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Non-Selective Cox 1&2 Inhibitors

Aspirin

Generic Name: Acetylsalicylic acid, ASA

Drug Class: NSAID
Mechanism of Action:
aspirin (acetylsalicylic acid) acetylates a serine residue in the active sites for both
COX-1 & COX-2, which irreversibly inhibits these enzymes (as illustrated for COX-1
in Figure 1).

Figure 1. Aspirin-mediated inhibition of cyclooxygenase (COX). COX enzymes exist as dimers. In the
absence of aspirin (left panel), arachidonic acid (AA) that is formed by phospholipase A2 breakdown of
membrane phospholipids gains access to the active site of COX via a hydrophobic channel.
Metabolism of AA by COX produces an intermediate prostaglandin PGH2, which in platelets is broken
down by tissue isomerases to thromboxane A2. As shown on the right panel, aspirin irreversibly
inhibits COX activity by acetylation of a serine residue in the active site for COX (SER 529 in COX-1 &
SER 516 in COX-2). This produces a steric hindrance that prevents AA from being metabolized. Aspirin
works by the same mechanism to block COX-2 in other tissues. Adapted from Fitzgerald & FitzGerald
(2013).

Low doses of aspirin selectively inhibit COX-1. The effect on platelet COX-1 activity is
permanent for the lifetime of the platelet, since platelets lack DNA and cannot synthesize
new enzyme. This enables the use of low dose aspirin as a selective antiplatelet drug (Figure 2)

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At higher doses, aspirin inhibits both isoforms of COX (Figure 2).

The combination of COX-1 & (at higher doses) COX-2 inhibition are the molecular basis for
aspirin's analgesic, antipyretic & anti-inflammatory effects.

Figure 2. Selective inhibition of platelet COX-1 activity vs monocyte COX-2 activity measured in vitro
after the addition of aspirin to whole-blood samples drawn from healthy human subjects. Bars
represent Mean ±SD. Modified from Cipollone et al (1997).

Indications:
1. Anti-inflammatory. Aspirin interferes with the chemical mediators of the kallikrein
system, thus inhibiting granulocyte adherence to damaged vasculature, stabilizing
lysosomes, and inhibiting the chemotaxis of PMN leukocytes and macrophages.
2. Analgesia. Aspirin is effective in reducing pain of mild to moderate intensity through its
effects on inflammation and probably because it inhibits pain stimuli at a subcortical
(central) site. It is not effective for severe visceral pain.
3. Antipyretic. Aspirin reduces elevated body temperature (but it has little effect on body
temperature in normal healthy patients). This effect is probably mediated by both COX
inhibition in the CNS and inhibition of IL-1 (which is released by macrophages during
episodes of inflammation).
4. Antiplatelet Effects. Single low doses of aspirin (81 mg daily) produce a slightly
prolonged bleeding time, which doubles if administration is continued for a week. The
change is due to irreversible inhibition of platelet COX-1, so that aspirin's antiplatelet
effect lasts 8-10 days (the life of the platelet).
5. MI Prophylaxis: Aspirin is indicated to reduce the risk of death and/or nonfatal
myocardial infarction in patients with a previous infarction or unstable angina pectoris.
6. Transient Ischemic Attacks: Aspirin is indicated for reducing the risk of recurrent
transient ischemic attacks (TIAs) or stroke in men who have transient ischemia of the
brain due to fibrin emboli. There is currently no evidence that aspirin is effective in
reducing TIAs in women, or is of benefit in the treatment of completed strokes in men or
women.
Contraindications:
Hypersensitivity to NSAIDs or history of bleeding disorders, such as GI bleeding or
hemophilia
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Not recommended during pregnancy, but may be valuable in treating preeclampsia-

