Antiinflammatory Agents and Nonsteroidal Antiinflammatory Drugs (NSAIDs)

AntiinflammatAntiinflammatory Agents ory Agents

and and Nonsteroidal Nonsteroidal

AntiinflammatAntiinflammatory Drugs ory Drugs (NSAIDs)(NSAIDs)

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)

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

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

Arachidonic Acid Arachidonic Acid PathwayPathway

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

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

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

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

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)

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

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)

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)

NSAIDs: Other AgentsNSAIDs: Other Agents

COX-2 InhibitorsCOX-2 Inhibitors celecoxib (Celebrex)celecoxib (Celebrex) rofecoxib (Vioxx)rofecoxib (Vioxx)

Acetylsalicylic acidAcetylsalicylic acid

Aspirin Aspirin СС

Aspirin Aspirin

Butadion Butadion

Indometacin (methyndolIndometacin (methyndol))

Ibuprofen Ibuprofen ((brufenbrufen))

Piroxicam Piroxicam

Sodium diclofenacSodium diclofenac

Voltaren Voltaren

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)

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

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

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

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.

NSAIDs: Side EffectsNSAIDs: Side Effects

RenalRenal reductions in creatinine clearancereductions in creatinine clearance acute tubular necrosis with renal failureacute tubular necrosis with renal failure

NSAIDs: Side EffectsNSAIDs: Side Effects

CardiovascularCardiovascular noncardiogenic pulmonary edemanoncardiogenic pulmonary edema

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.

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).

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

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.

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.

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

• 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

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

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

GRGR

GRGR

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

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

Glucocorticoids: Side EffectsGlucocorticoids: Side Effects

The beneficial effects of systemic glucocorticoids to limit inflammation is counter-balanced by its many adverse side effects

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.

From Glass and RosenfeldFrom Glass and Rosenfeld

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)

IMPORTANT CONCEPT 7: Structural modifications of the natural glucocorticoid cortisol generate hormones with enhanced half-life and more potent and efficacious glucocorticoid activity

Antiseptics and Antiseptics and DisinfectantsDisinfectants

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

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

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

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

Antiseptics and Antiseptics and DisinfectantsDisinfectantsHeavy Metal Heavy Metal CompoundsCompounds

silver nitrate silver nitrate zinc oxide (Desitin Creamy)zinc oxide (Desitin Creamy)

Drug List

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

Antiseptics and Antiseptics and DisinfectantsDisinfectants

OthersOthers benzalkonium chloride (Zephiran)benzalkonium chloride (Zephiran) hydrogen peroxide hydrogen peroxide phenytoin (Dilantin)phenytoin (Dilantin)

Drug List

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