This a presentation on Non Steroidal Anti Inflammatory Drugs

1. NONSTEROIDAL
ANTI INFLAMMATORY DRUGS
MODERATOR: Dr. M E Sham
PRESENTED BY: Dr. Rayan

2. CONTENTS:
 Introduction
 Classification
 NSAIDs and Prostaglandins
 Mechanism of action
 Beneficial actions due to PG synthesis inhibition
 Shared toxicities due to PG synthesis inhibition
 Individual drugs
 References

3. INTRODUCTION

4. Antiinflammatory drugs
 Steroid- Glucocorticoids
 Nonsteroidal-Aspirin like

5. All drugs grouped in this class have three main actions in different
measures:
 ANALGESIC
 ANTIINFLAMMATORY
 ANTIPYRETIC
They are also called
“Nonnarcotic ,Nonopioid ,or Aspirin like analgesics”
Definition:
NSAIDs are chemically diverse class of drugs(>70 NSAIDs in use) that
have antiinflammatory , analgesic, and antipyretic properties.

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

7. B) Preferential cox-2 inhibitor
Nimesulide, Meloxicam, Diclofenac
C) selective cox- 2 inhibitors-
Celecoxib, Etoricoxib, Parecoxib
D) Analgesics- Antipyretics with poor anti-inflammatory
1.Paraaminophenol derivative: Paracetamol
2.Pyrazolone derivatives: Metamizol
3.Benzoxazocine derivative: Nefopam

8. NSAIDs and Prostaglandins
 Prostaglandins, Prostacyclins,Thromboxane A2 are produced from
arachidonic acid by the enzyme cyclooxygenase
 Cyclooxygenase exists in two forms. They are:
1.Cox-1-Constitutive
(House keeper)
Mucus secretion, Haemostasis, renal functions
2. Cox-2 Inducible-
Inflammatory response
Sites-brain, JG cells (constitutive)

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

10. Biosynthesis of prostaglandins

11. Mechanism of action
 When a tissue is injured, from any cause, prostaglandin synthesis in
that tissue increases.
 PGs have TWO major actions:
They are mediators of inflammation
They also sensitize pain receptors at the nerve endings,
lowering their threshold of response to stimuli and allowing
the other mediators of inflammation

12.  Naturally, a drug that prevents the synthesis of PGs is likely to be
effective in relieving pain due to inflammation of any kind
 In 1971 Vane and coworkers made the landmark observation that
aspirin and some NSAIDs blocked PG generation.
 This they do by inhibiting cyclo –oxygenase (COX) enzyme in the
pathway for PGs synthesis

13. Beneficial actions due to PG synthesis inhibition
 Analgesia
 Antipyresis
 Antiinflammatory
 Antithrombotic
 Closure of ductus arteriosus
 Dysmenorrohea

14. 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.
 NSAIDS block this pain sensitizing mechanism induced by these
algesics, therefore effective against inflammation associated pain.

15. Antipyresis
 Fever in infection is produced by pyrogens, TNF, ILs, interferon-
induce production of PGs in hypothalamus-raise its temprature set
point.
 NASIDs block the action of pyrogens(cox-2).

16. Anti-inflammatory
 Inhibition of PG synthesis at the site of injury.
 Anti-inflammatory action of each drug corresponds with their
potency to inhibit COX.

17. Antiplatelet
 Inhibit synthesis of TXA2 by acetylating platelet COX irreversibly.
 By inhibiting platelet aggregation lowers the incidence of
reinfarction.

18. Ductus arteriosus closure
 PGE2, responsible for maintaining patency in foetal circulation.
 At birth ductus closes

19. Dysmenorrhea
Involvement of PG’s in dysmenorrhea is demonstrated by
 Increase levels of PGs in menstrual blood flow
 Endometrial biopsies
 PGF2 metabolite in circulation are raised in dysmenorrhoeic
women
Myometrial ischemia –menstrual cramps.
 NSAIDs-lowers uterine PGs--relief

20. Renal effects
 Conditions like hypovolaemia, decrease renal perfusion, and Na+
loss- induce renal PG synthesis –leading to vasodilatation, inhibition
of cl, Na, water reabsorption and opposing Antidiuretic action.
 NSAIDs produce renal effects by-
1. Cox-1 dependent impairment of renal blood flow and reduction in
gfr- can worsen renal 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 patients of
CHF, hypovolemia, hepatic cirrhosis, renal disease and patients on
diuretics and antihypertensives----edema can occur

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

22. Shared toxicities due to PG synthesis
inhibition
 Gastric mucosal damage
 Bleeding
 Limitation of renal blood flow/Na+ & water retention
 Delay/prolongation of labour
 Asthma and anaphylactoid reactions in susceptible individuals

23. Gastric mucosal damage
 Inhibition of synthesis of gastro protective PGS (E2,I2)- decrease in
mucus,HCO3,increases acid secretion, may promote mucosal
ischemia.

