Nonsteroidal AntiinflammatorNonsteroidal Antiinflammatory Drugs (NSAIDs)y Drugs (NSAIDs)

Medical Author: Omudhome Ogbru, Pharm.D.Medical Author: Omudhome Ogbru, Pharm.D.Medical Editor: Jay Marks, M.D.Medical Editor: Jay Marks, M.D.

What are NSAIDs and how do they What are NSAIDs and how do they work?work?

Drug with analgesic( without impairing Drug with analgesic( without impairing consciousness ), antipyretic, and anti-i consciousness ), antipyretic, and anti-inflamammatory effectsnflamammatory effects

weak acids, PH 3-5, well absorbed froweak acids, PH 3-5, well absorbed from stomach and intestinal mucosam stomach and intestinal mucosa

protein-bound in plasma ( albumin),protein-bound in plasma ( albumin), metabolised in the livermetabolised in the liver

ProstaglandinsProstaglandins

Prostaglandins : produced by the cells, Prostaglandins : produced by the cells, promote inflammation, pain, and fever; blood promote inflammation, pain, and fever; blood clotting function of platelets; protect the lining clotting function of platelets; protect the lining of the stomach from damaging effects of acid.of the stomach from damaging effects of acid.

two COX enzymes, COX-1 and COX-2. two COX enzymes, COX-1 and COX-2. produce prostaglandins that promote produce prostaglandins that promote inflammation, pain, and fever inflammation, pain, and fever

What are NSAIDs and how do they What are NSAIDs and how do they work work ??

NSAIDs block the COX enzymes , reduce prostaglanNSAIDs block the COX enzymes , reduce prostaglandins, inflammation, pain, and fever are reduced. dins, inflammation, pain, and fever are reduced.

COX-1 produced prostaglandins that support platelets COX-1 produced prostaglandins that support platelets and protect the stomach.and protect the stomach.

Reduced prostaglandins that protect the stomach and Reduced prostaglandins that protect the stomach and support blood clotting, so NSAIDs can cause ulcers isupport blood clotting, so NSAIDs can cause ulcers in the stomach and promote bleeding. n the stomach and promote bleeding.

For what conditions are NSAIDs useFor what conditions are NSAIDs used?d?

RARA OAOA Infalmmatory arthritis, Infalmmatory arthritis,

AS, psoriatic arthritis, RAS, psoriatic arthritis, Reter’s syndromeeter’s syndrome

Acute goutAcute gout Metastatic bone painMetastatic bone pain

DysmenohhoeaDysmenohhoea Headache, migrainHeadache, migrain Postoperative painPostoperative pain Pyrexia ( fever)Pyrexia ( fever) IleusIleus Renal colicRenal colic

For what conditions are NSAIDs For what conditions are NSAIDs used?used?

AspirinAspirin (also an NSAID) : inhibit the clotting (also an NSAID) : inhibit the clotting of blood( platelet aggregation ) ,prevent of blood( platelet aggregation ) ,prevent strokes and cardiovascular attacksstrokes and cardiovascular attacks

Differences between NSAIDsDifferences between NSAIDs

vary in potency, duration , eliminated from vary in potency, duration , eliminated from body, how strongly they inhibit COX-1body, how strongly they inhibit COX-1

(tendency to cause ulcers and promote (tendency to cause ulcers and promote bleeding )bleeding )

The more an NSAID blocks COX-1, the The more an NSAID blocks COX-1, the greater to cause ulcers and promote bleeding. greater to cause ulcers and promote bleeding.

Differences between NSAIDsDifferences between NSAIDs

Celecoxib (Celebrex),Celecoxib (Celebrex), blocks COX-2 but little blocks COX-2 but little on COX-1, classified as a selective COX-2 inhon COX-1, classified as a selective COX-2 inhibitor ,ibitor ,cause less bleeding and fewer ulcerscause less bleeding and fewer ulcers..

AspirinAspirin is a unique NSAID, the only NSAID is a unique NSAID, the only NSAID inhibits clotting of blood for a prolonged perioinhibits clotting of blood for a prolonged period (4 to 7 days), ideal for preventing blood clots d (4 to 7 days), ideal for preventing blood clots that cause heart attacks and strokes that cause heart attacks and strokes

Differences between NSAIDsDifferences between NSAIDs Most NSAIDs inhibit the clotting of blood for only a few Most NSAIDs inhibit the clotting of blood for only a few

hours hours Ketorolac (Keto)Ketorolac (Keto) is a very is a very potentpotent NSAID and is used for NSAID and is used for

moderately severe acute pain that usually requires narcoticmoderately severe acute pain that usually requires narcotics s

Ketorolac (Keto)Ketorolac (Keto) causes ulcers more frequently than othe causes ulcers more frequently than other NSAID. Therefore, r NSAID. Therefore, it is not used for more than five daysit is not used for more than five days. .

