Antiinflammatory Agents and Nonsteroidal Antiinflammatory Drugs (NSAIDs)
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Transcript of Antiinflammatory Agents and Nonsteroidal Antiinflammatory Drugs (NSAIDs)
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AntiinflammatAntiinflammatory Agents ory Agents
and and Nonsteroidal Nonsteroidal
AntiinflammatAntiinflammatory Drugs ory Drugs (NSAIDs)(NSAIDs)
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Groups of anti-inflammatory agents and mechanism of action:1) nonsteroidal anti-inflammatory drugs - NSAI2) glucocorticosteroids (GCS)
glucocorticosteroids LK+ -
PhospholipaseА2
Phospholipids
Arachidonic acid
Cyclic endoperoxydases
Prostaglandins Thromboxan
Inflammation Pain Fever Vasoconstriction
Increasing of platelets aggregation
-
+
- depressing effect
- stimulating effect
NSAID
-Cyclooxygenases(COG-1, COG-2, COG-3)
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NSAIDsNSAIDs
Large and chemically diverse group Large and chemically diverse group of drugs with the following of drugs with the following properties:properties: AnalgesicAnalgesic AntiinflammatoryAntiinflammatory AntipyreticAntipyretic
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NSAIDs: Mechanism of NSAIDs: Mechanism of ActionAction
Activation of the arachidonic acid Activation of the arachidonic acid pathway causes:pathway causes:
painpain headacheheadache feverfever inflammationinflammation
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Arachidonic Acid Arachidonic Acid PathwayPathway
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NSAIDs: Mechanism of NSAIDs: Mechanism of ActionAction
Analgesia—treatment of headaches Analgesia—treatment of headaches and painand pain
Block the undesirable effects of Block the undesirable effects of prostaglandins, which cause headachesprostaglandins, which cause headaches
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NSAIDs: Mechanism of NSAIDs: Mechanism of ActionAction
Antipyretic: reduce feverAntipyretic: reduce fever Inhibit prostaglandin EInhibit prostaglandin E22 within the area of within the area of
the brain that controls temperaturethe brain that controls temperature
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NSAIDs: Mechanism of NSAIDs: Mechanism of ActionAction
Relief of inflammationRelief of inflammation Inhibit the leukotriene pathway, the Inhibit the leukotriene pathway, the
prostaglandin pathway, or bothprostaglandin pathway, or both
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NSAIDsNSAIDs
Six structurally related groups:Six structurally related groups: Acetic acidsAcetic acids Carboxylic acidsCarboxylic acids Propionic acidsPropionic acids Enolic acidsEnolic acids Fenamic acidsFenamic acids Nonacidic compoundsNonacidic compounds
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NSAIDs: Acetic AcidNSAIDs: Acetic Acid
diclofenac sodium (Voltaren)diclofenac sodium (Voltaren) diclofenac potassium (Cataflam)diclofenac potassium (Cataflam) etodolac (Lodine)etodolac (Lodine) indomethacin (Indocin)indomethacin (Indocin) sulindac (Clinoril)sulindac (Clinoril) tolmetin (Tolectin)tolmetin (Tolectin)
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NSAIDs: Carboxylic NSAIDs: Carboxylic AcidsAcids
AcetylatedAcetylated aspirin (ASA)aspirin (ASA)
choline magnesium salicylate (Trilisate)choline magnesium salicylate (Trilisate)
diflunisal (Dolobid)diflunisal (Dolobid)
NonacetylatedNonacetylated salicylamide salicylamide
salsalate (Disalcid)salsalate (Disalcid)
sodium salicylatesodium salicylate
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NSAIDs: Propionic AcidsNSAIDs: Propionic Acids
fenoprofen (Nalfon)fenoprofen (Nalfon) flurbiprofen (Ansaid)flurbiprofen (Ansaid) ibuprofen (Motrin, others)ibuprofen (Motrin, others) ketoprofen (Orudis)ketoprofen (Orudis) ketorolac (Toradol)ketorolac (Toradol) naproxen (Naprosyn)naproxen (Naprosyn) oxaprozin (Daypro)oxaprozin (Daypro)
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NSAIDs: Other AgentsNSAIDs: Other Agents
Enolic acidsEnolic acids phenylbutazone (Butazolidin)phenylbutazone (Butazolidin) piroxicam (Feldene)piroxicam (Feldene)
