Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Inflammation is a defense reaction caused by tissue damage or injury Can be elicited by numerous stimuli including: infectious agents antigen-antibody interaction ischemia thermal and physical injury

Characterized by: 1.Redness (rubor): vasodilation of capillaries to increase blood flow 2.Heat (calor): vasodilation 3.Pain (dolor): Hyperalgesia, sensitization of nociceptors 4.Swelling (tumor): Increased vascular permeability (microvascular structural changes and escape of plasma proteins from the bloodstream) 5.Loss of function (functio laesa) Inflammatory cell transmigration through endothelium and accumulation at the site of injury

Mediators of Inflammation 1. Vasoactive amines (Histamine, Serotonin) 2. Platelet activating factor (PAF) 3. Complement system 4. Kinin system 5. Cytokines 6. Nitric oxide 7. Adhesion Molecules 8. Arachidonic acid metabolites: Prostaglandins (PGs) Thromboxane A2 (TXA2) HETE (hydroxy-eicosatetraenoic acid) Leukotrienes (LTs) mediated by cyclooxygenases (COX) mediated by cyclooxygenases (COX)

Two main forms of Cyclooxygenases (COX) Cyclooxygenase-1 (COX-1)Cyclooxygenase-1 (COX-1) Produces prostaglandins that mediate homeostatic functions Constitutively expressed Plays an important role in Gastric mucosa Kidney Platelets Vascular endothelium Cyclooxygenase-2 (COX-2)Cyclooxygenase-2 (COX-2) Produces prostaglandins that mediate inflammation, pain, and fever. Induced mainly in sites of inflammation by cytokines

Inflammatory responses occur in three distinct phases: transient phase 1.An acute transient phase, characterized by: –local vasodilation –increased capillary permeability subacute phase 2.A delayed, subacute phase, most prominently characterized by: –infiltration of leukocytes and phagocytic cells proliferative phase 3.A chronic proliferative phase, in which: –tissue degeneration and fibrosis occur

Mechanism of action of NSAIDs 1.Antiinflammatory effect –due to the inhibition of the enzymes that produce prostaglandin H synthase (cyclooxygenase, or COX), which converts arachidonic acid to prostaglandins, and to TXA2 and prostacyclin.

–Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue. –This distinguishes it from other NSAIDs, which reversibly inhibit COX-1 and COX-2.

2.Analgesic effect A.The analgesic effect of NSAIDs is thought to be related to: –the peripheral inhibition of prostaglandin production –may also be due to the inhibition of pain stimuli at a subcortical site. B.NSAIDs prevent the potentiating action of prostaglandins on endogenous mediators of peripheral nerve stimulation (e.g., bradykinin).

3.Antipyretic effect –The antipyretic effect of NSAIDs is believed to be related to: inhibition of production of prostaglandins induced by interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus the “resetting” of the thermoregulatory system, leading to vasodilatation and increased heat loss.

Therapeutic uses 1.Inflammation –NSAIDs are first-line drugs used to arrest inflammation and the accompanying pain of rheumatic and nonrheumatic diseases, including rheumatoid arthritis, juvenile arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Reiter syndrome, and dysmenorrhea. –Pain and inflammation of bursitis and tendonitis also respond to NSAIDs.

–NSAIDs: do not significantly reverse the progress of rheumatic disease they slow destruction of cartilage and bone allow patients increased mobility and use of their joints.

–Treatment of chronic inflammation requires use of these agents at doses well above those used for analgesia and antipyresis –the incidence of adverse drug effects is increased.

–Drug selection is generally dictated by the patient's ability to tolerate the adverse effects, and the cost of the drugs. –Antiinflammatory effects may develop only after several weeks of treatment.

2. Analgesia NSAIDs alleviate mild-to-moderate pain by: –decreasing PGE- and PGF-mediated increases in pain receptor sensitivity. They are more effective against pain associated with integumental structures (pain of muscular and vascular origin, arthritis, and bursitis) than with pain associated with the viscera.

