learning objectives :cyclooxygenase pathway and NSAIDS, silent features of : Aspirin,Diclofenac,piroxicam ,etoricoxib.

1. Nonsteroidal
Anti-inflammatory Drugs
Dr Uma Advani
Assistant professor pharmacology
SMS Medical College, Jaipur

2. Learning objectives
• Introduction & Cyclo-oxygenase (COX) pathway
• Mecanism of action of NSAIDS
• Pharmacokinetics & Adverse effects of NSAIDS
• Irreversible nonselective cox inhibitor :Aspirin
• Reversible nonselective cox inhibitors : Diclofenac
Indomethacin
• Preferential cox 2 inhibitor: Nimesulide
• Selective cox-2 inhibitors: Etoricoxib
• Paracetamol
• Summary

3. Introduction
• Antipyretic, Analgesic & Anti-inflammatory drugs
• Grouped in different classes based on there chemical
structures
• Share similar pharmacological effects, mechanism of
action & adverse effects
• Inhibit biosynthesis of Prostaglandins

4. Cyclo-oxygenase pathway

5. Cox-1 Pathway
• Constitutive → Housekeeping enzyme
• Homeostatic function
• Gastric protection (PGE2 and PGI2)
– ↓ acid production & ↑ mucous production
– ↑ mucosal blood flow so less chances of peptic ulcers
• Regulation of platelet aggregation (PGI2 and TXA2)
• Regulation of renal blood flow (PGI2 and TXA2)

6. • Induced → expression increases during inflammation
• Facilitate inflammatory response & cause fever and pain
• Expressed in brain, vascular endothelium & kidney
• Cox 2 inhibitors ↓ vasodilatation & ↑ platelet aggregation
• Chances of thrombosis are ↑ on prolonged use
• Little GI toxicity
Cox-2 Pathway

7. NSAIDS : inhibit cyclooxygenase pathway

8. 1.Antipyretic Effect
• Body temperature regulation
• Only ↓ the body temperature of those who have
fever and no effect on normal ones
• Fever → generation of pyrogens → PGE2 production
in hypothalamus → raise temperature set point
• NSAIDs block action of pyrogens but not of PGE2

9. 2.Analgesic Effect
• Cause of pain: in tissue injury or inflammation
chemical algesiogenic substances
are produced and released such as
bradykinin, TNFα together with PGs
• Bradykinin: cause pain through stimulating the
algesireceptors directly
• PG: Hyperalgesia
PG(E1 E2 F2α) have algesiogenic effect
NSAIDs inhibit the synthesis of PGs in periphery

10. 3.Anti-inflammatory Effect
• Inhibition of PGs synthesis at site of injury
• Activated endothelial cells express adhesion molecules
(ECAM, ICAM) → direct circulating leucocytes to site of
inflammation (chemotaxis)
• Inflammatory cells express selectins & integrins
• Inhibiting expression & activity of these molecules and
generation of superoxide & free radicals
• Inhibit growth factors & lymphocyte transformation factors

11. Other actions of NSAIDS due to inhibition PG
Synthesis
4.Gastric damage
5.Nephropathy
6.Delay labour
7.Closure of ductus arteriosus
8.Precipitation of asthma, due to increase in
lipoxygenase in sensitive individuals.

12. Pharmacokinetics
• Weak organic acids (except Nabumetone → ketone prodrug)
• Metabolized by CYP3A or CYP2C P450 enzymes in liver
• Renal excretion most common along with
biliary excretion & reabsorption
• Highly protein bound (~ 98%)
• Found in synovial fluid after repeated dosing
Drugs with short half lives remain in joints longer

13. Common Adverse Effects
• Platelet Dysfunction
• Gastritis and peptic ulceration with bleeding
• Acute Renal Failure in susceptible
• Sodium and water retention → edema
• Analgesic nephropathy
• Headaches, tinnitus & dizziness
• Hypersensitivity (not immunologic but due to PG inhibition)

14. NSAID
↑ Leukocyte-Endothelial
Interactions
Capillary
Obstruction
Ischemic
Cell Injury
Proteases +
Oxygen Radicals
Endo/Epithelial
Cell Injury
Mucosal Ulceration
Loss of PGI2 induced inhibition of LTB4 mediated
endothelial adhesion and activation of neutrophils

15. Nonselective Cox inhibitors
1. Salicylates: Aspirin
2. Propionic acid derivatives: Ibuprofen, Flurbiprofen,
Ketoprofen, Naproxen
3. Anthranilic acid derivative: Mephenamic acid
4. Acetic acid derivatives: Diclofenac, Aclofenac
5. Oxicam derivatives: Piroxicam
6. Pyrrolo – pyrrole derivative: Ketorolac
7. Indole derivative: Indomethacin
8. Pyrazolone derivatives: Phenylbutazone

16. Aspirin
• Only irreversible inhibitor of Cox enzyme
• At low doses (50- 300 mg) acts as an Antiplatelet drug
– Prophylaxis of MI and stroke
– Reduces transient ischemic attacks
– Colonic polyp
• ↓ TXA2 (platelet aggregator) also ↓ PGI2 (anti aggregatory)
– TXA2 synthesized by platelets is exposed to aspirin in portal circulation
but very little aspirin reaches systemic circulation to inhibit PGI2 synthesis
– Platelets lack nuclei & cannot synthesize new Cox once inhibited but
endothelium regenerate Cox to produce PGI2
• Useful in dysmenorrhoea & pre eclampsia

