Dr. Eduardo D. Rosas Blum Department of Pharmacology
Slide 2
A 5-year-old girl is brought to the emergency department by her
parents in a comatose state. Her parents refers that she felt ill
recently with high fever. Physical examination: comatose,
papilledema, hepatomegaly. A CT Scan reveals cerebral edema. What
agent is most likely to be involved in this patient? a) Aspirin b)
Acetaminophen c) Codein d) Celecoxib e) Ibuprofen
Slide 3
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Pain is an unpleasant sensory and emotional experience
associated with actual or potential tissue damage or described in
terms of such damage.
Slide 5
NSAIDs Relief of pain. Relief of pain. A major presenting
symptoms in common complaints. A major presenting symptoms in
common complaints. Suppress the signs and symptoms of inflammation.
Suppress the signs and symptoms of inflammation. Exert antipyretic
and analgesic effect. Exert antipyretic and analgesic effect.
Useful in pain related to inflammation. Useful in pain related to
inflammation.
Slide 6
Pharmacokinetics Weak organic acids (nabumetone) Weak organic
acids (nabumetone) Well absorbed Well absorbed Food doesnt change
their bioavailability. Food doesnt change their bioavailability.
Metabolized in phase I and II. Metabolized in phase I and II. Also
in CYP3A, CYP2C (part CYP450) Also in CYP3A, CYP2C (part CYP450)
Renal, most important route of excretion. (biliary excretion and
absorption) Renal, most important route of excretion. (biliary
excretion and absorption) 98% Bound to Albumin. 98% Bound to
Albumin. Found synovial fluid after repeating doses. Found synovial
fluid after repeating doses.
Slide 7
Pharmacodynamics Inhibition of biosynthesis of prostaglandins.
Inhibition of biosynthesis of prostaglandins. Inhibition
chemotaxis, down-regulation of IL-1, decrease production of free
radicals. Inhibition chemotaxis, down-regulation of IL-1, decrease
production of free radicals. Decrease sensitivity of vessels to
bradykinin and histamine. Decrease sensitivity of vessels to
bradykinin and histamine. Gastric irritants, nephrotoxity,
hepatotoxicity. Gastric irritants, nephrotoxity, hepatotoxicity.
Aspirin irreversibly blocks COX. Aspirin irreversibly blocks
COX.
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Aspirin & Salicylates Acetylsalicylic Acid. Acetylsalicylic
Acid. 400 BC: Greek physician Hippocrates prescribes the bark and
leaves of the willow tree (rich salicin) to relieve pain and fever.
400 BC: Greek physician Hippocrates prescribes the bark and leaves
of the willow tree (rich salicin) to relieve pain and fever. 1897:
Chemist, Felix Hoffmann, at Bayer in Germany, synthesizes a stable
form of ASA powder that relieves his father's rheumatism. 1897:
Chemist, Felix Hoffmann, at Bayer in Germany, synthesizes a stable
form of ASA powder that relieves his father's rheumatism. The
compound later becomes the active ingredient in aspirin named - "a"
from acetyl, "spir" from the spirea plant (which yields salicin)
and "in," a common suffix for medications. The compound later
becomes the active ingredient in aspirin named - "a" from acetyl,
"spir" from the spirea plant (which yields salicin) and "in," a
common suffix for medications.
Slide 11
Pharmacokinetics pKa 3.5, rapidly absorbed in the stomach and
upper small bowel. pKa 3.5, rapidly absorbed in the stomach and
upper small bowel. Short serum half-life (20 - 25min), peak plasma
level 1- 2hrs. Short serum half-life (20 - 25min), peak plasma
level 1- 2hrs. Bound to serum albumin 70%. Renal excretion. Bound
to serum albumin 70%. Renal excretion. As Aspirin dose increases
the half-life increases. At low doses its elimination follows first
order kinetics. At high doses, zero-order kinetics prevails. As
Aspirin dose increases the half-life increases. At low doses its
elimination follows first order kinetics. At high doses, zero-order
kinetics prevails. Alkalinization of the urine increases the rate
of excretion. Alkalinization of the urine increases the rate of
excretion.
Slide 12
Mechanism Actions Anti-inflammatory effect Anti-inflammatory
effect Irreversible non-selective COX inhibitor. Irreversible
non-selective COX inhibitor. Inhibits platelet aggregation.