24. Bleeding
 Inhibition of platelet function
 Bleeding time is prolonged
 Risk of surgical bleeding is increased

25. Anaphylactoid reaction
 Aspirin precipitates bronchial asthma, angioneurotic swellings,
urticaria, rhinitis
 By inhibiting COX

26. Salicylates-Aspirin
 Aspirin is acetyl salicylic acid converted in body to salicylic acid.
 Mechanism of action - aspirin inhibits COX irreversibly by
acetylating one of its serine residue.

27. Pharmacological actions
1.Analgesic- Relives pain related to inflammation, tissue injury,
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 and reduces fever by
promoting heat loss.

28. 3.Antiinflammatory-
Signs of inflammation like pain, tenderness, swelling, vasodilatation and
leukocyte infiltration are suppressed.
4.Metabolic effects-
At anti-inflammatory doses there is:
-Increased cellular metabolism
-Increased heat production
-decrease blood sugar level(especially in diabetics)
But in toxic doses hyperglycemia is often seen.

29. 5. Respiration:
-At anti-inflammatory doses – respiration is stimulated
-In salicylate poisoning- hyperventilation is prominent
-Further rise in salicylate level causes respiratory depression
6. Acid – base and electrolyte balance:
-Initially increased Co2 production and its washout causes respiratory alkalosis.
-Later Co2 retention causes respiratory acidosis (high doses)
-Followed by metabolic acidosis.
-Dehydration occurs in poisoning.

30. 7. CVS:
-In therapeutic doses – no direct effect
-At toxic doses –depresses vasomotor centre – BP may fall
-CHF may be precipitated
8. GIT:
-Causes epigastric distress, nausea and vomiting
-Focal necrosis of mucosal cells and capillaries- acute ulcers, erosive
gastritis, congestion and microscopic hemorrhages

31. 9. Urate excretion: Dose related effect:
< 2g/day - urate retention and antagonism of all other uricosuric drugs.
2-5g/day – often no change
>5g/day – increased urate excretion
10.Blood:
-TXA2 synthesis inhibition
-Interferes with platelet aggregation
-Bleeding time is prolonged

32. Pharmacokinetics
 Absorbed from stomach and small intestine
 Poor water solubility is the limiting factor
 Solubility is more at higher pH
 Rapidly deacetylated in the gut wall, liver, plasma and other tissues
to salicylic acid
 80% bound to proteins
 Volume of distribution=0.17L/kg
 Slowly enters the brain but freely crosses placenta

33.  Conjugated in the liver by glycine and glucuronic acid
 Excreted by glomerular filtration as well as tubular secretion
 t1/2 of aspirin as such is 15-20min
 Taken together with that of released salicylic acid is 3-5hrs
 Metabolic processes get saturated over therapeutic range
 t1/2 of antiinflammatory doses may be 8-12hrs
 While that during poisoning may be upto 30hrs
 Thus elimination is dose dependant

34. Adverse effects
a) Gastrointestinal:
 Most common
 Epigastric distress, Nausea, Vomiting
 Increased occult blood loss in stools
 Gastric mucosal damage and peptic ulcer
b) Rey’s syndrome:
 Occurs in infants and children
 Occurs when aspirin given during viral infections
 Characterized by liver damage and encephalopathy
 Replaced by acetaminophen in such condition to reduce fever

35. c) Hypersensitivity:
 Though infrequent, these can be serious
 Reactions include; rashes, urticaria, angioedema, rhinorrhoea,
asthma and anaphylactoid shock
d) Salicylism:
 High doses(at antiinflammatory doses) or chronic use of aspirin
may induce a syndrome characterised by tinnitus, hearing defects,
blurring of vision, dizziness, headache and mental confusion
 Effects are reversible

36. e) Acute salicylate poisoning:
 More common in children
 Fatal dose in adults estimated to be 15-30gm, but considerably low
in children
 Serious toxicities seen at serum levels >50mg/dl
Manifestations are:
-vomiting, dehydration, electrolyte imbalance, acidotic breathing,
hyper/hypoglycemia, petecheal hemorrhages, restlessness, delirium,
hallucinations, hyperpyrexia, convulsions, coma and death due to
respiratory and cardiovascular failure