17. Adverse Effects
• Dose dependent effects on acid base balance
– Respiratory alkalosis occurs at high doses → headache, vertigo, tinnitus,
vomiting & hyperventilation (salicylism)
– Excessive metabolic compensation causes metabolic acidosis → loss of
vision , hyperpyrexia, dehydration, convulsions & coma
– More common in infants
– Treated by supportive measures, gastric lavage, correcting metabolic
acidosis & urine alkalinization to ↑ excretion
• Hyperuricemia
• Prolongs bleeding time
• Reyes syndrome in children (hepatic encephalopathy)

18. Indomethacin
• Inhibits phospholipase A & C
↓ T cell & B cell proliferation
• Potent anti-inflammatory → Gout & Ankylosing spondylitis
• Accelerate closure of PDA
• Headache & sedation common
• Combined with potassium repletion to improve symptoms of
Bartter’s syndrome

19. • 99% protein bound
Good tissue penetrability & conc. in synovial fluid
maintained 3 times longer than in plasma
• Most extensively used NSAID in rheumatoid & osteoarthritis,
bursitis and toothache
• Combined with misoprostol ↓ upper GI ulceration
Combined with omeprazole ↓ recurrent bleeding
• 0.1% preparation → postoperative ophthalmic inflammation
3% preparation → solar keratosis
Diclofenac

20. Other Non selective Cox inhibitors
• Flurbiprofen 5% topical ophthalmic formulation for inhibition of
intraoperative miosis
• Naproxen is long acting that inhibits leucocytes
migration,symptomatic relief in gout.
• Mephenamic acid → PG receptor antagonist + PLPA2 inhibitor
useful in dysmenorrhoea(diarrhoea common adverse effect)
• Ketorolac inhibit Lipoxygenase also,used i.v. for mild to moderate
post surgical pain
• Piroxicam is longest acting NSAID → incidence of peptic ulcer
is 10 times higher than with other NSAIDs

21. Nimesulide
• NSAID with preferential Cox 2 inhibitor
• Anti-inflammatory action :
– inhibition of PAF & TNFα
– ↓ superoxide by neutrophils
– free radical scavenging
– ↓ metalloproteinase activity in cartilage
• Short painful inflammatory conditions like sports injuries,
sinusitis, tooth ache, low backache
• Withdrawn from some countries due to instances of fulminant
hepatic failure
• Pediatric preparations banned in India

22. Selective Cox 2 inhibitors
• Celecoxib, Etoricoxib & Parecoxib
• Advantage of little GI toxicity
• Rofecoxib & Valdecoxib withdrawn due to ↑ risk of MI
• Celecoxib is sulfonamide derivative & cause rash &
hypersensitivity
• Etoricoxib long acting coxib & requires monitoring of hepatic
function

23. Paracetamol (Acetaminophen)
• No anti-inflammatory activity
Best drug to be used as antipyretic
• Very little GI toxicity & can be given to patients
intolerant to other NSAIDs
• Metabolized to N acetyl paraaminobenzo quinone (NAPQ)
→ high affinity for sulfhydryl groups → hepatotoxicity
• Safe drug because glutathione (containing sulfhydryl group)
produced by liver combines with NAPQ to detoxify it

24. Paracetamol
• Chronic alcoholics are predisposed to toxicity because
– Glutathione production ↓ due to liver disease
– Alcohol powerful inducer of microsomal enzymes (↑ NAPQ production)
• Acetaminophen overdose (15g) is a medical emergency
– 90% pts develop hepatotoxicity with centrilobular necrosis
– sometimes renal tubular necrosis & hypoglycemia → coma
– Gastric lavage with activated charcoal prevents further absorption
but ineffective after 4 hrs of ingestion
– ↓ by N acetylcystine (replenishes glutathione stores of liver)
• Common OTC analgesic for headache, mild migraine,
musculoskeletal pain

25. Situation NSAID
Mild to moderate pain with little
inflammation
Paracetamol or low dose ibuprofen
Post operative or short lasting pain Ketorolac, Ibuprofen, Diclofenac,
Nimesulide
Acute musculoskeletal, osteoarthritic,
injury pain
Paracetamol, Ibuprofen Or Diclofenac
RA, Ankylosing spondylitis, acute gout,
acute rheumatic fever
Naproxen, Piroxicam, Indomethacin,
high dose Aspirin
Gastric intolerance to traditional NSAIDs Selective Cox 2 inhibitor or Paracetamol
Pts with history of asthma or
anaphylactoid reaction to NSAIDs
Nimesulide or Cox 2 inhibitor
Pediatric patients Paracetamol, Ibuprofen and Naproxen
Pregnancy Paracetamol safest, low dose Aspirin
second best

27. SUMMARY
All NSAIDS are weak acids except nabumetone.
All NSAIDs are racemic mixtures
except naproxen (present as single enantiomer) and
diclofenac (have no chiral center)
Sulindac and nabumetone are prodrugs. Piroxicam
and tenoxicam are longest acting NSAIDs due to
enterohepatic cycling.
All NSAIDs are almost equally efficacious except–
Aspirin is less effective for ankylosing spondylitis

28. SUMMARY
Paracetamol (acetaminophen) has no anti-inflammatory
activity
Nimesulide and nefopam: do not act by decreasing Pg
synthesis
Ketorolac is the only NSAID that can be used i.v.
– Aspirin is contraindicated inchildren (<12 yrs old) due to
increased risk of Reye’s syndrome
- Nephrotoxicity and hepatotoxicity may occur with any
NSAID.
Rofecoxib and valdecoxib were withdrawn due to increased
risk of thrombotic disorders like myocardial infarction.