eclampsia.
Children and teenagers should not use this medicine for chicken pox or flu
symptoms before a doctor is consulted about Reye's syndrome, a rare but serious illness
reported to be associated with aspirin.
Pharmacokinetics:
Aspirin is rapidly hydrolyzed primarily in the liver to salicylic acid, which is conjugated
with glycine (forming salicyluric acid) and glucuronic acid and excreted largely in the
urine
As a result of rapid hydrolysis, plasma concentrations of aspirin are always low and rarely
exceed 20 mcg/ml at ordinary therapeutic doses
The peak salicylate level for uncoated aspirin occurs in about 2 hours; however with
enteric coated aspirin tablets this is delayed.
The plasma half-life for aspirin is approximately 15 minutes; that for salicylate lengthens
as the dose increases:
Doses of 300 to 650 mg have a half-life of 3.1 to 3.2 hours
Doses of 1 gram have a half-life of 5 hours and with 2 grams it is increased to about
9 hours
Salicylates are excreted mainly by the kidney. Studies in man indicate that salicylate is
excreted in the urine as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic
(10%) and acyl (5%) glucuronides and gentisic acid (<1%).
Side Effects:
Aspirin may trigger asthmatic symptoms in some patients (seeWebMD.com)
Other expected side effects are dose-dependent
With therapeutic doses:
gastric upset, gastric and duodenal ulcers are the most common side
effects
With higher doses:
“salicylism” can occur - vomiting, tinnitus, decreased hearing, vertigo
(reversible)
With very large doses:
Hyperpnea (increased depth & rate of respiration) through a direct effect on
the medulla resulting in a respiratory alkalosis
Body temperature may be elevated due to uncoupling of oxidative
phosphorylation, potentially resulting in severe hyperthermia (Olson,
2009).
At progressively higher and potentially fatal doses (300 to 500 mg/kg)(or 20-35
full strength 325 mg tablets):
Respiratory alkalosis combined with a severe metabolic acidosis (due to
salicylate accumulation & compensatory responses to respiratory alkalosis)
develop
Potassium moves from the intracellular space to the extracellular space
Excretion of hydrogen ions produces acidic urine along with the depletion of
sodium bicarbonate and potassium
Seizures, coma, pulmonary edema & cardiovascular collapse can
occur
Death is caused by CNS failure & CV collapse.
Major drug interactions:
Aspirin may contribute to increasing bleeding time by decreasing prothrombin in the
plasma
Large doses have a hypoglycemic action that can enhance the effect of oral hypoglycemic

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drugs and affect the diabetic's insulin requirements.

Aspirin low to moderate doses (75 mg-2 gm/day) inhibit uric acid secretion &
increase the risk of gout attacks (Caspi et al, 2000; Zhang et al, 2014). Therefore
aspirin is contraindicated in the treatment of pain & inflammation associated with gout.
The effect of low dose aspirin to inhibit urate excretion may result from aspirin-induced
inhibition of urate secretion by the proximal tubule (Yu & Gutman, 1958).
Paradoxically, much larger doses of aspirin (>3 gm/day; or over ten 325 mg tablets/day)
have been observed to be uricosuric (increase urate elimination in the urine). This has
been hypothesized to result from aspirin-induced inhibition of urate reabsorption (aspirin
inhibiting a different urate transporter involved in reabsorption) in the proximal tubule
(Figure 2). Because urate reabsorption has a greater transport capacity compared to
urate secretion mechanisms, the net effect of high dose aspirin is “uricosuric”, with more
urate being eliminated in the urine (Yu & Gutman, 1959).

Figure 2. Aspirin's bimodal dose-dependent effect on the renal clearance of urate/uric acid (UA). In
patients, low doses of aspirin (75 mg-2 gm/day) cause retention of uric acid by inhibiting uric acid
secretion. In contrast, high doses (>3 gm/day) increase the excretion of uric acid in the urine by
inhibiting its reuptake in the proximal tubule (Yu & Gutman, 1959). While several clinical studies have
confirmed the bimodal effect of aspirin on uric acid clearance, the precise transporters involved have
not been clearly identified.

