1. NONSTEROIDAL
ANTIINFLAMMATORY
DRUGS

2. Antiinflammatory drugs
 Steroid- Glucocorticoids
 Nonsteroidal-Aspirin like

3. INTRODUCTION
 ANALGESIC
 ANTIINFLAMMATORY
 ANTIPYRETIC
They are also called
“Nonnarcotics,Nonopiodids,or Aspirin like
analgesics”

4. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
1. Overview
Definition: NSAIDs are chemically diverse class of drugs
(>70 NSAIDs in use) that have anti-inflammatory,
analgesic, and antipyretic properties.
Among the most frequently prescribed drugs
-worldwide: 70 million people/day prescribed NSAIDs
230 million people/day take OTC NSAIDs
-USA: 80 billion aspirin tablets consumed/year
constitute 4% of all prescriptions

5. CLASSIFICATION
 A) Nonselective Cox inhibitors
1.Salicylates2.Pyrazolone derivatives-
Aspirin
Phenylbutazone, oxyphenbutazone
3.Indole derivatives-
Indomethacin, Sulindac
4.Propionic acid derivatives-
Ibuprofen, Naproxen, Ketoprofen
5.Anthranilic acid derivatives-
Mephenaimic acid
6.Aryl-acetic acid derivatives-
Diclofenac sodium
7.Oxicam derivatives-
Piroxicam, Tenoxicam
8.Pyrrole derivatives-
Ketorolac

6. B) Preferential cox-2 inhibitor
Nimesulide, Meloxicam.
C) selective cox- 2 inhibitorsCelecoxib, Rofecoxib,Valdecoxib
D) Analgesics- Antipyretics-
Paracetamol, Metamizol, Nefopam
(non opiod analgesic which donot inhibit PG synthesis)

7. NSAIDs and Prostaglandins
 PGs, Prostacyclins,TXA2-Arachidonic acid
 Cyclooxygenase Cox-1-Constitutive
(House keeper),
Mucus secretion, Haemostasis, renal functions
Cox-2 InducibleInflammatory response
Sites-brain, JG cells (constitutive)

8. COX-2 Hypothesis (1990s)
Normal Tissue
Arachidonic Acid
COX-1
Constitutive
Inflammation Site
Cytokines
+
Growth factors
ILs,TNF
COX-2
Inducible
COX-2
Inhibitors
NSAIDs
Physiolgical
Prostaglandin
Production
Normal Functions
Pathological
Prostaglandin
Production
Inflammation, pain, fever

9. Properties of Prostaglandins

10. Properties of Prostaglandins
•Physiological Functions of Prostaglandins
Pain: PGI2 and PGE2 sensitize nerve endings to bradykinin,
Histamine and substance P
Inflammation: PGI2, PGD2 and PGE2 are vasodilators
(edema, erythema)
Protection of the gastric mucosa: PGI2
Maintenance of renal blood flow: PGE2
Fever: PGE2
Platelets: PGI2 and PGD2 inhibit platelet aggregation
TXA2 stimulates platelet aggregation
Uterus: PGD2 contracts uterus

11. Analgesia
 PGs---induce hyperalgesia by increasing
sensitivity of afferent nerve endings to chemical
and mechanical stimuli and thus amplify action of
other algesics-bradykinins, histamine, TNF-alpha,
ILs.
 PGs in CNS lowers threshold of central pain
circuit.
 NSAIDS block this pain sensitizing mechanism
therefore effective against inflammation asso. Pain

12.  The opioids are the drugs of choice for the
treatment of moderate-to-severe pain, the NSAIDs are
most frequently used for mild-to-moderate pain.
 Prostaglandins by themselves do not cause pain but
lower the threshold of the C fiber nociceptors.
 As a result, lower concentrations of bradykinin and
histamine are required to activate the nociceptor.

13. Antipyresis
 Fever in infection is produced by pyrogens, TNF,
ILs, interferon-induce production of PGs in
hypothalamus-raise its temp. set point.
 NASIDs block the action of pyrogens.(cox-2).
 Fever also can occur through non PG mediated
mech.—incomplete explanation ???

