Nonsteroidal Anti-Inflammatory Drugs(NSAIDs)
Dr. Jawad Al-MusawiINTRODUCTION
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 Administration (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; and 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-AcetaminophenAcetaminophen [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 usesAcetaminophen 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. PharmacokineticsAcetaminophen 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 effectsWith 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.
Action of Aspirin (…following)
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 derivativesIbuprofen, ketoprofin, oxaprozin,4-Acetic acid derivativesindomethacin, sulindac , etodolac5-Oxicam derivativesPiroxicam and meloxicam6-FenamatesMefenamic 7-Heteroaryl acetic acidsDiclofenac, Tolmetin 8-NabumetoneNabumetone8-CelecoxibCelecoxib