NSAID Interference with Aspirin's Antiplatelet Effects

As illustrated in Figure 3, non-aspirin NSAIDs can interfere with aspirin's ability to gain
access to its COX-1 binding site by steric interference(2 drugs can't occupy the same

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active site at the same time), thus reducing aspirin's antiplatelet effects when the two
drug types are taken concomitantly.
When taken 2 hours prior to aspirin, ibuprofen interferes with aspirin's ability to inhibit the
production of thromboxane A2, whereas if ibuprofen is taken 2 hours after aspirin,
aspirin's antiplatelet effects are preserved (Catella-Lawson et al, 2001).
Naproxen taken once a day has also been observed to interfere with aspirin's antiplatelet
effects mediated by inhibiting COX-1 (Capone et al, 2005).

Figure 3. Concomitant administration of other NSAIDs can interfere with the antiplatelet effect of
aspirin. Left panel: When aspirin is taken alone, it produces an irreversible effect to inhibit COX-1
activity by acetylation of a serine residue in the active site of the enzyme. Right panel: When
another non-aspirin NSAID such as ibuprofen or naproxen is taken prior to aspirin administration, it
can occupy the active site of COX and prevent aspirin from acetylating COX serine residues before
aspirin is eliminated or converted to non-active metabolites (e.g. salicylate). This can reduce the
cardioprotective effect of aspirin therapy. Because non-aspirin NSAIDs bind reversibly, their effect is
relatively transient, and will not provide the same long-term benefit to suppress platelet activity as
aspirin. Adapted from Fitzgerald & FitzGerald (2013).

Pharmwiki Groups:NSAIDs, DMARDs, Rx of Arthritis & Gout; Antiplatelet Drugs

Pronunciation: :aspirin.mp3AS prin (In Canada: AS prin ã?)
References:
Capone ML et al (2005): Pharmacodynamic interaction of naproxen with low-dose aspirin
in healthy subjects. J Am Coll Cardiol 45(8):1295-1301.
Caspi D, Lubart E et al (2000): The effect of mini-dose aspirin on renal function and uric
acid handling in elderly patients. Arthritis Rheum 43(1):103-108.
Catella-Lawson F et al (2001): Cyclooxygenase inhibitors and the antiplatelet effects of
aspirin. N Engl J Med 345(25):1809-1817.
Cipollone F et al (1997): Differential suppression of thromboxane biosynthesis by
indobufen and aspirin in patients with unstable angina. Circulation. 96:1109-1116.

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Fitzgerald DJ, FitzGerald GA (2013): Historical lessons in translational medicine.

Cyclooxygenase inhibition and P2Y12 antagonism. Circ Res 112:174-194.
Flomenbaum NE (2006): Salicylates (Chapter 35). In: Toxicologic Emergencies. 6th
Edition. Flomenbaum, Goldfrank, Hoffman, Howland, Lewin & Nelson (Editors). McGraw-
Hill. (ISBN: 0-07-143763-0)
Furst DE, Ulrich RW, Varkey-Altamirano C (2012e): Nonsteroidal Anti-Inflammatory Drugs,
Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout
(Chapter 36). In: Basic and Clinical Pharmacology. 12th Edition. Katzung BG, Masters SB,
Trevor AJ (Editors). McGraw-Hill / Lange. (Access-Medicine).
Olson KR (2007): Poisoning & Drug Overdose. 5th Edition. McGraw-Hill (Lange). (ISBN:
978-0-07-144333-3).
Olson KR (2012): Management of the Poisoned Patient (Chapter 58). In: Katzung's Basic &
Clinical Pharmacology. 12e. McGraw-Hill / Lange.
Yu TF, Gutman AB (1959): Study of the paradoxical effects of salicylate in low,
intermediate, and high dosage on the renal mechanisms of excretion of urate in man. J
Clin Invest 38:1298-1313.
Zehnder JL (2012): Drugs Used in Disorders of Coagulation (Chapter 34). In: Basic &
Clinical Pharmacology. 12e. Katzung BG, Masters SB, Trevor AJ (Editors). McGraw-Hill /
Lange. (Access-Medicine)
Zhang Y, Neogi T et al (2014): Low-dose aspirin use and recurrent gout attacks. Ann
Rheum Dis 73(2):385-390. doi: 10.1136/annrheumdis-2012-202589.
Emedicine: Salicylate Toxicology
www.rxlist.com (aspirin)

