NSAID Pharmacology
Dr. Jawad Al-Musawi
Nonsteroidal Anti-Inflammatory Drugs(NSAIDs)
INTRODUCTION
The NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic,
analgesic, and anti-inflammatory activities. They act primarily by inhibiting the
cyclooxygenase enzymes that catalyze the first step in prostanoid biosynthesis. This leads
to decreased prostaglandin synthesis with both beneficial and unwanted effects.
Detection of serious cardiovascular events associated with COX-2 inhibitors have led to
withdrawal of rofecoxib and valdecoxib from the market (although celecoxib is still
available for use in patients with RA). Additionally, the U.S. Food and Drug Association
(FDA) has required that the labeling of the traditional NSAIDs and elecoxibc be updated to
include the following:
1) a warning of the potential risks of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal; additionally, a warning that the risk may
increase with duration of use and that patients with cardiovascular disease or risk
factors may be at greater risk.
2) a warning that use is contraindicated for the treatment of perioperative pain in the
setting of coronary artery bypass graft surgery.
3) a notice that there is increased risk of serious gastrointestinal (GI) adverse events,
including bleeding, ulceration, and perforation of the stomach or intestines, which can
be fatal.
CLASSIFICATION OF NSAIDs
1-Acetaminophen
Acetaminophen [a-SEAT-a-MIN-oh-fen] inhibits prostaglandin synthesis in the CNS. This
explains its antipyretic and analgesic properties. Acetaminophen has less effect on
cyclooxygenase in peripheral tissues, which accounts for its weak anti-inflammatory
activity. Acetaminophen does not affect platelet function or increase blood clotting time.
aspirin, these drugs may have the potential to increase myocardial infarctions and strokes.
A. Therapeutic uses
Acetaminophen is a suitable substitute for the analgesic and antipyretic effects of
aspirin for those patients with gastric complaints, those in whom prolongation of
bleeding time would be a disadvantage, or those who do not require the anti-
inflammatory action of aspirin. Acetaminophen is the analgesic/antipyretic of choice for
children with viral infections or chickenpox (recall that aspirin increases the risk of
Reye's syndrome). Acetaminophen does not antagonize the uricosuric agents
probenecid or sulfinpyrazone and, therefore, may be used in patients with gout who are
taking these drugs.
B. Pharmacokinetics
Acetaminophen is rapidly absorbed from the GI tract. A significant first-pass metabolism
occurs in the luminal cells of the intestine and in the hepatocytes. Under normal
circumstances, acetaminophen is conjugated in the liver to form inactive glucuronidated or
sulfated metabolites. A portion of acetaminophen is hydroxylated to form N-
acetylbenzoiminoquinone a highly reactive and potentially dangerous metabolite that
reacts with sulfhydryl groups. At normal doses of acetaminophen, the N-
acetylbenzoiminoquinone reacts with the sulfhydryl group of glutathione, forming a
nontoxic substance . Acetaminophen and its metabolites are excreted in the urine.
C. Adverse effects
With normal therapeutic doses, acetaminophen is virtually free of any significant adverse
effects. Skin rash and minor allergic reactions occur infrequently. There may be minor
alterations in the leukocyte count, but these are generally transient. Renal tubular necrosis
and hypoglycemic coma are rare complications of prolonged, large-dose therapy. With large
doses of acetaminophen, the available glutathione in the liver becomes depleted, and N-
acetylbenzoiminoquinone reacts with the sulfhydryl groups of hepatic proteins, forming
covalent bonds .
Hepatic necrosis, a very serious and potentially life-threatening condition, can result. Renal
tubular necrosis may also occur. [Note: Administration of N-acetylcysteine, which contains
sulfhydryl groups to which the toxic metabolite can bind, can be lifesaving if administered
within 10 hours of the overdose.] This agent should be avoided in patients with severe hepatic
impairment. Periodic monitoring of liver enzymes tests is recommended for those on high-
dose acetaminophen.