Fenamic acidsFenamic acids meclofenamic acid (Meclomen)meclofenamic acid (Meclomen) mefenamic acid (Ponstel)mefenamic acid (Ponstel)
Nonacidic compoundsNonacidic compounds nabumetone (Relafen)nabumetone (Relafen)
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NSAIDs: Other AgentsNSAIDs: Other Agents
COX-2 InhibitorsCOX-2 Inhibitors celecoxib (Celebrex)celecoxib (Celebrex) rofecoxib (Vioxx)rofecoxib (Vioxx)
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Acetylsalicylic acidAcetylsalicylic acid
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Aspirin Aspirin СС
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Aspirin Aspirin
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Butadion Butadion
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Indometacin (methyndolIndometacin (methyndol))
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Ibuprofen Ibuprofen ((brufenbrufen))
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Piroxicam Piroxicam
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Sodium diclofenacSodium diclofenac
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Voltaren Voltaren
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NSAIDs: Drug EffectsNSAIDs: Drug Effects
Analgesic (mild to moderate)Analgesic (mild to moderate) AntigoutAntigout AntiinflammatoryAntiinflammatory AntipyreticAntipyretic Relief of vascular headachesRelief of vascular headaches Platelet inhibition (ASA)Platelet inhibition (ASA)
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NSAIDs: Therapeutic NSAIDs: Therapeutic UsesUses
Relief of mild to moderate painRelief of mild to moderate pain Acute goutAcute gout Various bone, joint, and muscle painVarious bone, joint, and muscle pain OsteoarthritisOsteoarthritis Rheumatoid arthritisRheumatoid arthritis Juvenile rheumatoid arthritisJuvenile rheumatoid arthritis DysmenorrheaDysmenorrhea FeverFever
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NSAIDs: Specific AgentsNSAIDs: Specific Agents
salicylates (aspirin)salicylates (aspirin) More potent effect on platelet aggregation More potent effect on platelet aggregation
and thermal regulatory center in the brainand thermal regulatory center in the brain analgesicanalgesic antipyreticantipyretic antiinflammatoryantiinflammatory
Antithrombotic effect: used in the Antithrombotic effect: used in the treatment of MI and other treatment of MI and other thromboembolic disordersthromboembolic disorders
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NSAIDs: Specific AgentsNSAIDs: Specific Agents
phenylbutazone (Butazolidin)phenylbutazone (Butazolidin) Greater effects on uric acid production Greater effects on uric acid production
and excretion, in addition to and excretion, in addition to antiinflammatory effectsantiinflammatory effects
More commonly used for treatment of More commonly used for treatment of goutgout
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NSAIDs: Side EffectsNSAIDs: Side Effects
GastrointestinalGastrointestinal dyspepsia, heartburn, epigastric distress, dyspepsia, heartburn, epigastric distress,
nauseanausea
**GI bleeding**GI bleeding
**mucosal lesions (erosions or **mucosal lesions (erosions or ulcerations)ulcerations)
Misoprostol (Cytotec) can be used to Misoprostol (Cytotec) can be used to reduce these dangerous effects.reduce these dangerous effects.
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NSAIDs: Side EffectsNSAIDs: Side Effects
RenalRenal reductions in creatinine clearancereductions in creatinine clearance acute tubular necrosis with renal failureacute tubular necrosis with renal failure
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NSAIDs: Side EffectsNSAIDs: Side Effects
CardiovascularCardiovascular noncardiogenic pulmonary edemanoncardiogenic pulmonary edema
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NSAIDs: Salicylate NSAIDs: Salicylate ToxicityToxicity
Adults: tinnitus and hearing lossAdults: tinnitus and hearing loss Children: hyperventilation and CNS Children: hyperventilation and CNS
effectseffects Effects arise when serum levels Effects arise when serum levels
exceed 300exceed 300g/mL.g/mL. Metabolic acidosis and respiratory Metabolic acidosis and respiratory
alkalosis may be present.alkalosis may be present.
