This document provides information on non-narcotic analgesics (NSAIDs) that have analgesic, antipyretic, and anti-inflammatory properties. It discusses the inflammatory process and pain pathway, how NSAIDs work by inhibiting prostaglandin synthesis via inhibition of cyclooxygenase enzymes, and the classification of various NSAIDs including aspirin, ibuprofen, naproxen, indomethacin, and others. It covers the pharmacological actions, pharmacokinetics, uses, and adverse effects of different NSAID classes.

1. Non Narcotic Analgesics/NSAIDs
[Analgesic, Antipyretic, Antiinflammatory]
Presented By
Mohammad Sharique
M Pharm 1st Sem (Pharmacology)
KLE College of Pharmacy Bangalore
Submitted to : (Prof) Dr. Bhagya. V. Rao
1

2. Inflammation
 Immune system’s protective response to an injurious stimulus.
 It can be evoked by noxious agents, infections, and physical injuries.
 The ability to mount an inflammatory response is essential for survival in
the face of environmental pathogens and injury.
 In some situations and diseases, inflammation may be exaggerated and
sustained without apparent benefit and even with severe adverse
consequences - (e.g., hypersensitivity, automimmune diseases, chronic
inflammation).
2

3. The inflammatory response is characterized by
• transient local vasodilation and increased capillary permeability,
• increased leukocyte migration,
• fibrosis.
3

4.  Nociceptors and peripheral
terminals of primary afferent
fibers that sense pain, can be
activated by various stimuli, such
as heat, acids, or pressure.
 Inflammatory mediators »»
bradykinin, 5HT, ATP,
neurotrophins (nerve growth
factor), LTs, and PGs. PGE2 and
PGI2 increase the sensitivity of
nociceptors and potentiate pain
perception.
4
Fig. no. 1

5. 5
Fig. no. 2 Pain Pathway

6. NSAIDs and prostaglandin (PG) synthesis
inhibition
• Prostaglandins, prostacyclin (PG I2) and thromboxane A2 (TXA2) are produced
from arachidonic acid by the enzyme cyclooxygenase.
• COX in 2 isoforms : constitutive COX 1 and inducible COX 2, COX 1 serves house
keeping functions, COX-2 is generated by cytokines during inflammation
(constitutive in brain and JG cells) – PG synthesis.
• NSAIDs inhibits prostaglandin synthesis.
• Most NSAIDs inhibit COX-1 and COX-2 non-selectively and inhibit PG synthesis.
6

7. 7
Fig. no : 3. COX LOX Pathway

8. 8
Fig. no. 4 : Synthesis and inhibition of PGs, TXA.

9. Non Narcotic Analgesic
• Also called nsaids, nonopioid or aspirin like analgesics
• All drugs grouped in this class have analgesic, antipyretic and
antiinflammatory actions in different measures.
• Do not depress CNS, do not produce physical dependence, have no abuse
liability and are weaker analgesics.
• They act primarily on peripheral pain mechanisms, but also in the CNS to
raise pain threshold.
9

10. CLASSIFICATION
A. Nonselective COX inhibitor (traditional NSAIDs)
1. Salicylates: Aspirin.
2. Propionic acid derivatives : Ibuprofen, Naproxen, Ketoprofen,
Flubiprofen.
3. Fenamate: Mephenamic acid.
4. Enolic acid derivatives: Piroxicam, Tenoxicam.
5. Acetic acid derivatives: Ketorolac, Indomethacin, Nabumetone.
6. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone.
B. Preferential COX-2 inhibitors
Nimesulide, Diclofenac, Aceclofenac, Meloxicam, Etodolac.
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11. CLASSIFICATION
C. Selective COX-2 inhibitors
Celecoxib, Etoricoxib, Parecoxib.
D. Analgesic-antipyretics with poor antiinflammatory action
1. Paraaminophenol derivative : Paracetamol (Acetaminophen).
2. Pyrazolone derivatives : Metamizol (Dipyrone), Propiphenazone.
3. Benzoxazocine derivative : Nefopam.
11

12. Analgesic effect
 PGs induce hyperalgesia »» affecting the transducing property of free
nerve endings.
 Primarily inhibits COX-2.
 NSAIDs block the pain sensitizing mechanism induced by bradykinin, TNFα,
interleukins (ILs) and other algesic substances.
 This constitutes the peripheral component of the analgesic action of
NSAIDs. They are, therefore, more effective against inflammation
associated pain.
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13. Antipyretic effect
 Body temperature is elevated in fever, infection, tissue damage,
inflammation, graft rejection.
 These conditions enhances formation of cytokines such as IL-1β, IL-6, TNF-
α, and interferons, which act as endogenous pyrogens.
 Mediators stimulates synthesis of PGs.
 PGE2 can cross the blood-brain barrier and acts on EP3 and EP1 receptors
on thermosensitive neurons »» triggers the hypothalamus to elevate body
temperature »» increase in heat generation and decrease in heat loss.
NSAIDs suppress this response by inhibiting COX-2–dependent PGE2
synthesis.
13

