1) The document discusses various classes of non-steroidal anti-inflammatory drugs (NSAIDs) including their mechanisms of action, examples, and uses. 2) It covers traditional non-selective NSAIDs that inhibit both COX1 and COX2 as well as preferential and selective COX2 inhibitors with reduced gastrointestinal side effects. 3) The mechanisms of analgesia, antipyresis and anti-inflammation of these drugs are described as inhibiting prostaglandin synthesis through cyclooxygenase (COX) inhibition.

2. 1) None of them is steroid
2) All of them are analgesic-antipyretic and, barring paracetamol,
all are anti inflammatory
3) No CNS depression, respiratory depression & drug dependence
4) Act by inhibiting prostaglandin synthesis except nimesulide &
nefopam

3. A) Nonselective COX inhibitors(traditional NSAIDs)
1) Salicylates: aspirin, diflunisal, sodium salicylate,
methylsalicylate, sulfsalazine, salicylic acid
2 )Propionic acid derivatives: ibuprofen, naproxen, ketoprofen,
flurbiprofen, oxaprozin
3) Fenamate: mephenamic acid
4) Enolic acid derivatives: piroxicam, tenoxicam
5 )Acetic acid derivatives: ketorolac, indomethacin, nabumetone,
sulindac, tolmetin
6) Pyrazolone derivatives: phenylbutazone, oxyphenbutazone

4. B) Preferential COX2 inhibitors: nimesulide, diclofenac,
aceclofenac, meloxicam, etodolac
C) Selective COX2 inhibitors: celecoxib, etoricoxib, parecoxib,
rofecoxib, valdecoxib
D) Analgesic-antipyretic with poor antiinflammatory action
1 Paraaminophenol derivative: paracetamol(acetaminophen)
2 Pyrazolone derivatives: metamizol(dipyrone), propiphenazone
3 Benzoxazocine derivative: nefopam

5. Tissue injured ↑synthesis of PGs
PGs
Mediators of inflammation
sensitise pain receptors at
nerve endings, lowering
pain threshold to stimuli
Excitability of spinal
neuron
Hyperalgesia
NSAIDs act by inhibit cyclo-oxygenase(COX) enzyme in
arachidonic acid cascade to prevent synthesis of prostanoids.

6. 1) COX1
 constitutively expressed
 Analgesic-antipyretic & antiplatelet aggregation effect
 most of nonselective reversible inhibitor of COX have
selectivity for COX1
 Housekiping function: gastric cytoprotection, haemostasis
 Unwanted GI effect are result of COX1 inhibition
2) COX2
 Inducible in inflammatory cells by inflammatory stimulus
(eg. Cytokine, TNFα)
 Anti inflammatory action due to COX2 inhibition
 Constitutively – brain, juxtaglomelural cells, foetus
3 types of COX

7. 3) COX3
 In cerebral cortex & in heart
 Involve in pain & fever, not in inflammation
 Poor ability to inhibit COX1 in presence of peroxides which
are generated peripherally at inflammatory site, not in
hypothalamus

8.  Aspirin inhibit COX irreversibly
• Return of COX activity depends on synthesis of fresh enzyme
 Other NSAIDs are competitive & reversible inhibitor of COX
• Return of COX activity depends on their dissociation from the
enzyme
 Nimesulide has strong oxygen free radical scavenging effect
which prevent further tissue damage.
• Also inhibit PAF synthesis, TNF-α release & metalloproteinase
activity in cartilage.

9. Salicylates:
• Aspirin
• diflunisal
• sodium salicylate
• methylsalicylate
• sulfsalazine
• salicylic acid

10.  Prototype drug
 aspirin is acetylsalicylic acid → salicylic acid
Aspirin

12. • Relieves inflammatory, tissue injury related, connective tissue
& integumental pain
• But ineffective in severe visceral & ischaemic pain
 Action: block pain sensitising mechanism induced by
bradykinin & TNF-α
• Central action- raise threshold of pain perception
• No sedation, tolerance or drug dependence
 Uses: headache, backache, myalgia, joint pain, toothache,
pulled muscle, neuralgia, dysmenorrhoea, pain of cancer
metastases
 Dose: 300-600 mg 6-8 hrly
Analgesia

13. Antipyretic action
• ↓ temperature in fever not normal body temperature
• Effective in fever of any origin(except heat stroke)
• Fever during infection & tissue injury produced by pyrogens
↓ PGE2 production
raise set point of temperature
 Action: reduce PG synthesis & reset hypothalamic thermostat

14.  Dose same as for analgesia
• But in acute rheumatic fever high dose 75-100mg/kg/day
(in divided dose) needed
• Dose reduction after 4-7 days
• Maintenance dose 50mg/kg/day for 2-3 week & withdrawal
gradually over next 2-3 weeks.

