Antiinflammatory and nsai ds

Antiinflammatory Agents Antiinflammatory Agents and Nonsteroidal and Nonsteroidal

Antiinflammatory Drugs Antiinflammatory Drugs (NSAIDs)(NSAIDs)

NSAIDsNSAIDs

• Large and chemically diverse group of drugs Large and chemically diverse group of drugs with the following properties:with the following properties:

– AnalgesicAnalgesic

– AntiinflammatoryAntiinflammatory

– AntipyreticAntipyretic

NSAIDs: Mechanism of ActionNSAIDs: Mechanism of Action

• Activation of the arachidonic acid Activation of the arachidonic acid pathway causes:pathway causes:

• painpain

• headacheheadache

• feverfever

• inflammationinflammation


Analgesia—treatment of headaches and painAnalgesia—treatment of headaches and pain

• Block the undesirable effects of prostaglandins, Block the undesirable effects of prostaglandins, which cause headacheswhich cause headaches


Antipyretic: reduce feverAntipyretic: reduce fever

• Inhibit prostaglandin EInhibit prostaglandin E22 within the area of the brain within the area of the brain that controls temperaturethat controls temperature


Relief of inflammationRelief of inflammation

• Inhibit the leukotriene pathway, the prostaglandin Inhibit the leukotriene pathway, the prostaglandin pathway, or bothpathway, 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 AcidsNSAIDs: Carboxylic Acids

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)

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 UsesNSAIDs: Therapeutic Uses

• 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 and More potent effect on platelet aggregation and thermal regulatory center in the brainthermal regulatory center in the brain

– analgesicanalgesic

– antipyreticantipyretic

– antiinflammatoryantiinflammatory

• Antithrombotic effect: used in the treatment of MI Antithrombotic effect: used in the treatment of MI and other thromboembolic disordersand other thromboembolic disorders

NSAIDs: Specific AgentsNSAIDs: Specific Agents

phenylbutazone (Butazolidin)phenylbutazone (Butazolidin)

• Greater effects on uric acid production and Greater effects on uric acid production and excretion, in addition to antiinflammatory effectsexcretion, in addition to antiinflammatory effects

• More commonly used for treatment of goutMore commonly used for treatment of gout

NSAIDs: Side EffectsNSAIDs: Side Effects

GastrointestinalGastrointestinal

• dyspepsia, heartburn, epigastric distress, nauseadyspepsia, heartburn, epigastric distress, nausea

**GI bleeding**GI bleeding

**mucosal lesions (erosions or ulcerations)**mucosal lesions (erosions or ulcerations)

• Misoprostol (Cytotec) can be used to reduce these Misoprostol (Cytotec) can be used to reduce these dangerous effects.dangerous effects.


RenalRenal

• reductions in creatinine clearancereductions in creatinine clearance

• acute tubular necrosis with renal failureacute tubular necrosis with renal failure


CardiovascularCardiovascular

• noncardiogenic pulmonary edemanoncardiogenic pulmonary edema

NSAIDs: Salicylate ToxicityNSAIDs: Salicylate Toxicity

• Adults: tinnitus and hearing lossAdults: tinnitus and hearing loss

• Children: hyperventilation and CNS effectsChildren: hyperventilation and CNS effects

• Effects arise when serum levels exceed Effects arise when serum levels exceed 300300g/mL.g/mL.

• Metabolic acidosis and respiratory alkalosis Metabolic acidosis and respiratory alkalosis may be present.may be present.

NSAIDs: Nursing ImplicationsNSAIDs: Nursing Implications

• Before beginning therapy, assess for Before beginning therapy, assess for conditions that may be contraindications to conditions that may be contraindications to therapy, especially: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 (cardiac, Perform lab studies as indicated (cardiac, renal, liver studies, CDC, platelet count).renal, liver studies, CDC, platelet count).


• Perform a medication history to assess for Perform a medication history to assess for potential drug interactions.potential drug interactions.

• Several serious drug interactions exist:Several serious drug interactions exist:

– alcoholalcohol

– heparinheparin

– phenytoinphenytoin

– oral anticoagulantsoral anticoagulants

– steroidssteroids

– sulfonamidessulfonamides


• Salicylates are NOT to be given to children Salicylates are NOT to be given to children under age 12 because of the risk of Reye’s under age 12 because of the risk of Reye’s syndrome.syndrome.

• Because these agents generally cause GI Because these agents generally cause GI distress, they are often better tolerated if distress, they are often better tolerated if taken with food, milk or an antacid to avoid taken with food, milk or an antacid to avoid GI irritation.GI irritation.

• Explain to patients that therapeutic effects Explain to patients that therapeutic effects may not be seen for 3 to 4 weeks.may not be seen for 3 to 4 weeks.


• 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.