37. Treatment:
 Symptomatic and supportive
 Gastric lavage
 i.v. infusion of Na+, K+, HCO3 and glucose(dextrose-5%)
 Vitamin K 10mg i.v.
 Haemodialysis

39. Interactions
 Aspirin displaces warfarin, naproxen, phenytoin from its binding sites-
toxicity of these agents.
 Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to interact with
the oral anticoagulant warfarin and can cause a serious bleeding
complication. NSAIDs can affect the pharmacologic action of warfarin
through their direct interaction. High protein binding and the cytochrome
P450 (CYP)-dependent clearance mechanisms of NSAIDs can affect the
serum levels of warfarin
Choi KH et al. Risk Factors of Drug Interaction between Warfarin and Nonsteroidal Anti-Inflammatory Drugs in Practical
Setting.
Journal of Korean Medical Science. 2010;25(3):337-341

40.  Sequential administration of naproxen and low-dose aspirin interferes with
the irreversible inhibition of platelet cyclooxygenase 1 afforded by aspirin.
 Salicylates displace phenytoin from plasma binding sites, thus raising its
level in plasma and producing anticonvulsant effect
Anzellotti P et al, Low-dose naproxen interferes with the antiplatelet effects of aspirin in healthy subjects: recommendations
to minimize the functional consequences;Arthritis Rheum. 2011 Mar;63(3):850-9

41. Precautions and contraindications
 Peptic ulcer
 Sensitive patients
 Children suffering from influenza, chickenpox
 Chronic liver diseases
 Diabetics
 CHF, lower cardiac reserve
 Pregnancy
Delayed or prolonged labor, more postpartum blood loss, premature closure of
ductus arteriosus
 G6PD deficiency
 Before elective surgery
 Breastfeeding mothers

42. Interactions
 Aspirin displaces warfarin, naproxen, sulfonylureas, phenytoin from
its plasma proteins binding sites-toxicity of these agents.
 Inhibits tubular secretion of uric acid and antagonizes action of
uricosuric agents.
 Blunts action of diuretics

43. Uses:
1. As analgesic-
Aspirin 300mg-600mg 6-8.hlly
2. As antipyretic
3. Acute rheumatic fever 4-5 g/day
4. Rheumatoid arthritis 3-5 g/day
5. Osteoarthitiis
6. Post myocardial infraction & post stroke patients
Aspirin 60-100mg/day
7. Other-
pregnancy induced hypertension
preeclampsia
to delay labour
to close patent ductus arteriosus

44. Aspirin – Doses(oral)
 As analgesic and antipyretic:
 0.3-0.6gm, 6-8 hourly
 Acute rheumatic fever:
 75-100mg/kg/day in divided doses/4-6 days
 50mg/kg/day/2-3wks- maintenance dose
 Rheumatoid arthritis:
 3-5gm/day
 Cardio protective:
 80-100mg/day
Trade name:
ECOSPRIN(75,150,325 mg tab), DISPRIN(350mg tab)
LOPRIN(75,162.5mgtab)

45. Propionic acid Derivatives
These are:
Ibuprofen, naproxen, flurbiprofen and ketoprofen
 Analgesic, antipyretic and anti-inflammatory efficacy is lower
than high dose of aspirin.
 All inhibit PG synthesis

46. Adverse effects
Better tolerated than aspirin
 Gastric discomfort
 Gastric erosion
 Nausea & vomiting
 Dizziness
 Blurring of vision
 Tinnitus & depression
 Rashes & hypersensitivity reaction

47. Pharmacokinetics
 Well absorbed orally
 Highly bound to plasma proteins
 Can cross placenta
 Metabolised in liver by hydroxylation
 Excreted in urine as well as bile

48. Uses:
 As simple analgesic and antipyretic
 Dysmenorrhea
 Rheumatoid arthritis, osteoarthritis
 Soft tissue injuries
 Fractures
 Tooth extraction
 Postpartum & postoperatively

49. Dosage:
 Ibuprofen 400-600mg TDS
 Naproxen 250mg BD…(Gout)
 Ketoprofen 50-100mg BD
 Flurbiprofen- ocular anti inflammatory, 1 drop 6 hourly
Trade name:
BRUFEN(200,400,600 mg tab)
NAPROSYN(250 mg tab)
KETOFEN(50,100 mg tab)
ARFLUR(50,100 mg tab)

50. Anthranilic acid derivatives-
Mephenamic acid
 Analgesic, antipyretic, anti-inflammatory
 Inhibits COX
 Antagonizes certain actions of PGs
 Exerts peripheral as well as central analgesic action
 Adverse effects:
diarrhea,
epigastric distress,
skin rashes, dizziness
haemolytic anaemia