15. Anti inflammatory effect
 Action: Inhibit vasodilator PGs - lesser vasodilation & oedema
• Inhibtion of chemotactic, growth factor prevent
• Stabililization of lysosomal membrane spread of
• ↑ resistance of connective tissue inflammation
• ↓free radical & superoxide production
 Uses: higher dose 3-6 gm/day used for osteoarthritis,
rheumatoid arthritis
• Provide symptomatic relief but not affect disease progression

16. Inhibition of platelet aggregation
• NSAIDs inhibit both proaggregatory (TXA2) & antiaggregatory
(PGI2)
• In low dose irreversible inhibit TXA2 (because platelet lack
nuclei & can not synthesis COX)
↓
inhibit platelet aggregation
• High doses reverse beneficial effect by inhibiting PGI2.

17.  Uses:
• 60-100mg/day → ↓ reinfarction in post MI patient
• ↓ risk of transient ischaemic attack, deep vein thrombosis,
pulmonary embolism, stroke

18. Relief in dysmenorrhoea
• Levels of PGE in menstrual flow & PGF2α in circulation are
raised in dysmenorrhoea
• Menstrual cramps occur due to intermittent ischaemia of
myometrium & ischaemia results due to PG induced uterine
contraction
• Aspirin decrease uterine PG to provide relief in
dysmenorrhoea & excessive flow may be normalized

19. Closure of ductus arteriosus
• During foetal circulation ductus arteriosus kept patent by
PGE2 & PGF2α
• Unknown mechanism switch off this synthesis at birth &
ductus closes
• When this fails to occur low dose aspirin bring this closure
Colonic & rectal cancer
• COX2 inhibitor more effective as colonic tumours express
large quantities of COX2

20.  Pre-eclampsia - benefit by suppressing TXA2 production
 Familial colonic polyposis - suppress polyp formation &
provide symptomatic relief
 Niacin induced cutaneous flush & pruritus
• This probably is mediate through PG & it reduced by
premedication with low dose aspirin
 To slow down cataract progression
• High dose aspirin protect lens protein against non enzymatic
glycosylation & carbamylation

22. Gastric mucosal damage
 Mechanism
• at analgesic dose
• PGE2 & PGI2 inhibit gastric acid secretion and stimulate
mucous & bicarbonate formation
• Aspirin inhibit COX1 & nulifies gastroprotective effect of PGs
• Also local ‘ion trapping’ of aspirin cause damage
 Common side effects: dyspepsia, diarrhoea, nausea,
vomiting, gastric bleeding & necrosis and ulceration
 COX2 inhibitors & paracetamol cause less damage

23. Metabolic effects
↑heat production
↑ cellular metabolism
↑utilization of glucose → hypoglycemia
 At high dose central sympathetic stimulation
release Adr & corticosteroid
Hyperglycemia
 Protein catabolism → negative nitrogen balance
 Inhibit lipolysis → ↑ free fatty acid

24.  At inflammatory dose:
Direct stimulation of respiratory centre
↓
CO2 wash out & ↓ PCO2
↓
Respiratory alkalosis
 Compensatory renal mechanism → ↑HCO3 excretion
 Still high dose:
respiratory depression
↓
accumulation of CO2 & ↑ PCO2 level
↓
respiratory acidosis

25. Increase in bleeding tendency
• Aspirin irreversibly inhibit TXA2 & interferes platelet aggregation
↓
Bleeding time prolonged (twice the normal value)
• Long term use ↓ synthesis of clotting factor(prothrombin)
 Should be stopped 1 week before surgery
Hypersensitivity
• With inhibition of COX, consequent diversion of arachidonic acid to
lipoxygenase pathway
↓
↑ formation of leukotrines
 Aspirin precipitates asthma, rhinitis, urticaria, angioneurotic
oedema

26. Effect on urilc acid excretion
• < 2 gm/day → ↓uric acid excretion
• 2-5 gm/day → no change
• > 5gm/day → ↑uric acid excretion
 aspirin not suitable drug for gout
Renal effects
• impairment of renal blood flow & ↓ GFR
• Na & water retention → ↑ BP
• Papillary necrosis on habitual intake
 This effects significant in→ CHF, hypovolaemia, hepatic
cirrhosis, renal disease

