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Pharmacology-1 PHL 211
2nd Term
6th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
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
 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 t1/2. Diclofenac is
metabolized in the liver by a member of the CYP2C subfamily
 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
 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
 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
 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
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 t1/2 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 antiinflammatory 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
 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)
 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
 Ketoprofen:
Ketoprofen shares the pharmacological properties of other
propionic acid derivatives. It inhibits both COX (nonselectively)
and lipoxygenase
 Oral doses are readily absorbed. Peak plasma concentration is achieved within 2 hrs. It
has a t1/2 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
 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 t1/2 permits once-daily dosing (this is their main advantage)
 Piroxicam
 Piroxicam is absorbed completely after oral administration;
peak concentrations in plasma occur within 2 to 4 hrs. It
has a t1/2 in plasma of about 50 hours
 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
 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
Enolic Acids (Oxicams), Meloxicam
 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)
 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 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
 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
COX-2 Selective NSAIDs (Coxibs), Celecoxib
 Celecoxib is a selective COX-2 inhibitor, about 10-20 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 t1/2 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