• Monitor for therapeutic effects, which vary Monitor for therapeutic effects, which vary according to the condition being treated:according to the 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

Nonsteroidal Anti-inflammatory Nonsteroidal Anti-inflammatory Drugs (NSAIDs)Drugs (NSAIDs)

• Common therapeutic indicationsCommon therapeutic indications

• Common adverse effectsCommon adverse effects

• Different pharmacokinetics and potencyDifferent pharmacokinetics and potency

• Different chemical familiesDifferent chemical families

• Common mechanism of action Common mechanism of action (cyclooxygenase inhibition)(cyclooxygenase inhibition)

• Different selectivities to COX I and IIDifferent selectivities to COX I and II

Similarities more striking than DifferencesSimilarities more striking than Differences

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Common Pharmacological EffectsCommon Pharmacological Effects

• AnalgesicAnalgesic (CNS and peripheral effect) may (CNS and peripheral effect) may involve non-PG related effectsinvolve non-PG related effects

• AntipyreticAntipyretic (CNS effect) (CNS effect)

• Anti-inflammatoryAnti-inflammatory (except acetaminophen) (except acetaminophen) due mainly to PG inhibition. due mainly to PG inhibition.

Some shown to inhibit activation, Some shown to inhibit activation, aggregationaggregation, , adhesion of neutrophils & release of lysosomal adhesion of neutrophils & release of lysosomal enzymesenzymes

• Some are Some are UricosuricUricosuric


Common Adverse EffectsCommon Adverse Effects

• Platelet Dysfunction Platelet Dysfunction

• Gastritis and peptic ulceration with bleeding Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects)(inhibition of PG + other effects)

• Acute Renal Failure in susceptible Acute Renal Failure in susceptible

• Sodium+ water retention and edemaSodium+ water retention and edema

• Analgesic nephropathyAnalgesic nephropathy

• Prolongation of gestation and inhibition of labor.Prolongation of gestation and inhibition of labor.

• Hypersenstivity (not immunologic but due to PG Hypersenstivity (not immunologic but due to PG inhibition)inhibition)


NSAID

↑ Leukocyte-EndothelialInteractions

Capillary Obstruction

IschemicCell Injury

Proteases +Oxygen Radicals

Endo/EpithelialCell Injury

Mucosal Ulceration

Loss o

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E 2 an

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I 2 m

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Loss of PGI2 induced inhibition of LTB4 mediated endothelial adhesion and activation of neutrophils


The Salicylates - AspirinThe Salicylates - Aspirin

• Effect on Respiration: triphasicEffect on Respiration: triphasic

1.1. Low doses: uncoupling phosphorylation → ↑ Low doses: uncoupling phosphorylation → ↑ COCO2 2 → stimulates respiration. → stimulates respiration.

2.2. Direct stimulation of respiratory center → Direct stimulation of respiratory center → Hyperventilation → resp. alkalosis → renal Hyperventilation → resp. alkalosis → renal compensationcompensation

3.3. Depression of respiratory center and Depression of respiratory center and cardiovascular center → ↓ BP, respiratory cardiovascular center → ↓ BP, respiratory acidosis, no compensation + metabolic acidosis, no compensation + metabolic acidosis alsoacidosis also


• GI systemGI system

1.1. Dose dependent hepatitisDose dependent hepatitis

2.2. Reye’s syndromeReye’s syndrome

• MetabolicMetabolic

1.1. Uncoupling of Oxid. PhosphorylationUncoupling of Oxid. Phosphorylation

2.2. Hyperglycemia and depletion of muscle and Hyperglycemia and depletion of muscle and hepatic glycogenhepatic glycogen

• Endocrine: Endocrine: corticosteroids, thyroidcorticosteroids, thyroid

AspirinAspirin


• Antipyretic, analgesicAntipyretic, analgesic

• Anti-inflammatory: rheumatic fever, Anti-inflammatory: rheumatic fever, rheumatoid arthritis, other rheumatological rheumatoid arthritis, other rheumatological diseases. High dose needed (5-8 g/day)diseases. High dose needed (5-8 g/day)

• Prophylaxis of diseases due to platelet Prophylaxis of diseases due to platelet aggregation (CAD, post-op DVT)aggregation (CAD, post-op DVT)

• Pre-eclampsia and hypertension of Pre-eclampsia and hypertension of pregnancy (?excess TXApregnancy (?excess TXA22))

Aspirin - Therapeutic UsesAspirin - Therapeutic Uses


Generation of Lipoxins by Aspirin


Role of Lipoxins in Anti-inflammatory effects of Aspirin


Effect of NSAID’s on Platelet-Endothelial Interactions


http://jpet.aspetjournals.org/content/vol300/issue2/images/large/pt0222074003.jpeg

Use of Aspirin in Unstable Angina


Use of Aspirin in Unstable Angina


• Headache - timmitus - dizziness – hearing impairment – Headache - timmitus - dizziness – hearing impairment – dim visiondim vision

• Confusion and drowzinessConfusion and drowziness

• Sweating and hyperventilationSweating and hyperventilation

• Nausea, vomitingNausea, vomiting

• Marked acid-base disturbancesMarked acid-base disturbances

• HyperpyrexiaHyperpyrexia

• DehydrationDehydration

• Cardiovascular and respiratory collapse, coma Cardiovascular and respiratory collapse, coma convulsions and deathconvulsions and death

