Pharmacology-1 PHL nd Term 6 th Lecture By Abdelkader Ashour, Ph.D. Phone:

Phenylacetic Acid Derivatives, Diclofenac  Diclofenac is a phenylacetic acid derivative that is relatively nonselective as a COX inhibitor. It is the most commonly used tNSAID in Europe  Like diflunisal, sulindac and etodolac, it is weakly COX-2-selective  Therapeutic uses include:  Symptomatic treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis  Treatment of acute musculoskeletal pain, postoperative pain, and dysmenorrhea  an ophthalmic solution of diclofenac is available for treatment of postoperative inflammation following cataract extraction  Diclofenac in rectal suppository form can be considered a drug of choice for preemptive analgesia and postoperative nausea  Diclofenac has rapid absorption, extensive protein binding, and a short half-life. There is a substantial first-pass effect, such that only about 50% of diclofenac is available systemically  Diclofenac accumulates in synovial fluid after oral administration, which may explain why its duration of therapeutic effect is considerably longer than the plasma t 1/2. Diclofenac is metabolized in the liver by a member of the CYP2C subfamily  Consistent with its preference for COX-2, and unlike ibuprofen, diclofenac does not interfere with the antiplatelet effect of aspirin  There is some evidence that diclofenac inhibits the lipoxygenase pathways

Phenylacetic Acid Derivatives, Diclofenac  Adverse effects include:  GI distress, GI bleeding, and gastric ulceration, though ulceration may occur less frequently than with some other NSAIDs. A preparation combining diclofenac and misoprostol (Arthrotec ® ) decreases upper GI ulceration but may result in diarrhea  Diclofenac at a dosage of 150 mg/d appears to impair renal blood flow and glomerular filtration rate. Impairment of renal function rarely occurs  Elevation of serum aminotransferases may occur more commonly with this drug than with other NSAIDs  Diclofenac is more likely to produce hepatic injury than are most other NSAIDs, exceeded only by sulindac  Other untoward responses to diclofenac include CNS effects, rashes, allergic reactions, fluid retention, and edema  The drug is not recommended for children, nursing mothers, or pregnant women  Consistent with its preference for COX-2, and unlike ibuprofen, diclofenac does not interfere with the antiplatelet effect of aspirin

Acetic Acid Derivatives, ketorolac  Ketorolac is a heterocyclic acetic acid derivative. It is a potent analgesic but only a moderately effective antiinflammatory drug  It has a rapid onset of action, extensive protein binding, and a short duration of action. Oral bioavailability is about 80%. Urinary excretion accounts for about 90% of eliminated drug  Like other NSAIDs, aspirin sensitivity is a contraindication to the use of ketorolac  Toxicities are similar to those of other NSAIDs, although renal toxicity may be more common with chronic use. It is highly COX-1-selective  Side effects at usual oral doses include somnolence, dizziness, headache, GI pain, dyspepsia and nausea  The GI and renal side effects of ketorolac limit its use  Ketorolac is used as a short-term alternative to opioids for the treatment of moderate to severe pain and is administered i.m., i.v., or orally. Unlike opioids, tolerance, withdrawal, and respiratory depression do not occur. When used with an opioid, it may decrease the opioid requirement by 25-50%  Ketorolac is used widely in postoperative patients  Topical (ophthalmic) ketorolac is FDA approved for the treatment of seasonal allergic conjunctivitis and postoperative ocular inflammation after cataract extraction

Other Nonselective Cox Inhibitors, Propionic Acid Derivatives  Ibuprofen:  Ibuprofen was the first member of the propionic acid class of NSAIDs to come into general use, and it is the most commonly used tNSAID in the USA  It is absorbed rapidly, bound extensively to plasma protein, and undergoes hepatic metabolism and renal excretion of metabolites. The t 1/2 is roughly 2 hrs  Doses of up to 800 mg four times daily can be used in the treatment of rheumatoid arthritis and osteoarthritis. The usual dose for mild to moderate pain, such as that of primary dysmenorrhea, is 400 mg every 4 to 6 hours as needed  It is also indicated for ankylosing spondylitis and acute gouty arthritis  Ibuprofen is effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin  The use of ibuprofen concomitantly with aspirin may decrease the total anti- inflammatory effect  Ibuprofen also has been shown to interfere with the antiplatelet effects of aspirin  Prior occupancy of the active site of platelet COX-1 by ibuprofen impedes access of aspirin to its target Ser 529 and prevents irreversible platelet inhibition by aspirin  In theory, this interaction should not occur with selective COX-2 inhibitors, because mature human platelets lack COX-2