Keywords

Ibuprofen

Trade Names: generic, Motrin, Rufen, Advil, Nuprin, ® others

Drug Class: NSAID
Mechanism of Action:
Nonselective Cox Inhibitor
Analgesic, antipyretic & antiinflammatory.
Indications:
1. relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis
2. relief of mild to moderate pain
3. treatment of primary dysmenorrhea.
Contraindications:
history of drug hypersensitivity to NSAIDs
Pharmacokinetics:
Ibuprofen is often prescribed at lower doses (<2400 mg/d) at which it has analgesic and
less anti-inflammatory efficacy
2400 mg ibuprofen is equivalent to 4 g of aspirin in anti-inflammatory efficacy
The serum half-life is ~ 2.0 hours
Side Effects:
gastrointestinal complaints occur in patients, but in about half that for aspirin.

FDA Warning: Non-Aspirin NSAIDs - Increased Chance of Heart Attack or

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Stroke (7/9/15)

Based upon new safety information, the FDA has strengthened an

existing warning label that non-aspirin NSAIDs increase the chance of a
heart attack or stroke.
The risk of heart attack or stroke can occur as early as the first weeks of
using an NSAID. The risk may increase with longer use of the NSAID.
The risk appears greater at higher doses.
It was previously thought that all NSAIDs may have a similar risk. Newer
information makes it less clear that the risk for heart attack or stroke is
similar for all NSAIDs; however, this newer information is not sufficient for
us to determine that the risk of any particular NSAID is definitely higher
or lower than that of any other particular NSAID.
NSAIDs can increase the risk of heart attack or stroke in patients with or
without heart disease or risk factors for heart disease. A large number of
studies support this finding, with varying estimates of how much the risk
is increased, depending on the drugs and the doses studied.
In general, patients with heart disease or risk factors for it have a greater
likelihood of heart attack or stroke following NSAID use than patients
without these risk factors because they have a higher risk at baseline.
Patients treated with NSAIDs following a first heart attack were more
likely to die in the first year after the heart attack compared to patients
who were not treated with NSAIDs after their first heart attack.
There is an increased risk of heart failure with NSAID use.
For more information, see the online FDA Safety Announcement from
7/9/15.

Major drug interactions:

If taken concomitantly with aspirin it will interfere with the irreversible platelet inhibition
induced by aspirin, and may thus limit the cardioprotective effects of aspirin.(If both drugs
need to be taken, one could reduce the extent of this interaction by giving aspirin 30 min
prior to taking ibuprofen, since aspirin's effect on COX is irreversible).
Ibuprofen can reduce the natriuretic effect of furosemide and thiazides in some
patients. This response has been attributed to inhibition of renal prostaglandin synthesis.
During concomitant therapy with ibuprofen, the patient should be observed closely for
signs of renal failure, as well as to assure diuretic efficacy.
Ibuprofen may also increase lithium plasma levels in patients taking this drug, due to
decreased renal clearance.
Ibuprofen may be used in combination with gold salts and/or corticosteroids.
Use of NSAIDs in patients who are receiving ACE inhibitors may potentiate renal
disease states.
Pharmwiki Group:NSAIDs, DMARDs, Rx of Arthritis & Gout
Pronunciation: :ibuprofen.mp3EYE bue PROE fen

References:
Furst DE, Ulrich RW, Varkey-Altamirano C (2012e): Nonsteroidal Anti-Inflammatory Drugs,
Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout
(Chapter 36). In: Basic and Clinical Pharmacology. 12th Edition. Katzung BG, Masters SB,
Trevor AJ (Editors). McGraw-Hill / Lange. (Access-Medicine).
rxlist.com (Ibuprofen)

