NSAIDs.pdf

Nonsteroidal Anti-inflammatory Drugs “NSAIDs” Professor Dr. Haidar Al-Muthaffar M.B.Ch.B., M.Sc., Ph.D.  Overview NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic, analgesic, and anti- inflammatory activities. ...

Nonsteroidal Anti-inflammatory Drugs “NSAIDs” Professor Dr. Haidar Al-Muthaffar M.B.Ch.B., M.Sc., Ph.D.  Overview NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic, analgesic, and anti- inflammatory activities.  The class includes derivatives of: ✓ Salicylic acid (aspirin, diflunisal, salsalate), ✓ Propionic acid (ibuprofen, fenoprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin), ✓ Acetic acid (diclofenac, etodolac, indomethacin, ketorolac, nabumetone, sulindac, tolmetin), ✓ Enolic acid (meloxicam, piroxicam), ✓ Fenamates (mefenamic acid, meclofenamate), ✓ And the selective COX-2 inhibitor (celecoxib).  [ in role integrity of GIT mediator lsthma.im inflammatory late allergic. Edema plate agvigation  b- Therapeutic - → effect 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. Differences in safety and efficacy of the NSAIDs may be explained by relative selectivity for the COX-1 or COX-2 enzyme. Inhibition of COX-2 is thought to lead to the anti- inflammatory and analgesic actions of NSAIDs, whereas inhibition of COX-1 is responsible for prevention of cardiovascular events and most adverse events.  Aspirin and other NSAIDs Aspirin is the traditional NSAID, it exhibits anti-inflammatory activity only at relatively high doses that are rarely used. It is used more frequently at lower doses to prevent cardiovascular events such as stroke and myocardial infarction (MI). Aspirin is often differentiated from other NSAIDs since it is an irreversible inhibitor of cyclooxygenase activity.  Mechanism of action Aspirin is a weak organic acid that irreversibly acetylates and, thus, inactivates cyclooxygenase. The other NSAIDs are reversible inhibitors of cyclooxygenase. The NSAIDs, including aspirin, have three major therapeutic actions reducing: Inflammation (anti-inflammatory). Pain (analgesic effect). Fever (antipyretic effect). However, not all NSAIDs are equally effective in each of these actions.  irreversible * prin binding :) µ dÉ * µ , reversals le - Anelgisc  a. Anti-inflammatory actions ↳%:* if few Inhibition of cyclooxygenase diminishes the formation of prostaglandins and, thus, modulates aspects of inflammation mediated by prostaglandins. NSAIDs inhibit inflammation in arthritis, but they neither arrest the progression of the disease nor induce remission.  b. Analgesic action 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, the sensation of pain can be decreased. As COX-2 is expressed during times of inflammation and injury, it is thought that inhibition of this enzyme is responsible for the analgesic activity of NSAIDs.  No single NSAID has demonstrated superior efficacy over another, and they are generally considered to have equivalent analgesic efficacy. The NSAIDs are used mainly for the management of mild to moderate pain arising from musculoskeletal disorders. (somatic pain) One exception is ketorolac, which can be used for more severe pain, but for only a short duration.  c. Antipyretic action Fever occurs when the set-point of the anterior hypothalamic thermoregulatory center is elevated. This can be caused by PGE2 synthesis, which is stimulated when endogenous fever-producing agents (pyrogens), such as cytokines, are released from WBCs that are activated by: infection hypersensitivity malignancy inflammation armors The NSAIDs lower body temperature in patients with fever by impeding PGE2 synthesis and release, resetting the “thermostat” back toward normal. This rapidly lowers the body temperature of febrile patients by increasing heat dissipation through peripheral vasodilation and sweating. NSAIDs have no effect on normal body temperature.  Therapeutic uses a. Anti-inflammatory and analgesic uses NSAIDs are used in the treatment of osteoarthritis, gout, RA, and common conditions requiring analgesia (for example, headache, arthralgia, myalgia, and dysmenorrhea). Combinations of opioids and NSAIDs may be effective in treating pain caused by malignancy. Furthermore, the addition of NSAIDs may lead to an opioid- sparing effect, allowing for lower doses of opioids to be utilized.  The salicylates exhibit analgesic activity at lower 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.  b. Antipyretic uses Aspirin, ibuprofen, and naproxen may be used to treat fever. Aspirin should be avoided in patients less than 19 years old with viral infections, such as varicella (chickenpox) or influenza, to prevent Reye syndrome—a syndrome that can cause fulminating hepatitis with cerebral edema, often leading to death.  c. Cardiovascular applications Aspirin irreversibly inhibits COX-1–mediated production of TXA2, thereby reducing TXA2-mediated vasoconstriction and platelet aggregation and the subsequent risk of cardiovascular events. The antiplatelet effects persist for the life of the platelet. Low doses of aspirin (75 to 162 mg—commonly 81 mg) are used prophylactically to reduce the risk of recurrent cardiovascular events, transient ischemic attacks (TIAs), stroke, and death in patients with a history of previous MI, TIA, or stroke.  