14. Antiinflammatory
 Inhibition of PG synthesis : Arachidonic acid » COX » PGs.
 Inhibition of chemotaxis : Decreases proinflammatory mediator.
 Down regulation of Interleukin-I production.
 Decreases production of free radicals : reduces oxidative stress (-COX 2).
 Decreases sensitivity of blood vessels to bradykinin and histamine.
14

15. Antiplatelet aggregatory
 Therapeutic doses of most NSAIDs inhibit platelet aggregation : bleeding
time is prolonged.
 Except COX 2 selective and non acetylated salicylate all NSAIDs has
antiplatelet action.
 Risk of surgical and anticoagulant associated bleeding is enhanced.
15

16. Ductus arteriosus closure
The ductus arteriosus is a hole that allows the blood to skip the circulation to
the lungs.
When the baby is born, the blood must receive oxygen in the lungs and this
hole is supposed to close. If the ductus arteriosus is still open (or patent) the
blood may skip this necessary step of circulation.
Every baby is born with a ductus arteriosus. After birth, the opening is no
longer needed and it usually narrows and closes within the first few days.
When this fails to occur, small doses of indomethacin or aspirin bring about
closure in majority of cases within a few hours by inhibiting PG production.
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17. Ductus arteriosus closure
17
Fig. no. 5

18. Dysmenorrhoea
 Severe pain during menstruation – Caused by increased release of PGs
(PGF2α).
 Intermittent ischaemia of myometrium – menstrual cramps.
 NSAIDs - decrease PG release.
18

19. SALICYLATES
ASPIRIN
 Aspirin is acetylsalicylic acid.
 Converted in the body to salicylic acid.
 Oldest analgesic, antiinflammatory drug.
 Lower doses -- for the prevention of cardiovascular events, such as stroke
and myocardial infarction (MI).
 Aspirin is a weaker analgesic than morphine type drugs: aspirin 600 mg ~
codeine 60 mg.
19

20. 1. Analgesic, antipyretic,
antiinflammatory actions
 Aspirin irreversibly inhibits COX-1 & COX-2
activity by acetylation.
 Mainly effective in pains related to
inflammation, tissue injury, connective tissue
and integument pain. Not much effective in
visceral and ischemic pain.
20
Fig. no. 6 : Inactivation of COX

21. Pharmacological Actn Cntnd
 Antiinflammatory action is exerted at high doses (3–6 g/day or 100 mg/kg/
day).
 The analgesic action is mainly due to obtunding of peripheral pain
receptors and prevention of PG-mediated sensitization of nerve endings.
 Aspirin resets the hypothalamic thermostat and rapidly reduces fever by
promoting heat loss, but does not decrease heat production.
21

22. Pharmacological Actn Cntnd
2. Metabolic effects
 Cellular metabolism is increased in skeletal muscles.
 There is increased utilization of glucose → blood sugar may decrease
(especially in diabetics) and liver glycogen is depleted.
 Hyperglycaemia often occurs at toxic doses : due to central sympathetic
stimulation → release of Adr and corticosteroids.
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23. Pharmacological Actn Cntnd
3. Acid Base and electrolyte balance
 In therapeutic dose salycilates cause respiratory alkalosis.
 In toxic dose respiratory centre is depressed and can lead to respiratory
acidosis.
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24. Pharmacological Actn Cntnd
4. GIT
 Salicylic acids are irritant to mucosa causing nausea, also stimulates CTZ
and causes vomiting.
 Aspirin (pKa 3.5) remains unionized and diffusible in the acid gastric juice,
but on entering the mucosal cell (pH 7.1) it ionizes and becomes
indiffusible. This ‘ion trapping’ in the gastric mucosal cell enhances gastric
toxicity »» acute ulcers, erosive gastritis.
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25. Pharmacological Actn Cntnd
5. Blood
 It inhibits the platelet aggregation by decreasing the production of TXA2
lasts for a week.
 In doses greater than 6 gm/day, aspirin may reduce plasma prothrombin
levels.
 Prolonged use – decrease in synthesis of clotting factors »» bleeding. This
can be prevented by prophylactic vit K therapy.
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26. Pharmacokinetics
 Absorbed from stomach and small intestine.
 Poorly water soluble.
 Deacetylated in the gut wall, liver, plasma and other tissues to release
salicylic acid.
 80% bound to plasma proteins and has a volume of distribution 0.17 L/kg.
 Entry into brain is slow, but aspirin freely crosses placenta. Both aspirin
and salicylic acid are conjugated in liver with glycine to form salicyluric
acid.
26