Individuals who do not respond to one NSAID may respIndividuals who do not respond to one NSAID may respond to another. ond to another.

Side effects of NSAIDsSide effects of NSAIDs

CardiovascularCardiovascular 80% increase in AMI risk with newer COX-280% increase in AMI risk with newer COX-2

and high dose traditional NSAIDand high dose traditional NSAID Heart failure risk Heart failure risk

( with CHF history x10, without x2)( with CHF history x10, without x2)

Side effects of NSAIDsSide effects of NSAIDs

GastrointestinalGastrointestinal Direct irritation : acidic molecules Direct irritation : acidic molecules Indirect irritation: inhibit COX-1, reduce Indirect irritation: inhibit COX-1, reduce

protective prostaglandinsprotective prostaglandins S/S: nausea, vomiting, dyspepsia, gastric S/S: nausea, vomiting, dyspepsia, gastric

ulcer/bleeding, diarrheaulcer/bleeding, diarrhea Duration of therapy, doseDuration of therapy, dose

Table: 各種 NSAIDs對胃腸的影響

Drug*Drug* High RiskHigh Risk Moderate RiskModerate Risk Low RiskLow Risk

Aspirin (Bokey, Tapal)Aspirin (Bokey, Tapal)     XX    

Celecoxib (Celecoxib (CelebrexCelebrex) )         XX

Diclofenac (Cataflam, Eunac) Diclofenac (Cataflam, Eunac)     XX    

Etodolac Etodolac         XX

Flurbiprofen Flurbiprofen XX        

Ibuprofen Ibuprofen     XX XX

Indomethacin Indomethacin XX XX    

Ketoprofen Ketoprofen     XX    

Ketorolac (Keto) Ketorolac (Keto) XX        

Meloxicam Meloxicam ****         XX

Nabumetone Nabumetone         XX

Naproxen (Anaprox) Naproxen (Anaprox)     XX    

Piroxicam Piroxicam XX        

Sulindac (Weisu) Sulindac (Weisu)         XX

** Meloxicam risk increases with doses >7.5 mg.

Side effects of NSAIDsSide effects of NSAIDs

RenalRenal Decrease prostaglandinsDecrease prostaglandins→→ constriction of affe constriction of affe

rent arteriole rent arteriole →→ decreased renal perfusion decreased renal perfusion

→→alter renal functionalter renal function S/S: salt and fluid retension, hypertensionS/S: salt and fluid retension, hypertension Caution: NSAID with ACE inhibitor, diureticCaution: NSAID with ACE inhibitor, diuretic Rare: ARF, ATN, nephrotic syn.Rare: ARF, ATN, nephrotic syn.

Side effects of NSAIDsSide effects of NSAIDs

OthersOthers Allergy: shortness of breath Allergy: shortness of breath Asthma : a higher risk for serious allergic Asthma : a higher risk for serious allergic

reactionreaction with a serious allergy to one NSAID are likely with a serious allergy to one NSAID are likely

to have similar reaction to a different NSAID to have similar reaction to a different NSAID photosensitivityphotosensitivity

Combinational RiskCombinational Risk

If COX-2 inhibitor taken, should not use a tradIf COX-2 inhibitor taken, should not use a traditional NSAID concomitantlyitional NSAID concomitantly

With daily aspirin therapy, should use other NWith daily aspirin therapy, should use other NSAID carefully, they may block the cardioprotSAID carefully, they may block the cardioprotective effect of aspirinective effect of aspirin

During pregnancyDuring pregnancy

Not recommended during pregnancy, particulaNot recommended during pregnancy, particular 3rd trimesterr 3rd trimester

Cause early closure of fetal ductus arteriosus, Cause early closure of fetal ductus arteriosus,

and fetal renal toxicity, premature birthand fetal renal toxicity, premature birth Acetaminophen ia more safe during pregnancyAcetaminophen ia more safe during pregnancy In France, NSAID and aspirin is contra-indicatIn France, NSAID and aspirin is contra-indicat

ed after 6 months of pregnancyed after 6 months of pregnancy

Classification of NSAIDClassification of NSAID

Acetic acid derivativesAcetic acid derivatives

Arthrotec (diclofenac/misoprostol)Arthrotec (diclofenac/misoprostol) Diclofenac (Voltaren® Diclofenac (Voltaren® Meitifen,FormaxMeitifen,Formax ®) ®) Ketorolac (Toradol Ketorolac (Toradol Keto, Painoff,Keto Inj,Keto, Painoff,Keto Inj,

