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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:

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Nonsteroidal antiinflammatory drugs nsaids

NonsteroidalAntiinflammatory Drugs (NSAIDs)

  • Characterized by: or injury

  • Redness (rubor): vasodilation of capillaries to increase blood flow

  • Heat (calor): vasodilation

  • Pain (dolor): Hyperalgesia, sensitization of nociceptors

  • Swelling (tumor): Increased vascular permeability (microvascular structural changes and escape of plasma proteins from the bloodstream)

  • Loss of function (functiolaesa)

  • Inflammatory cell transmigrationthrough endothelium and accumulation at the site of injury

Mediators of Inflammation or injury

  • Vasoactive amines (Histamine, Serotonin)

  • Platelet activating factor (PAF)

  • Complement system

  • Kinin system

  • Cytokines

  • Nitric oxide

  • Adhesion Molecules

  • Arachidonic acid metabolites:

    • Prostaglandins (PGs)

    • Thromboxane A2 (TXA2)

    • HETE (hydroxy-eicosatetraenoic acid)

    • Leukotrienes (LTs)

  • mediated by cyclooxygenases (COX)

  • Two main forms of or injuryCyclooxygenases (COX)

    • 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)

    • Produces prostaglandins that mediate inflammation, pain, and fever.

    • Induced mainly in sites of inflammation by cytokines

    Inflammatory responses occur in three distinct phases: or injury

    • An acute transient phase, characterized by:

      • local vasodilation

      • increased capillary permeability

  • A delayed, subacute phase, most prominently characterized by:

    • infiltration of leukocytes and phagocytic cells

  • A chronic proliferative phase, in which:

    • tissue degeneration and fibrosis occur

  • Mechanism of action of nsaids
    Mechanism of action of NSAIDs or injury

    • 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 or injuryirreversibly 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.

    • Analgesic effect or injury

      • 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.

      • NSAIDs prevent the potentiating action of prostaglandins on endogenous mediators of peripheral nerve stimulation (e.g., bradykinin).

    • Antipyretic effect or injury

      • 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
    Therapeutic uses or injury

    • 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: or injury

      • 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.

    • Analgesia ability to tolerate the adverse effects, and the cost of the drugs.

    • 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.

    • Antipyresis ability to tolerate the adverse effects, and the cost of the drugs.

    • NSAIDs reduce elevated body temperature with little effect on normal body temperature.

    • Aspirin (acetylsalicylic acid) ability to tolerate the adverse effects, and the cost of the drugs.

    • Nonacetylatedsalicylates:

      • sodium salicylate

      • magnesium salicylate

      • cholinesalicylate

      • sodium thiosalicylate

      • sulfasalazine

      • mesalamine

      • salsalate

    • Pharmacologic properties: ability to tolerate the adverse effects, and the cost of the drugs.

      • 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.


    • Metabolism esterases to acetic acid and the active metabolite

    • Salicylates have a t1/2 of 3—6 hours after esterases to acetic acid and the active metabolite 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.

    Therapeutic uses of salicylates
    Therapeutic uses of Salicylates : esterases to acetic acid and the active metabolite

    • Salicylatesare 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 esterases to acetic acid and the active metabolite is used topically to treat:

      • plantar warts

      • fungal infections

      • corns

    • Aspirin esterases to acetic acid and the active metabolite

      • has significantly greater antithrombotic activity than other NSAIDs

    Adverse effects
    Adverse effects: esterases to acetic acid and the active metabolite

    • 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: esterases to acetic acid and the active metabolite

      • a direct chemical effect on gastric cells or

      • 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 esterases to acetic acid and the active metabolite 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.

    • Hypersensitivity (intolerance) esterases to acetic acid and the active metabolite

    • 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 esterases to acetic acid and the active metabolite 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 esterases to acetic acid and the active metabolite aspirin and other salicylatesto 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.

    Miscellaneous adverse effects and contraindications
    Miscellaneous adverse effects and contraindications esterases to acetic acid and the active metabolite

    • May decrease the glomerular filtration rate, particularly in patients with renal insufficiency.

    • Occasionally produce mild hepatitis

    • Prolong bleeding time.

    • Aspirin esterases to acetic acid and the active metabolite 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 esterases to acetic acid and the active metabolite

    Aspirin toxicity
    Aspirin Toxicity esterases to acetic acid and the active metabolite

    • 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.

    • Treatment esterases to acetic acid and the active metabolite of Aspirin Toxicityincludes:

      • correction of acid—base disturbances

      • replacement of electrolytes and fluids

      • cooling

      • alkalinization of urine with bicarbonate to reduce salicylate reabsorption

      • forced diuresis, hemodialysis

      • gastric lavage or emesis

    Other nonsteroidal antiinflammatory drugs
    Other esterases to acetic acid and the active metabolite nonsteroidalantiinflammatory 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 esterases to acetic acid and the active metabolite

      • metabolized in the liver

      • excreted by the kidney

    • The half-lives of these agents vary greatly (from 1 to 45 h, with most between 10 and 20 h).