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Keywords

Indomethacin

Trade Names: generic, Tivorbex ®

Drug Class: NSAID
Mechanism of Action:
Nonselective Cox (1 & 2) inhibitor
Side Effects:
similar to Ibuprofen
References:
Furst DE, Ulrich RW, Varkey-Altamirano C (2012e): Nonsteroidal Anti-Inflammatory Drugs,
Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout
(Chapter 36). In: Basic and Clinical Pharmacology. 12th Edition. Katzung BG, Masters SB,
Trevor AJ (Editors). McGraw-Hill / Lange. (Access-Medicine).
rxlist.com (Tivorbex ®)

Keywords

Naproxen

Trade Names: generic, Naprelan, Naprosyn, Anaprox, Aleve - OTC ®

Drug Class: NSAID
Mechanism of Action:
Nonselective Cox (1 & 2) inhibitor
Indications:
the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis,
bursitis, and acute gout
relief of mild to moderate pain and primary dysmenorrhea
Contraindications:
history of drug hypersensitivity to NSAIDs
Pharmacokinetics:
elimination half-life of naproxen is approximately 15 hours (relatively long
duration)
Side Effects:
the incidence of upper GI bleeding is low but is double that of OTC ibuprofen (perhaps due
to a dose effect)
Rare cases of allergic pneumonitis
Other risk factors & side effects are similar to Ibuprofen
Major drug interactions:
similar to ibuprofen
Pharmwiki Group:NSAIDs, DMARDs, Rx of Arthritis & Gout
Pronunciation: :naproxen.mp3nah-PROX-en

References:
Furst DE, Ulrich RW, Varkey-Altamirano C (2012e): Nonsteroidal Anti-Inflammatory Drugs,
Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout

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(Chapter 36). In: Basic and Clinical Pharmacology. 12th Edition. Katzung BG, Masters SB,
Trevor AJ (Editors). McGraw-Hill / Lange. (Access-Medicine).
rxlist.com (Naprelan ®)

Keywords

Nabumetone

Trade Name: Relafen ®

Drug Class: NSAID (prodrug)
Mechanism of Action:
non selective COX inhibitor
a prodrug that is converted to a naproxen-like drug in the body
Indications:
acute and chronic treatment of signs and symptoms of osteoarthritis and rheumatoid
arthritis
Contraindications:
similar to ibuprofen
Pharmacokinetics:
Half life of >24 hrs permits once-daily dosing
Renal impairment results in a doubling of its half-life & increased plasma levels
Side Effects:
similar to Ibuprofen
Major drug interactions:
similar to ibuprofen
Notes:
An expensive NSAID
Pharmwiki Group:NSAIDs, DMARDs, Rx of Arthritis & Gout
Pronunciation: :nabumetone.mp3nab-YOU-meh-tone

References:
Furst DE, Ulrich RW, Varkey-Altamirano C (2012e): Nonsteroidal Anti-Inflammatory Drugs,
Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout
(Chapter 36). In: Basic and Clinical Pharmacology. 12th Edition. Katzung BG, Masters SB,
Trevor AJ (Editors). McGraw-Hill / Lange. (Access-Medicine).
rxlist.com (Relafen ®)

Keywords

Diclofenac

Trade Names: generic, Cataflam ®

Drug Class: NSAID
Mechanism of Action:
Non-selective COX inhibitor
Indications:
acute and chronic treatment of signs and symptoms of osteoarthritis and rheumatoid

