Nonsteroidal Antiinflammatory Drugs (NSAIDs) Medical Author: Omudhome Ogbru, Pharm.D. Medical Editor: Jay Marks, M.D.

What are NSAIDs and how do they work? Drug with analgesic( without impairing consciousness ), antipyretic, and anti-inflamammatory effects weak acids, PH 3-5, well absorbed from stomach and intestinal mucosa protein-bound in plasma ( albumin), metabolised in the liver

Prostaglandins Prostaglandins : produced by the cells, promote inflammation, pain, and fever; blood clotting function of platelets; protect the lining of the stomach from damaging effects of acid. two COX enzymes, COX-1 and COX-2. produce prostaglandins that promote inflammation, pain, and fever

What are NSAIDs and how do they work ? NSAIDs block the COX enzymes , reduce prostaglandins, inflammation, pain, and fever are reduced. COX-1 produced prostaglandins that support platelets and protect the stomach. Reduced prostaglandins that protect the stomach and support blood clotting, so NSAIDs can cause ulcers in the stomach and promote bleeding.

For what conditions are NSAIDs used? RA OA Infalmmatory arthritis, AS, psoriatic arthritis, Reter’s syndrome Acute gout Metastatic bone pain Dysmenohhoea Headache, migrain Postoperative pain Pyrexia ( fever) Ileus Renal colic

For what conditions are NSAIDs used? Aspirin (also an NSAID) : inhibit the clotting of blood( platelet aggregation ) ,prevent strokes and cardiovascular attacks

Differences between NSAIDs vary in potency, duration , eliminated from body, how strongly they inhibit COX-1 (tendency to cause ulcers and promote bleeding ) The more an NSAID blocks COX-1, the greater to cause ulcers and promote bleeding.

Differences between NSAIDs Celecoxib (Celebrex), blocks COX-2 but little on COX-1, classified as a selective COX-2 inhibitor ,cause less bleeding and fewer ulcers. Aspirin is a unique NSAID, the only NSAID inhibits clotting of blood for a prolonged period (4 to 7 days), ideal for preventing blood clots that cause heart attacks and strokes

Differences between NSAIDs Most NSAIDs inhibit the clotting of blood for only a few hours Ketorolac (Keto) is a very potent NSAID and is used for moderately severe acute pain that usually requires narcotics Ketorolac (Keto) causes ulcers more frequently than other NSAID. Therefore, it is not used for more than five days. Individuals who do not respond to one NSAID may respond to another.

Side effects of NSAIDs Cardiovascular 80% increase in AMI risk with newer COX-2 and high dose traditional NSAID Heart failure risk ( with CHF history x10, without x2)

Side effects of NSAIDs Gastrointestinal Direct irritation : acidic molecules Indirect irritation: inhibit COX-1, reduce protective prostaglandins S/S: nausea, vomiting, dyspepsia, gastric ulcer/bleeding, diarrhea Duration of therapy, dose

Table: 各種NSAIDs對胃腸的影響 Drug* High Risk Moderate Risk Low Risk Aspirin (Bokey, Tapal)   X Celecoxib (Celebrex) Diclofenac (Cataflam, Eunac) Etodolac Flurbiprofen Ibuprofen Indomethacin Ketoprofen Ketorolac (Keto) Meloxicam ** Nabumetone Naproxen (Anaprox) Piroxicam Sulindac (Weisu) ** Meloxicam risk increases with doses >7.5 mg.

Side effects of NSAIDs Renal Decrease prostaglandins→ constriction of afferent arteriole → decreased renal perfusion →alter renal function S/S: salt and fluid retension, hypertension Caution: NSAID with ACE inhibitor, diuretic Rare: ARF, ATN, nephrotic syn.