27.  The metabolites are excreted by glomerular filtration and tubular
secretion.
 30 - 50 mg - t1/2 is 15-20 minutes.
 300 to 650 mg - t1/2 is 3 hours.
 1 gram and 2 gram - t1/2 is 5 - 9 hours.
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28. Adverse effects
 Gastrointestinal disturbances - Nausea, vomiting, epigastric distress and
gastric mucosal damage
 Rash, urticaria, asthma (bronchospasm – aspirin sensitive asthmatics)
 Salicylism : on repeated administration (3-5 gm/day)
– headache, mental confusion, drowsiness
– tinnitus and difficulty in hearing
– hyperthermia, sweating, hyperventilation
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29.  Hepatotoxicity – Reye's Syndrome – rare disease of hepatic
encephalopathy when given in viral conditions of influenza and varicella.
 Nephrotoxicity
 Prolongation of bleed time.
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30. Contraindications
 Children with viral diseases.
 Peptic ulcer disease and bleeding disorders.
 Chronic liver diseases.
 Stop prior to surgery, near term pregnancy, breast feeding mothers etc.
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31. Interactions
 Aspirin and Probenecid
– Antagonize Uricosuric action of probenecid
– Probenecid become ineffective in Gout
 Aspirin and oral anticoagulants (warfarin and sulfonylureas) – Toxicity
(increased tendency of bleeding).
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32. Uses
 Analgesic : Backache, myalgia, toothache, joint pain, pulled muscle and
dysmenorrhoea.
 Acute Rheumatic fever : 75 – 100 mg/kg/day (or, 4 – 5 gm/day) – marked
symptomatic relief in all cases – dose reduced after 4 - 7 days and
maintained for 2 - 3 weeks till s/s stops.
 Rheumatoid Arthritis : Reduction in pain, swelling and stiffness – large
dose.
 Osteoarthritis.
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33.  Post-myocardial infarction and post stroke : Routinely used – inhibits
platelet aggregation (TXA2) at low dose (60 – 100mg/day).
 New onset or sudden onset angina (risk of infarction) - 75 to 150 mg/day
for 12 weeks.
 Other uses: PIH (pregnancy induced hypertension), PDA (Patent ductus
arteriosus).
33

34. Propionic acid derivative
Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen
• Analgesic, antipyretic and anti-inflammatory efficacy is lower than aspirin
(low potency) – all inhibits PG synthesis (Naproxen – most potent)
– Antiplatelet activity – short with Ibuprofen but longer with naproxen
• Adverse Effects: Better tolerated than aspirin and Indomethacin, milder –
gastric discomfort, nausea, vomiting, gastric erosion rarely.
– CNS effects - headache, dizziness, blurring of vision, tinnitus.
– Rash, itching and hypersensitivity are less.
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35. Pharmacokinetics
- All are well absorbed orally.
- 90-99% plasma protein bound.
- Inhibits platelet function – use with anticoagulants are avoided.
- Decreases antihypertensive and diuretic actions of furosemide, thiazides and beta
blockers.
Uses
Ibuprofen
Simple analgesic and antipyretic – like low dose aspirin, effective in dysmenorrhoea,
also in Rh. Arthritis, OA and musculoskeletal disorders. Also in soft tissue injuries,
fractures, vasectomy, tooth extraction, postpartum and post operative pain.
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36. Naproxen
Inhibition of leucocyte migration
Preferred in acute gout – stronger anti-inflammatory.
Longer half-life (12-16 hours)
Flurbiprofen
More effective than ibuprofen, but gastric side effects are also more. It is used
as an ocular antiinflammatory.
36

