Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Pain
Definition
An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage
International Association for the Study of Pain

Pain Scores
Visual Analogue Scale (VAS) 0 10

Numeric Rating Scale (NRS)

Verbal scale
No Pain Mild Moderate Severe Pain

Wong-Baker Faces Scale

What are NSAIDs and how do they work?

Drug with analgesic ( without impairing consciousness ), antipyretic, and antiinflamammatory effects weak acids, PH 3-5, well absorbed from stomach and intestinal mucosa protein-bound in plasma ( albumin), metabolised in the liver

Different Pathways Of inflammation

Inflammation is induced by following 4 chemical mediators . Prostaglandins Amines: Histamine & 5-OH Tryptamine Small peptides; Bradykinin Larger peptides; Interleukin-1 NSAIDs can benefit only where prostaglandins are the chemical mediators.

Classification
Propionic] acid derivatives
Naproxen Ibuprofen Ketoprofen Flurbiprofen Oxaprozin

Fenamic acid derivatives

Mefenamic acid Meclofenamic acid Flufenamic acid Tolfenamic acid

Acetic acid derivatives

Indomethacin Sulindac Etodolac Diclofenac (Safety alert by FDA

Selective COX-2 inhibitors (Coxibs)

Celecoxib (FDA alert) Rofecoxib (withdrawn from market) Valdecoxib (withdrawn from market) Parecoxib FDA withdrawn Lumiracoxib TGA cancelled registration Etoricoxib FDA withdrawn Firocoxib used in dogs and horses

Enolic acid (Oxicam) derivatives

Piroxicam Meloxicam Tenoxicam Droxicam Lornoxicam Isoxicam

Mechanism of Action of NSAIDs:

CO2H

Arachidonic acid
COX-1 Constitutive Non-specific NSAIDs COX-2 NSAIDs GI Mucosa Platelet COX-2 Inducible

Prostaglandins

Prostaglandins GI mucosal Protection

Thromboxane Mediate pain, inflammation, and fever

Hemostasis

Bakhle et al. Med Inflamm. 1996;5:305-323. Vane et al. Inflamm Res. 1995;44:1-10.

NSAIDs: Cyclooxygenase
Cyclooxygenase has 2 forms:
COX-1 (good COX) : found in all tissues
Mediates housekeeping chores Protect gastric mucosa Support renal function Promote platelet aggregation

COX-2 (bad COX) : found at sites of tissue injury

Mediates inflammation and sensitize receptors to painful stimuli Also present in brain- mediates fever and contributes to perception of pain Mediates a cytoprotective effect in damaged GI mucosa

Dosage of NSAID

Acetaminophen
Mechanism of action unclear A weak PG inhibitor No anti-inflammatory effects Causes liver toxicity at high doses
Max dose: 4 gm/day, if no liver disease Newest recommendation 2.6 gm/day

Ref. 1,2

Pharmacokinetics
Administered orally Absorption: related to rate of gastric emptying Peak blood conc: 30-60 min Slightly protein bound Partially metabolized by hepatic microsomal enzyme acetaminophen SO4 & glucuronide Excretion: unchanged < 5% A minor but highly active metabolite (N-acetyl-pbenzoquinone) is important liver & kidney toxicity t1/2: 2-3 hrs

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

Pharmacokinetics
Rapidly absorbed following oral administration 99% protein bound t1/2: 1-2 hrs Accumulates in synovial fluid t1/2 of 2-6 hrs 30% biliary clearance, urine (65%)

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

Pharmacokinetics
Rapidly well absorbed 80% bioavailability Strongly bound to plasma proteins (99%) Enterohepatic circulation t1/2: 7 hrs Excreted in the urine

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.

 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.

Pharmacokinetics
Rapidly absorbed after oral or IM administration Also given IV Peak concentration: 30-50 min. Almost totally protein bound t1/2: 4-6 hrs Excreted in the urine (90%)

Sulindac (Clinoril )
Unidac 200mg Adults: 150-200 mg twice daily or 300400 mg once daily; Should be administered with food or milk. Maximum Daily Dose : 400 mg

Pharmacokinetics
90% absorbed after oral administration Peak concentration: 1 hr t1/2: 7 hrs

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

Pharmacokinetics
An enolcarboxamide Slightly COX-2 selective Slowly absorbed t1/2: 20 hrs Clearance: 40% decreased in elderly Slightly less ulcerogenic