Chronic use of aspirin allows for continued inhibition as new platelets are generated. Aspirin is also used acutely to reduce the risk of death in acute MI and in patients undergoing certain revascularization procedures.  d. External applications Salicylic acid is used topically to treat acne, corns, calluses, and warts. Methyl salicylate (“oil of wintergreen”) is used externally as a cutaneous counterirritant in liniments, such as arthritis creams and sports rubs. Diclofenac is available in topical formulations (gel or solution) for treatment of osteoarthritis in the knees or hands. In addition, ocular formulations of ketorolac are approved for management of seasonal allergic conjunctivitis and inflammation and pain related to ocular surgery.  Pharmacokinetics Aspirin After oral administration, aspirin is rapidly deacetylated by esterases in the body to produce salicylate. Unionized salicylates are passively absorbed mainly from the upper small intestine. Salicylates (except for diflunisal) cross both the blood–brain barrier and the placenta and are absorbed through intact skin (especially methyl salicylate). Salicylate is converted by the liver to water-soluble conjugates that are rapidly cleared by the kidney, resulting in first-order elimination and a serum half-life of 3.5 hours.  At anti-inflammatory dosages of aspirin (more than 4 g/day), the hepatic metabolic pathway becomes saturated, and zero- order kinetics are observed, leading to a half-life of 15 hours or more. Salicylate is secreted into the urine and can affect uric acid excretion. Therefore, aspirin should be avoided in gout, if possible, or in patients taking probenecid. Alkalinization of urine increases the rate of excretion of salicylate and its water-soluble conjugates (ion trapping)  Other NSAIDs Most NSAIDs are well absorbed after oral administration and circulate highly bound to plasma proteins. The majority are metabolized by the liver, mostly to inactivate metabolites. Few (for example, nabumetone and sulindac) have active metabolites. Excretion of active drug and metabolites is primarily via the urine.  Adverse events Because of the adverse event profile, it is preferable to use NSAIDs at the lowest effective dose for the shortest duration possible.  Gastrointestinal These are the most common adverse effects of NSAIDs, ranging from dyspepsia to bleeding. Normally, production of prostacyclin (PGI2) inhibits gastric acid secretion, and PGE2 and PGF2α stimulate synthesis of protective mucus in both the stomach and small intestine. Agents that inhibit COX-1 reduce beneficial levels of these prostaglandins, resulting in; ✓ Increased gastric acid secretion. ✓ Diminished mucus protection. ✓ Increased risk for GI bleeding and ulceration.  Agents with a higher relative selectivity for COX-1 may have a higher risk for GI events compared to those with a lower relative selectivity for COX-1 (that is, higher COX-2 selectivity). NSAIDs should be taken with food or fluids to diminish GI upset. If NSAIDs are used in patients at high risk for GI events, proton pump inhibitors or misoprostol should be used concomitantly to prevent NSAID-induced ulcers.  Increased risk of bleeding (antiplatelet effect) Aspirin inhibits COX-1–mediated formation of TXA2 and reduces platelet aggregation for the lifetime of the platelet (3 to 7 days). Platelet aggregation is the first step in thrombus formation, and the antiplatelet effect of aspirin results in a prolonged bleeding time. For this reason, aspirin is often withheld for at least 1 week prior to surgery.  NSAIDs other than aspirin are not utilized for their antiplatelet effect but can still prolong bleeding time, especially when combined with anticoagulants. Concomitant use of NSAIDs and aspirin can prevent aspirin from binding to cyclooxygenase. Patients who take aspirin for cardioprotection should avoid concomitant NSAID use if possible or take aspirin at least 30 minutes prior to the NSAID.  Renal effects NSAIDs prevent the synthesis of PGE2 and PGI2, prostaglandins that are responsible for maintaining renal blood flow. Decreased synthesis of prostaglandins can result in retention of sodium and water and may cause edema. Patients with a history of heart failure or kidney disease are at particularly high risk. These effects can also reduce the beneficial effects of antihypertensive medications. In susceptible patients, NSAIDs have led to acute kidney injury.  Cardiac effects Agents such as aspirin, with a very high degree of COX-1 selectivity at low doses, have a cardiovascular protective effect thought to be due to a reduction in the production of TXA2. Agents with higher relative COX-2 selectivity have been associated with an increased risk for cardiovascular events, possibly by decreasing PGI2 production mediated by COX-2.  An increased risk for cardiovascular events, including MI and stroke, has been associated with all NSAIDs except aspirin. All NSAIDs carry a boxed warning regarding the increased risk for cardiovascular events. Use of NSAIDs, other than aspirin, is discouraged in patients with established cardiovascular disease. For patients with cardiovascular disease in whom NSAID treatment cannot be avoided, naproxen may be the least likely to be harmful.  