Basics of Non Steroidal Anti Inflammatory Drugs

1. NON STEROIDAL ANTI-INFLAMMATORY
DRUGS
POST GRADUATE STUDENT
DEPARTMENT OF PERIODONTOLOGY

2. CONTENTS
 Introduction
 History
 Classification
 Mechanism of action
 Common properties of all NSAIDs
 Individual drugs
 Choice of NSAIDS
 NSAIDS in periodontics
 Conclusion
 References

4. PAIN
 Definition: An unpleasant emotional experience usually initiated by a noxious
stimulus and transmitted over a specialized neural network to the central nervous
system where it is interpreted as such- (Monheims)

6. PAIN CONTROL
• ANALGESICS: A drug that selectively relieves pain by acting in CNS or on peripheral pain
mechanism, without significantly altering consciousness.
ANALGESICS
Opioid analgesics Non opioid analgesics

7. COMPARED TO OPIODs, NSAIDS ARE :
• Weaker analgesics (except for inflammatory pain)
• Don’t depress CNS
• Don’t produce physical dependence
• No abuse liability

12. NSAIDS
Nonselective COX
inhibitors
(traditional
NSAIDs)
B. Preferential
COX-2 inhibitors
Analgesic-
antipyretics with
poor
antiinflammatory
action
Selective COX-2
inhibitors

14.  Preferential COX-2
inhibitors Nimesulide,
Meloxicam, Etodolac.
Selective COX-2 inhibitors
Celecoxib, Etoricoxib,
Parecoxib.

15. ANALGESIC-ANTIPYRETICS WITH POOR ANTI INFLAMMATORY ACTION
Paraaminophenol derivative: Paracetamol
Pyrazolone derivatives: Metamizol,
Benzoxazocine derivative: Nefopam.

16. MECHANISM OF ACTION
• NSAIDs – inhibits COX-1 and COX-2 isoforms
• Decrease in PG and Thromboxane synthesis
• Antiinflammatory – reversible inhibition of COX-2
• Aspirin- irreversible inhibition of COX

19. SALICYLATES
Aspirin is acetyl salicylic acid , the prototype converted in the body to
salicylic acid – oldest analgesic .
Other important salicylates – Sulfasalazine , Diflunisal
Natural sources – fruits , vegetables, herbs , spices, nuts and tea

20. PHARMACOLOGICAL ACTIONS
• Analgesic action
• Antipyretic
• Anti inflammatory
• Antiplatelet
• GIT
• CVS

21. PHARMACOKINETICS
• Salicylates – rapidly absorbed from upper GI tract
• Distributed throughout the tissues and body fluids
• Metabolized – liver- glycine and glucuronide conjugation
• Low doses elimination First order kinetics
• High doses elimination Zero order kinetics

22. CONTRA INDICATIONS
• In patients with peptic ulcer, bleeding tendencies, in children
sufffering from chicken pox or influenza.
• In chronic liver disease: cases of hepatic necrosis have been
reported.
• Should be avoided in those with low cardiac reserve or frank CHF
and in juvenile RA.
• To be avoided in pregnant and breast feeding women.

27. PROPIONIC ACID DERIVATIVES
• Ibuprofen was the first member of this class to be introduced in
1969.
• Moderate anti-inflammatory effect.
• Better tolerated than Aspirin.
• Can be used in children (doesn’t cause Reye’s syndrome)
• Naproxen being most potent.

29. • The plasma t1/2 of Ibuprofen is 2hrs .
• Dosage is 400-600mg TDS.
• The plasma t1/2 of Naproxen is 12-16hrs.
• Dosage:- 250mg BD-TDS.
• CONTRAINDICATIONS:-
• Not to be prescribed to pregnant women and peptic ulcer patients

31. ANTHRANILIC ACID DERIVATIVE (FENAMATE)
Mephenamic acid :
• An analgesic, antipyretic and anti-inflammatory drug, known from
1950s, but has not gained popularity because of lower efficacy.
• Mephanamic acid exerts central as well as peripheral analgesic
actions.