    • These agents commonly produce: esterases to acetic acid and the active metabolite

      • gastrointestinal disturbances

      • they demonstrate cross-sensitivity with aspirin and with each other.

    • NSAIDs are associated with non-dose-related instances of esterases to acetic acid and the active metabolite acute renal failure and nephrotic syndrome, and they may lead to renal toxicity in combination with angiotensin-converting enzyme (ACE) inhibitors.

    • Indomethacin, meclofenamate, tolmetin, and phenylbutazone are generally more toxic than other NSAIDs.

    Propionic acid derivatives
    Propionic esterases to acetic acid and the active metabolite 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, esterases to acetic acid and the active metabolite 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 esterases to acetic acid and the active metabolite

    • 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 esterases to acetic acid and the active metabolite not recommended as a simple analgesic or antipyretic because of the potential for severe adverse effects.

    • Bleeding, ulceration, and other adverse effects are more likely with indomethacin than with most other NSAIDs.

    • Headache is a common adverse effect

    • Tinnitus, dizziness, or confusion also occasionally occurs.

    Piroxicam esterases to acetic acid and the active metabolite

    • Piroxicam is an oxicam derivative of enolic acid.

    • Piroxicam has t1/2 of 45 hours.

    • Like aspirin and indomethacin, bleeding and ulcerationare more likely with piroxicam than with other NSAIDs.

    Meclofenamate mefenamic acid
    Meclofenamate, mefenamic acid esterases to acetic acid and the active metabolite

    • t1/2 of 2 hours.

    • A relatively high incidence of gastrointestinal disturbances is associated with these agents.

    Nabumetone esterases to acetic acid and the active metabolite

    • Compared with NSAIDs, nabumetone is associated with reduced:

      • inhibition of platelet function

      • incidence of gastrointestinal bleeding.

    • Nabumetone inhibits COX-2 more than COX-1.

    Other nsaids include flurbiprofen diclofenac and etodolac
    Other NSAIDS esterases to acetic acid and the active metabolite include flurbiprofen, diclofenac, and etodolac.

    • Flurbiprofen is also available for topical ophthalmic use.

    Cox 2 selective agents
    COX-2 Selective agents esterases to acetic acid and the active metabolite

    • 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:

      • inhibition of COX-2 would reduce the inflammatory response and pain

      • not inhibit the cytoprotective action of prostaglandins in the stomach, which is largely mediated by COX-1.

    • Rofecoxib and valdecoxib esterases to acetic acid and the active metabolite have been removed from the market due to a doubling in the incidence of heart attack and stroke

    • 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
    Other antiinflammatory drugs esterases to acetic acid and the active metabolite 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: esterases to acetic acid and the active metabolite Gold compounds

    • Serious:

      • gastrointestinal disturbances, dermatitis, and mucous membrane lesions.

    • Less common effects:

      • aplastic anemia

      • proteinuria

    • Occasional:

      • nephrotic syndrome.

    Penicillamine esterases to acetic acid and the active metabolite

    • 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.

    • Methotrexate esterases to acetic acid and the active metabolite

      • Methotrexate is an antineoplastic drug used for rheumatoid arthritis that does not respond well to NSAIDs or glucocorticoids.

      • Methotrexate commonly produces hepatotoxicity.

    • Chloroquine 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

    • Adrenocorticosteroids

    Nonopioid analgesics and antipyretics
    Nonopioid esterases to acetic acid and the active metabolite 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 esterases to acetic acid and the active metabolite

    • 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: absorbed.

    • accumulation of a minor metabolite, N-acetyl-p-benzoquinone,

    • which is responsible for hepatotoxicity.

    • Overdose is treated by: absorbed.

      • 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
    Disease-modifying absorbed. 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-a drugs

    Anti tnf a drugs
    Anti-TNF- absorbed. a drugs

    • 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
    Immunotherapeutic Treatment of absorbed. Rheumatoid Arthritis

    • Adalimumab absorbed.

    • is approved for the treatment of rheumatoid arthritis.

    • It is a humanized (no murine components) anti-TNF-α antibody administered subcutaneously every other week.

    • 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.

    • Anti-IL1 drugs absorbed.

      • Anakinra is a recombinant protein essentially identical to IL-1a, 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
    Drugs Used for Gout absorbed.

    • 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: absorbed.

      • Nonsalicylate NSAIDs, particularly indomethacin

      • colchicine.

    • Chronic gout is treated with:

      • uricosuric agents probenecid or sulfinpyrazone, which increase the elimination of uric acid

      • allopurinol, which inhibits uric acid production.

    • Colchicine absorbed.

      • 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: in 80% of patients at a dose near that necessary to relieve gout, include 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 sulfinpyrazone in 80% of patients at a dose near that necessary to relieve gout, include

    • 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:

      • the ingestion of large volumes of fluid or

      • alkalinization of urine with potassium citrate.

    • Common adverse effects include gastrointestinal disturbances and dermatitis; rarely, these agents cause blood dyscrasias

    • Allopurinol actively secreted by renal tubules, including

    • 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.