Inhibits platelet aggregation. Interferes with the mediators of the
kallikrein system (bradykinins). Interferes with the mediators of
the kallikrein system (bradykinins). Inhibits chemotaxis of PMN
leukocytes and macrophages. Inhibits chemotaxis of PMN leukocytes
and macrophages.
Slide 13
Mechanism Actions Analgesic effect Analgesic effect Probably
inhibits pain stimuli at a subcortical site. Probably inhibits pain
stimuli at a subcortical site. Antipyretic effect Antipyretic
effect COX inhibition in the CNS, inhibition of IL-1 (released in
macrophages). COX inhibition in the CNS, inhibition of IL-1
(released in macrophages).
Clinical Uses As analgesic to mild to moderate pain. As
analgesic to mild to moderate pain. Combine with opiod analgesics
for cancer pain. Combine with opiod analgesics for cancer pain. As
anti-inflammatory in rheumatoid arthritis rheumatic, fever and
inflammatory joint conditions. As anti-inflammatory in rheumatoid
arthritis rheumatic, fever and inflammatory joint conditions.
Antipyretic, when reducing the fever is desirable. Antipyretic,
when reducing the fever is desirable. Prophylaxis of ischemic heart
disease, to reduce incidence of coronary artery disease.
Prophylaxis of ischemic heart disease, to reduce incidence of
coronary artery disease.
Adverse Effects Hepatotoxicity. Hepatotoxicity. Elevation of
liver enzymes, hepatitis. Elevation of liver enzymes, hepatitis.
Hypersensibility (Asthma, Rashes) Hypersensibility (Asthma, Rashes)
Renal toxicity (decrease function). Renal toxicity (decrease
function). Changes in uric acid levels (low doses high serum
levels) Changes in uric acid levels (low doses high serum
levels)
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Adverse Effects Reyess-like syndrome ( Hepatoencephalopathy)
highly lethal. Reyess-like syndrome ( Hepatoencephalopathy) highly
lethal. Avoid aspirin in children with influenza or chickenpox
infections (give Tylenol). Avoid aspirin in children with influenza
or chickenpox infections (give Tylenol).
Slide 20
Aspirin Overdose Acid-base disturbance. Acid-base disturbance.
1 st Respiratory Alkalosis (low levels). 1 st Respiratory Alkalosis
(low levels). Direct effect on the CNS respiratory centers and as a
compensatory mechanism of a metabolic acidosis. Direct effect on
the CNS respiratory centers and as a compensatory mechanism of a
metabolic acidosis. 2 nd Metabolic Acidosis (High levels) 2 nd
Metabolic Acidosis (High levels) Depletion of HCO3, accumulation of
salicylic acids derivatives, respiratory depression. Depletion of
HCO3, accumulation of salicylic acids derivatives, respiratory
depression. 3 rd Mixed Acidosis (respiratory and metabolic). 3 rd
Mixed Acidosis (respiratory and metabolic).
Slide 21
Drug Interaction Acetazolamine, ammonium chloride enhances
aspirin toxicity. Acetazolamine, ammonium chloride enhances aspirin
toxicity. EtOH increases GI bleeding. EtOH increases GI bleeding.
Reduces the activity of spironolactone. Reduces the activity of
spironolactone. Antagonizes the effect of heparin in the platelets.
Antagonizes the effect of heparin in the platelets. Competes with
Penicillin G for renal tubular secretion. Competes with Penicillin
G for renal tubular secretion.
Slide 22
Drug Interactions Inhibits the uricosuric effect of
sulfinpyrazone and probenecid. Inhibits the uricosuric effect of
sulfinpyrazone and probenecid. Displaces drugs from proteins in
serum Displaces drugs from proteins in serum Oral hypoglycemic
agents, methotrexate, other NSAIDs. Oral hypoglycemic agents,
methotrexate, other NSAIDs.
Slide 23
Nonacetylated Salicylates Mg Choline salicylate, sadium
salicylate, salicylsalicylate. Mg Choline salicylate, sadium
salicylate, salicylsalicylate. Chemically different for aspirin.
Chemically different for aspirin. Reversible platelet inhibition.