32. Pharmacokinetics :
• Oral absorption is slow but almost complete. Highly bound to
plasma proteins .
• plasma t ½ is 2-4 hours.
• Dose: 250-500mg TDS
Uses :
• Analgesic in muscle, joint and soft tissue pain, dsymenorrohea,
rheumatoid and osteoarthritis.
• Antipyretic
• Weak anti-inflammatory effect

33. Adverse effects :
• Epigastric distress, skin rashes, dizziness and other CNS
manifestations.
• Haemolytic anaemia is rare but serious complication.

34. ARYL-ACETIC ACID DERIVATIVES
DICLOFENAC SODIUM:
• Potent atnti-inflammatory effect
• Gets concentrated in synovial fluid, hence preferred in
inflammatory conditions of joint
• Incidence of hepatotoxicity is more
• Diclofenac + misoprostol – reduces GI irritation and peptic ulcer

35. USES:-
• Diclofenac is the most extensively used NSAID; employed in
Rheumatoid and Osteo Arthritis, toothache, ankylosing spondylitis,
dysmenorrhoea, post traumatic and post inflammatory conditions-
affords quick relief of pain and wound edema.
• Dosage:-
• 50mg BD, 1OOmg OD

36. Pharmacokinetics
• It is well absorbed orally, 99% protein bound, metabolized and
excreted both in urine and bile.
• The plasma t1⁄2 is ~2 hours. Due to good tissue penetrability,
concentration in joints and other sites of inflammation is maintained
for longer period extending the therapeutic effect
Adverse effects :
• Epigastric pain, nausea, headache, dizziness, rashes.
• Gastric ulceration and bleeding are less common.

37. OXICAM DERIVATIVE
PIROXICAM
• It is long lasting action with potent anti inflammatory and good
analgesic action.
• It is a reversible inhibitor of COX, lowers PG synthesis and inhibits
platelet aggregation.
• In addition, it decreases the production of IgM Rheumatoid Factor
and reduces leucocyte chemotaxis-thus inhibits inflammation in
diverse ways.
• It is 99%plasma protein bound , plasma t1/2 is nearly 2 days.
• Dose is 20mg BD for two days followed by 20 mg OD.

38. Uses:-
• Short term analgesic as well as long term anti inflammatory in
Rheumatoid and OsteoArthritis, Ankylosing Spondylitis, Acute Gout,
musculoskeletal injuries and in dentistry.
Adverse effects:-
• Heart burn
• Rashes
• Nausea
• Edema

39. PYRROLE DERIVATIVE
KETOROLAC:
• This NSAID has potent analgesic , efficacy almost equal to morphoine
• Relieves pain without causing respiratory depression, hypotension and
drug dependence.
• Used in renal colic, postoperative and metastatic cancer pain

40. Pharmacokinetics:
• Ketorolac is rapidly absorbed after oral and i.m. administration.
• It is highly plasma protein bound and 60% excreted unchanged in
urine.
• plasma t1⁄2 is 5–7 hours.

41. Adverse effects :
• Nausea, abdominal pain, ulceration, loose stools, drowsiness,
headache, dizziness, nervousness, pruritus, pain at injection site, rise
in serum transaminase and fluid retention have been noted.
Uses:
• Ketorolac is frequently used in postoperative, dental and acute
musculoskeletal pain: 15– 30 mg i.m. or i.v. every 4–6 hours (max. 90
mg/ day).
• It may also be used for renal colic, migraine and pain due to bony
metastasis.

42. INDOLE DERIVATIVE:
Indomethacin:-
• This indole acetic acid derivative is a potent anti inflammatory drug
with prompt antipyretic action.
• Very effective in ankylosing spondylitis and psoriatic arthritis
• Side effects- GI, CNS
• Contraindicated in epileptic, psychiatric patients and drivers.

43. Pharmacokinetics:
• Indomethacin is well absorbed orally.
• It is 90% bound to plasma proteins, partly metabolized in liver to inactive products
and excreted by kidney.
• Plasma t1⁄2 is 2–5 hours.
Adverse effects:
• A high incidence (up to 50%) of gastrointestinal and CNS side effect is produced.
• Gastric irritation, nausea, anorexia, gastric bleeding and diarrhoea are prominent.
• Frontal headache (very common), dizziness, ataxia, mental confusion,
hallucination, depression and psychosis can occur.
Leukopenia, rashes and other hypersensitivity reactions are also reported.
• Increased risk of bleeding due to decreased platelet aggregability.