14. Anti-inflammatory
 Inhibition of PG synthesis at the site of injury.
 Anti-inflammatory action of each drug
corresponds with their potency to inhibit COX.
 NSAIDs -also inhibit expression/ activity of
adhesion molecules, growth factors like GMCSF,IL-6,and lymphocyte transformation factorsaffected.
 NSAIDs-Stabilises leucocytes lysosomal
membrane, and antagonizes certain act.. Of
kinkins

15. Dysmenorrhea
 Increase levels of PGs in menstrual blood
flow, endometrial biopsies, and their
metabolites is seen in dysmennorhic
women.—myometrial ischaemia –menstrual
cramps.
 NSAIDs-lowers uterine PGs--relief

16. Antiplatelet
 Inhibit synthesis of TXA2 by acetylating
platelet COX irreversibly.

17. Ductus arteriosus
closure
 PGE2, PGI2-
responsible for maintaining
patency in foetal circulation.

18. Parturition
 Sudden increase in PG synthesis by uterus
triggers labour and facilitate progression.
 NSAIDs –delay and retard labour

19. Gastric mucosal damage
 Inhibition of synthesis of gastro protective PGS
(E2,I2)- decrease in mucus,HCO3,increases acid
secretion, may promote mucosal ischemia.
 Ion trapping with NSAIDs also play role.

20. Renal effects
 Conditions like hypovoleumia, decrease renal perfusion,
and Na+ loss- induce renal PG synthesis –leading to
vasodilatation, inhibition of cl - reabsorption…
 NSAIDs-
1. Cox dependent impair renal bl.flow.—decrease in gfrrenal insufficiency.
2. JG Cox 2 dependent Na and water retention.
3. Rare ability to cause papillary necrosis on habitual
intake.
Renal effects more marked in pts of
CHF, Hypovolemia, hepatic cirrhosis renal disease, pts on
diuretics and antihypertensive----edema

21. Anaphylactoid reaction
 Aspirin precipitates
Bronchial asthma, angioneurotic swelling…

22. Aspirin
 Aspirin is acetyl salicylic acid converted in
body to salicylic acid.
 MOA-aspirin inhibits COX irreversibly by
acetylating one of its serine residue.

23. Pharmacological actions
1.Analgesic- relives pain related to inflammation, tissue
injury, connective tissue etc.
MOA:
-obtunding peripheral receptors
-prevents PGs mediated nerve ending sensitization.
-raises threshold for pain perception in central sub
cortical regions.
2.Antipyretic- resets the hypothalamic thermostat.
3.Antiinflammatorysigns of inflammation like pain, tenderness, swelling,
vasodilatation and leukocyte infiltration are suppressed.

24.  Metabolic effects:
At anti-inflammatory doses: 1.↑ heat loss 2.↓ blood sugar
 Respiration:
At anti-inflammatory doses - increased respiratory rate.
In salicylate poisoning- resp.depression
 Acid base balance and electrolyte balance
-Initially Increased Co2 production and its washout resp.alkalosis.
-Later Co2 retention –resp. acidosis (high doses)
-Followed by metabolic acidosis.
-dehydration occurs in poisoning.
 CVS:
At toxic doses –depresses VMC, BP falls, CHF may precipitate
 Urate excretion:
Dose related effect….

25.  Blood
TXA2 inhibition.
 GITEpigastric distress, nausea and vomiting
Ion trapping
Back diffusion of H+ ions
Focal necrosis of mucosal cells
Acute ulcers

26. Adverse effects
 Side effects
Nausea, vomiting ,gi distress
Gastric mucosal damage, peptic ulceration.
 Hypersensitivity
 Anti-inflammatory doses-
Salicylism-(3-6g/day)
Dizziness, tinnitus, vertigo, reversible impairment in hearing and vision,
excitement ,mental confusion, hyperventilation, electrolyte imbalance.
In children-
Liver damage
Reye’s syndrome-hepatic encephalopathy esp. in children
having viral infection.
 Acute salicylate poisoningMore common in childrens, fatal dose for adults 15-16g