27. Analgesic nephropathy
• After years of heavy ingestion of analgesic (phenacetin)
• Papillary necrosis, tubular atrophy followed by renal fibrosis
• Urine concentrating ability lost & kidney shrink
Reye’s syndrome
• association between aspirin intake & Reye’s syndrome
• rare & fatal disorder in children
• Liver damage & encephalopathy when recovering from febrile
viral infection(chickenpox & influenza)
• Paracetamol preferred in fever of unknown origin in children
below 12 years

28. Salicylism
• At high dose (3-5 gm/day)
• Dizziness, tinnitus, vertigo, reversible impairment of hearing &
vision,mental confusion, hyperventilation & electrolyte
imbalance
• Dose should be titerated
Acute salicylate poisoning
• Common in children
• Fatal dose in adult → 15-30 gm
• Vomiting, dehydration, electrolyte imbalance, restlessness,
hypo/hyperglycemia, petechial haemorrhage, delirium,
hallucination, convulsion, coma, death due to respi failure
 Symptomatic & supportive treatment

29. • sensitive to aspirin, in peptic ulcer, bleeding tendencies
• In children suffering from chicken pox or influenza
• Chronic liver disease – hepatic necrosis
• Diabetes, CHF patient
• Stop 1 week before elective surgery
• during pregnancy – low birth baby, prolonged labour, great
postpartum blood loss, premature closure of ductus
arteriosus
• Breastfeeding mothers
• G-6PD deficient patient - hemolysis

30. Propionic acid derivatives
• Ibuprofen,
• Naproxen,
• Ketoprofen
• Flurbiprofen,
• Oxaprozin

31. Mechanism
• All members inhibit PG synthesis
• naproxen being the most potent

32. ADR
• Gastric discomfort, nausea and vomiting
• CNS side effects :
– headache, dizziness
– blurring of vision, tinnitus and depression
• Rashes, itching and other hypersensitivity
phenomena are infrequent
• C/I: peptic ulcer & pregnancy

33. Pharmakokinetics
• well absorbed orally
• Highly bound to plasma proteins (90–99%)
• Largely metabolized in liver by hydroxylation
and glucuronide conjugation
• excreted in urine

34. Uses
• Ibuprofen is used as a simple analgesic and
antipyretic
• Rheumatoid arthritis, osteoarthritis
• Soft tissue injuries, fractures, vasectomy,
tooth extraction, postpartum and
postoperatively
– Suppress pain & inflammation

35. • Safest; Weak anti-inflammatory
• Prevent irreversible COX inhibition by aspirin; by occupying
serine residue of COX1 & prevent its acetylation by aspirin
• Antiplatelet action short lasting
• Antagonizes antiplatelet & cardioprotection of aspirin
• S/E: hypersensitivity, blurred vision, thrombocytopenia
• Dose: 400mg TDS
• More effective than ibuprofen; more gastric side effect
• Use: ocular inflammation
• Dose: 50-100mg TDS
Ibuprofen
Flurbiprofen

36. Fenamate
• Analgesic, antipyretic, weak anti inflammatory
 Uses: Muscle, joint, soft tissue pain & dysmenorrhoea
 Side effects:
• Diarrhoea, epigastric distress, skin rashes, dizziness
• Haemolytic anaemia rare but serious
 Dose: 250-500mg TDS
Mephenamic acid

37. • Potent antiinflammatory → suppresses neutrophil motility
• Toxic dose → uncouples oxidative phosphorylation (like aspirin)
• Use: reserve drug for potent inflammatory condition
: malignancy associated refractory fever
: used for patent ductus arteriosus
: bartter’s syndrome
• S/E:
• GIT & CNS effects(50%),
• Gastric irritation, nausea, anorexia, gastric bleeding and diarrhoea
• Frontal headache (very common), dizziness, ataxia, mental confusion,
hallucination, depression and psychosis
• Skin reaction, leukopenia,bleeding
Indomethacin

38. Contd.
• C/I: machinery operators, drivers, psychiatric
patient,epilepsy, pregnant women, children
• Dose: 25-50 mg BD/QID

39. • Prodrug
• active metabolite 6-MNA(6methoxy2naphthylacetic acid)
• Use: RA, osteoarthritis, soft tissue injury
• S/E: abdominal cramps & diarrhoea
: low incedence of gastric erosion, ulcer, bleeding
• Dose: 500 mg OD
• Prodrug, Active sulfide metabolite →long duration of action
• Less toxic
• Dose: 150-200mg BD
• Efficacy similar to ibuprofen
• Dose: 400mg TDS
Nabumetone
Sulindac
Tolmetin