44. Uses:
• Indomethacin is used as a reserve drug in conditions requiring potent
anti inflammatory action like ankylosing spondylitis, , psoriatic arthritis
and acute gout or rheumatoid arthritis that are not responding to
better tolerated NSAIDs.
• Malignancy associated fever.
• medical closure of patent ductus arteriosus.

45. PYRAZOLONES
• Antipyrine (phenazone) and amidopyrine (aminopyrine) were introduced in
1884 as antipyretic and analgesic.
• Phenylbutazone was introduced in 1949 and soon its active metabolite
oxyphenbutazone was also marketed.
• These two are potent anti inflammatory drugs, inhibit COX, but have slow
onset, weak analgesic and antipyretic action.

46. PREFERENTIAL COX-2 INHIBITORS
NIMESULIDE:
• It is a week inhibitor of PG synthesis and indicate relative cox 2
selectively.
• Used in sports injury , sinusitis, dental surgery, post op pain , fever.
• Absorbed orally,99% plasma protein bound.
• T1/2 of 2-5hrs

47. SELECTIVE COX-2 INHIBITORS (Coxibs)
• The theoretical advantage of inhibiting COX-2 without affecting
COX-1 function, some highly selective COX-2 inhibitors are
introduced.
• They cause less gastric mucosal damage; occurrence of peptic ulcer
and ulcer bleeds is clearly lower than with traditional NSAIDs.
• They do not depress TXA2 production by platelets (COX-1
dependent); do not inhibit platelet aggregation or prolong bleeding
time, but reduce PGI2 production by vascular endothelium.

49. • Currently, 3 selective COX-2 inhibitors (also called coxibs) Celecoxib,
Etoricoxib and Parecoxib are available in India.
• Rofecoxib and Valdecoxib were withdrawn within few years of marketing
for increasing cardiovascular (CV) risk.
• It has been concluded that selective COX-2 inhibitors should be used only
in patients at high risk of peptic ulcer, perforation or bleeds.
• If selected, they should be administered in the lowest dose for the shortest
period of time.

50. CELECOXIB:
• It exerts anti inflammatory, analgesic and antipyretic actions with low
ulcerogenic potential.
• Comparative trials in rheumatoid arthritis have found it to be as effective as
naproxen or diclofenac, without affecting COX-1 activity in gastro duodenal
mucosa.
Pharmacokinetics:
• Celecoxib is slowly absorbed,
• 97% plasma protein bound . t1⁄2 of ~10 hours.
Dose:
• It is approved for use in osteo- and rheumatoid arthritis in a dose of 100–200 mg
BD.

52. Analgesic –antipyretics with poor anti-inflammatory effe
• PARACETAMOL:
• (Acetaminophen) the de ethylated active metabolite of phenacetin, was introduced in 1950.
• ACTIONS:
• The central analgesic action of paracetamol is like aspirin, i.e. it raises pain threshold, but has
weak peripheral anti inflammatory component.
• Analgesic action of aspirin and paracetamol is additive. Paracetamol is a good and promptly
acting antipyretic.
• Paracetamol has negligible anti inflammatory action. It is a poor inhibitor of PG synthesis in
peripheral tissues, but more active on COX in the brain.

53. PHARMACOKINETICS:
• Paracetamol is well absorbed orally, only about 1/4th is protein bound in plasma and it is
uniformly distributed in the body.
• Metabolism occurs mainly by conjugation with glucuronic acid and sulfate: conjugates are
excreted rapidly in urine.
• Plasma t1⁄2 is 2–3 hours. Effects after an oral dose last for 3–5 hours.
USES
• Paracetamol is one of the most commonly used ‘over-the-counter’ analgesic for headache,
mild migraine, musculoskeletal pain, dysmenorrhoea, etc. but is relatively ineffective when
inflammation is prominent as in rheumatoid arthritis.
• Paracetamol is recommended as first choice analgesic for osteoarthritis by many professional
bodies.
• In contrast to Aspirin, Paracetamol does not stimulate respiration or affect acid-base balance;
does not increase cellular metabolism. It has no effects on CVS, platelet function , gastric
mucosa.