Reversible platelet inhibition. Effective anti-inflammatory effect,
less analgesic effect than aspirin. Effective anti-inflammatory
effect, less analgesic effect than aspirin. Can use in patient with
asthma, bleeding tendencies or renal dysfunction. Can use in
patient with asthma, bleeding tendencies or renal dysfunction.
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Nonselective COX inhibitors Mechanism is similar to aspirin
(exceptions) Mechanism is similar to aspirin (exceptions) All are:
inhibitors of prothrombin synthesis, analgesic, anti-inflammatory,
antipyrectic, inhibit platelet aggregation (variations). All are:
inhibitors of prothrombin synthesis, analgesic, anti-inflammatory,
antipyrectic, inhibit platelet aggregation (variations). As a
group: cause less gastric irritation (exceptions), nephrotoxicity.
As a group: cause less gastric irritation (exceptions),
nephrotoxicity.
Slide 27
PROPIONIC ACID DERIVATIVES Ibuprofen, Naproxen, Fenoprofen.
Ibuprofen, Naproxen, Fenoprofen. Very similar in mechanism of
action and effects (compared to aspirin). Very similar in mechanism
of action and effects (compared to aspirin). More effective as
analgesics, and have less adverse effects in the GI tract. More
effective as analgesics, and have less adverse effects in the GI
tract. Ibuprofen and Fenoprofen half-life of 2 hrs. Ibuprofen and
Fenoprofen half-life of 2 hrs. Naproxen has a longer half-life (13
hrs). Dysmenorrhea. Naproxen has a longer half-life (13 hrs).
Dysmenorrhea. Adverse effects are similar: nephrotoxicity,
jaundice, nausea, dyspepsia, edema, rash, pruritus, tinnitus.
Adverse effects are similar: nephrotoxicity, jaundice, nausea,
dyspepsia, edema, rash, pruritus, tinnitus. Interactions and
contraindications: same as aspirin. Interactions and
contraindications: same as aspirin.
Slide 28
ACETIC ACIDS Indomethacin Indomethacin Most potent inhibitor of
prostaglandin synthesis (COX-1) more effective but more toxic than
aspirin. Most potent inhibitor of prostaglandin synthesis (COX-1)
more effective but more toxic than aspirin. Orally absorbed, highly
bound to plasma proteins, half-life 2hrs. Orally absorbed, highly
bound to plasma proteins, half-life 2hrs. Metabolized in liver,
excreted in bile and urine. Metabolized in liver, excreted in bile
and urine.
Slide 29
Indomethacin High incidence of dose-related toxic effects: High
incidence of dose-related toxic effects: GI, severe migraine
(20-25%), dizziness, confusion and depression, risk of fluid
retention, hyperkalemia and blood dyscrasias. GI, severe migraine
(20-25%), dizziness, confusion and depression, risk of fluid
retention, hyperkalemia and blood dyscrasias. Contraindicated in
pregnancy and in patients with psychosis. Contraindicated in
pregnancy and in patients with psychosis.
Slide 30
Indomethacin Uses Uses Treatment of patent ductus arteriosus in
premature babies. Treatment of patent ductus arteriosus in
premature babies. Acute gouty arthritis, ankylosing spondylitis,
osteoarthritis. Acute gouty arthritis, ankylosing spondylitis,
osteoarthritis. Pericarditis and pleurisy. Pericarditis and
pleurisy.
Slide 31
Sulindac Is a pro-drug closely related to Indomethacin. Is a
pro-drug closely related to Indomethacin. It should be converted to
the active form of the drug. It should be converted to the active
form of the drug. Indications and toxicity similar to Indomethacin.
Indications and toxicity similar to Indomethacin. May inhibit the
development of breast, colon and prostate cancer. May inhibit the
development of breast, colon and prostate cancer. Suppresses
familial intestinal polyposis disease. Suppresses familial
intestinal polyposis disease.
Slide 32
Tolmetin Approved for treatment of juvenile arthritis. Approved
for treatment of juvenile arthritis. Has a short half-life (60
min.). Has a short half-life (60 min.). Fewer GI and CNS side
effects than Indomethacin. Rare IgM related TTP. Fewer GI and CNS
side effects than Indomethacin. Rare IgM related TTP. Not often
used. Ineffective for gout. Not often used. Ineffective for
gout.
