NSAIDs

In this lecture drugs that are anti-inflammatory, analgesics, and antipyretics will be considered; their mechanism of action differ from those of the anti-inflammatory steroids and opioid analgesics. The anti-inflammatory, analgesic, and antipyretic drugs are a heterogeneous group of compounds, often chemically unrelated (although most of them are organic acids), which share certain therapeutic actions and side effects. The prototype is aspirin; hence these compounds are often referred to as aspirin-like drugs. They are also frequently designated as nonsteroidal anti-inflammatory drugs (NSAIDs).

History: The medicinal effect of the bark of willow has been known to several cultures for centuries. The active ingredient in the willow bark (called salicin) was first isolated in a pure form in 1829 by Leroux. The latter compound can be converted into salicylic acid. Sodium salicylate was first used for the treatment of rheumatoid fever and as an antipyretic in 1875. The enormous success of this drug prompted Hoffman, a chemist employed by Bayer, to prepare acetylsalicylic acid. This compound was introduced into medicine in 1899 by Dreser under the name of aspirin.

I. Overview
Inflammation is a normal, protective response to tissue injury caused by physical trauma, noxious chemicals, or microbiologic agents. Inflammation is the body’s effort to inactivate or destroy invading organisms, remove irritants, and set the stage for tissue repair. However, inflammation is sometimes inappropriately triggered by an innocuous agent, such as pollen, or by an autoimmune response, as in asthma or rheumatoid arthritis. In such cases, the defense reactions themselves may cause injury, and anti-inflammatory drugs may be required to modulate the inflammatory process. Inflammation is triggered by the release of chemical mediators from injured tissues and migrating cells. The specific mediators vary with the type of inflammation and include amines, such as histamine and 5-hydroxytryptamine; lipids, such as prostaglandins; small peptides, such as bradykinin; and larger peptides, such as interleukin-1. Discovery of the wide variation among chemical mediators has clarified the apparent paradox that an anti-inflammatory drugs may interfere with the action of a particular mediator important in one type of inflammation but be without effect in process not involving the drug’s target mediator.

II. Prostaglandins
Many of the nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the synthesis of prostaglandins. Thus, an understanding of NSAIDs requires a comprehension of the actions and biosynthesis of prostaglandins–unsaturated fatty acid derivatives containing 20 carbons that include a cyclic ring structure. [Note: These compounds are sometimes referred to as eicosanoids; “eicosa” refers to the 20 carbon atoms.]

A. Role of prostaglandins

Prostaglandins and related compounds are produced in minute quantities by virtually all tissues. They generally act locally on the tissues in which they are synthesized, and are rapidly metabolized to inactive products. Therefore, the prostaglandins do not circulate in the blood in significant concentration. Thromboxanes, leukotrienes, and the hydroperoxyeicosatetraenoic and hydroxyeicosatetraenoic acids (HPETEs and HETEs) are related lipid, synthesized from the same precursors as are the prostaglandins, using interrelated pathways.

B. Synthesis of prostaglandins

Arachidonic acid, a 20-carbon fatty acid, is the primary precursor of the prostaglandins. Arachidonic acid is present as a component of the phospholipids of cell membranes. Free arachidonic acid is released from tissue phospholipids by the action of phospholipase A2. There are two major pathways in the synthesis of the eicosanoids from arachidonic acid.

1.Cyclooxygenase pathway:

All eicosanoids with ring structures, that is, the prostaglandins, thromboxanes, and prostacyclins, are synthesized via the cyclooxygenase pathway. Two cyclooxygenases have been identified: COX-1 and COX-2. The former is ubiquitous and constitutive, whereas the latter is induced in response to inflammatory stimuli.

2.Lipoxygenase pathway: Alternatively, several lipoxygenases can act on arachidonic acid to form 5-HPETE, 12-HPETE and 15-HPETE, which are unstable peroxidated derivatives that are converted to the corresponding hydroxylated derivatives (the HEPEs), or to leucotrienes or lipoxins, depending on the tissue.