KopKop Inj Inj )) Tolmetin (Tolectin ®)Tolmetin (Tolectin ®) Etodolac (Lodine ® Etodolac (Lodine ® LonineLonine ) ) Indomethacin (Indocin® Indomethacin (Indocin® AcemetAcemet ) ) Sulindac (Clinoril Sulindac (Clinoril Unidac Unidac ®)®)

Carboxylic acid derivatives Carboxylic acid derivatives

Diflunisal (Dolobid ®)Diflunisal (Dolobid ®) Salsalate (Disalcid ®)Salsalate (Disalcid ®)

Enolic acid (oxicam) derivatives Enolic acid (oxicam) derivatives

Meloxicam ( Mobic ® Meloxicam ( Mobic ® Subic Subic )) Piroxicam (Feldene Piroxicam (Feldene Tonmax inj, FoglugenTonmax inj, Foglugen)) Tenoxicam ( Tenoxicam ( Tencam, SutondinTencam, Sutondin ) )

Napthylkanone derivatives Napthylkanone derivatives

Nabumetone (Relafen ® Nabumetone (Relafen ® Relifex, No-tonRelifex, No-ton ) )

Proprionic acid derivatives Proprionic acid derivatives

Flurbiprofen (Ansaid ® Flurbiprofen (Ansaid ® Flufen,Lefenine, FlFlufen,Lefenine, Flur Di Fenur Di Fen ) )

Ketoprofen (Orudis ®)Ketoprofen (Orudis ®) Ketoprofen injKetoprofen inj Oxaprozin (Daypro ® )Oxaprozin (Daypro ® ) Ibuprofen (Motrin ® Ibuprofen (Motrin ® Purfen ,Mac Safe syr, Purfen ,Mac Safe syr,

Arfen injArfen inj ) ) Naproxen (Naprosyn ® Naproxen (Naprosyn ® NaptonNapton))

COX-2 inhibitors COX-2 inhibitors

Celecoxib (Celebrex ® )Celecoxib (Celebrex ® ) Rofecoxib (Vioxx ® )Rofecoxib (Vioxx ® ) Valdecoxib (Bextra ® )Valdecoxib (Bextra ® )

Dosage of NSAIDDosage of NSAID

Diclofenac (Voltaren ® Cataflam Diclofenac (Voltaren ® Cataflam ®)®)

Meitifen 75mg, Formax 75mgMeitifen 75mg, Formax 75mg Rheumatoid arthritisRheumatoid arthritis: 150-200 mg/da: 150-200 mg/da

y orally in 2-4 divided doses y orally in 2-4 divided doses OsteoarthritisOsteoarthritis: 100-150 mg/day orally : 100-150 mg/day orally in 2-3 divided doses. in 2-3 divided doses.

Maximum Daily DoseMaximum Daily Dose:  225 mg;  XR: :  225 mg;  XR: 200 mg 200 mg

Etodolac  (Lodine ® )Etodolac  (Lodine ® )

Lonine 200mgLonine 200mg Acute pain: 200-400 mg every 6-8 hourAcute pain: 200-400 mg every 6-8 hour

s, s, Rheumatoid arthritis, osteoarthritis: InitRheumatoid arthritis, osteoarthritis: Init

ial: 600-1200 mg/day given in divided ial: 600-1200 mg/day given in divided doses: doses:

Maximum Daily Dose::  1200 mg Maximum Daily Dose::  1200 mg

Ketorolac  (Toradol ® ) Ketorolac  (Toradol ® )

Keto Inj 30mg, Kop Inj 30mg, Keto, Painoff 10mgKeto Inj 30mg, Kop Inj 30mg, Keto, Painoff 10mg IMIM: 60 mg x 1 or 30 mg q6h (maximum daily dose: 12: 60 mg x 1 or 30 mg q6h (maximum daily dose: 12

0 mg). 0 mg).   IVIV: 30 mg x 1 or 30 mg q6h (maximum daily dose: 12: 30 mg x 1 or 30 mg q6h (maximum daily dose: 12

0 mg). 0 mg). OralOral: 20 mg, followed by 10 mg every 4 to 6 hours (M: 20 mg, followed by 10 mg every 4 to 6 hours (M

ax 40 mg/day)ax 40 mg/day) NoteNote: The maximum duration of treatment (for parente: The maximum duration of treatment (for parente

ral and oral) is 5 days. ral and oral) is 5 days.