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NSAIDs: Nursing NSAIDs: Nursing ImplicationsImplications
Before beginning therapy, assess for Before beginning therapy, assess for conditions that may be contraindications conditions that may be contraindications to therapy, especially:to therapy, especially: GI lesions or peptic ulcer diseaseGI lesions or peptic ulcer disease Bleeding disordersBleeding disorders
Assess also for conditions that require Assess also for conditions that require cautious use.cautious use.
Perform lab studies as indicated Perform lab studies as indicated (cardiac, renal, liver studies, CDC, (cardiac, renal, liver studies, CDC, platelet count).platelet count).
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NSAIDs: Nursing NSAIDs: Nursing ImplicationsImplications
Perform a medication history to assess Perform a medication history to assess for potential drug interactions.for potential drug interactions.
Several serious drug interactions exist:Several serious drug interactions exist: alcoholalcohol heparinheparin phenytoinphenytoin oral anticoagulantsoral anticoagulants steroidssteroids sulfonamidessulfonamides
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NSAIDs: Nursing NSAIDs: Nursing ImplicationsImplications
Salicylates are NOT to be given to Salicylates are NOT to be given to children under age 12 because of the children under age 12 because of the risk of Reye’s syndrome.risk of Reye’s syndrome.
Because these agents generally cause GI Because these agents generally cause GI distress, they are often better tolerated distress, they are often better tolerated if taken with food, milk or an antacid to if taken with food, milk or an antacid to avoid GI irritation.avoid GI irritation.
Explain to patients that therapeutic Explain to patients that therapeutic effects may not be seen for 3 to 4 weeks.effects may not be seen for 3 to 4 weeks.
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NSAIDs: Nursing NSAIDs: Nursing ImplicationsImplications
Educate patients about the various side Educate patients about the various side effects of NSAIDs, and to notify their effects of NSAIDs, and to notify their physician if these effects become severe physician if these effects become severe or if bleeding or GI pain occur.or if bleeding or GI pain occur.
Patients should watch closely for the Patients should watch closely for the occurrence of any unusual bleeding, occurrence of any unusual bleeding, such as in the stool.such as in the stool.
Enteric-coated tablets should not be Enteric-coated tablets should not be crushed or chewed.crushed or chewed.
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NSAIDs: Nursing NSAIDs: Nursing ImplicationsImplications
Monitor for therapeutic effects, Monitor for therapeutic effects, which vary according to the which vary according to the condition being treated:condition being treated:
decrease in swelling, pain, stiffness, decrease in swelling, pain, stiffness, and tenderness of a joint or muscle areaand tenderness of a joint or muscle area
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• Reduce inflammation and immune responsesReduce inflammation and immune responses
• In clinical practice since 1948In clinical practice since 1948
• $10,000,000,000./year market size in US$10,000,000,000./year market size in US
GLUCOCORTICOIDSGLUCOCORTICOIDS
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Steroid Hormones: Derived from CholesterolSteroid Hormones: Derived from CholesterolLipid Soluble: Able Lipid Soluble: Able to cross plasma to cross plasma membrane by membrane by passive diffusionpassive diffusion
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PHYSIOLOGICAL EFFECTS OF GLUCOCORTICOIDS
Regulation of carbohydrate, protein and lipid metabolism Maintenance of fluid and electrolyte balancePreservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system and the nervous systemPreservation of organismal homeostasis
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GRGR
GRGR
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CELL TYPE FACTOR COMMENTS
Macrophages Prostaglandins, Inhibition of COX-2,Monocytes Leukotrienes Phospholipase A2
IL-1, IL-6. TNF Inhib. Transcript., Release
Endothelial Cells ICAM-1. ELAM-1 Inhib. Transcript., ReleaseIL-1, Prostagl., Leuko. As above
Basophils Histamine, Leukotriene Inhib. IgE Release
Lymphocytes IL-1, IL-2, IL-3, etc As above
Effects of Glucocorticoids on Components of Inflammatory/Immune Responses
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The anti-inflammatory and immunosuppressive actions of glucocorticoids play an important role in preventing potential damaging effects of an unopposed inflammatory response and can be exploited therapeutically
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Glucocorticoids: Side EffectsGlucocorticoids: Side Effects
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The beneficial effects of systemic glucocorticoids to limit inflammation is counter-balanced by its many adverse side effects
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The broad anti-inflammatory actions of glucocorticoids are due primarily to transcriptional repression of many pro-inflammatory genes in multiple cell types by the glucocorticoid receptor.
