1. Pharmacology-1 PHL 211 2 nd Term 5 th Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212Email: aeashour@ksu.edu.sa

2. Other Nonselective Cox Inhibitors  Diflunisal is more potent than aspirin in the anti-inflammatory effects and it is a competitive inhibitor of COX. However, it is largely devoid of antipyretic effects, perhaps because of poor penetration into the CNS  The drug is used primarily as an analgesic in the treatment of osteoarthritis and musculoskeletal strains or sprains; in these circumstances it is about 3-4 times more potent than aspirin  It is claimed to be particularly effective for cancer pain with bone metastases and for pain control in dental (third molar) surgery  In terms of adverse effects, diflunisal qualitatively resembles aspirin. However, diflunisal does not produce auditory side effects and it causes fewer and less intense GI and antiplatelet effects than does aspirin  Diflunisal  Diflunisal (DOLOBID) is a difluorophenyl derivative of salicylic acid. It is weakly COX-1-selective  It is almost completely absorbed after oral administration, and peak plasma concentrations occur within 2 to 3 hrs  It is extensively bound to plasma albumin (99%). At the usual analgesic dose, the plasma t 1/2 averages between 8 and 12 hours (cf. salicylate; about 2.5 hrs)  Although diflunisal is derived from salicylic acid, it is not metabolized to salicylic acid or salicylate. It undergoes an enterohepatic cycle with reabsorption of its glucuronide metabolite followed by cleavage of the glucuronide to again release the active moiety

3. Other Nonselective Cox Inhibitors, Acetic Acid Derivatives  Oral indomethacin has excellent bioavailability. Peak concentrations occur 1 to 2 hrs after dosing. Indomethacin is 90% bound to plasma proteins and tissues. Its concentration in synovial fluid is equal to that in plasma within 5 hrs of administration  The t 1/2 of indomethacin in plasma is variable (averages ~ 2.5 hours), perhaps because of enterohepatic cycling of the drug  Indomethacin:  Indomethacin has prominent antiinflammatory and analgesic- antipyretic properties similar to those of the salicylates. It is a more potent inhibitor of the COX than is aspirin (patient intolerance generally limits its use to short-term dosing), and it may also inhibit phospholipase A and C, and reduce neutrophil migration  When tolerated, indomethacin is very effective in the treatment of acute gout, although it is not uricosuric. It is more effective than aspirin in the treatment of ankylosing spondylitis and osteoarthritis  It is effective for relieving joint pain, swelling, and tenderness, increasing grip strength, and decreasing the duration of morning stiffness  It is suitable for moderate to severe disease  Indomethacin is FDA approved for closure of persistent patent ductus arteriosus

4. Acetic Acid Derivatives, Indomethacin  A very high percentage of patients receiving usual therapeutic doses of indomethacin experience untoward symptoms (~ 20% must discontinue its use because of the side effects. Most adverse effects are dose-related  GI complaints are common and can be serious. Diarrhoea may occur and sometimes is associated with ulcerative lesions of the bowel. Underlying peptic ulcer disease is a contraindication to indomethacin use  The most frequent CNS effect is severe frontal headache. Caution is advised when administering indomethacin to elderly patients or to those with underlying epilepsy, psychiatric disorders, or Parkinson's disease, because they are at greater risk for the development of serious CNS adverse effects  Hematopoietic reactions include neutropenia, thrombocytopenia, and rarely aplastic anemia. As is common with other tNSAIDs, platelet function is impaired transiently during the dosing interval

5. Acetic Acid Derivatives, Sulindac  The typical GI side effects but less severe at common doses than with indomethacin  CNS side effects as described for indomethacin  Transient elevations of hepatic transaminases; it is more likely to produce hepatic injury than are most other NSAIDs  Rash, pruritus, thrombocytopenia, agranulocytosis  Because the sulfide may be reoxidized to the inactive prodrug in the kidney, sulindac may inhibit renal COX less than other NSAIDs, though reversible renal failure and nephrotic syndrome have been observed with this drug  Sulindac is a prodrug whose anti-inflammatory activity resides in its sulfide metabolite. About 90% of it is absorbed after oral administration. Peak plasma concentrations of sulindac are attained within 1 to 2 hrs, while those of the sulfide metabolite occur about 8 hrs after the oral administration of sulindac  Sulindac has been used mainly for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and acute gout. It may also inhibit the development of colon, breast, and prostate cancer in humans  Even though sulindac is closely related to indomethacin, it is less than half as potent as indomethacin  Sulindac is weakly COX-2-selective and there is a lower incidence of adverse effects with sulindac as compared with indomethacin which include:  The t 1/2 of sulindac itself is about 7 hrs, but the active sulfide has a t 1/2 as long as 18 hrs. Sulindac and its metabolites undergo extensive enterohepatic circulation, and all are bound extensively to plasma protein

6. Acetic Acid Derivatives, Etodolac  Etodolac is slightly more COX-2-selective than most other tNSAIDs, with a COX-2:COX-1 activity ratio of about 10. Thus, at antiinflammatory doses, the frequency of gastric irritation may be less than with other tNSAIDs  Etodolac is rapidly and well absorbed orally. It is highly bound to plasma protein and undergoes hepatic metabolism and renal excretion. The drug may undergo enterohepatic circulation in humans; its t 1/2 in plasma is about 7 hrs  Etodolac indications include:  Postoperative analgesia that may last for 6 to 8 hours  Treatment of osteoarthritis and rheumatoid arthritis  Etodolac appears to be relatively well tolerated. About 5% of patients who have taken the drug for up to 1 year discontinue treatment because of side effects, which include GI intolerance, rashes, and CNS effects