Slide 33
Diclofenac Gastrointestinal distress, gastrointestinal
bleeding, gastric ulceration. Gastrointestinal distress,
gastrointestinal bleeding, gastric ulceration. Less frequent than
other NSAIDs. Less frequent than other NSAIDs. Combinations with
misoprostol and omeprazol reduce incidence. Combinations with
misoprostol and omeprazol reduce incidence. High doses impairs
renal function. Elevates liver enzymes. High doses impairs renal
function. Elevates liver enzymes.
Slide 34
FENAMATES Meclofenamate, Mefenamic acid. Meclofenamate,
Mefenamic acid. Analgesic, anti-inflammatory properties less
effective than aspirin and clearly more toxic. Analgesic,
anti-inflammatory properties less effective than aspirin and
clearly more toxic. Short half-lives, and should not be used for
longer than one week and never in pregnancy and in children. Short
half-lives, and should not be used for longer than one week and
never in pregnancy and in children. Diarrhea and abdominal pain.
Diarrhea and abdominal pain. Enhances oral anticoagulants. Enhances
oral anticoagulants.
Slide 35
PYRAZOLONE DERIVATIVES Phenylbutazone Phenylbutazone Withdrawn
from the market. Withdrawn from the market. Adverse effects of this
drug are: agranulocytosis, aplastic anemia, hemolytic anemia,
severe gastric irritation, nephrotic syndrome, optic neuritis,
deafness, serious allergic reactions, exfoliative dermatitis,
hepatic and renal tubular necrosis. Adverse effects of this drug
are: agranulocytosis, aplastic anemia, hemolytic anemia, severe
gastric irritation, nephrotic syndrome, optic neuritis, deafness,
serious allergic reactions, exfoliative dermatitis, hepatic and
renal tubular necrosis.
Slide 36
PYRAZOLONE DERIVATIVES Oxyphenbutazone: one of the metabolites
of phenylbutazone. Oxyphenbutazone: one of the metabolites of
phenylbutazone. Apazone.- Similar to phenylbutazone, but less
likely to cause agranulocytosis. Apazone.- Similar to
phenylbutazone, but less likely to cause agranulocytosis.
Slide 37
OXICAM Piroxicam. Piroxicam. Half-life of 45 hrs. Once-daily
dosing. Delay onset of action. Half-life of 45 hrs. Once-daily
dosing. Delay onset of action. High doses inhibits PMN migration,
decrease oxygen radical production, inhibits lymphocyte function
(high doses). High doses inhibits PMN migration, decrease oxygen
radical production, inhibits lymphocyte function (high doses). Used
in osteoarthritis, ankylosing spondylitis and rheumatoid arthritis.
Used in osteoarthritis, ankylosing spondylitis and rheumatoid
arthritis. Adverse effects: GI symptoms, dizziness, tinnitus,
headache, rash. Peptic ulcer (9.5 higher) Adverse effects: GI
symptoms, dizziness, tinnitus, headache, rash. Peptic ulcer (9.5
higher)
Slide 38
Ketorolac Analgesic, no anti-inflammatory effect (market). Have
typical NSAIDs properties. More analgesic efficacy. Analgesic, no
anti-inflammatory effect (market). Have typical NSAIDs properties.
More analgesic efficacy. Can replace morphine in mild to moderate
postsurgical pain. Can replace morphine in mild to moderate
postsurgical pain. VO, IM, IV. VO, IM, IV. Similar toxicities.
Renal toxicity common with chronic use. Similar toxicities. Renal
toxicity common with chronic use.
Slide 39
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COX-2 Selective Celecoxib, Etoricoxib, Rofecoxib, Valdecoxib,
Meloxicam (preferential). Celecoxib, Etoricoxib, Rofecoxib,
Valdecoxib, Meloxicam (preferential). Inhibit prostacyclin (COX-2)
in sites of inflammation. Inhibit prostacyclin (COX-2) in sites of
inflammation. Do not block housekeeping effect of COX-1. Do not
block housekeeping effect of COX-1. Antipyretic, analgesic and
anti- inflammatory effect. Antipyretic, analgesic and anti-
inflammatory effect.