51.  Pharmacokinetics:
 Oral absorption is slow but complete
 Highly bound to plasma proteins.
 Excreted in urine as well as bile.
 Plasma t1/2 is 2-4 hours
 Uses- analgesic,
effective in dysmenorrhea
 Dose- 250-500mg TDS
 Trade name:
MEDOL(250, 500mg cap), MEFTAL(250,500mg tab)

52. Aryl - acetic acid derivative-
Diclofenac sodium, Aceclofenac
 Analgesic, antipyretic, anti-inflammatory
 Similar in efficacy to naproxen
 Inhibits PG synthesis and is somewhat cox-2 selective
 Anti inflammatory action- reduces neutrophil chemotaxis and
superoxide production at the inflammatory site

53. Pharmacokinetics
 Well absorbed orally
 99% protein bound
 Metabolised and excreted both in urine and bile
 Plasma t1/2 is 2 hours
 Has good tissue penetrability and concentration in synovial fluid is
maintained for 3 times longer than in plasma

54.  Adverse effects:
epigastric distress,
skin rashes, dizziness,
nausea, headache
 Uses:
Rheumatoid and osteoarthritis,
ankylosing spondylitis,
toothache,
dysmenorrhea

55.  Dose:
Diclofenac sodium – 50mg bd
Aceclofenac - 100mg bd
 Trade name:
VOVERAN, DICLONAC(50mg,100mg tab)
ACECLO, DOLOKIND(100mg tab)

56. Para-amino phenol Derivatives
Paracetamol:(acetaminophen)
 Deethylated active metabolite of phenacetin
Mechanism of action:
 Poor inhibitor of PG synthesis in peripheral tissues
 More active on cox in brain
 So, poor peripheral antiinflammatory component , more potent as
analgesic and antipyretic

57. Pharmacokinetics:
 Well absorbed orally
 25% plasma protein bound
 Metabolism occurs mainly by conjugation with glucuronic acid and
sulfate
 Excreted rapidly in urine
 T1/2 is 2-3 hours
Adverse effects:
 In isolated antipyretic doses paracetamol is safe and well tolerated
 Rashes and nausea occur occasionally

58.  Analgesic nephropathy:
• Occurs after years of heavy ingestion
• Papillary necrosis, tubular atrophy, renal fibrosis occurs
• Urine concentrating ability is lost
• Kidneys shrink
 Acute paracetmol poisoning:
• Occurs in small children having low hepatic glucuronide conjugating
ability
• If a large doses is taken (>150mg/kg or >10 gm in an adult)

59. Manifestations:
 Nausea, vomiting, abdominal pain, liver tenderness
 After 12-18 hours centrilobular hepatic necrosis
 Hypoglycaemia may progress to coma
Treatment:
 Vomiting should be induced
 Gastric lavage
 Activated charcoal is given
 N-acetylcysteine(MUCOMIX, ANTIFEN 2OOmg/ml inj)

60. Uses:
 As analgesic for headache, mild migraine, musculoskeletal pain
 Dysmenorrhoea
 Osteoarthritis
 As antipyretic
Dose:
0.5-1gm TDS
Trade name:
CROCIN(0.5,1gm tab), CALPOL(500mg tab)

61. Oxicam derivatives- Piroxicam
 Long acting potent NSAID with anti inflammatory potency similar
to Indomethacin
 Good analgesic and antipyretic action
 Reversible inhibitor of cox
 In addition it decreases the production of IgM rheumatoid factor and
leucocyte chemotaxis

62. Pharmacokinetics
 Rapidly and completely absorbed
 99% plasma protein bound
 Metabolised in liver by hydroxylation and glucuronide conjugation
 Excreted in urine and bile
 Plasma t1/2 is 2 days
Adverse effects:
• Gastrointestinal side effects are more than ibuprofen, but it is better tolerated and
less ulcerogenic than indomethacin.
• Less faecal blood loss than aspirin

63. Uses:
Rheumatoid and osteoarthritis
ankylosing spondylitis,
toothache, dysmenorrhea
acute gout
Dose:
20 mg bd for two days followed by 20 mg od
Trade name:
DOLONEX, PIROX(10,20 mg cap)

64. Pyrrolo-pyrrole derivative-Ketorolac
 Acetic acid derivative
 Potent analgesic and modest anti inflammatory activity.
 In post operative pain it has equaled efficacy of morphine but do
not have morphine like side effects.
 It inhibits PG synthesis

65. PHARMACOKINETICS:
 Rapidly absorbed after oral and IM administration
 Highly plasma protein bound
 Excreted in urine
 Plasma t1/2 is 5-7 hours
Adverse effects:
Nausea, abdominal pain,
dyspepsia, ulceration,
ulceration, loose stools
drowsiness, pain at injection site