C. Function in the body

Prostaglandins act as local signals that fine-tune the response of a specific cell type. Their functions vary widely depending on the tissue. For example, the release of TXA2 from platelets triggers the recruitment of new platelets for aggregation (the first step in clot formation). However, in other tissues, elevated levels of TXA2 convey a different signals; e.g. in certain smooth muscle, this compound induces contraction. Prostaglandins are one of the chemical mediators that are released in allergic and inflammatory processes.

III. Nonsteroidal anti-inflammatory drugs (NSAIDs)
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 but not the lipoxygenase enzymes. Aspirin is the prototype of this group; it is the most commonly used and the drug to which all other anti-inflammatory agents are compared. Some of the newer NSAIDs are marginally superior to aspirin in certain patients, because they have greater anti-inflammatory activity and/or cause less gastric irritation, or can be taken less frequently. However, the newer NSAIDs are considerably more expensive than aspirin, and some have proved to be more toxic in other ways.

A. Aspirin and other salicylates
Aspirin is a weak organic acid that is unique among the NSAIDs in irreversibly acetylating (and thus inactivating) 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.

1. Mechanism of action: The antipyretic and anti-inflammatory effects of the salicylates are due primarily to the blockade of prostaglandin synthesis at the thermoregulatory centers in the hypothalamus and at the peripheral target sites. By decreasing prostaglandin synthesis, the salicylates also prevent 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).

2. Actions: The NSAIDs have three major therapeutic actions, namely they reduce inflammation (ant inflammation), pain (analgesia), and fever (antipyrexia). However, not all of the NSAIDs are equally potent in each of these actions.

2.1 Anti-inflammatory actions: Aspirin modulates those aspects of inflammation in which prostaglandins act as mediators. Aspirin inhibits inflammation in arthritis, but it neither arrest the progress of the disease nor does it induce remission. 2.2 Analgesic action: Prostaglandin E2 is thought to sensitize nerve endings to the action of bradykinin, histamine, and other chemicals mediators released locally by the inflammatory process. Thus, by decreasing PGE2 synthesis, aspirin and other NSAIDs repress the sensation of pain. The salicylates are used mainly for the management of pain of low to moderate intensity arising from integumental structures rather than that arising from the viscera. NSAIDs are superior to opioids in the management of pain in which inflammation is involved; combination of opioids and NSAIDs are effective in treating pain in malignancy.

2.3 Antipyretic action: Fever occurs when the set-point of the anterior hypothalamic thermoregulatory center is elevated. This can be caused by PGE2 synthesis, stimulated when an endogenous fever-producing agents (pyrogen) such as a cytokine is released from white cells that are activated by infection, hypersensitivity, malignancy, or inflammation. The salicylates lower body temperature in patients with fever by impeding PGE2 synthesis. Aspirin resets the “thermostat” towards normal and lowers the body temperature by increasing heat dissipation as a result of peripheral vasodilation and sweating. Aspirin has no effect on normal body temperature.

2.4 Gastrointestinal effects: Normally, prostacyclin (PGI2) inhibits gastric acid secretion, whereas PGE2 and PGF2 stimulate synthesis of protective mucus in both the stomach and small intestine. In presence of aspirin, these prostanoids are not formed, resulting in increased gastric acid secretion and diminished mucous protection. This may cause epigastric distress, ulceration, and/or hemorrhage. At ordinary aspirin doses, as much as 3 to 8 ml of blood may be lost in feces per day. [Note: Buffered and enteric-coated preparations are only marginally helpful in dealing with this problem. The PGE1 derivative, misoprostol, is used in the treatment of gastric damage induced by NSAIDs.]

2.5 Effect on platelets: TXA2 enhances platelet aggregation, whereas PGI2 decreases it. Low doses (60 to 80 mg daily) of aspirin can irreversibly inhibit thromboxane production platelets without markedly affecting PGI2 production in the endothelial cells of the blood vessel. [Note: The acetylation of cyclooxygenase is irreversible. Because platelets lack nuclei, they cannot synthesize new enzyme, and the lack of thromboxane persist for the lifetime of the platelet (3 to 7 days). This contrasts with endothelial cells, which have nuclei and therefore can produce new cyclooxygenase.]

