This document provides information on paracetamol and various nonsteroidal anti-inflammatory drugs (NSAIDs). It describes paracetamol's mechanism of action, pharmacokinetics, uses, advantages over aspirin, and toxicity in overdose. It then discusses several classes of NSAIDs including propionic acid derivatives like ibuprofen and naproxen, fenamate derivatives like mefenamic acid, acetic acid derivatives like indomethacin, selective COX-2 inhibitors like celecoxib and meloxicam, and their mechanisms, pharmacokinetics, uses, and adverse effects. Clinical indications and formulations of specific NSAIDs are also mentioned.

5. DR.V.SATHYANARAYANAN M.B.B.S., M.D., ACME
PROFESSOR OF PHARMACOLOGY
NSAIDs II

8. PARACETAMOL
(ACETAMINOPHEN )
 Para-amino Phenol derivative
 Analgesic like aspirin and has additive action with
aspirin
 Good and promptly acting antipyretic
 But has negligible anti-inflammatory action
 Poor inhibitor of PG synthesis in peripheral tissues
but more active on COX in brain
 UNLIKE ASPIRIN  does not stimulate respiration
or affect acid-base balance or increase cellular
metabolism, no CVS action, not uricosuric

11. PARACETAMOL – PK and ADVERSE
EFFECTS
 Well absorbed orally, uniformly distributed
 Metabolism by  glucuronide and sulfate conjugation
 Rapidly excreted in urine
 T1/2  2-3 hrs, effects last for 3-5 hrs
 SAFE and WELL TOLERATED
 Nausea, rashes  occasional
 Gastric irritation is insignificant – mucosal erosion,
bleeding occur rarely only in overdose
 Does not affect platelet function or clotting factors

12. PARACETAMOL - USES
 Most commonly used ‘OVER-THE COUNTER’
ANALGESIC
 Headache, mild migraine, Dysmenorrhoea,
musculoskeletal pain etc
 Relatively ineffective when inflammation is
prominent
 First choice analgesic for osteoarthritis
 Fever due to any cause, especially in children (
except heat stroke )

14. ADVANTAGES OF PARACETAMOL OVER
ASPIRIN
 Safer in terms of gastric irritation, ulceration and
bleeding
 Can be given to ulcer patients
 Used in all age groups ( infants to elderly)
 Does not prolong bleeding time
 Hypersensitivity reactions are rare
 No metabolic effects
 No acid-base disturbances
 Safe in pregnant/lactating women
 Safe in the presence of other diseases
 No significant drug interactions

18. ACUTE PARACETAMOL POISONING
 Occurs especially in children ( low hepatic glucuronide
conjugating ability )
 > 10 g in an adult  serious toxicity
 Fatalities common > 250 mg/kg
 MANIFESTATIONS  Nausea, vomiting, abdominal
pain and liver tenderness, no impairment of
consciousness ( EARLY)
 AFTER 12-18 HRS  centrilobular hepatic necrosis, May
be accompanied by renal tubular necrosis and
hypoglycemia  may progress to COMA
 JAUNDICE  starts after 2 days
 High plasma levels  hepatic failure and death
 Lower levels  recovery with supportive treatment

24. MECHANISM OF TOXICITY
 N-acetyl-p-benzoquinoneimine (NABQI) is a highly
 reactive arylating metabolite of paracetamol  detoxicated
by conjugation with glutathione.
 When a very large doses of paracetamol are taken the
glucuronidation capacity is saturated more NABQI is formed,
 hepatic glutathione is depleted
 NABQI binds covalently to proteins in liver cells (and renal
tubules) causing necrosis.
 In chronic alcoholics even 5 g/d can result in hepatotoxicity
 because ethanol induces CYP 2E1, that metabolizes Paracetamol
to NABQI.