Piroxicam (Feldene )
Tonmax Inj 20mg, Foglugen 20mg Adults: 10-20 mg/day once daily May be taken with food to decrease GI adverse effect. Maximum Daily Dose : 20 mg

Pharmacokinetics
Rapidly absorbed from the stomach & upper intestine Peak plasma concentration: 1 hr 99% protein bound Elimination: renal

Flurbiprofen (Ansaid )
Flufen50 mg,Lefenine100mg, Flur Di Fen Patch 12mg Inflammatory disease: 50-100 mg/dose 34 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 dose: 3200 mg/day in severe hepatic impairment: avoid use

Pharmacokinetics
Rapidly absorbed after oral or IM administration Also given IV Peak concentration: 30-50 min. Almost totally protein bound t1/2: 4-6 hrs Excreted in the urine (90%)

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

Pharmacokinetics
Is a naphthylpropionic acid A nonselective COX inhibitor Elimination serum t1/2: 12 hrs High albumin binding Prep: SR formulation, oral susp

Aspirin - Dosage
Analgesic/antipyretic dose for adults is 325-650 mg every 4 hrs which results in a plasma concentration of approximately 60 mg/ml. The half-life is 2-3 hours. Anti-inflammatory dose is usually 4-6 g daily which results in a plasma concentration of 150-300 mg/ml. The half-life is usually 12 hours. Fatal dose is 10-30 g resulting in plasma concentrations exceeding 450 mg/ml. The half-life can be as long as 15-30 hours.

Pharmacokinetics
Rapidly absorbed from the stomach & upper small intestine Peak plasma level: 1-2 hrs 80-90% protein bound t1/2: 3-5 hrs Cross BBB & placental barrier Undergoes hepatic metabolism Excretion: kidneys

MECLOFENAMATE & MEFENAMIC ACID

Fenamic acid derivatives Inhibit both COX Peak plasma level: 30-60 min t1/2: 1-3 hrs

CELECOXIB
Highly selective COX-2 inhibitor Absorption: 20-30% decreased by food t1/2: 11 hrs Highly protein bound Clearance affected by hepatic impairment Effective dose: 100-200mg b.i.d. Does not affect platelet aggregation

ROFECOXIB
A furanose derivative A potent highly selective COX-2 inhibitor Well absorbed Dosage range: 12.5-50mg/d Slightly less protein-bound (87%) t1/2: 17 hrs Metabolized by cytosolic liver enzymes Does not inhibit platelet aggregation Have little effect on gastric mucosal PGs Associated with fewer gastric or duodenal gastroscopic ulcers

Comparative action between COX inhibitors 1. Analgesic action 2. Antipyretic action (+) (+)

COX-1/COX-2 inhibitors

COX-2 inhibitors (+) (+) (+)

3. Antiinflammatory action
4. Antiplatelet aggregatory 5. Gastric mucosal damage 6. Renal salt / water retention 7. Ductus arteriosus closure 8. Cardiotoxicity

(+)
(+) (+) (+) (+) (+) (+)

(+) (+)
(-) (+) (+) ?

(-)

(+) (+)

Side effect of NSAIDs

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)

GIT
The acidic molecules directly irritate the gastric mucosa, Inhibition of COX-1 reduces the levels of protective prostaglandins. Inhibition of prostaglandin synthesis in the GI tract causes Increased gastric acid secretion, Diminished bicarbonate secretion, Diminished mucous secretion and Diminished trophic effects on epithelial mucosa. Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time, a practice which studies show is not often followed. Recent studies show that over 50% of patients taking NSAIDs have sustained damage to their small intestine.

Table: NSAIDs
High Risk Drug* Aspirin (Bokey, Tapal) X Moderate Risk Low Risk

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.

X
X X X X X X X X X X X X X X

Side Effects: Kidneys

NSAIDs reduce the blood flow to the kidneys leading to salt & fluid retention. This can lead to edema and hypertension. If high doses are used for longer periods of times as in chronic conditions, can lead to renal failure. Combination with nephrotoxic agents increase the risk of renal failure. Renal failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor and a diuretic. NSAIDs are excreted by kidneys.

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 contraindicated after 6 months of pregnancy

Drug interactions with NSAIDs

Drugs Diuretics Beta-blockers ACE inhibitors Anticoagulants Sulfonylurea Cyclosporine Alcohol Result Decrease diuresis Decrease antihypertensive effect Decrease antihypertensive effect Increase of GI bleeding Increase hypoglycemic risk Increase nephrotoxicity Increase of GI bleeding

The End