2.6 Actions on the kidney: Cyclooxygenase inhibitors prevent the synthesis of PGE2 and PGI2–prostaglandins that are responsible for maintaining renal blood flow. Decreased synthesis of prostaglandins can result in intrarenal vasoconstriction, retention of sodium and water in some patients. Interstitial nephritis can also occur with all of the NSAIDs except aspirin.

3. Therapeutic uses

3.1 Antipyretics and analgesics: Sodium salicylate and aspirin are used as antipyretics and analgesics in the treatment of gout, rheumatic fever, and rheumatoid arthritis. Commonly treated conditions requiring analgesia include headache, arthralgia, and myalgia.

3.2 External applications: Salicylic acid is used topically to treat corns, calluses, and epidermophytosis (eruption caused by fungi). Methyl salicylate is used externally as a cutaneous counterirritant in liniments.

3.3 Cardiovascular applications: Aspirin inhibits platelet aggregation. Low doses are used prophylactically to decrease the incidence of transient ischemic attack and unstable angina as well as that of coronary artery thrombosis.

3.4 Colon cancer: There is evidence that chronic use of aspirin reduces the incidence of colorectal cancer.

4. Pharmacokinetics

4.1 Administration and distribution: Salicylates, especially methyl salicylate, are absorbed through intact skin. After oral administration, the unionized salicylates are passively absorbed from the stomach and small intestine. Rectal absorption is slow and unreliable, but it is a useful route to vomiting children. Salicylates cross both the blood-brain barrier and placenta.

4.2 Dosage: The salicylates exhibit analgesic activity at low doses; only at higher doses do these drugs show anti-inflammatory activity. e.g. two 300 mg aspirin tablets administered 4 times a day produce analgesia, whereas 12 to 20 tablets per day produce both analgesic and anti- inflammatory activity. Low doses of aspirin (160 mg every other day) have been shown to reduce the incidence of recurrent myocardial infarction and to reduce mortality in postmyocardial infarction patients. Further, aspirin 160 to 325 mg/day appears to be beneficial in the prevention of a first myocardial infarction, at least in men over the age of 50 years. Thus, prophylactic aspirin therapy is advocated in patients with clinical manifestations of coronary disease if no specific contraindications are present. 4.3 Fate: At normal low doses (600 mg/day), aspirin is hydrolyzed to salicylate and acetic acid by esterases present in tissues and blood. Salicylate is converted by the liver to water-soluble conjugates that are rapidly cleared by the kidney, resulting in elimination with first-order kinetics and a serum half-life of 3.5 hours. At anti-inflammatory dosages (>4 g/day), the hepatic metabolic pathway becomes saturated, and zero-order kinetics are observed, with the drug having a half-life of 15 hours or more. Saturation of the hepatic enzymes requires treatment for several days to 1 week. Being an organic acid, salicylate is secreted into the urine and can affect uric acid secretion. At low doses of aspirin, uric acid secretion is decreased; at high doses, it is increased. [Note: Alkalinization of the urine promotes excretion.]

5. Adverse effects

5.1 GI:The most common GI effects of the 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 the mucosal cells where it ionizes and becomes trapped. Aspirin should be taken with food and large volumes of fluids to diminish GI disturbances. Alternatively, misoprostol may be taken concurrently.

5.2 Blood: The irreversible acetylation of platelet cyclooxygenase reduces the level of platelet TXA2, resulting in inhibition of platelet aggregation and prolonged bleeding time. For this reason aspirin should not be taken at least 1 week prior to surgery.

5.3 Respiration: In toxic doses, salicylates cause respiratory depression and a combination of uncompensated respiratory and metabolic acidosis.

5.4 Metabolic processes: Large doses of salicylates uncouple oxidative phospho-rylation. The energy normally used for the production of ATP is dissipated as heat, which explains the hyperthermia caused by salicylates when taken in toxic quantities.

5.5 Hypersensitivity: Approximately 15% of patients taking aspirin experience hyper-sensitivity reactions. Symptoms of true allergy include urticaria, bronchoconstriction, or angioneurotic edema. Fatal anaphylactic shock is rare.

5.6 Reye’s syndrome: Aspirin given during viral infections has been associated with an increased incidence of Reye’s syndrome, an often fatal, fulminating hepatitis with cerebral edema. This is especially encountered in children, who therefore should be given paracetamol instead of aspirin.