3.Antipyresis NSAIDs reduce elevated body temperature with little effect on normal body temperature.

Aspirin (acetylsalicylic acid)Aspirin (acetylsalicylic acid) Nonacetylated salicylates:Nonacetylated salicylates: –sodium salicylate –magnesium salicylate –choline salicylate –sodium thiosalicylate –sulfasalazine –mesalamine –salsalate

Pharmacologic properties: –Salicylates are weak organic acids; –aspirin has a pKa of 3.5. –These agents are rapidly absorbed from the intestine as well as from the stomach, where the low pH favors absorption.

–Salicylates are hydrolyzed rapidly by plasma and tissue esterases to acetic acid and the active metabolite salicylic acid. esterases

–Metabolism

–Salicylates have a t1/2 of 3—6 hours after short-term administration. –Long-term administration of high doses (to treat arthritis) or toxic overdose –increases the t1/2 to 15—30 hours because the enzymes for glycine and glucuronide conjugation become saturated.

–Unmetabolized salicylates are excreted by the kidney. –If the urine pH is raised above 8, clearance is increased approximately fourfold as a result of decreased reabsorption of the ionized salicylate from the tubules.

Therapeutic uses of Salicylates : Salicylates are used to treat: –rheumatoid arthritis –juvenile arthritis –osteoarthritis –other inflammatory disorders 5-Amino salicylates (mesalamine, sulfasalazine) –can be used to treat Crohn's disease.

Salicylic acid is used topically to treat: –plantar warts –fungal infections –corns

Aspirin –has significantly greater antithrombotic activity than other NSAIDs

Adverse effects: 1.Gastrointestinal effects –most common adverse effects of high-dose aspirin use (70% of patients): nausea vomiting diarrhea or constipation dyspepsia (impaired digestion) epigastric pain bleeding, and ulceration (primarily gastric).

These gastrointestinal effects are thought to be due to: 1.a direct chemical effect on gastric cells or 2.a decrease in the production and cytoprotective activity of prostaglandins, which leads to gastric tissue susceptibility to damage by hydrochloric acid.

–The gastrointestinal effects may contraindicate aspirin use in patients with an active ulcer. –Aspirin may be taken with prostaglandins to reduce gastric damage. –Decrease gastric irritation by: Substitution of enteric-coated or timed- release preparations, or the use of nonacetylated salicylates, may decrease gastric irritation.

2.Hypersensitivity (intolerance) Hypersensitivity is relatively uncommon with the use of aspirin (0.3% of patients); hypersensitivity results in: –rash –bronchospasm –rhinitis –Edema, or –an anaphylactic reaction with shock, which may be life threatening. The incidence of intolerance is highest in patients with asthma, nasal polyps, recurrent rhinitis, or urticaria. Aspirin should be avoided in such patients.

Cross-hypersensitivity may exist: –to other NSAIDs –to the yellow dye tartrazine, which is used in many pharmaceutical preparations. Hypersensitivity is not associated with: –sodium salicylate or –magnesium salicylate.

The use of aspirin and other salicylates to control fever during viral infections (influenza and chickenpox) in children and adolescents is associated with an increased incidence of Reye's syndrome, an illness characterized by vomiting, hepatic disturbances, and encephalopathy that has a 35% mortality rate. Acetaminophen is recommended as a substitute for children with fever of unknown etiology.

3.Miscellaneous adverse effects and contraindications May decrease the glomerular filtration rate, particularly in patients with renal insufficiency. Occasionally produce mild hepatitis Prolong bleeding time.

Aspirin irreversibly inhibits platelet COX-1 and COX-2 and, thereby, TXA2 production, suppressing platelet adhesion and aggregation. The use of salicylates is contraindicated in patients with bleeding disorders Salicylates are not recommended during pregnancy; they may induce: –postpartum hemorrhage –premature closure of the fetal ductus arteriosus.

Drug interactions

Aspirin Toxicity In adults, salicylism (tinnitus, hearing loss, vertigo) occurs as initial sign of toxicity after aspirin or salicylate overdose or poisoning. In children, the common signs of toxicity include hyperventilation and acidosis, with accompanying lethargy and hyperventilation.

