Nonsteroidal Antiinflammatory Drugs (NSAIDs)

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Nonsteroidal Antiinflammatory Drugs (NSAIDs)
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• 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

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• Characterized by
• 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 (functio laesa)
• Inflammatory cell transmigration through
  endothelium and accumulation at the site of
  injury

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Mediators of Inflammation

• 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)

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Two main forms of Cyclooxygenases (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

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Inflammatory responses occur in three distinct
phases

• 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

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Mechanism of action of NSAIDs

• 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.

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• 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.

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• Analgesic effect
• 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).

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• 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.

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Therapeutic uses

• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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

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

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• 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.

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

esterases
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• Metabolism

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• Salicylates have a t1/2 of 36 hours after
  short-term administration.
• Long-term administration of
• high doses (to treat arthritis) or
• toxic overdose
• increases the t1/2 to 1530 hours because the
  enzymes for glycine and glucuronide conjugation
  become saturated.

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• 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.

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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.

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

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• Aspirin
• has significantly greater antithrombotic activity
  than other NSAIDs

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Adverse effects

• 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).

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• These gastrointestinal effects are thought to be
  due to
• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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Miscellaneous adverse effects and
contraindications

• May decrease the glomerular filtration rate,
  particularly in patients with renal
  insufficiency.
• Occasionally produce mild hepatitis
• Prolong bleeding time.

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• 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.

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Drug interactions
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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.

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• Treatment of Aspirin Toxicity includes
• correction of acidbase disturbances
• replacement of electrolytes and fluids
• cooling
• alkalinization of urine with bicarbonate to
  reduce salicylate reabsorption
• forced diuresis, hemodialysis
• gastric lavage or emesis

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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.

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• NSAIDs are
• metabolized in the liver
• excreted by the kidney
• The half-lives 1 -45 h
• most 10 -20 h

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• 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

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Antiinflammatory Antipyresis Analgesia Prototype Chemical Class
Aspirin Salicylates
Marginal Acetaminophen Para-aminophenols
Indomethacin Indoles
Tolmentin, mefenamic acid Pyrrol acetic acids
Ibuprofen, naproxen Propionic acids
Phenylbutazone, piroxicam Enolic acids
Nabumetone Alkanones
Celecoxib Sulfonamide
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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.

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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.

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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.

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

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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.

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Meclofenamate, mefenamic acid

• t1/2 of 2 hours.
• A relatively high incidence of gastrointestinal
  disturbances is associated with these agents.

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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.

Other NSAIDS include flurbiprofen, diclofenac,
and etodolac.
Flurbiprofen is also available for topical
ophthalmic use.
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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
• 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.

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• Rofecoxib and valdecoxib 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.

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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.

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

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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.

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• Methotrexate
• 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

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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

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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.

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• 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.

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

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Disease-modifying antiarthritic drugs (DMAARDs)

• Tumor Necrosis Factor
• TNF-a is responsible for inducing IL-1 and IL-6
  and other cytokines that further the disease.

Anti-TNF-a drugs
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Anti-TNF-a drugs

• Infliximab
• is a recombinant antibody with human constant and
  murine variable regions that specifically binds
  TNF-a, 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

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Immunotherapeutic Treatment ofRheumatoid
Arthritis
Use Molecular Target Characteristic Drug
Rheumatoid arthritis Plasma tissue TNF-a Anti-TNF-a antibody Adalimumab
Rheumatoid arthritis, Crohn's disease, uveitis, psoriasis Plasma tissue TNF-a Anti-TNF-a antibody Infliximab
Rheumatoid arthritis, psoriasis Plasma tissue TNF-a TNF-receptorfusion protein Etanercept
Rheumatoid arthritis Interleukin-1 Recombinant IL-1a Anakinra
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• Adalimumab
• is approved for the treatment of rheumatoid
  arthritis.
• It is a humanized (no murine components)
  anti-TNF-a antibody administered subcutaneously
  every other week.
• Etanercept
• is a fusion protein composed of the
  ligand-binding pocket of a TNF-a 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.

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• Anti-IL1 drugs
• 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.

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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.

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

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• Colchicine
• 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 1224 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.

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• 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 (612 h) but increases the risk of
  sloughing skin and subcutaneous tissue.
• Higher doses may (rarely) result in liver damage
  and blood dyscrasias.

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• 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.

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• Probenecid 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.

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• 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

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• 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.

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