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From Glass and RosenfeldFrom Glass and Rosenfeld
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Relative Potencies of GlucocorticoidsRelative Potencies of Glucocorticoids
Compound Anti-Inflammatory Na+ -Retaining Duration
Potency Potency of Action
Cortisol 1 1 S
Cortisone 0.8 0.8 S
Prednisolone 4 0.8 I
Triamcinolone 5 0 I
Betamethasone 25 0 L
Dexamethasone 25 0 L
S, short (i.e., 8–12 hour biological half-life); I, intermediate (i.e., 12–36 hour biological half-life); L, long (i.e., 36–72 hour biological half-life)
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IMPORTANT CONCEPT 7: Structural modifications of the natural glucocorticoid cortisol generate hormones with enhanced half-life and more potent and efficacious glucocorticoid activity
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Antiseptics and Antiseptics and DisinfectantsDisinfectants
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Antiseptics and Antiseptics and DisinfectantsDisinfectants
Most desirable quality is the ability Most desirable quality is the ability to destroy microorganismsto destroy microorganisms
They have 2 uses: disinfect They have 2 uses: disinfect instruments and treat infections in instruments and treat infections in oral cavity and on body surfacesoral cavity and on body surfaces
2 different agents may have to be 2 different agents may have to be used to achieve adequate cleaningused to achieve adequate cleaning
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Actions of Antiseptics and Actions of Antiseptics and DisinfectantsDisinfectants
AgentAgent ActionAction
antisepticantiseptic inhibits growth of inhibits growth of microorganismsmicroorganisms
disinfectantdisinfectant chemical applied to objectschemical applied to objects
fungicidefungicide destroys fungidestroys fungi
germicidegermicide destroys bacteriadestroys bacteria
preservativepreservative prevents decompositionprevents decomposition
sanitizersanitizer reduces the number of reduces the number of bacteriabacteria
sporicide sporicide destroys sporesdestroys spores
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Antiseptics and Antiseptics and DisinfectantsDisinfectants
alcohol, isopropyl alcohol, isopropyl hexachlorophene (pHisoHex)hexachlorophene (pHisoHex) povidone-iodine (Betadine)povidone-iodine (Betadine) sodium hypochlorite (Clorox)sodium hypochlorite (Clorox)
Drug List
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hexachlorophene hexachlorophene (pHisoHex)(pHisoHex)
Surgical scrub and bacteriostatic Surgical scrub and bacteriostatic skin cleanserskin cleanser
Especially effective against gram-Especially effective against gram-positive bacteriapositive bacteria
Do not leave on skin for an extended Do not leave on skin for an extended period of timeperiod of time
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Antiseptics and Antiseptics and DisinfectantsDisinfectantsHeavy Metal Heavy Metal CompoundsCompounds
silver nitrate silver nitrate zinc oxide (Desitin Creamy)zinc oxide (Desitin Creamy)
Drug List
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Antiseptics and Antiseptics and DisinfectantsDisinfectants
OralsOrals benzocaine (Hurricaine, Orabase-B)benzocaine (Hurricaine, Orabase-B) carbamide peroxide (Gly-Oxide carbamide peroxide (Gly-Oxide
Oral)Oral) cevimeline (Evoxac)cevimeline (Evoxac) chlorhexidine gluconate (Hibiclens)chlorhexidine gluconate (Hibiclens) clove oil (Eugenol)clove oil (Eugenol)
Drug List
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Antiseptics and Antiseptics and DisinfectantsDisinfectants
OthersOthers benzalkonium chloride (Zephiran)benzalkonium chloride (Zephiran) hydrogen peroxide hydrogen peroxide phenytoin (Dilantin)phenytoin (Dilantin)
Drug List
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What characteristics make an ideal What characteristics make an ideal antiseptic?antiseptic?
Answer:Answer: can inhibit all forms of can inhibit all forms of microorganisms, nontoxic, does not microorganisms, nontoxic, does not induce sensitization, can penetrate induce sensitization, can penetrate tissues and body fluids, water tissues and body fluids, water soluble, noncorrosive, inexpensivesoluble, noncorrosive, inexpensive