Aspirin ToxicityTreatment of Aspirin Toxicity includes: 1.correction of acid—base disturbances 2.replacement of electrolytes and fluids 3.cooling 4.alkalinization of urine with bicarbonate to reduce salicylate reabsorption 5.forced diuresis, hemodialysis 6.gastric lavage or emesis

Other nonsteroidal antiinflammatory drugs –NSAIDs are absorbed rapidly after oral administration. –These agents are extensively bound to plasma proteins, especially albumin. –They cause drug interactions due to the displacement of other agents, particularly anticoagulants, from serum albumin; these interactions are similar to those seen with aspirin.

NSAIDs are metabolized in the liver excreted by the kidney The half-lives: #1 -45 h # most: h

These agents commonly produce: –gastrointestinal disturbances –cross-sensitivity with aspirin Non-dose-related acute renal failure and nephrotic syndrome: –in combination with ACE inhibitors –More nephrotoxic: »Indomethacin »Meclofenamate »Tolmetin »phenylbutazone

Antiinflammatory AntipyresisAnalgesia PrototypeChemical Class +++ AspirinSalicylates Marginal+++ AcetaminophenPara-aminophenols IndomethacinIndoles +++ Tolmentin, mefenamic acid Pyrrol acetic acids Ibuprofen, naproxen Propionic acids Phenylbutazone, piroxicam Enolic acids NabumetoneAlkanones CelecoxibSulfonamide

Propionic acid derivatives (Ibuprofen, Fenoprofen, ketoprofen, naproxen) –There is no reported interaction of ibuprofen or ketoprofen with anticoagulants. –Fenoprofen has been reported to induce nephrotoxic syndrome. –Long-term use of ibuprofen is associated with an increased incidence of hypertension in women.

Sulindac, tolmetin, Ketorolac  Sulindac: is a prodrug that is oxidized to a sulfone and then to the active sulfide has a relatively long t1/2 (16 h) because of enterohepatic cycling.  Tolmetin: has minimal effect on platelet aggregation; it is associated with a higher incidence of anaphylaxis than other NSAIDs. Tolmetin has a relatively short t1/2 (1 h).  Ketorolac: is a potent analgesic with moderate antiinflammatory activity can be administered: –intravenously or –topically in an ophthalmic solution.

Indomethacin  Use: As anti-inflammatory  Treatment of Ankylosing spondylitis Reiter syndrome Acute gouty arthritis.  to speed the closure of patent ductus arteriosus in premature infants (otherwise, it is not used in children); it inhibits the production of prostaglandins that prevent closure of the ductus.

–Indomethacin is not recommended as a simple analgesic or antipyretic because of the potential for severe adverse effects. –Bleeding, ulceration –Headache –Occasional:Tinnitus, dizziness, or confusion

Piroxicam –Piroxicam is an oxicam derivative of enolic acid. –Piroxicam has t1/2 of 45 hours. –Like aspirin and indomethacin, bleeding and ulceration are more likely with piroxicam than with other NSAIDs.

Meclofenamate, mefenamic acid –t1/2 of 2 hours. –A relatively high incidence of gastrointestinal disturbances is associated with these agents.

Nabumetone –Compared with NSAIDs, nabumetone is associated with reduced: inhibition of platelet function incidence of gastrointestinal bleeding. –Nabumetone inhibits COX-2 more than COX-1. flurbiprofen, diclofenac, and etodolac. Other NSAIDS include flurbiprofen, diclofenac, and etodolac. Flurbiprofen is also available for topical ophthalmic use.

COX-2 Selective agents –Celecoxib [Celebrex] –Rofecoxib [Vioxx] –Valdecoxib [Bextra] –that inhibit COX-2 more than COX-1 have been developed and approved for use. –The rationale behind development of these drugs was that: A.inhibition of COX-2 would reduce the inflammatory response and pain B.not inhibit the cytoprotective action of prostaglandins in the stomach, which is largely mediated by COX-1.