2. Aspirin and other salicylic acid derivatives
Aspirin [AS-pir-in] is the prototype of traditional NSAIDs and was officially approved by the
FDA in 1939. It is the most commonly used and is the drug to which all other anti-
inflammatory agents are compared.
Mechanism of action: Aspirin is a weak organic acid that is unique among the NSAIDs in that it
irreversibly acetylates (and, thus, inactivates) cyclooxygenase . The other NSAIDs, including
salicylate, are all reversible inhibitors of cyclooxygenase. Aspirin is rapidly deacetylated by
esterases in the body producing salicylate, which has anti-inflammatory, antipyretic, and
analgesic effects. The antipyretic and anti-inflammatory effects of salicylate are due primarily
to the blockade of prostaglandin synthesis at the thermoregulatory centers in the
hypothalamus and at peripheral target sites. Furthermore, by decreasing prostaglandin
synthesis, salicylate also prevents the sensitization of pain receptors to both mechanical and
chemical stimuli. Aspirin may also depress pain stimuli at subcortical sites (that is, the
thalamus and hypothalamus).
Actions of Aspirin: The NSAIDs, including aspirin, have three major therapeutic actions
namely, they reduce inflammation (anti-inflammation), pain (analgesia), and fever . Not all
NSAIDs are equally potent in each of these actions.
• Anti-inflammatory actions :Because aspirin inhibits cyclooxygenase activity, it
diminishes the formation of prostaglandins and, thus, modulates those aspects of
inflammation in which prostaglandins act as mediators. Aspirin inhibits inflammation in
arthritis, but it neither arrests the progress of the disease nor induces remission.
Analgesic action: Prostaglandin E2 (PGE2) is thought to sensitize nerve endings to the action
of bradykinin, histamine, and other chemical mediators released locally by the inflammatory
process. Thus, by decreasing PGE2 synthesis, aspirin and other NSAIDs repress the sensation
of pain.
The salicylates lower body temperature in patients with fever by impeding PGE2 synthesis and
release. Aspirin resets the thermostat toward normal, and it rapidly lowers the body
temperature of febrile patients by increasing heat dissipation as a result of peripheral
vasodilation and sweating. Aspirin has no effect on normal body temperature.
Respiratory actions: At therapeutic doses, aspirin increases alveolar ventilation. [Note:
Salicylates uncouple oxidative phosphorylation, which leads to elevated CO2 and increased
respiration.] Higher doses work directly on the respiratory center in the medulla, resulting in
hyperventilation and respiratory alkalosis
Gastrointestinal effects: Normally, prostacyclin (PGI2) inhibits gastric acid secretion, whereas
PGE2 and PGF2α stimulate synthesis of protective mucus in both the stomach and small
intestine. In the presence of aspirin, these prostanoids are not formed, resulting in increased
gastric acid secretion and diminished mucus protection. This may cause epigastric distress,
ulceration, hemorrhage, and iron-deficiency anemia. Aspirin doses of 1 to 4.5 g/day can
produce loss of 2 to 8 mL of blood in the feces per day.
Effect on platelets: TXA2 enhances platelet aggregation, whereas PGI2 decreases it. Low doses
81 mg daily) of aspirin can irreversibly inhibit thromboxane production in platelets via
acetylation of cyclooxygenase. Because platelets lack nuclei, they cannot synthesize new
enzyme, and the lack of thromboxane persists for the lifetime of the platelet (7 days). As a
result of the decrease in TXA2, platelet aggregation (the first step in thrombus formation) is
reduced, producing an anticoagulant effect with a prolonged bleeding time. Finally, aspirin
also inhibits cyclooxygenase in endothelial cells, resulting in reduced PGI2 formation;
however, endothelial cells possess nuclei able to re-synthesize new cyclooxygenase.
Therefore, PGI2 is available for antiplatelet action
Therapeutic uses:
Anti-inflammatory, antipyretic, and analgesic uses: The salicylic acid derivatives are used in
the treatment of gout, rheumatic fever, osteoarthritis, and RA. Commonly treated conditions
requiring analgesia include headache, arthralgia, and myalgia.