Sulindac  (Clinoril ®)  Sulindac  (Clinoril ®) 

Unidac 200mgUnidac 200mg Adults: 150-200 mg twice daily or 300-Adults: 150-200 mg twice daily or 300-

400 mg once daily; not to exceed 400 400 mg once daily; not to exceed 400 mg/day.mg/day.

Should be administered with food or mShould be administered with food or milk. ilk.

Maximum Daily Dose :  400 mg Maximum Daily Dose :  400 mg

Meloxicam  (Mobic ® ) Meloxicam  (Mobic ® )

Subic 7.5mgSubic 7.5mg Oral: Initial: 7.5 mg once daily; may Oral: Initial: 7.5 mg once daily; may

increased dose of 15 mg once dailyincreased dose of 15 mg once daily maximum dose: 15 mg/day maximum dose: 15 mg/day

Piroxicam (Feldene ®)  Piroxicam (Feldene ®) 

Tonmax Inj 20mg, Foglugen 20mgTonmax Inj 20mg, Foglugen 20mg Adults: 10-20 mg/day once dailyAdults: 10-20 mg/day once daily doses >20 mg/day have been used (ie, 30-40 mg/day) doses >20 mg/day have been used (ie, 30-40 mg/day) May be taken with food to decrease GI adverse effect.May be taken with food to decrease GI adverse effect. Maximum Daily Dose :  20 mg Maximum Daily Dose :  20 mg Dosing adjustment in Dosing adjustment in hepatichepatic impairment impairment

Nabumetone  (Relafen ® ) Nabumetone  (Relafen ® )

No-ton 500mg ,Relifex No-ton 500mg ,Relifex 1000 mg orally with or without food1000 mg orally with or without food may obtain more symptomatic relief frmay obtain more symptomatic relief fr

om 1500 mg to 2000 mg per day (in twom 1500 mg to 2000 mg per day (in two divided doses) o divided doses)

Maximum Daily Dose:  2000 mg Maximum Daily Dose:  2000 mg

Flurbiprofen  (Ansaid ® ) Flurbiprofen  (Ansaid ® )

Flufen50 mg,Lefenine100mg, Flur Di Fen PatcFlufen50 mg,Lefenine100mg, Flur Di Fen Patch 12mgh 12mg

Inflammatory disease: 50-100 mg/dose 3-4 timInflammatory disease: 50-100 mg/dose 3-4 times/day (maximum dose: 400 mg/day )es/day (maximum dose: 400 mg/day )

Tenoxicam Tenoxicam

Tencam 20mg, Sutondin 20mg, Tencam inj 20Tencam 20mg, Sutondin 20mg, Tencam inj 20mgmg

Adults: 20-40 mg/day ,1-2 times dailyAdults: 20-40 mg/day ,1-2 times daily Acute gout: 40mg x 2days, then 20mg qdAcute gout: 40mg x 2days, then 20mg qd

Ibuprofen  (Motrin ® ) Ibuprofen  (Motrin ® )

Purfen 400mg ,Mac Safe syr, Arfen injPurfen 400mg ,Mac Safe syr, Arfen inj 400mg400mg

Inflammatory disease: 400-800 mg/dose 3-4 times/day Inflammatory disease: 400-800 mg/dose 3-4 times/day Analgesia/pain/fever/dysmenorrhea: 200-400 mg/dose every Analgesia/pain/fever/dysmenorrhea: 200-400 mg/dose every

4-6 hours (maximum daily dose: 1.2 g )4-6 hours (maximum daily dose: 1.2 g ) maximum dose: 3200 mg/day maximum dose: 3200 mg/day in severe hepatic impairment: avoid use in severe hepatic impairment: avoid use

Naproxen  (Naprosyn ®) Naproxen  (Naprosyn ®)

Napton 750mgNapton 750mg

• Rheumatoid arthritis, osteoarthritis, and ankyloRheumatoid arthritis, osteoarthritis, and ankylosing spondylitis: 250-500 mg orally twice dailsing spondylitis: 250-500 mg orally twice daily y

• May increase to 1.5 g/day May increase to 1.5 g/day

TTestest Time Time

Q 1Q 1: which of the following NSAID in our hos: which of the following NSAID in our hospital is the most COX 2 selective?pital is the most COX 2 selective?

(1) no-ton (2) unidac (3) subic (4) lonine(1) no-ton (2) unidac (3) subic (4) lonine Q 2: Q 2: which of the following NSAID should nowhich of the following NSAID should no

t been used more than 5 days?t been used more than 5 days?

(1) lefenine ( 2) ketoprofen ( 3) sutondin(1) lefenine ( 2) ketoprofen ( 3) sutondin

(4) painoff(4) painoff