–Rofecoxib and valdecoxib –Rofecoxib and valdecoxib have been removed from the market due to a doubling in the incidence of heart attack and stroke –Celecoxib –Celecoxib remains on the market and is approved for: –Osteoarthritis and rheumatoid arthritis –Pain including bone pain, dental pain, and headache –Ankylosing spondylitis.

Other antiinflammatory drugs are used in the more advanced stages of some rheumatoid diseases. Gold compounds: –Aurothioglucose –Gold sodium thiomalate –Auranofin –may retard the destruction of bone and joints by an unknown mechanism. –These agents have long latency. –Aurothioglucose and gold sodium thiomalate are administered intramuscularly. –Auranofin is administered orally and is 95% bound to plasma proteins.

 Side effects: Gold compounds  Serious: gastrointestinal disturbances, dermatitis, and mucous membrane lesions.  Less common effects: aplastic anemia proteinuria  Occasional: nephrotic syndrome.

Penicillamine –Penicillamine is a chelating drug (will chelate gold) that is a metabolite of penicillin. –Penicillamine has immunosuppressant activity, but its mechanism of action is unknown. –This agent has long latency. –The incidence of severe adverse effects is high; these effects are similar to those of the gold compounds.

MethotrexateMethotrexate –Methotrexate is an antineoplastic drug used for rheumatoid arthritis that does not respond well to NSAIDs or glucocorticoids. –Methotrexate commonly produces hepatotoxicity. Chloroquine and hydrochloroquineChloroquine and hydrochloroquine –Chloroquine and hydrochloroquine are antimalarial drugs. –These agents have immunosuppressant activity, but their mechanism of action is unknown. –Used to treat joint pain associated with lupus and arthritis AdrenocorticosteroidsAdrenocorticosteroids

Nonopioid analgesics and antipyretics –Aspirin, NSAIDs, and acetaminophen (Paracetamol): –are useful for the treatment of mild-to-moderate pain associated with integumental structures, including pain of muscles and joints, postpartum pain, and headache. –These agents have: antipyretic activity have antiinflammatory activity at higher doses except for acetaminophen

Acetaminophen (Paracetamol): –does not displace other drugs from plasma proteins –it causes minimal gastric irritation –has little effect on platelet adhesion and aggregation –Acetaminophen has no significant antiinflammatory activity.

–Acetaminophen is administered orally and is rapidly absorbed. –It is metabolized by hepatic microsomal enzymes to sulfate and glucuronide. –Acetaminophen is a substitute for aspirin to treat mild-to-moderate pain for selected patients who are: intolerant to aspirin have a history of peptic ulcer or hemophilia are using anticoagulants or a uricosuric drug to manage gout are at risk for Reye's syndrome.

Overdose with acetaminophen: accumulation of a minor metabolite, N-acetyl-p-benzoquinone, which is responsible for hepatotoxicity.

Overdose is treated by: –emesis or gastric lavage –oral administration of N-acetyl cystine within 1 day to neutralize the metabolite. Long-term use of acetaminophen has been associated with: –a 3-fold increase in kidney disease –women taking more than 500 mg/day had a doubling in the incidence of hypertension.

Disease-modifying antiarthritic drugs (DMAARDs) Tumor Necrosis Factor –TNF-α is responsible for inducing IL-1 and IL-6 and other cytokines that further the disease. Anti-TNF-  drugs

1.Anti-TNF-  drugs A.Infliximab: is a recombinant antibody with human constant and murine variable regions that specifically binds TNF-α, thereby blocking its action. –Approved for use for rheumatoid arthritis, Crohn's disease, psoriasis, and other autoimmune diseases –Administered by IV infusion at 2-week intervals initially and repeated at 6 and 8 weeks