66. Uses:
1. Post operative pain
2. Acute musculoskeletal pain
3. Renal colic
4. Migraine
5. Pain due to metastasis
6. Dental pain
Dose:
 15-30mg i.m. or i.v. every 4-6 hours(max. 90mg/day)
 Orally 10-20 mg 6 hourly for not more than 5 days
Trade name:
KETOROL, KETANOV(10mg tab)

67. Indole derivatives- Indomethacin
• Potent anti-inflammatory with prompt antipyretic action
• Inhibits PG synthesis
• Suppresses the neutrophil motility
PHARMACOKINETICS:
 Well absorbed orally, rectal absorption is slow
 Highly plasma protein bound
 Metabolised in liver
 Excreted in urine
 Plasma t1/2 is 2-5 hours

68. Adverse effects:
• High incidence of GIT and CNS side effects
Gastric irritation, nausea, anorexia
gastric bleeding, diarrhea
frontal headache, dizziness
mental confusion, psychosis
Uses:
Because of prominent adverse effects indomethacin is used as a reserve
drug in conditions requiring potent anti-inflammatory action like:
Ankylosing spondylitis,
acute exacerbation of destructive arthropathies,
psoriatic arthritis,
acute gout

69.  Other uses:
Malignancy associated fever
Bartter’s syndrome
For closure of patent ductus arteriosus
 Dose:
25-50mg bd orally
Three 12 hourly doses of 0.1-0.2 mg/kg for closure of ductus
arteriosus
 Trade name:
INDOFLAM(25, 75 mg cap), IDICIN(25,27 mg cap)

70. Pyrazolone Derivatives
Aminopyrine and antipyrine:
 Introduced in 1884
 Associated with agranulocytosis, are banned in many countries
including India.
Phenylbutazone and oxyphenbutazone:
 Introduced in 1949
 Potent anti-inflammatory drugs
 Gastric toxicity is high
 Edema and CNS side effects are seen
 Hence now it is rarely used

71. Metamizol:
 Derivative of amidopyrine
 Potent analgesic and antipyretic
 Gastric irritation and pain at injection site occurs
 Few cases agranulocytosis were reported
 Rarely used now a days
 Dose: 0.5-1.5 gm oral/i.m./i.v
 Trade name: ANALGIN, NOVALGIN(0.5 gm tab)

72. Preferential COX-2 inhibitors
Nimesulide:
Newer NSAID which is relatively weak inhibitor of PG synthesis
Mechanism of action:
 Preferential COX-2 inhibitor
 Antiinflammatory action may be exerted by other mechanisms also
such as:
-Reduced generation of superoxide by neutrophils
-Inhibition of TNF-alpha release

73. Pharmacokinetics:
 Well absorbed orally
 99% plasma protein bound
 Excreted mainly in urine
 T1/2 2-5 hours
Adverse effects:
Gastrointestinal- epigastralgia, heart burn, nausea, loose motions
Dermatological- rash, pruritus
CNS- dizziness
Liver- hepatic faliure
Renal- haematuria in children

74. Uses:
 Used mainly for short-lasting painful conditions-
sport injuries, sinusitis, ear nose disorders,
dental surgery, bursitis, low backache,
dysmenorrhoea, post operative pain,
osteoarthritis
Dose:
100mg bd
Trade name:
NIMULID, NIMEGESIC, NIMODOL(100mg tab)

75. Selective COX-2 Inhibitors
 Selectively block COX-2 activity more than COX-1 activity
This group includes:
Celecoxib, Rofecoxib and Valdecoxib
 Celecoxib is available in india
 Rofecoxib and Valdecoxib have been withdrawn for increasing
cardiovascular risk

76. Celecoxib:
 It exerts anti-inflammatory, analgesic, antipyretic action with low
ulcerogenic potential
Pharmacokinetics:
 Slowly absorbed, 97% plasma protein bound
 Metabolised primarily by CYP2C9
 T1/2 is 10 hours

77. Adverse effects:
Abdominal pain, dyspepsia, mild diarrhoea
Uses:
Rheumatoid arthritis
Dose:
100-200mg bd
Trade name:
CELACT, COLCIBRA(100, 200 mg caps.)

78. REFERENCES
- Goodman and Gilman’s: The pharmacological basis of Therapeutics
12th edition
- Essentials of medical pharmacology, KD Tripathi
- Pharmacology and pharmacotherapeutics, R.S.Satoskar,
S.D.Bhandarkar, 19th edition

79. THANK YOU