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arthritis;
treatment of ankylosing spondylitis
the Cataflam ® formulation is designed to provide more rapid increases in plasma
concentrations of diclofenac, and is indicated for the management of pain and primary
dysmenorrhea
Contraindications:
history of drug hypersensitivity
Pharmacokinetics:
half life of 1-2 hrs
accumulates in synovial fluid (one site of action)
Side Effects:
adverse effects occur in about 20% of patients & include GI distress, GI bleeding & gastric
ulceration
high doses can impair renal blood flow & GFR
other side effects are similar to Ibuprofen
Major drug interactions:
similar to ibuprofen
concomitant administration of diclofenac and aspirin is not recommended because
diclofenac is displaced from its binding sites during the concomitant administration of
aspirin
Pharmwiki Group:NSAIDs, DMARDs, Rx of Arthritis & Gout
Pronunciation: :diclofenac.mp3dye KLOE fen ak

References:
Furst DE, Ulrich RW, Varkey-Altamirano C (2012e): Nonsteroidal Anti-Inflammatory Drugs,
Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout
(Chapter 36). In: Basic and Clinical Pharmacology. 12th Edition. Katzung BG, Masters SB,
Trevor AJ (Editors). McGraw-Hill / Lange. (Access-Medicine).
rxlist (Voltaren ®)

Keywords

Acetaminophen

Trade Names: generic, Tylenol ®, also known as paracetamol in Europe (Wikipedia:

paracetamol)
Drug Class: Analgesic & Antipyretic; but it is not a NSAID!
Mechanism of Action (Debated):
“COX-associated Peroxidase Hypothesis”:
The “prevailing” hypothesis is that acetaminophen acts as a reducing agent to
inhibit a secondary peroxidase step involved in prostanoid synthesis by
cyclooxgenase (COX-1 & COX-2) enzymes (see Figure 1). Because it inhibits the
peroxidase reaction, its inhibitory effects are surmounted in the presence
of high levels of lipid hydroperoxides that are produced by activated
leukocytes & platelets. This prevents acetaminophen from being effective
in sites of inflammation or activated platelets. Hence acetaminophen exerts
little or no anti-platelet or anti-inflammatory effects. In contrast, because
hydroperoxide levels are relatively low in vascular endothelial cells and neurons,
acetaminophen is able to exert antipyretic and analgesic effects by blocking the

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production of prostaglandins in these locations (Aronoff et al, 2009).

Figure 1. The prevailing hypothesis on the mechanism of action of acetaminophen. The enzyme
responsible for synthesis of prostnoids has been given several names, including prostaglandin H2-
synthase (PGHS), but is now most commonly referred to as cyclooxygenase (COX). This bifunctional
enzyme contains two separate catalytic domains that are responsible for converting arachidonic acid
to PGH2: i) a cyclooxyginase domain that produces an unstable peroxide intermediate (PGG2), and ii)
a peroxidase (POX) domain containing a heme group that converts the unstable intermediate to PGH2.
Experiments published by Boutaud et al (2002, 2010) and Aronoff et al (2009) indicate that
acetaminophen acts as a PGG2 cosubstrate & heme reducing agent that inhibits the POX catalytic step
by converting its heme group to an inactive reduced state (as illustrated in the box, bottom right).
Because acetaminophen acts as a heme reducing agent, its effects are nearly abolished in the
presence of high levels of lipid hydroperoxides (such as inflammatory HETEs) that oxidize the heme
back to its active state. As a result, acetaminophen is ineffective in tissues with high peroxide tone,
such as in platelets or activated lymphocytes (e.g. inflammatory conditions). However,
acetaminophen is effective in inhibiting prostanoid synthesis in vascular endothelial cells and neurons
that have a low basal peroxide tone, which can account for its antipyretic and (central) analgesic
effects.