Side effects of NSAIDs Others Allergy: shortness of breath Asthma : a higher risk for serious allergic reaction with a serious allergy to one NSAID are likely to have similar reaction to a different NSAID photosensitivity

Combinational Risk If COX-2 inhibitor taken, should not use a traditional NSAID concomitantly With daily aspirin therapy, should use other NSAID carefully, they may block the cardioprotective effect of aspirin

During pregnancy Not recommended during pregnancy, particular 3rd trimester Cause early closure of fetal ductus arteriosus, and fetal renal toxicity, premature birth Acetaminophen ia more safe during pregnancy In France, NSAID and aspirin is contra-indicated after 6 months of pregnancy

Classification of NSAID

Acetic acid derivatives Arthrotec (diclofenac/misoprostol) Diclofenac (Voltaren® Meitifen,Formax ®) Ketorolac (Toradol Keto, Painoff,Keto Inj, Kop Inj ) Tolmetin (Tolectin ®) Etodolac (Lodine ® Lonine ) Indomethacin (Indocin® Acemet ) Sulindac (Clinoril Unidac ®)

Carboxylic acid derivatives Diflunisal (Dolobid ®) Salsalate (Disalcid ®)

Enolic acid (oxicam) derivatives Meloxicam ( Mobic ® Subic ) Piroxicam (Feldene Tonmax inj, Foglugen) Tenoxicam ( Tencam, Sutondin )

Napthylkanone derivatives Nabumetone (Relafen ® Relifex, No-ton )

Proprionic acid derivatives Flurbiprofen (Ansaid ® Flufen,Lefenine, Flur Di Fen ) Ketoprofen (Orudis ®) Ketoprofen inj Oxaprozin (Daypro ® ) Ibuprofen (Motrin ® Purfen ,Mac Safe syr, Arfen inj ) Naproxen (Naprosyn ® Napton)

COX-2 inhibitors Celecoxib (Celebrex ® ) Rofecoxib (Vioxx ® ) Valdecoxib (Bextra ® )

Dosage of NSAID

Diclofenac (Voltaren ® Cataflam ®) Meitifen 75mg, Formax 75mg Rheumatoid arthritis: 150-200 mg/day orally in 2-4 divided doses Osteoarthritis: 100-150 mg/day orally in 2-3 divided doses. Maximum Daily Dose:  225 mg;  XR: 200 mg

Etodolac (Lodine ® ) Lonine 200mg Acute pain: 200-400 mg every 6-8 hours, Rheumatoid arthritis, osteoarthritis: Initial: 600-1200 mg/day given in divided doses: Maximum Daily Dose::  1200 mg

Ketorolac (Toradol ® ) Keto Inj 30mg, Kop Inj 30mg, Keto, Painoff 10mg IM: 60 mg x 1 or 30 mg q6h (maximum daily dose: 120 mg).  IV: 30 mg x 1 or 30 mg q6h (maximum daily dose: 120 mg). Oral: 20 mg, followed by 10 mg every 4 to 6 hours (Max 40 mg/day) Note: The maximum duration of treatment (for parenteral and oral) is 5 days.

Sulindac (Clinoril ®) Unidac 200mg Adults: 150-200 mg twice daily or 300-400 mg once daily; not to exceed 400 mg/day. Should be administered with food or milk. Maximum Daily Dose :  400 mg

Meloxicam (Mobic ® ) Subic 7.5mg Oral: Initial: 7.5 mg once daily; may increased dose of 15 mg once daily maximum dose: 15 mg/day

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

Nabumetone (Relafen ® ) No-ton 500mg ,Relifex 1000 mg orally with or without food may obtain more symptomatic relief from 1500 mg to 2000 mg per day (in two divided doses) Maximum Daily Dose:  2000 mg

Flurbiprofen (Ansaid ® ) Flufen50 mg,Lefenine100mg, Flur Di Fen Patch 12mg Inflammatory disease: 50-100 mg/dose 3-4 times/day (maximum dose: 400 mg/day )

Tenoxicam Tencam 20mg, Sutondin 20mg, Tencam inj 20mg Adults: 20-40 mg/day ,1-2 times daily Acute gout: 40mg x 2days, then 20mg qd

Ibuprofen (Motrin ® ) Purfen 400mg ,Mac Safe syr, Arfen inj 400mg Inflammatory disease: 400-800 mg/dose 3-4 times/day Analgesia/pain/fever/dysmenorrhea: 200-400 mg/dose every 4-6 hours (maximum daily dose: 1.2 g ) maximum dose: 3200 mg/day in severe hepatic impairment: avoid use

Naproxen (Naprosyn ®) Napton 750mg Rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis: 250-500 mg orally twice daily May increase to 1.5 g/day

Test Time Q 1: which of the following NSAID in our hospital is the most COX 2 selective? (1) no-ton (2) unidac (3) subic (4) lonine Q 2: which of the following NSAID should not been used more than 5 days? (1) lefenine ( 2) ketoprofen ( 3) sutondin (4) painoff