54. PARACETAMOL TOXICITY
• Acute paracetamol poisoning- hepatotoxicity
• Symptoms- nausea, vomiting , diaeehoea, abdominal pain,
hypoglycemia, hypotension.
• Death- heaptic necrosis

55. MECHANISM OF TOXICITY AND TREATMENT
• Toxic metabolite – detoxified by conjugation with glutathione and gets
eliminated
• High doses- depletion of glutathione
• Toxic metabolites- proteins- liver and kidney- necrosis
• Alcoholics and premature infants – hepatotoxicity
• Oral methionine replenishes glutathione store of liver and protects the liver
• Activated charcoal – decrease the absorption of paracetamol from gut

56. GUIDELINES FOR USAGE OF NSAIDS
• Mild-to-moderate pain with little inflammation: paracetamol or low-dose ibuprofen.
• Postoperative or similar acute but short- lasting pain: ketorolac, a propionic acid
derivative.
• Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, acute
rheumatic fever: naproxen, piroxicam, indomethacin, high dose aspirin.
• Gastric intolerance to traditional NSAIDs or predisposed patients: a selective COX-2
inhibitor or paracetamol.
• Patients with history of asthma or anaphylactoid reaction to Aspirin or other NSAIDs:
Nimesulide, COX-2 inhibitor.
• Paediatric patients: only paracetamol, aspirin, ibuprofen and naproxen have been
adequately evaluated in children — should be preferred in them. Due to risk of
Reye’s syndrome, aspirin should be avoided.

57. HOST MODULATION BY NSAIDS
• Goldhaber and coworkers examined whether prostaglandins might be
responsible in part for the gingival-tissue extract mediated bone resorption. They
were studying by adding indomethacin to the culture media, as an inhibitor of
cyclooxygenase.
• The prostaglandin production blocked by indomethacin decreased the bone
resorption in tissue culture by up to 50% .
• Free arachidonic acid (AA) is produced in the hosts when phospholipase A2
acts on the phospholipids present in plasma membranes of the cells which can
then be metabolized to produce prostaglandins via the cyclooxygenase (COX)
pathway as well as leukotrienes via the lipoxygenase (LOX) pathway.

58. • Non steroidal anti inflammatory (NSAIDs) drugs block the activity of both
‐ ‐
cyclooxygenase isozymes (COX- 1 and -2) and many authors have demonstrated
the role of NSAIDs like flurbiprofen, indomethacin, and naproxen, in inhibiting
gingivitis and progression of periodontitis
• Since NSAIDs are lipophilic and are well absorbed into gingival tissues, its topical
application is possible.
• NSAIDs that have been evaluated for topical administration include ketorolac,
tromethamine rinse and S-ketoprofen dentifrice, piroxicam and meclofenamic
acid in inhibiting gingivitis and progression of periodontitis.

59. • Waite et al (1981) demonstrated that subjects taking several types of NSAIDs,
which included phenylbutazone, indomethacin, aspirin, a combination of
phenylbutazone and indomethacin, as well as other medications, had less
gingival inflammation and shallower pocket depths than a control population
not taking medications.
• In studying the NSAID ibuprofen and its effect on periodontal disease, Williams
et al. (1988) demonstrated that high (4 mg/kg) and low (0.4 mg/kg) doses of
ibuprofen in both sustained release and normal release formulations resulted
in reduction in the rate of bone loss.
THE EFFECT OF NSAIDS ON PERIODONTAL DISEASE

60. CONCLUSION

61. REFERENCES
• Tara V Shanbhag, Pharmacology for dentistry
• Tripati KD. Non steroidal anti inflammatory drugs. In: Essentials of medical pharmacology: 7, Jaypee
publishers; 2013: 192-205.
• General physiology book sembulingam.
• Caranza text book .8th edition.
• Tripati KD. Prostaglandins, leukotrienes and platelet activating factor. In: Essentials of medical
pharmacology: 7, Jaypee publishers; 2013: 181-191.
• Sembulingam for physiologyDewhirst. F. E.: 6-Keto-Prostaglandin El Stimulated Bone Resorption in Organ
Culture. Calcif. Tissue Int. 1984; 36:380-383.
• Heasman, P. A. and R. A. Seymour. The Effect of a Systemically-administered Nonsteroidal Anti
inflammatory Drug (Flurbiprofen) on Experimental Gingivitis in Humans. J Clin.Periodontol 1989; 16:551- 556.