“Cannabinoid Hypothesis”:
An acetaminophen metabolite (AM404) inhibits COX, and activates both TRP (transient
receptor potential) and TRPV1 & TRPA1 channels, receptors involved in pain transmission
that are also sensitive to cannabinoids (Hogestatt et al, 2005; Mallet et al, 2010).
These hypotheses are not “mutually exclusive” and could both be true. Other hypotheses are

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also being investigated (Drahl, 2014)

Figure 2. An American Chemical Society YouTube video published in July 2014 that “pokes fun” at
our state of knowledge concerning how acetaminophen works. Acetaminophen was first synthesized
in 1878, and became an over-the-counter medication in 1960. There were more than 27 billion doses
of acetaminophen sold in 2009 alone. It can reduce fever, reduce aches & pains, help with cough
relief. But it is NOT anti-inflammatory. How does it work? There are multiple hypotheses based upon
years of research, and not everyone believes that we have the answer to that question (Drahl, 2014).

Indications:
Acetaminophen has antipyretic & analgesic effects, but has little effect on platelets
or inflammation (Boutaud et al, 2002; Aronoff et al, 2009; Furst et al, 2015).
mild to moderate pain such as headache, myalgia, postpartum pain, and other
circumstances in which aspirin is also an effective analgesic.
It is a preferred drug for the treatment of pain & fever in patients allergic to
aspirin, when salicylates are poorly tolerated, in patients with bleeding
disorders, history of peptic ulcers, and patients in whom bronchospasm is
precipitated by aspirin.
Acetaminophen is preferred to aspirin for the treatment of pain/fever in
children with viral infections.
Pharmacokinetics:
Well absorbed orally, with absorption being related to the rate of gastric emptying. Peak
blood levels are usually reached in 30-60 mins.
The half life of acetaminophen is 2-3 hrs. With toxic doses or liver disease, the half-life
may be increased two-fold or more.
Acetaminophen is partially metabolized by hepatic microsomal enzymes and converted to
acetaminophen sulfate and glucuronide, which are inactive. Less than 5% is excreted
unchanged. A minor but highly active metabolite (N-acetyl-p-
benzoquinone)(NAPQI) is important in large doses because of its toxicity to both
liver and kidney.
Side Effects:
In therapeutic doses, a mild reversible increase in hepatic enzymes may occasionally
occur in the absence of jaundice. With larger doses, dizziness, excitement, and
disorientation are seen.
Ingestion of 15 g of acetaminophen may be fatal, death being caused by severe
hepatotoxicity with centrilobular necrosis, sometimes associated with acute renal
tubular necrosis.
Early symptoms of hepatic damage include: nausea, vomiting, diarrhea & abdominal
pain.
Toxicity is treated with supportive therapy and N-acetylcysteine to neutralize the toxic
metabolites. Clinical and laboratory evidence of hepatic toxicity may not be apparent until
48 to 72 hours post-ingestion.
Notes:
Acetaminophen is equal to aspirin in analgesic and antipyretic effectiveness, but differs
by lacking anti-inflammatory properties
It does not affect uric acid levels and lacks platelet-inhibitiing propertie
Note that acetaminophen is not a NSAID
Pharmwiki Group:NSAIDs, DMARDs, Rx of Arthritis & Gout
Pronunciation: :acetaminophen.mp3a seet oh MIN oh fen

References:

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Aronoff DM et al (2009): New insights into the mechanism of action of acetaminophen: Its
clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2
synthases. Clinical Pharmacology & Therapeutics. 79:9-19. DOI:
10.1016/j.clpt.2005.09.009
Boutaud O et al (2002): Determinants of the cellular specificity of acetaminophen as an
inhibitor of prostaglandin H2 synthases. Proc Natl Acad Sci 99(10): 7130-7135. doi
10.1073 pnas.102588199
Boutaud O et al (2010): Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation
and attenuates rhabdomyolysis-induced renal failure. Proc Natl Acad Sci
107(6):2699-2704. doi: 10.1073/pnas.0910174107
Drahl C (2014): How does acetaminophen work? Researchers still aren't sure. Chemical &
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rxlist.com (Tylenol ®)

Keywords

Keywords
NSAIDS, cox2-inhibitors, cox1-inhibitors, aspirin, acetaminophen, ibuprofen, acetaminophen,
ibuprofen, naproxen, nabumetone, diclofenac, NSAID-side-effects

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