Salicylate intoxication may be mild or severe. The mild form is called salicylism and is characterized by nausea, vomiting, marked hyperventilation, headache, mental confusion, dizziness, and tinitus (ringing or roaring in the ears). When large doses are administered, severe salicylate intoxication may result. The symptoms listed above are followed by restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure. Children are particularly prone to salicylate intoxication. Ingestion of as little as 10 g of aspirin can cause death in children. Treatment of salicylism should include measurement of serum salicylate concentrations and of pH to determine the best form of therapy. In mild cases, symptomatic treatment is usually sufficient. Increasing the urinary pH enhances the elimination of salicylates. In serious cases, mandatory measures include the intravenous administration of fluid, dialysis, and correction of acid-base and electrolyte balances.

B. Propionic acid derivatives
Ibuprofen was first in this class of agents to become available. It has been joined by naproxen, ketoprofen, flurbiprofen, and others. All of these drugs possess anti-inflammatory, analgesic and antipyretic activity and have gained wide acceptance in the chronic treatment of rheumatoid and osteoarthritis because their GI effects are generally less intense than that of aspirin. These drugs are reversible inhibitors of the cyclooxygenase and thus, like aspirin, inhibit the synthesis of prostaglandins but not that of leukotrienes. All are well absorbed on oral administration and are almost totally bound to serum albumin. They undergo hepatic metabolism and are excreted by the kidney. The most common adverse effect is gastrointestinal, ranging from dyspepsia to bleeding. Side effects involving the CNS, such as headache, tinnitus and dizziness, have also been reported.

C. Indoleacetic acids
This group includes indomethacin, sulindac and etodolac. All have anti-inflammatory, analgesic and antipyretic activity. They act by reversibly inhibiting cyclooxygenase. They are generally not used to lower fever.

1. Indomethacin:
This NSAID is more potent than aspirin as an anti-inflammatory agent, but it is inferior to the salicylates at doses tolerated by rheumatoid arthritic patients. In certain instances (acute gouty arthritis, ankylosing spondylitis, and osteo-arthritis of the hip) indomethacin is more effective than is aspirin or any of the other NSAIDs. It is also effective in treating patent ductus arteriosus. Like aspirin, indomethacin can delay labor by suppressing uterine contractions. Indomethacin’s toxicity limits its use. Adverse effects occur in up to 50% of patients; approximately 20% find the adverse effects to be intolerable and discontinue use of the drug. Most adverse effects are dose-related. GI complaints consist of nausea, vomiting, anorexia, diarrhea, and abdominal pain. Ulceration of the upper GI tract can occur, sometimes with perforation and hemorrhage. The most severe and frequent CNS effect is frontal headache, which occurs in 25 to 50% of patients who chronically use indomethacin. Other CNS effects are dizziness, vertigo, and mental confusion. Concurrent administ-ration of indomethacin may decrease the antihypertensive effects of furosemide, the thiazide diuretics, -blockers and ACE inhibitors.

2. Sulindac:
This inactive pro-drug is closely related to indomethacin. Metabolism of hepatic microsomal enzymes produces the active form (a sulfide) of the drug, which has a long duration of action. Although the drug is less potent than indomethacin, it is useful in the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, and acute gout. The adverse reactions are similar to but less severe than those of the other NSAIDs, including indomethacin.

D. Pyrazolon derivatives
This group of drugs includes butadion, analgin, antipyrine, amidopyrine. All these drugs have been in clinical use for many years. Although not a first-line drug, butadion (phenylbutazone) is the most important from the therapeutic viewpoint. Antipyrine and amidopyrine are seldom used today. Analgin (metamizole) is not yet available in certain countries.

1. Butadion (Phenylbutazone):
Butadion has powerful anti-inflammatory effects but weak analgesic and antipyretic activities. Butadion is prescribed chiefly in short-term therapy when other NSAIDs have failed. The usefulness of butadion is limited by its toxicity. The most serious adverse effects are agranulocytosis and aplastic anemia. However, the most common adverse effects are nausea, vomiting, skin rashes, and epigastric discomfort. Other side effects include fluid and electrolyte retention, diarrhea, vertigo, insomnia. Butadion reduces the uptake of iodine by thyroid gland, sometimes resulting in goiter and myxedema. Because of all these potential side-effects, the drug should be given for short period of time–up to 1 week only.