27. Precautions and
contraindications
Peptic ulcer
Sensitive pts
Children suffering from influenza, chickenpox
Chronic liver diseases
Diabetics
CHF, lower cardiac reserve
Pregnancy
Delayed labor, more postpartum bleed, premature
closure of ductus arteiosus
 G6PD deficiency








28. Interactions
 Aspirin displaces warrfarin,
naproxen,sulfonylurese, phenytoin from its
pp binding sites-toxicity of these agents.
 Inhibits tubular secretion of uric acid and
antagonizes action of uricosuric agents.
 Blunts action of diuretics

29. Pharmacological actions
 Analgesia
 Antipyretic
 Antiinflammatory
 Dysmenorrhea
 Antiplatelet
 Ductus arteriosus closure
 Parturition

30. 1. As
Uses of aspirin
analgesic-condn.
Aspirin 300mg-600mg 6-8.hlly
2. As antipyretic- in various infections, PUO
3. Acute rheumatic fever4. Rheumatoid arthritis5. Osteoarthitiis6. Postmyocardial infraction & poststroke patients.
Aspirin 60-100mg/day
7. Otherpregnancy induced hypertension
preeclamcia
to delay labour
to close patent ductus arteriosus

31. Indole derivatives-
Indomethacin
•
•
•
Potent anti-inflammatory, antipyretic, analgesic.
Inhibit neutrophil motility.
High incidences of GIT and CNS side effects.
•
Uses:
1.
2.
3.
4.
5.
6.
7.
RA not responding to Aspirin.
Ankylosing spondilytis.
Acute exacerbation of destructive orthopathies.
Psoriatic arthritis
Malignancy asso. refractory fever.
DOC- PDA- dose:0.1-0.2mg/ kg12 hourly
Bartter’s syndrome.

32. Ibuprofen,
Naproxen, Ketoprofen
Propionic acid derivatives-
 Analgesic
Antipyretics
Antiiflammatory
 Inhibit PG synthesis (Nonselective COX in.)
 Naproxen being most potent & better tolerated anti-
inflammatory drug.
 Longer acting twice dosing require.
 They inhibit platelet aggregation & prolong bleeding time.

33. Pharmacokinetics Ibuprofen 400-800mg TDS
 Naproxen 250mg BD…(Gout)
 Ketoprofen 50-100mg BD
 Flubiprofen- ocular anti inflammatory
- Better tolerated orally and the incidences of adverse
reactions are low.
- Highly protein bound drugs like aspirin can displace
warrfarin, sulfonylurese, phenytoin from its pp binding
sites…..toxicity of these agents.

34. Adverse effects
Better tolerated than aspirin
 Gastric discomfort
 Gastric erosion
 N&V
 Dizziness
 Blurring of vision
 Tinnitus & depression
 Rashes & hypersensitivity reaction

35. uses









Simple analgesics and antipyretic
(as low dose aspirin)
Dysmenorrhea as inhibit PGs OTC
RA, ankylosing spondilytis
OA
Musculoskeletal pain
Soft tissue injuries
Fractures
Tooth extraction
Postpartum & postoperatively

36. Anthranyllic acid derivatives-
Mephenaimic acid

Analgesic, antipyretic, anti-inflammatory.
inhibit COX
antagonizes certain actions of PGs.

M.A. :
exerts peripheral as well as central analgesic
action.

S/E-
diarrhea
epigastric distress
skin rash, dizziness

Uses-
 Dose-
analgesic, effective in dysmenorrhea
250-500mg TDS

37. Aryl acetic acid derivative-
Diclofenac sodium
 Similar in efficacy to Naproxen.
 Anti inflammatory action- reduces
neutrophil chemotaxis and superoxide
production.
 Dose:50mg BDUses-same as Ibuprofen.

38. Oxicam derivatives-
Piroxicam, Tenoxicam
 Long acting potent NSAIDs similar to
Indomethacin.
 Decreases production of IgM rheumatoid factor.
 Reduces leucocytes proliferation and ratio of T
-helper cells to T- suppressor cells.
 Meloxicam new congener of Piroxicam is
selective for COX II 10 times more than COX I.