Aspirin Toxicity - SalicylismAspirin Toxicity - Salicylism


• Decrease absorptionDecrease absorption - activated charcoal, - activated charcoal, emetics, gastric lavageemetics, gastric lavage

• Enhance excretionEnhance excretion - alkalinize urine, - alkalinize urine, forced diuresis, hemodialysisforced diuresis, hemodialysis

• Supportive measures Supportive measures - fluids, decrease - fluids, decrease temperature, bicarbonate, electrolytes, temperature, bicarbonate, electrolytes, glucose, etc…glucose, etc…

Aspirin Toxicity - TreatmentAspirin Toxicity - Treatment


Other NSAID’sOther NSAID’s

• Phenylbutazone: additional uricosuric effect. Phenylbutazone: additional uricosuric effect. Aplastic anemia.Aplastic anemia.

• Indomethacin: Common ADR’s. CNS most Indomethacin: Common ADR’s. CNS most common: halucinations, depression, seizurescommon: halucinations, depression, seizures

• Propionic acids: better tolerated. Differ in Propionic acids: better tolerated. Differ in pharmacokineticspharmacokinetics

• Acetaminophen: differes in effects and ADR’s from Acetaminophen: differes in effects and ADR’s from rest. Main toxicity: hepatitis due to toxic rest. Main toxicity: hepatitis due to toxic intermediate which depletes glutathione. Treat intermediate which depletes glutathione. Treat with N-acetylcysteine.with N-acetylcysteine.



Attempts to Decrease Toxicity of NSAID’s – Nitroaspirins



Selective COX-II InhibitorsSelective COX-II Inhibitors

• Anti-inflammatory with less adverse Anti-inflammatory with less adverse effects, especially GI events.effects, especially GI events.

• Potential toxicities: kidney and Potential toxicities: kidney and platelets - ? increased risk of platelets - ? increased risk of thrombotic events thrombotic events

• Role in Cancer preventionRole in Cancer prevention

• Role in Alzheimer’s diseaseRole in Alzheimer’s disease


Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved.

VIGOR - Summary of GI EndpointsVIGOR - Summary of GI Endpoints

†p < 0.001. * p = 0.005.

0

1

2

3

4

5

Confirmed Clinical Upper GI Events

ConfirmedComplicated

Upper GI Events

All ClinicalGI Bleeding

RR: 0.46†

(0.33, 0.64)

RR: 0.43*(0.24, 0.78)

RR: 0.38†

(0.25, 0.57)

Ra

tes

per

100

Pat

ien

t-Y

ear

s

RofecoxibNaproxen

( ) = 95% CI.

Source: Bombardier, et al. N Engl J Med. 2000.


Patients with Events (Rates per 100 Patient-Years)

Event CategoryRofecoxibN=4047

NaproxenN=4029

Relative Risk(95% CI)

Confirmed CV events

45 (1.7) 19 (0.7) 0.42(0.25, 0.72)

Cardiac events

28 (1.0) 10 (0.4) 0.36(0.17, 0.74)

Cerebrovascular events

11 (0.4) 8 (0.3) 0.73(0.29, 1.80)

Peripheral vascular events

6 (0.2) 1 (0.04) 0.17(0.00, 1.37)

VIGOR - Confirmed Thrombotic VIGOR - Confirmed Thrombotic Cardiovascular EventsCardiovascular Events

Source: Data on file, MSDwww.freelivedoctor.com

Effect of Celecoxib & Rofecoxib Effect of Celecoxib & Rofecoxib on PGIM on PGIM

* p<0.05 vs. placebo.

0

40

80

120

160

200

PlaceboN=7

Celecoxib 400 mg

N=7

Ibuprofen 800 mg

N=7

Urin

ary

PG

I-M

(pg

/mg

crea

tinin

e)

(Mea

n ±

SE

)

***

PlaceboN=12

Rofecoxib50 mg QD

N=12

Indomethacin50 mg TID

N=10

****

Single Dose Rx† Two Weeks Rx††

0

40

80

120

160

200

† Proc. Natl. Acad Sci. USA 1999;96:272-277.

Urinary 2,3 dinor-6-keto-PGF1(PGIM)

†† J. Pharmacol. Exp. Ther. 1999;289:735-741.**p<0.01 vs. placebo.


0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Months of Follow-up0 2 4 6 8 10 12 14

Cu

mu

lativ

e In

cid

en

ce %

Rofecoxib (OA)

Investigator-Reported Thrombotic Investigator-Reported Thrombotic Cardiovascular Events in the VIGOR Study Cardiovascular Events in the VIGOR Study Compared with Phase IIb/III OA StudyCompared with Phase IIb/III OA Study

Rofecoxib (VIGOR)

Naproxen (VIGOR)

FDA files

Ibuprofen, Diclofenac, Nabumetone (OA)


Treatment of Gout


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Antiinflammatory and nsai ds