true of allopurinol? inhibitor of xanthine oxidase interferes with the uricosuric action of probenecid is used in the treatment of chronic hyperuricemia of gout and polycythemia vera its use in treatment of gouty arthritis is predicated on its antiinflammatory action Good. Partly. Partly. No. The first and third foils are correct. 22. Probenecid is used in the treatment of gout because of its: general analgesic and anti-inflammatory properties inhibitory effect on the enzyme xanthine oxidase which will reduce uric acid formation specific actions on tophi which dissolves the uric acid deposits ability to block tubular reabsorption of uric acid Correct. No. Only the fourth foil is correct. 23. Frequent side effects of colchicine therapy are: abdominal pain nausea vomiting bone marrow depression That is correct. Partly. Partly. Partly. No. The first three foils are correct. 24. Indicated for use for lowering serum urate levels following an attack of gouty renal colic. Allopurinol Probenecid Both Neither Correct. No. The answer is A. 25. A 56-year-old woman with severe rheumatoid arthritis was given an oral medication that inhibits dihydroorotate dehydrogenase. This drug was most likely: Anakinra Auranofin Celecoxib Etanercept Leflunomide Very good! Leflunomide is converted to an active metabolite that inhibits dihydroorotate dehydrogenase which is an enzyme located in mitochondria that catalyzes a key step in de novo pyrimidine synthesis. No, Anakinra is a recombinant human interleukin-1 receptor antagonist (IL-1Ra). It is recommended for reducing the signs and symptoms and slowing the progression of structural damage of moderately to severely active rheumatoid arthritis in individuals who have failed one or more DMARDs. No, Auranofin is an orally active gold compound used to treat early active cases of both adult and juvenile types of rheumatoid arthritis. The mechanism of the gold compounds remain unknown but they may inhibit antigen processing by macrophages or inhibit lysosomal enzyme release, thereby decreasing inflammation. No Celecoxib is a selective Cox-2 inhibitor with comparable efficacy to other NSAIDs, such as naproxen and diclofenac in the treatment of rheumatoid arthritis and osteoarthritis. No, Etanercept is anti-TNFalpha drug used for the treatment of rheumatoid arthritis, active polyarticular course juvenile rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. 26. A 46-year-old woman with rheumatoid arthritis was treated with penicillamine at a dose of 1000 mg/day for 4 months and no improvement was obtained. Penicillamine treatment was discontinued The patient was given a prescription for a different drug, but the physcian informed the patient to wait 24 hours before taking the new oral medication to allow the penicillamine to be cleared from the body so that it will not form a complex with the new medication. The new oral medication was most likely: Auranofin Aurothioglucose Etanercept Hydroxychloroquine Sulfasalazine Yes, Auranofin, the only gold compound available for oral administration, is an antiarthritic agent used to treat early active cases of both adult and juvenile types of rheumatoid arthritis. Penicillamine forms complexes with gold. It has a half-life of three hours so it would be mostly cleared from the body after 24 hours. No, Aurothioglucose is an intramuscular dosage form of gold. o, Etanercept is a dimeric fusion protein that is effective in the treatment of rheumatoid arthritis. It works by decreasing the effects of TNF. No, Hydroxychloroquine is similar to chloroquine but it is more commonly used to treat rheumatoid arthritis and lupus erythematosus. No, Sulfasalazine or salicylazosulfapyridine is a prodrug used in the treatment of ulcerative colitis and rheumatoid arthritis. Sulfasalazine is cleaved to yield sulfapyridine plus 5-aminosalicylic acid, the latter is an effective antiinflammatory agent. Sulfasalazine is used for the treatment of mild to moderate ulcerative colitis and to prolong the remission period between acute attacks of ulcerative colitis. For a severe acute attack of ulcerative colitis use steroids. 27. A 26-year-old woman, who has severe G.I. upset when taking naproxen, was given a new medication for the treatment of severe cramping associated with dysmenorrhea. The new medication which is supposed to relieve cramping with minimal affects on the G.I. system was most likely: Acetaminophen Indomethacin Ketorolac Sulindac Valdecoxib Yes, Valdecoxib is a selective COX-2 inhibitor indicated for the management of dysmenorrhea, osteoarthritis, and rheumatoid arthritis. COX-2 inhibitors are supposed to have minimal affects on the G.I. system and do not interfere with platelet aggregation. Not the best!! Acetaminophen helps relieve pain but does not relieve severe cramping due to the production of peripheral prostaglandins. No, Indomethacin would be affective but would also cause G.I. upset. No, Ketorolac is likely to cause severe G.I. distress in this patient. It is available for pareneteral administration, thus, making it a useful drug to use in the hospital post surgery. No, Sulindac is likely to cause severe G.I. symptoms in this patient.