39. Pyrrole derivatives

Ketorolac
Novel analgesic, modest anti inflammatory drug.
In post operative pain it has equaled efficacy of
Morphine but do not have morphine like side effects.
Uses:
1. Post operative pains
2. Acute musculoskeletal pain
3. Renal colic
4. Migraine
5. Pain due to metastasis.
Dose-10-20mg 6hrly

40. preferential cox2 inhibitor
Nimesulide
 Used mainly short lasting painful conditions-
sport injuries, sinusitis, ear nose disorders, dental
surgery, bursitis, low backache, dysmenorrhea,
po. pain, o.a.
 S/E - fulminant hepatitis
bronchospasm
 Dose-100mg.

41. Cox-1 vs. Cox-2
The reality.
Arachidonic acid
COX-1
“Constitutive”
Prostaglandins
• GI cytoprotection
• Platelet activity
• Renal function
COX-2
“Inducible”
Prostaglandins
Pathological
• Inflammation
• Pain
• Fever
Physiological
• Renal function
• Vascular
• Tissue repair

42. Thromboxane A2 vs.
Prostacyclin
ARACHIDONIC ACID
COX -1
Platelet
TXA2
Vasoconstriction
Platelet Aggregation
COX -2
Endothelial PGI2
(Prostacyclin)
Vasodilation
Anti-Platelet Aggregation

43. Why do Cox-2 inhibitors increase risk for heart disease?
#1. Because they adversely effect the ratio of thromboxane to prostacyclin
Aspirin
COX-1
COX-2 inhibitors
Prostacyclin Thromboxane
Thromboxane
Decreased
CV events
COX-2
Prostacyclin
Increased
CV events

44. Selective COX2 inhibitors
 Celecoxib 100-200mgBD
 Rofecoxib 12.5-25mg OD
 Valdecoxib 20mg BD
 Low ulcerogenic potential
-TXA2 level were not reduced
-Other Side effects are low
 Pedal edema & rise in B.P occurs as a result of salt and water
retention due to inhibition of constitutive COX II in JG cells. This
may precipitate CHF.
 COX II inhibition –inhibits PGI2 –prothrombotic
influence….increased cardiovascular events. QT changes in ECG
 Use- for long term use as analgesic in chronic pain.

45. Paracetmol
 Acetaminophen
 Good & promptly acting antipyretic.
 Analgesic- central action
peripheral action
 Negligible anti-inflammatory action.
 Poor inhibitor of PG synthesis in
peripheral tissues
 More active on COX in brain

46.  In contrast to aspirin-
does not stimulate respiration
does not affect acid base balance.
or cellular metabolism.
 No effect on
CVS.
platelets.
 GIT-insignificant effects
P/K- metabolism by glucuronic acid conjugation.
S/E- safe drug at antipyretic dose.
Analgesic nephropathy (at toxic doses)
Papillary necrosis
Tubular atrophy
Renal fibrosis
Renal failure

47.  Acute paracetmol poisoning- small children
- having low hepatic glucuronide conjugating ability.
- if large doses >250mg/kg
Manifestations• Nausea , vomiting.
• Abdominal pain
• Liver impairment- hepatic necrosis
• Impaired consciousness
• Renal tubular necrosis
RxGastric lavage, activated charcoal
N-acetylcysteine 150mg/kg i.v over 15 mins followed by
same dose over 20 hrs.

48. Choice of NSAIDs
 Mild to moderate pain with inflammationParacetmol, Low dose Ibuprofen
 Acute musculosketal, OA, injury associated with
inflammationDiclfenac, Rofecoxib.
 Postoperative-
Ketorolac.
 Gastric intolerance –
Cox2 inhibitors.
 Pt. with allergy to aspirin & other NSAIDs -
Nimesulide.

49. Non-Opioid Analgesics
1. A suggested treatment algorithm
(American Journal of Medicine 105, 53S-60S, 1998)
Moderate-to-severe pain
Moderate pain
Mild-to-moderate pain
Opioids or Tramadol
NSAIDs or Tramadol
Acetaminophen or Ibuprofen