External applications: Salicylic acid is used topically to treat corns, calluses, and warts. Methyl
salicylate is used externally as a cutaneous counterirritant in liniments.
Cardiovascular applications: Aspirin is used to inhibit platelet aggregation. Low doses are used
prophylactically to 1) reduce the risk of recurring transient ischemic attacks (TIAs) and stroke
or death in those who have had single or multiple episodes of TIA or stroke; 2) reduce the risk
of death in those having an acute myocardial infarction; 3) reduce the risk of recurrent
nonfatal myocardial infarction and/or death in patients with previous myocardial infarction or
unstable angina pectoris; 4) reduce the risk of myocardial infarction and sudden death in
patients with chronic stable angina pectoris; 5) reduce the cardiovascular risk in patients
undergoing certain revascularization procedures.
Dosage of Aspirin: The salicylates exhibit analgesic activity at low doses; only at higher doses
do these drugs show anti-inflammatory activity . For example, two 325-mg aspirin tablets
administered four times daily produce analgesia, whereas 12 to 20 tablets per day produce
both analgesic and anti-inflammatory activity. For long-term myocardial infarction
prophylaxis, the dose is 81 to 162 mg/day.
For those with RA or osteoarthritis, the initial dose is 3 grams/day; for stroke prophylaxis, the
dose is 50 to 325 mg/day; in a patient having an acute mycardial infarction, the dose is 162 to
325 mg of non-enteric coated aspirin chewed and swallowed immediately.
Adverse effects:
Gastrointestinal: The most common GI effects of the salicylates are epigastric distress,
nausea, and vomiting. Microscopic GI bleeding is almost universal in patients treated with
salicylates. [Note: Aspirin is an acid. At stomach pH, aspirin is uncharged; consequently, it
readily crosses into mucosal cells, where it ionizes (becomes negatively charged) and becomes
trapped, thus potentially causing direct damage to the cells. Aspirin should be taken with food
and large volumes of fluids to diminish dyspepsia. Additionally, misoprostol or a PPI may be
taken concurrently.]
Dose-dependent effects of salicylate.
Blood: The irreversible acetylation of platelet cyclooxygenase reduces the level of platelet
TXA2, resulting in inhibition of platelet aggregation and a prolonged bleeding time. For this
reason, aspirin should not be taken for at least 1 week prior to surgery. When salicylates are
administered, anticoagulants may have to be given in reduced dosage, and careful monitoring
and counseling of patients are necessary.
Respiration: In toxic doses, salicylates cause respiratory depression and a combination of
uncompensated respiratory and metabolic acidosis.
Metabolic processes: Large doses of salicylates uncouple oxidative phosphorylation. The
energy normally used for the production of adenosine triphosphate is dissipated as heat,
which explains the hyperthermia caused by salicylates when taken in toxic quantities.
Hypersensitivity: Approximately 15 percent of patients taking aspirin experience
hypersensitivity reactions. Symptoms of true allergy include urticaria, bronchoconstriction, or
angioedema. Fatal anaphylactic shock is rare.
Reye's syndrome: Aspirin and other salicylates given during viral infections has been
associated with an increased incidence of Reye's syndrome, which is an often fatal,
fulminating hepatitis with cerebral edema. This is especially encountered in children, who
therefore should be given acetaminophen instead of aspirin when such medication is required
to reduce fever. Ibuprofen is also appropriate.
Other NSAIDs
3-Propionic acid derivatives
Ibuprofen, ketoprofin, oxaprozin,
4-Acetic acid derivatives
indomethacin, sulindac , etodolac
5-Oxicam derivatives
Piroxicam and meloxicam
6-Fenamates
Mefenamic
7-Heteroaryl acetic acids
Diclofenac, Tolmetin
8-Nabumetone
Nabumetone
8-Celecoxib
Celecoxib