40. • ↓generation of superoxide, inhibit PAF & TNF-α release, free
radical scavanging, inhibit metalloproteinase
• Use: short lasting painful inflammatory condition
• ADR:Gastic ulcer ,fulminant hepatitis
• C/I: hepatic impairment (sprcially in children)
• Dose: 100 mg BD
• Congener of piroxicam
• Plasma half life- 15-20 hrs
• S/E: mild gastric effect (ulcer complication on long term use)
• Dose: 7.5-15 mg OD
Nimesulide
Meloxicam

41. • No antiplatelet action
• Use: RA, osteoarthritis, renal colic, dysmenorrhoea, toothache
• S/E: mild epigastric pain, nausea, headache, dizziness, rashes
: ↑risk of heart attack & stroke
: reversible ↑aminotransferase; kidney damage
• Dose: 50mg BD / 75mg deep i.m.
• Congener of diclofenac
• ↑ glycosaminoglycan synthesis → chondroprotective
• Dose: 100mg BD
Diclofenac sodium
Aceclofenac

42. • Less gastric mucosal damage
• Less occurance of Peptic ulcer & ulcer bleeding
Not suppress TXA2 production
No inhibition of no prolonged
platelet aggregation bleeding time
prothrombotic effect on long term use
(devoid of cardioprotection)
• ↓ production of PGI2

43.  3 COX2 inhibitors available in india:
• Celecoxib, etoricoxib, parecoxib
 Rofecoxib & valdecoxib → withdraw due to cardiovascular risk
 Lumiracoxib – withdraw due to hepatotoxicity
 Use: only in risk of peptic ulcer, perforation or bleeding
 Avoid: ischaemic heart disease, hypertension, cardiac failure,
cerebrovascular disease

44. • Platelet aggregation remain intact
• Slowly absorbed
• Use: osteoarthritis & rheumatoidarthritis
• S/E: abdominal pain, dyspepsia, mild diarrhoea, rashes,
edema, rise in BP
• Dose: 100-200mg BD
• Prodrug of valdecoxib
• Suitable for injection
• Use: post operative or short term pain
• S/E: cutaneous reaction (stop on 1st appearance of rash)
• Dose: 40mg i.m./i.v., repeat after 6-12 hour
Celecoxib
Parecoxib

45. Etoricoxib
• t½ is ~ 24 hours
• Uses:
– osteo/rheumatoid/acute gouty arthritis,
ankylosing spondylitis, dysmenorrhoea, acute
dental surgery pain
• Side effects :
– dyspepsia, abdominal pain, pedal edema
– rise in BP, dry mouth, aphthous ulcers
– taste disturbance and paresthesias

46. • Paraaminophenol derivative
• Pyrazolone derivatives
• Benzoxazocine derivative

47. banned due to analgesic abuse nephropathy
o acetaminophen
o Deethylated metabolite of phenacetin
o Most commonly used non narcotic, analgesic-antipyretic agent
with negligible anti inflammatory action
o act by inhibiting COX3, raise pain threshold
 NO → stimulate respiration or affect acid-base balance
→ gastric mucosal damage
→ effect on platelet aggregation
→ uricosuric action
Phenacetin
Paracetamol

48.  Uses
o Mild-moderate pain → headache, myalgia, postpartum,
migraine, dysmenorrhoea,Osteoarthritis
o Ineffective where inflammation prominent(eg. RA)
o Best antipyretic,specially in children(no risk of reye’s syndrome)
o Much safer then aspirin, used in patient who are allergic to
aspirin
 Dose: 325-600mg TDS

49.  Adverse effect
 Safe & well tolerated but nausea, skin rashes, reversible mild
↑in hepatic enzyme rarely
 Acute paracetamol poisoning
• Children- less glucuronide capacity
• Adult- hepatic impairment or chronic alcoholics
• Fatal dose - >250mg/day

50. major glucuronide or sulfate
conjugation
minor
N-acetyl-p-benzoquinone imine
glucuronidation capacity saturated &
more metabolites formed
binds covalently to protein in liver & kidney cells → cell death
Paracetamol
Toxic dose of Paracetamol

51.  Menifestation:
• 1st 2 days gastric distress
• After 12-36 hrs →↑ transaminase level
• Within 2-4 days→ Rt subcostal pain, hepatomegaly, jaundice
• Hepatic encephalopathy or worsoning of coagulation → poor
prognosis

52.  Treatment:
• Vomiting should be induced or gastric lavage
• Activated charcol
• Supportive treatment
• Specific → N-acetylcysteine
– replenishes glutathione store & prevent binding of
metabolite to cellular protein
• Dose:150 mg/kg i.v. over 15 min, same dose i.v. over next 20
hours
• Ineffective → 16 hrs or more after paracetamol ingestion