Slide 41
COX-2 Selective Indications Indications Osteoarthritis,
rheumatoid arthritis, dysmenorrhea, acute gouty attacks, acute
musculoskeletal pain. Osteoarthritis, rheumatoid arthritis,
dysmenorrhea, acute gouty attacks, acute musculoskeletal pain.
Still under investigation. Still under investigation.
Slide 42
Rofecoxib (Vioxx) Withdrawn from the market. Withdrawn from the
market. Higher incidence of cardiovascular thrombotic events.
Higher incidence of cardiovascular thrombotic events. Inhibits
prostacyclin letting TXA 2 act freely and promote platelet
aggregation. Inhibits prostacyclin letting TXA 2 act freely and
promote platelet aggregation.
Slide 43
Acetaminophen Para-aminophenol. Para-aminophenol. Analgesic and
antipyretic actions equivalent aspirin. Analgesic and antipyretic
actions equivalent aspirin. No significant anti-inflammatory
effects. No significant anti-inflammatory effects. No occult
bleeding or gastric irritation,do not inhibit platelet aggregation,
or affect prothrombin time. No occult bleeding or gastric
irritation,do not inhibit platelet aggregation, or affect
prothrombin time. No relationship with Reyes syndrome. No
relationship with Reyes syndrome. Does not antagonize the effects
of uricosuric drugs. Does not antagonize the effects of uricosuric
drugs.
Slide 44
Acetaminophen Hepatic toxicity is its major problem. Hepatic
toxicity is its major problem. It is the drug of choice for
analgesia and fever reduction in patients who cannot tolerate
aspirin. It is the drug of choice for analgesia and fever reduction
in patients who cannot tolerate aspirin. Acetaminophen is the
active metabolite of Phenacetin. Acetaminophen is the active
metabolite of Phenacetin. But unlike phenacetin, doesnt produce
renal toxicity or hemolytic anemia and methemoglobinemia But unlike
phenacetin, doesnt produce renal toxicity or hemolytic anemia and
methemoglobinemia
Slide 45
Acetaminophen Pharmacokinetics and Toxicity: Pharmacokinetics
and Toxicity: Acetaminophen is orally absorbed, it is only slightly
bound to plasma proteins. Acetaminophen is orally absorbed, it is
only slightly bound to plasma proteins. In liver is metabolized to
acetaminophen glucuronide and sulfate. A minor but highly toxic
metabolite builds up when gluthatione is depleted (overdose,
hepatic insufficiency). In liver is metabolized to acetaminophen
glucuronide and sulfate. A minor but highly toxic metabolite builds
up when gluthatione is depleted (overdose, hepatic
insufficiency).
Slide 46
Acetaminophen Large doses of acetaminophen (or in patients with
liver disease), may cause severe liver damage and death. Large
doses of acetaminophen (or in patients with liver disease), may
cause severe liver damage and death. The signs of toxicity occur in
12-24: nausea, vomiting, diarrhea, abdominal pain, dizziness and
death being caused by severe hepatotoxicity The signs of toxicity
occur in 12-24: nausea, vomiting, diarrhea, abdominal pain,
dizziness and death being caused by severe hepatotoxicity Sometimes
associated with acute renal tubular necrosis. Sometimes associated
with acute renal tubular necrosis. Administration of
N-acetylcysteine, is a useful antidote. Administration of
N-acetylcysteine, is a useful antidote.
Slide 47
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High-Yield Slides. Dr. Rosas Blum
Slide 51
NSAIDs Prototype aspirin. Prototype aspirin. Ibuprofen,
naproxen, indomethacin. Ibuprofen, naproxen, indomethacin.
Traditionally NSAIDs are non-selective and inhibit COX-1 and COX
-2. Traditionally NSAIDs are non-selective and inhibit COX-1 and
COX -2.
Slide 52
Aspirin The only clinically marketed irreversible inhibitor of
COX-1. The only clinically marketed irreversible inhibitor of
COX-1. Inhibits platelet aggregation. Inhibits platelet
aggregation. Analgesia. Analgesia. Fever reduction. Fever
reduction. Anti-inflammatory effects. Anti-inflammatory
effects.