2. Analgin (Metamizole): Analgin was widely used as a potent antipyretic, analgesic and anti-inflammatory agent. However, its role was sharply limited after potentially fatal bone-marrow toxicity, agranulocytosis was recognized.

E. Other agents
1. Diclofenac: A cyclooxygenase inhibitor, diclofenac is approved for long-term treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondilitis. It is more potent than indomethacin. Diclofenac accumulates in synovial fluid. The urine is the primary route of excretion. Its toxicities are similar to those of the other NSAIDs, e.g. GI problems are common, and the drug can also give rise to elevated hepatic enzyme levels.

2. Mefenamic acid has no advantages over the others NSAIDs as anti-inflammatory agent. Its side effects, such as diarrhea, can be severe and associated with inflammation of the bowel. Cases of hemolytic anemia have been reported.

3. Piroxicam is one of the oxicam derivatives that possesses anti-inflammatory, analgesic, and antipyretic activity. In recommended doses, piroxicam appears to be equivalent to aspirin, indomethacin, or naproxen for the long-term treatment of rheumatoid arthritis or osteoarthritis. It may be tolerated better than aspirin or indomethacin. The principal advantage of piroxicam is its long half-life (50 hours), which permits the administration of a single daily dose. GI disturbances are encountered in approximately 20% of patients.

4. Ketorolac: This drug acts like other NSAIDs. In addition to the oral rout, ketorolac can be administered intramuscularly in the treatment of postoperative pain, and topically for allergic conjunctivitis. Ketorolac undergoes hepatic metabolism; the drug and its metabolites are eliminated via the urine. It causes the same side effects as the other NSAIDs.

IV. Non-narcotic analgesics
Non-narcotic analgesics, unlike the NSAIDs, have little or no anti-inflammatory activity. They have a therapeutic advantage of narcotic analgesics in that they do not cause physical dependence or tolerance.

Paracetamol and phenacetin

Paracetamol (acetaminophen) and phenacetin act by inhibiting prostaglandin synthesis in the CNS. This explains their antipyretic and analgesic properties. They have less effects on cyclooxygenase in peripheral tissues, which accounts for their weak anti-inflammatory activity. Paracetamol and phenacetin do not affect platelet function or increase blood clotting time, and they lack many of the side-effects of aspirin. [Note: Phenacetin can no longer be prescribed in many countries because of its renal toxicity. However, it is present in some proprietary preparations.]

1. Therapeutic uses: Paracetamol is a suitable substitute for the analgesic and antipyretic effects of aspirin in those patients with gastric complaints and in those for whom prolongation of bleeding time would be a disadvantage or who do not require the anti-inflammatory action of aspirin. Paracetamol is the analgesic-antipyretic of choice for children with viral infections or chicken pox (recall that aspirin increases the risk of Reye’s syndrome).

2. Pharmacokinetics: Paracetamol is rapidly absorbed from the GI tract. A significant first-pass metabolism occurs in the luminal cells of the intestine and in the hepatocytes. Phenacetin is largely converted to paracetamol within 3 hours of administration. Under normal circumstances, paracetamol is conjugated in the liver to form inactive glucuronidated or sulfated metabolites. A portion of paracetamol is hydroxylated to form N-acetyl-benzoquinoneimine–a highly reactive and potentially dangerous metabolite that reacts with sulfhydryl groups. At normal doses of paracet-amol, the N-acetyl-benzoquinoneimine reacts with groups of glutathione, forming a nontoxic substance. Paracetamol and its metabolites are excreted in the urine.

3. Adverse effects: With normal therapeutic doses, paracetamol is virtually free of any significant adverse effects. Skin rash and minor allergic reactions occur infre-quently. Renal tubular necrosis and hypoglycemic coma are rare complications of prolonged large-dose therapy. With large doses of paracetamol, the available glutathione in the liver becomes depleted and N-acetyl-benzoquinoneimine reacts with the sulfhydryl groups of hepatic proteins, forming covalent bounds. 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 life-saving if administered within 10 hours of the overdose.]