37. FENAMATE (Anthranilic acid derivative)
Mefinamic acid
Analgesic, antipyretic and weak anti-inflammatory – inhibition of certain PG
synthesis, peripheral + central analgesic action.
Pharmacokinetics : Slow oral absorption, but complete, bound to plasma
protein, t1/2 is 2 - 4 hours.
Uses: indicated primarily as analgesic in muscle, joint and soft tissue pain.
ADRs : Diarrhoea, epigastric distress, skin rash, dizziness.
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38. ENOLIC ACID DERIVATIVES (Oxicams)
Piroxicam
• Long acting, anti-inflammatory, analgesic-antipyretic action.
• Reversible, non-selective COX inhibition.
• Lowers PG concentration in synovial fluid and inhibits platelet
aggregation—prolonging bleeding time.
• Decreases the production of IgM rheumatoid factor and leucocyte
chemotaxis »» inhibit inflammation.
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39. Pharmacokinetics
 99% plasma protein bound; largely metabolized in liver by hydroxylation
and glucuronide conjugation; excreted in urine and bile.
 Plasma t½ is long— nearly 2 days.
Adverse effects
 g.i. side effects are more than ibuprofen.
 better tolerated and less ulcerogenic than indomethacin causes less faecal
blood loss than aspirin.
 Rashes and pruritus are seen in < 1% patients.
 Edema and azotaemia.
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40. Uses
Piroxicam is used in Rheumatoid and osteo-arthritis, ankylosing spondylitis,
acute gout, musculoskeletal injuries and in dentistry.
40

41. Acetic acid Derivatives
Indomethacin
• Indole acetic acid derivative - Potent anti-inflammatory and prompt
antipyretic.
• Relieves only inflammatory and injury related pain
• Highly potent inhibitor of PG and neutrophil motility
Pharmacokinetics : well absorbed orally, 90% PP bound and t1/2 2 – 5
Hours
41

42. Uses : ankylosing spondylitis, arthritis, postoperative pain, malignancy
associated fever, medical closure of PDA.
Contraindications: machinery operators, drivers, psychiatric & epileptic
patients, kidney disease, pregnancy & children.
ADRs : High incidence of gastric irritation, nausea, anorexia, bleeding and
diarrhoea, mental confusion, hallucination, depression and psychosis,
Leucopenia, etc.
– Increased risk of bleeding.
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43. Acetic acid derivatives
Ketorolac
 Potent analgesic – but modest anti-inflammatory – post operative pain –
equal efficacy with Morphine.
 Inhibits PG synthesis – inhibits pain peripherally
Uses
 Given IM and orally - Post-operative, dental, musculo-skeletal pain.
 Also in renal colic, migraine – short term management of moderate pain.
 Topical ketorolac is used for noninfective ocular conditions.
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44. Pharmacokinetics: Well absorbed orally and IM – highly plasma protein
bound; t1/2 5 - 7 Hrs, 60% excretes unchanged in urine.
ADRs : Nausea, abdominal pain, dyspepsia, ulceration, dizziness,
nervousness, pain in injection site.
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45. Pyrazolones
Metamizole
 Metamizole (Analgin) is a derivative of Amidopyrine.
 It is a potent and promptly acting analgesic, antipyretic, and spasmolytic
but poor antiinflammatory.
 Analgin can be given orally, i.m. as well as i.v. (very slowly)
ADR : Agranulocytosis
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46. Preferential COX-2 inhibitors
Nimesulide
 Weak PG synthesis inhibitor, moderate COX-2 selective.
 Other Mechanisms : reduced superoxide generation by neutrophils,
inhibition of PAF, TNFα release & free radical scavenging.
 Completely absorbed and 99% plasma protein bound.
 Half life – 4-5 hours and excreted in urine.
Uses : sports injuries, sinusitis, dental surgeries, renal colic, arthritis,
postoperative inflammatory condition, fever, low back pain, ear-nose-throat
disorders, dental surgery, bursitis, fever.
46

47. ADRs : epigastric pain, nausea, rash, pruritus, somnolence and dizziness,
Ulceration, Fulminant hepatic failure.
Diclofenac
 Analgesic-antipyretic and antiinflammatory.
 Inhibits PG synthesis – COX-2 selective.
 Reduced Neutrophil chemotaxis and reduced superoxide generation.
 No antiplatelet action (COX-1 sparing).
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48. Pharmacokinetics
» 99% plasma protein boung – 2 hours half-life
» Good tissue and synovial fluid penetration.
Uses : Most widely used drug – RA, OA, bursitis, alkylosig spondilytis,
toothache, dysmenorrhoea, renal colic, post trauma and post inflammatory
conditions.
ADRs : Mild epigastric pain, nausea, headache, dizziness and rashes
less gastric ulceration and bleeding.
Risk of heart attack and stroke.
48

49. Aceclofenac
 Aceclofenac is indicated for the relief of pain and inflammation in
osteoarthritis, rheumatoid arthritis and alkylosing spondylitis.
 Through COX-2 inhibition, aceclofenac downregulates the production of
various inflammatory mediators including prostaglandin E2 (PGE2), IL-1β,
and TNF from the arachidonic acid (AA) pathway.
 Volume of distribution is approximately 25 L.
 protein-bound (>99%)
49