26. TREATMENT
 Induce vomiting or Gastric lavage
 Activated charcoal is given orally or through the tube  to
prevent further absorption
 Other supportive measures ( A B C )
 SPECIFIC ANTIDOTE : N–acetylcysteine 150 mg/kg
infused I.V in 200 ml 5% Glucose solution over 15 minutes
followed by same dose I.V over next 20 hours
 Or 75 mg/kg may be given orally every 4-6 hours for 2-3
days
 Started 16 hours or more after paracetamol ingestion 
INEFFECTIVE
 It replenishes glutathione stores of liver  prevents
binding of toxic metabolite to other cellular constituents

29. NONSTEROIDAL ANTI-
INFLAMMATORY DRUGS
(NSAIDs)
 Common therapeutic indications
 Common adverse effects
 Different pharmacokinetics and potency
 Different chemical families
 Common mechanism of action
(cyclooxygenase inhibition)
 Different selectivities to COX I and II
Similarities more striking than
Differences..!!

31. PROPIONIC ACID DERIVATIVES
 Ibuprofen
 Naproxen
 Ketoprofen
 Flurbiprofen

32. IBUPROFEN
 SAFEST TRADITIONAL NSAID
 Better tolerated alternative to aspirin
 more efficacious than aspirin 650 mg +codeine 60 mg in relieving
dental surgery pain
 Weaker antiinlammatory
 Milder side effects
 Gastric discomfort, nausea, vomiting  most common
 CNS side effects headache, dizziness, tinnitus , blurring vision
 Hypersensitivity reactions  rashes, itching infrequent
 Ppt aspirin induced asthma
 Fluid retention  less marked
 C/I  PREGNANCY, PEPTIC ULCER

39. IBUPROFEN – PK & INTERACTIONS
 Well absorbed orally
 90-99% bound to plasma proteins
 Displacement reactions are not significant
 Likely to decrease the efficacy of antihypertensives
 Enters brain, synovial fluid
 Crosses placenta
 Metabolized in liver --. Hydroxylation and glucuronide
conjugation
 Excreted in urine and bile
 Abolishes the antiplatelet and cardio protective effect of low
dose aspirin

41. IBUPROFEN – USES
 Available as an “over the counter” drug
 Used as a simple analgesic and antipyretic as aspirin
 Particularly effective in dysmenorrhoea
 Widely used in rheumatoid arthritis, osteoarthritis and
other musculoskeletal disorders especially where pain is
predominant
 Soft tissue injuries, Fractures
 Tooth extraction
 Postpartum and post operatively  suppress pain &
inflammation

45. NAPROXEN
 Similar to Ibuprofen
 Stronger anti-inflammatory activity
 Potent in inhibiting leukocyte migration  more valuable in
acute gout  750 mg stat followed by 250 mg 8 hourly
 Also recommended for rheumatoid arthritis and ankylosing
spondylitis
 Longer t1/2  suppress platelet function
 Gastric bleeding more common than ibuprofen
 Carries lower thrombotic risk
 Reduce the dose in elderly
 MORE EFFICACIOUS AND BETTER among propionic acid
derivatives

51. KETOPROFEN
 Antiinflammatory efficacy  similar to ibuprofen
 Side effects are more
 Additional actions  stabilize lysosomes and inhibit
LOX

54. FLURBIPROFEN
 Has Additional mechanisms of antiinflammatory
actions  MORE EFFECTIVE THAN IBUPROFEN
 Gastric side effects are also more
 Also used as an OCULAR ANTIINFLAMMATORY

58. FENAMATE – MEPHENAMIC ACID
 ANALGESIC, ANTIPYRETIC AND WEAKER
ANTIINFLAMMATORY DRUG
 SIDE EFFECTS  Diarrhoea  most important,
 Epigastric distress, CNS side effects, Skin rashes
 Hemolytic anemia  rare but serious
 PK  Slow oral absorption, highly bound to PP
 USES  Primarily as an analgesic for muscle , joint and soft
tissue pain  250-500 mg TDS
 Quite effective in dysmenorrhoea
 May be useful in some cases of rheumatoid arthritis and
osteoarthritis