Immunotherapeutic Treatment of Rheumatoid Arthritis Use Molecular TargetCharacteristicDrug Rheumatoid arthritisPlasma & tissue TNF-α Anti-TNF-α antibodyAdalimumab Rheumatoid arthritis, Crohn's disease, uveitis, psoriasis Plasma & tissue TNF-α Anti-TNF-α antibodyInfliximab Rheumatoid arthritis, psoriasisPlasma & tissue TNF-α TNF-receptor fusion protein Etanercept Rheumatoid arthritisInterleukin-1 Recombinant IL-1  Anakinra

B.Adalimumab is approved for the treatment of rheumatoid arthritis. It is a humanized (no murine components) anti-TNF-α antibody administered subcutaneously every other week. C.Etanercept is a fusion protein composed of the ligand-binding pocket of a TNF-α receptor fused to an IgG1 Fc fragment. The fusion protein has two TNF-binding sites per IgG molecule and is administered subcutaneously weekly. The most serious adverse effect is infection including tuberculosis, immunogenicity, and lymphoma. Injection site infections are common.

2.Anti-IL1 drugs –Anakinra –Anakinra is a recombinant protein essentially identical to IL-1 , a soluble antagonist of IL-1 that binds to the IL-1 receptor but does not trigger a biologic response. –Anakinra is a competitive antagonist of the IL-1 receptor. –It is approved for use for the treatment of rheumatoid arthritis. –It has a relatively short half-life and must be administered subcutaneously daily.

Drugs Used for Gout Gout –Gout is a familial disease characterized by: recurrent hyperuricemia arthritis severe pain –it is caused by deposits of uric acid (the end-product of purine metabolism) in joints, cartilage, and the kidney.

–Acute gout is treated with: Nonsalicylate NSAIDs, particularly indomethacin & colchicine. –Chronic gout is treated with: 1.uricosuric agents: They increase the elimination of uric acid: –probenecid –sulfinpyrazone 2.inhibits uric acid production: –allopurinol

ColchicineColchicine –Colchicine is an alkaloid –It is used for relief of inflammation and pain in acute gouty arthritis. –Reduction of inflammation and relief from pain occur 12—24 hours after oral administration. –The mechanism of action in acute gout is unclear. –Colchicine: prevents polymerization of tubulin into microtubules and inhibits leukocyte migration and phagocytosis. inhibits cell mitosis.

–The adverse effects after oral administration, which occur in 80% of patients at a dose near that necessary to relieve gout, include nausea, vomiting, abdominal pain, and particularly diarrhea. –IV administration reduces the risk of gastrointestinal disturbances and provides faster relief (6—12 h) but increases the risk of sloughing skin and subcutaneous tissue. –Higher doses may (rarely) result in liver damage and blood dyscrasias.

NSAIDs:NSAIDs: acute gout –indomethacin –naproxen –sulindac –NSAIDs are preferred to the more disease-specific colchicine because of the diarrhea associated with the use of colchicine.

Probenecid and sulfinpyrazoneProbenecid and sulfinpyrazone are organic acids reduce urate levels by acting at the anionic transport site in the renal tubule to prevent reabsorption of uric acid. These agents are used for chronic gout, often in combination with colchicine. Probenecid and sulfinpyrazone undergo rapid oral absorption.

These agents inhibit the excretion of other drugs that are actively secreted by renal tubules, including penicillin, NSAIDs, cephalosporins, and methotrexate. Increased urinary concentration of uric acid may result in the formation of urate stones (urolithiasis). This risk is decreased with: 1.the ingestion of large volumes of fluid or 2.alkalinization of urine with potassium citrate. Common adverse effects include gastrointestinal disturbances and dermatitis; rarely, these agents cause blood dyscrasias

Allopurinol Allopurinol inhibits the synthesis of uric acid by inhibiting xanthine oxidase, an enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. Allopurinol is metabolized by xanthine oxidase to alloxanthine, which also inhibits xanthine oxidase. Allopurinol also inhibits de novo purine synthesis. Allopurinol commonly produces gastrointestinal disturbances and dermatitis. This agent more rarely causes hypersensitivity, including fever, hepatic dysfunction, and blood dyscrasias. Allopurinol should be used with caution in patients with liver disease or bone marrow depression.