50.  4'-hydroxyaceclofenac is the main metabolite, others are diclofenac, 4-
hydroxy diclofenac.
 elimination is via the urine.
 About 20% of the dose is excreted into feces.
 half life 4 hours.
 gastro-intestinal disorders (dyspepsia, abdominal pain, nausea), urticaria,
symptoms of enuresis, headache, dizziness, and drowsiness.
50

51. Etodolac
 moderately COX-2 selective with properties similar to diclofenac. At lower
doses, gastric tolerance is better than older NSAIDs.
 It is metabolized by hydroxylation and glucuronide conjugation, and
excreted in urine with a t½ of 7 hours.
 Side effects are abdominal pain, rashes and dizziness. It is approved for
use in osteo- and rheumatoid arthritis as well as in acute musculoskeletal
pain.
51

52. Selective COX-2 inhibitors
Celecoxib
 Inhibit COX-2, exerts antiinflammatory, analgesic and antipyretic actions
with low ulcerogenic potential.
 effective in Rheumatoid arthritis as naproxen, diclofenac.
 Celecoxib is slowly absorbed, 97% plasma protein bound and metabolized
primarily by CYP2C9 with a t½ of ~10 hours.
 abdominal pain, dyspepsia and mild diarrhoea are the common side
effects. Rashes, edema and a small rise in BP have also been noted.
52

53. Para-amino phenol derivatives
Paracetamol (acetaminophen)
• It is deethylated active metabolite of Phenacetin.
• Analgesic – Like aspirin - Antipyretic, raises pain threshold, no peripheral
anti-inflammatory action.
• Good promptly acting antipyretic.
• No stimulation of respiration or affect acid base balance (unlike aspirin), no
increase in cellular metabolism.
• No Gastric erosion or platelet function alteration.
53

54. Paracetamol – contd.
Pharmacokinetics : orally absorbed, 1/4th PP bound, t1/2 is 3 – 5 hours,
Metabolism by conjugation with glucoronic acid and sulfate.
Paracetamol Uses
• Most commonly used – over the counter drug.
• Headache, mild migraine, musculoskeletal pain dysmenorrhoea etc.
• 1st choice in osteoarthritis, not effective in Rheumatoid arthritis.
• Safest Antipyretic in children – no Reye`s syndrome.
54

55. ADRs : Dark urine, Yellowish skin, Liver damage.
Advantages
1) lesser gastric irritation, ulceration and bleeding (can be given in ulceration)
2) does not prolong bleeding time
3) Hypersensitivity rarely
4) no metabolic disturbances
55

56. Topical NSAIDS
Many NSAIDs have been marketed in topical formulations (mostly as gels) for
application over painful muscles or joints. These preparations are being used for
osteoarthritis, sprains, sports injuries, tenosinovitis, backache, spondylitis and
other forms of soft tissue rheumatism.
Slow absorption – 10 times longer time to attain peak plasma conc. to oral dosing.
Diclofenac sodium gel 1% gel (Voltaren)
Diclofenac epolamine 1.3 % patch (Flector)
56

57. Topical NSAIDS
Advantages
1. Attains higher conc. Locally in muscles and joints.
2. GI and other systemic ADRs are minimized
3. First pass metabolism avoided
57

58. Licofelone
 Belongs to a novel class of dual-acting anti-inflammatory drugs called
COX/LOX inhibitors.
 This group of drugs simultaneously inhibits the enzymes cyclooxygenase
(COX) and 5-lipoxygenase (LO), phase III trials have been successfully
completed in OA patients.
 reduces levels of inflammatory prostaglandins and leukotrienes.
58

59. Lumiracoxib
 For the acute and chronic treatment of the signs and symptoms of
osteoarthritis.
 Inhibition of prostaglandin synthesis via inhibition of cyclooygenase-2 (COX-2).
 Lumiracoxib does not inhibit COX-1 at therapeutic concentrations.
 more closely resembles the structure of diclofenac.
 bioavailablity of 74%.
 plasma proteins (>= 98%).
 4'-hydroxy-lumiracoxib, 5-carboxy-lumiracoxib, and 4'-hydroxy-5-carboxy-
lumiracoxib.
 half life 4 hours.
59

60. References
1. Lippincott Illustrated Review Pharmacology, 6th edition
2. Goodman Gilman's The Pharmacological basis of Therapeutics, 13th edition.
3. Essentials of Medical Pharmacology by KD tripathi 7th edition.
4. www.drugbank.com
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