62. PIROXICAM
 Enolic acid derivative
 Long acting potent antiinflammatory
 Good analgesic and antipyretic
 Nonselective reversible inhibitor of COX
 Inhibit inflammation in diverse ways  inhibit WBC
Chemotaxis, decreases free radicals production, IgM
Rheumatoid factor
 PK  rapidly absorbed, 99% protein bound,
enterohepatic cycling occurs,
 long t1/2  2 days  single daily dose

67. PIROXICAM – ADR & USES
 GI side effects  more than ibuprofen
 Low doses are better tolerated and less ulcerogenic than
indomethacin
 Ulcer, bleeding  frequent in higher doses
 Rashes, pruritus, edema, reversible azotemia
 USES Suitable for use as long-term antiinflammatory
drug in rheumatoid arthritis, ankylosing spondylitis,
osteoarthritis etc
 Also used in dentistry, acute gout, musculoskeletal injuries
 higher toxicity  NOT A FIRST CHOICE DRUG

72. TENOXICAM
 Congener of piroxicam
 Similar properties and uses

76. ACETIC ACID DERIVATIVES
 Ketorolac
 Indomethacin
 Nabumetone

77. KETOROLAC
 Potent analgesic but modest antiinflammatory
 Equalled the efficacy of morphine in postoperative
pain
 Free of opioid side effects
 Inhibits PG synthesis
 Rapidly absorbed after oral, I.M administration
 Highly plasma protein bound
 t1/2  5-7 hours

84. KETOROLAC – ADR and USES
 GI side effects  nausea, dyspepsia, abdominal pain,
ulceration, loose stools
 CNS side effects  drowsiness, headache, dizziness
 SKIN  pruritus
 Rise in serum transaminases, fluid retention
 USES  POSTOPERATIVE, DENTAL,
MUSCULOSKELETAL PAIN  15-30 mg I.M or I.V
every 4-6 hours
 Also used for renal colic, migraine, metastases in bone
 Non infective ocular conditions
 Orally  for short term management of moderate pain

90. KETOROLAC – PRECAUTIONS AND
CONTRAINDICATIONS
 Continuous use for more than 5 days  NOT
RECOMMENDED ( risk of GI and renal toxicity )
 Preanaesthetic medication  C/I
 Obstetric analgesia  C/I
 Not for RH. Arthritis or osteoarthritis

94. INDOMETHACIN
 is a potent nonselective COX inhibitor
 may also inhibit phospholipase A and C, reduce neutrophil
migration, and decrease T cell and B cell proliferation.
 indicated for use in juvenile rheumatoid arthritis, gout and
ankylosing spondylitis, postepisiotomy pain, etc.
 It has been used to treat patent ductus arteriosus.
 An ophthalmic preparation seems to be efficacious for
conjunctival inflammation and to reduce pain after traumatic
corneal abrasion.
 Gingival inflammation is reduced after oral rinse.
 A high incidence (up to 50%) of GI and CNS side effects is
produced: GI bleeding, diarrhoea, frontal headache, mental
confusion, etc.

98. Acetic acid derivatives
sulindac
 prodrug– metabolite is 500times more potent
 adverse skin reactions
aceclofenac
 has significant analgesic and anti-inflammatory
effect
 with good tolerance (low occurrence of GIT adverse
effects)
 higher adherence to treatment of chronic diseases

99. DICLOFENAC
 is a phenylacetic acid derivative.
 A 0.1% ophthalmic preparation is recommended for prevention of
postoperative ophthalmic inflammation and can be used after
intraocular lens implantation and strabismus surgery.
 A topical gel containing 3% diclofenac is effective for solar keratoses.
 Diclofenac in rectal suppository form can be considered a drug of
choice for analgesia and postoperative nausea.
 It is also available for intramuscular and oral administration
 – SR tablet: 100 mg/24 h).
 Side effects occur in approximately 20%: GI distress and occult
bleeding, gastric ulceration.
 A preparation combining diclofenac and misoprostol (PGE1) decreases
upper GI ulceration but may result in diarrhoea.