Propionic Acid Derivatives, Ibuprofen  Less frequent adverse effects include: thrombocytopenia, rashes, headache, dizziness, blurred vision. Patients who develop ocular disturbances should discontinue the use of ibuprofen  Ibuprofen can be used occasionally by pregnant women; however, the concerns apply regarding third-trimester effects, including delay of parturition  Excretion into breast milk is thought to be minimal, so ibuprofen also can be used with caution by women who are breastfeeding  Ibuprofen is better tolerated than aspirin and indomethacin and has been used in patients with a history of GI intolerance to other NSAIDs. Nevertheless, 5% to 15% of patients experience GI side effects (which can be modified by ingestion with meals)  Oral doses are readily absorbed. Peak plasma concentration is achieved within 2 hrs. It has a t 1/2 in plasma of about 2 hrs. It is conjugated with glucuronic acid in the liver, and the conjugate is excreted in the urine. Patients with impaired renal function eliminate the drug more slowly  It is indicated for rheumatoid arthritis, osteoarthritis, gout and dysmenorrhea  Ketoprofen:  Ketoprofen shares the pharmacological properties of other propionic acid derivatives. It inhibits both COX (nonselectively) and lipoxygenase  Common Adverse Effects:  Mild GI side effects, which are decreased if the drug is taken with food or antacids  Fluid retention and increased plasma concentrations of creatinine (transient and asymptomatic)

Enolic Acids (Oxicams)  The oxicam derivatives are enolic acids that have antiinflammatory, analgesic, and antipyretic activity  In general, they are nonselective COX inhibitors, although one member (meloxicam) shows modest COX-2 selectivity comparable to celecoxib  They are similar in efficacy to aspirin, indomethacin, or naproxen for the long-term treatment of rheumatoid arthritis or osteoarthritis  Their long t 1/2 permits once-daily dosing (this is their main advantage)  It is extensively bound to plasma proteins, undergoes enterohepatic recirculation, and is eventually eliminated in the urine after being extensively metabolized  Concentrations in plasma and synovial fluid are similar at steady state (e.g., after 7 to 12 days)  It is indicated for the treatment of rheumatoid arthritis and osteoarthritis  Due to its slow onset of action and delayed attainment of steady state, it is less suited for acute analgesia  Piroxicam  Piroxicam is absorbed completely after oral administration; peak concentrations in plasma occur within 2 to 4 hrs. It has a t 1/2 in plasma of about 50 hours  Approximately 20% of patients experience side effects with piroxicam, and about 5% of patients discontinue use because of these effects  Epidemiological studies ranked azapropazone, piroxicam, ketoprofen and indomethacin as the NSAIDs associated with highest risk regarding GI complications

 Meloxicam  The pharmacology and toxicity of meloxicam is similar to those of piroxicam  Like diflunisal, sulindac, etodolac and diclofenac, it is weakly COX-2-selective (particularly at its lowest therapeutic dose of 7.5 mg/d) Enolic Acids (Oxicams), Meloxicam  It provides good anti-inflammatory and analgesic actions with less gastric damage. It is better tolerated than piroxicam  There is significantly less gastric injury compared to piroxicam (20 mg/day) in subjects treated with 7.5 mg/day of meloxicam, but the advantage is lost with 15 mg/day  Like diclofenac, meloxicam would not seem like a desirable alternative to prescribing celecoxib to patients at increased risk of myocardial infarction or stroke

COX-2 Selective NSAIDs (Coxibs)  Coxibs were developed in an attempt to inhibit PG synthesis by the COX-2 isoenzyme induced at sites of inflammation without affecting the action of the constitutively active "housekeeping" COX-1 isoenzyme found in the GIT, kidneys, and platelets  Coxibs selectively bind to and block the active site of the COX-2 enzyme much more effectively than that of COX-1  Coxibs do not offer the cardioprotective effects of nonselective tNSAIDs, which has resulted in some patients taking low-dose aspirin in addition to a coxib regimen to maintain this effect  At usual doses, they have no impact on platelet aggregation, which is mediated by the COX-1 isoenzyme  Because COX-2 is constitutively active within the kidney, recommended doses of COX-2 inhibitors cause renal toxicities similar to those associated with tNSAIDs  Coxibs have analgesic, antipyretic, and anti-inflammatory effects similar to those of nonselective NSAIDs but with an approximate halving of GI adverse effects  As of August 2006, celecoxib is the only COX-2 inhibitor marketed in the USA. Rofecoxib and valdecoxib, highly selective COX-2 inhibitors, have been withdrawn from the market due to their association with increased cardiovascular thrombotic events

COX-2 Selective NSAIDs (Coxibs), Celecoxib  Celecoxib is a selective COX-2 inhibitor, about times more selective for COX-2 than for COX-1  Peak plasma concentration is achieved within 2 hrs. Celecoxib is bound extensively to plasma proteins. Most of the drug is excreted as carboxylic acid and glucuronide metabolites in the urine and feces. The elimination t 1/2 is 11 hrs. The drug commonly is given once or twice per day during chronic treatment  Celecoxib is as effective as other NSAIDs in the treatment of rheumatoid arthritis and osteoarthritis, with fewer endoscopic ulcers. However, the frequency of other adverse effects approximates that of other NSAIDs. It causes no more edema or renal effects than other NSAIDs, but edema and hypertension have been documented  It does not affect platelet aggregation at usual doses