Slide 53
Salicylates & IBD Salicylates derivatives are used in
intra- gut treatment of IBD. Salicylates derivatives are used in
intra- gut treatment of IBD. Oral drug dissociate in colon. Oral
drug dissociate in colon. Enema preparations. Enema preparations.
Mainly used in Ulcerative colitis than Crohns disease. Mainly used
in Ulcerative colitis than Crohns disease.
Slide 54
Aspirin Adverse effects. Adverse effects. GI Irritation
(ulcers, active bleeding) GI Irritation (ulcers, active bleeding)
Tinnitus and vertigo (early sign intoxication) Tinnitus and vertigo
(early sign intoxication) Hypersensitivity. Hypersensitivity.
Bleeding complications. Bleeding complications. Platelet
inhibition. Platelet inhibition.
Reyes Syndrome Highly Lethal Highly Lethal
Hepatoencephalopathy. Hepatoencephalopathy. Aspirin and derivatives
may be a trigger. Aspirin and derivatives may be a trigger. Do not
give in children with chickenpox or influenza B infection. Do not
give in children with chickenpox or influenza B infection.
Slide 57
Other Non-Selective NSAIDs Ibuprofen, Naproxen Ibuprofen,
Naproxen Analgesic, antipyretic and anti- inflammatory effects.
Analgesic, antipyretic and anti- inflammatory effects. Not as
effective for anti-platelet effects. Not as effective for
anti-platelet effects.
Slide 58
Selective COX-2 inhibitors Celecoxib, Rofecoxib. Celecoxib,
Rofecoxib. When dont what to inhibit COX-1. When dont what to
inhibit COX-1. Patients with gastric ulcers. Patients with gastric
ulcers. Similar anti-inflammatory effects as conventional NSAIDs.
Similar anti-inflammatory effects as conventional NSAIDs. Vioxx
produces heart attacks. Vioxx produces heart attacks.
Slide 59
Acetaminophen Does not inhibit COX-1 or COX-2. Does not inhibit
COX-1 or COX-2. Lacks of anti-inflammatory effects. Lacks of
anti-inflammatory effects. Excellent analgesic and antipyretic
activity. Excellent analgesic and antipyretic activity. Mechanism
of action unknown. Mechanism of action unknown. Acts directly in
the CNS to reduce fever. Acts directly in the CNS to reduce
fever.
Slide 60
NSAIDs vs Acethaminophen No antiplatelet action No antiplatelet
action Not implicated in Reyes syndrome. Not implicated in Reyes
syndrome. Not bronchospastic. Not bronchospastic. Minimal GI
effects. Minimal GI effects.
Slide 61
Acetaminophen overdose Disastrous. Disastrous. Mayor cause of
liver failure that require liver transplant. (Teenagers and young
adults). Mayor cause of liver failure that require liver
transplant. (Teenagers and young adults).
Slide 62
Acetaminophen Metabolism Metabolized by liver glucoronyl
transferase to form an inactive compound. Metabolized by liver
glucoronyl transferase to form an inactive compound. Minor
CYP-dependent pathway produces a N- acetyl-para-benzoquinonimine, a
reactive metabolite that is inactivated by glutathione. Minor
CYP-dependent pathway produces a N- acetyl-para-benzoquinonimine, a
reactive metabolite that is inactivated by glutathione. In serious
overdose glutathione becomes depleted, and metabolite damages
hepatocytes. In serious overdose glutathione becomes depleted, and
metabolite damages hepatocytes. EtOH enhances liver toxicity via
induction of CYP2E1 enzyme. EtOH enhances liver toxicity via
induction of CYP2E1 enzyme.
Slide 63
Acetaminophen overdose Antidote N-acetylcysteine. Antidote
N-acetylcysteine. Replenishes glutathione stores. Replenishes
glutathione stores. Most effective when used in the first 12 hrs
before liver damage becomes irreversible. Most effective when used
in the first 12 hrs before liver damage becomes irreversible.
Slide 64
A 5-year-old girl is brought to the emergency department by her
parents in a comatose state. Her parents refers that she felt ill
recently with high fever. Physical examination: comatose,
papilledema, hepatomegaly. A CT Scan reveals cerebral edema. What
agent is most likely to be involved in this patient? a) Aspirin b)
Acetaminophen c) Codein d) Celecoxib e) Ibuprofen