Other adverse effects NSAIDs are inhibitors of cyclooxygenases and, therefore, inhibit the synthesis of prostaglandins but not of leukotrienes. For this reason, NSAIDs should be used with caution in patients with asthma, as inhibition of prostaglandin synthesis can cause a shift toward leukotriene production and increase the risk of asthma exacerbations.  Central nervous system (CNS) adverse events, such as headache, tinnitus, and dizziness, may occur. Approximately 15% of patients taking aspirin experience hypersensitivity reactions. Symptoms of true allergy include urticaria, bronchoconstriction, and angioedema. Patients with severe hypersensitivity to aspirin should avoid using NSAIDs.  Drug interactions Salicylate is roughly 80% to 90% plasma protein bound (albumin) and can be displaced from protein- binding sites, resulting in increased concentration of free salicylate. Alternatively, aspirin can displace other highly protein-bound drugs, such as warfarin, phenytoin, or valproic acid, resulting in higher free concentrations of these agents.  Toxicity Mild salicylate toxicity is called salicylism and is characterized by nausea, vomiting, marked hyperventilation, headache, mental confusion, dizziness, and tinnitus (ringing or roaring in the ears). When large doses of salicylate are administered, severe salicylate intoxication may result. Restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure may occur. Children are particularly prone to salicylate intoxication; ingestion of as little as 10 g of aspirin can be fatal. Alkalinization of urine increases the rate of excretion of free salicylate and reduce toxicity  Pregnancy NSAIDs should be used in pregnancy only if benefits outweigh risks to the developing fetus. [Note: Acetaminophen is preferred if analgesic or antipyretic effects are needed during pregnancy.] In the third trimester, NSAIDs should generally be avoided due to the risk of premature closure of the ductus arteriosus.  Celecoxib Celecoxib, a selective COX-2 inhibitor, is significantly more selective for inhibition of COX-2 than COX-1. Unlike the inhibition of COX-1 by aspirin (which is irreversible), the inhibition of COX-2 is reversible.  Therapeutic uses Celecoxib is approved for the treatment of RA, osteoarthritis, and acute pain. Celecoxib has similar efficacy to NSAIDs in the treatment of pain.  Pharmacokinetics Celecoxib is readily absorbed after oral administration. It is extensively metabolized in the liver by cytochrome P450 (CYP2C9), and the metabolites are excreted in feces and urine. The half-life is about 11 hours, and the drug may be dosed once or twice daily. The dosage should be reduced in those with moderate hepatic impairment, and celecoxib should be avoided in patients with severe hepatic or renal disease.  Adverse effects Headache, dyspepsia, diarrhea, and abdominal pain are the most common adverse effects. Celecoxib is associated with less GI bleeding and dyspepsia than other NSAIDs. However, this benefit is lost when aspirin is added to celecoxib therapy. Patients who are at high risk of ulcers and require aspirin for cardiovascular prevention should avoid the use of celecoxib.  Like other NSAIDs, celecoxib has a similar risk for cardiovascular events. Patients who have had anaphylactoid reactions to aspirin or nonselective NSAIDs may be at risk for similar effects with celecoxib. Inhibitors of CYP2C9, such as fluconazole, may increase serum levels of celecoxib.  Acetaminophen Acetaminophen (N-acetyl-p-aminophenol or APAP) inhibits prostaglandin synthesis in the CNS, leading to antipyretic and analgesic effects. Acetaminophen has less effect on cyclooxygenase in peripheral tissues (due to peripheral inactivation), which accounts for its weak anti-inflammatory activity. Acetaminophen does not affect platelet function or increase bleeding time. It is not considered an NSAID.  Therapeutic uses Acetaminophen is used for the treatment of fever and the relief of pain. It is useful in patients with gastric complaints/risks with NSAIDs and those who do not require the anti-inflammatory action of NSAIDs. Acetaminophen is the analgesic/antipyretic of choice for children with viral infections or chickenpox (due to the risk of Reye syndrome with aspirin).  Pharmacokinetics Acetaminophen is rapidly absorbed from the GI tract and undergoes significant first-pass metabolism. It is conjugated in the liver to form inactive glucuronidated or sulfated metabolites. A portion of acetaminophen is hydroxylated to form N-acetyl- p-benzoquinoneimine, or NAPQI, a highly reactive metabolite that can react with sulfhydryl groups and cause liver damage.  At normal doses of acetaminophen, NAPQI reacts with the sulfhydryl group of glutathione produced by the liver, forming a nontoxic substance. Acetaminophen and its metabolites are excreted in urine. The drug is also available in intravenous and rectal formulations.  Adverse effects At normal therapeutic doses, acetaminophen has few significant adverse effects. With large doses of acetaminophen, the available glutathione in the liver becomes depleted, and NAPQI reacts with the sulfhydryl groups of hepatic proteins. Hepatic necrosis, a serious and potentially life-threatening condition, can result.  Patients with hepatic disease, viral hepatitis, or a history of alcoholism are at higher risk of acetaminophen-induced hepatotoxicity. [Note: N-acetylcysteine is an antidote in cases of overdose.] Acetaminophen should be avoided in patients with severe hepatic impairment.