105. Clinical uses
DICLOFENAC
 A) Any inflammatory conditions
 B) Musculoskeletal pain
 C) Dysmenorrhoea
 D)Acute gouty arthritis
 E) Fever
 F) Locally to prevent or treat post opthalmic
inflammation
 G) A topical gel for solar keratoses

107. COX-2 inhibitors
(1) Selective COX-2
inhibitors (Coxibs)
• Celecoxib
• Etoricoxib
• Parecoxib
(2) Preferential
COX-2 inhibitors
• Meloxicam
• Nimesulide
• Nabumetone

109. • are selective COX-2 inhibitors
• They exert antiinflammatory, analgesic,
and antipyretic action with low
ulcerogenic potential.
• can cause infertility.
•They have prothrombotic cardiovascular
risk.
COXIBS

115. • is as effective as other NSAIDs in the treatment of
rheumatoid arthritis and osteoarthritis
• in trials it has caused fewer endoscopic
ulcers than most other NSAIDs.
• because it is a sulfonamide, celecoxib may
cause rashes.
• It does not affect platelet aggregation at usual
doses.
• It interacts occasionally with warfarin –
Celecoxib

118. •is a second-generation COX-2-selectiveinhibitor with the
highest selectivity ratio of any coxibs.
•has an eliminationt1/2 of 22 h.
•for the treatment of the symptoms of osteoarthritis (60 mg
once daily) and rheumatoid arthritis (90 mg once daily),
•acute gouty arthritis (120 mg once daily), and for the relief of
acute musculoskeletal pain (60 mg once daily).
•Ninety mg daily of etoricoxib has superior efficacy compared
with 500 mg of naproxen twice daily in the treatment of
rheumatoid arthritis over 12 weeks.
• Etoricoxib has similar efficacy to traditional NSAIDs for osteo
arthritis, acute gouty arthritis, and primary dysmenorrhea and
has a GI safety profile similar to other coxibs.
Etoricoxib

120. •is an enolcarboxamide
•preferentially inhibit COX-2 over COX-1,
• particularly at its lowest therapeutic dose of 7.5
mg/d.
•It is not as selective as the other coxibs
• may be considered “preferentially" selective rather
than “highly” selective.
•approved for the treatment of osteoarthritis and
rheumatoid arthritis.
•It is associated with fewer clinical GI symptoms
and complications than piroxicam, diclofenac, and
naproxen..
Meloxicam

127. •is a derivative of pyrazolone.
•It is a potent and promptly acting analgesic, antipyretic, and spasmolytic but has poor
antiinflammatory and not uricosuric activity.
•Analgin can be given orally, i.m. as well as i.v. (very slowly).
•Pain at the i.m. injection site and rarely abscess can occur. Occasionally
an i.v. injection produces fall in BP.
• Few cases of agranulocytosis were reported and
•metamizole was banned in the USA and some European country.
•However, it has been extensively used in Bulgaria and many other as well
as in India and Russia.
•Adverse reaction data collected over four decades shows that the risk of
serious toxicity with metamizole is very low than with Aspirin or many other
NSAIDs.
METAMIZOLE

133. Comparative action between
COX inhibitors
COX-1/COX-2
inhibitors
COX-2
inhibitors
1. Analgesic action (+) (+) (+)
2. Antipyretic action (+) (+)
3. Antiinflammatory action (+) (+) (+)
4. Antiplatelet aggregatory (+) (-)
5. Gastric mucosal damage (+) (+) (+) (+)
6. Renal salt / water retention (+) (+)
7. Delay/prolongation of labor
8. Infertility
(+) (+)
(-)
(+)
(+) (+)
9. Ductus arteriosus closure (+) ?
10. Aspirin-like asthma
11. Cardiotoxicity
(+)
(-)
?
(+) (+)

136. Prevention of Adverse effects
 Dose reduction
 Combination with protective drugs
 Antiulcerotics– proton pump inhibitors (lansoprazole,
omeprazole)
 prostaglandine analogues (substitution)
 H2 antihistamines – (cimetidine, ranitidine, famotidine)
 antacids
 think about selective COX-2 inhibitors

140. THANK YOU!