The document discusses non-steroidal anti-inflammatory drugs (NSAIDs) and their role in periodontal disease treatment. It covers the definition of NSAIDs, their history of use, classification, mechanisms of action including inhibition of prostaglandin synthesis, and various types including salicylates, propionic acid derivatives, and selective COX-2 inhibitors. NSAIDs are proposed to have host modulatory properties for periodontal disease by suppressing inflammation and bone resorption mediated by prostaglandins. However, risks of adverse gastrointestinal effects must be weighed against potential benefits for periodontitis.

1. PREPARED BY:
DR. BEENA VIJAYAN PARVATHY
Ist YEAR MDS
DEPARTMENT OF PERIODONTICS AND
IMPLANTOLOGY
NSAIDs
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2. CONTENTS
• Introduction
• Definition
• History
•Classification
•Mechanism of Action
•Prostaglandins and Periodontitis
•Salicylates
•Propionic Acid Derivatives
•Anthranilic Acid Derivatives
•Aryl-acetic Acid Derivatives
•Oxicam Derivatives
•Pyrollo-pyrolle Derivatives

3. • Indole Derivatives
•Pyrazolone Derivatives
•Preferential Cox-2 Inhibitors
• Selective Cox-2 Inhibitors(coxibs)
•Para Amino Phenol Derivatives
•Choice Of NSAID’s
•NSAID’s As Host Modulatory Agents
•Risk vs Benefits of NSAIDs for Periodontal Disease Treatment
•NSAID’s – Enzymes Combinations
•Commercially Available Combinations
•NSAID’s And Periodontitis Review
•Conclusion
• References

4. INTRODUCTION
The inflammatory response is complex, involving immune system
and various endogenous agents like prostaglandins, bradykinin,
histamine, chemotactic factors & superoxide free radicals formed by
the action of lysosomal enzymes.
The NSAIDs have anti-inflammatory, analgesic, and
antipyretic properties.
Prostaglandins, prostacyclins and TXA2(Thromboxane A2) have
been associated with gingivitis, periodontitis and alveolar bone
resorption. (Goodson et al, 1974, Williams, 1990).

5. DEFINITION
NSAIDs are chemically diverse class of drugs that have
anti-inflammatory, analgesic, and antipyretic properties.
In 1971, John Vane and co-workers made the landmark observation
that aspirin and some NSAIDs blocked prostaglandin generation.
This is now considered to be the main mechanism of action of
NSAIDs.
NSAIDs are used to suppress the symptoms of inflammation
associated with rheumatic disease.

6. HISTORY
•Willow bark (Salix alba) had been used for many centuries. Salicylic
acid was prepared by hydrolysis of the bitter glycoside obtained from
this plant.
•Sodium salicylate was used for fever and pain in 1875. Its great
success led to the introduction acetylsalicylic acid (aspirin) in 1899
(Fredrich Bayer & Co).
•Phenacetine and antipyrine were also introduced.
•The development of phenylbutazone in 1949 having anti -
inflammatory activity almost comparable to corticosteroids.

7. •Indomethacin was introduced in 1963.
•A host of compounds heralded by the propionic acid derivative,
ibuprofen have been added since then and cyclooxygenase (COX)
inhibition is recognised to be their most important mechanism of
action.
•Some selective COX-2 inhibitors (rofecoxib, celecoxib) have also
been added.

8. CLASSIFICATION (KD Tripathi 1 st ed)
A. Non selective COX inhibitors
1. Salicylates: Aspirin
2. Propionic acid deriviatives : Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.
3. Anthranilic acid deriviatives : Mephenamic acid.
4. Aryl acetic acid derivatives : Diclofenac, Aceclofenac.
5. Oxicam deriviatives : Piroxicam, Tenoxicam.
6. Pyrrolo pyrrole deriviative : Ketorolac.
7. Indole deriviative : Indomethacin.
8. Pyrazolone deriviative : Phenylbutazone.
B. Preferential COX – 2 inhibitors
Nimesulide, Meloxicam, Nabumetone.
C. Selective COX – 2 inhibitors
Celecoxib, Etoricoxib, Parecoxib.
D. Analgesic – antipyretics with poor antiinflammatory action
1. Paraaminophenol deriviative : Paracetamol.
2. Pyrazolone deriviative : Metamizol.
3. Benzoxazocine deriviative : Nefopam.

9. MECHANISM OF ACTION OF NSAIDs
Inflammation occurs when tissue get injured by any cause.
Inflammation is defined as the local response of living tissues to injury
due to any agent.
Due to inflammation various inflammatory mediators are released
such as prostaglandin,histamine,bradykinin,IL-1,TNFalpha etc.
Prostaglandins 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.

10. A drug that prevents the synthesis of prostaglandin is likely to be
effective in relieving pain due to inflammation of any kind.
This is done by inhibiting cyclo – oxygenase (COX) enzyme in the
pathway for prostaglandin synthesis.
COX exists in two isoforms:
1.COX-1-Constitutive (House keeper) Mucus secretion, Haemostasis,
renal functions. It is physiologic enzymes.
2.COX-2-Inducible (Inflammatory response) Sites-brain,
Juxtaglomerular cells (constitutive). It is pathologic enzymes.

13. Beneficial actions due to Prostaglandin synthesis inhibition
Analgesia
Antipyresis
Anti inflammatory
Anti thrombotic
Closure of ductus arteriosus
Shared toxicities due to Prostaglandin 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.

14. Analgesia
Prostaglandins induce hyperalgesia by increasing sensitivity of
afferent nerve endings to chemical and mechanical stimuli and thus
amplify action of other first line inflammatory mediators.
Prostaglandins in CNS lowers threshold of central pain circuit.
NSAIDs block this pain sensitizing mechanism therefore effective
against inflammation associated pain.
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.

15. Antipyresis
Fever in infection is produced by pyrogens, TNF, ILs, interferon-
induce production of Prostaglandins in hypothalamus-raise its temp.
set point.
NASIDs block the action of pyrogens(COX2).

16. Anti-inflammatory
Inhibition of Prostaglandin 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 granulocyte macrophage-CSF,IL-6,and
lymphocyte transformation factors.
NSAIDs-Stabilises leucocytes lysosomal membrane, and antagonizes
certain action of kinins.

17. Antiplatelet
Inhibit synthesis of TXA2 by acetylating platelet COX irreversibly.
Anaphylactoid reaction
Aspirin precipitates bronchial asthma, angioneurotic swelling, urticaria
or rhinitis in certain individuals. These subjects react similarly to
chemically diverse NSAIDs, ruling out immunological basis for the
reaction.

18. PROSTAGLANDINS AND PERIODONTITIS
Prostaglandins - mediators of the cardinal signs of inflammation:
redness, edema, pain, heat, and loss of function. (Weeks et al 1972,
Hinman et al 1972, Kuehl et al 1980) .
Multiple studies found that in addition to prostaglandins, the
prostacyclines and phospholipases also caused bone resorption.
(Raisz et al 1977, Dewhirst et al 1984, Newman et al 1984, Loning et
al, 1980; El Attar et al, 1981; Ohm et al, 1984; Yoda et al, 1984; Mend
ieta et al, 1985; El Attar et al, 1986; Williams et al, 1988; Dewhirst et a
l, 1983).

19. SALICYLATES
ASPIRIN
Aspirin is acetyl salicylic acid converted in body to salicylic acid.
It was obtained from ‘willow bark’ (Salicaceae) but is now synthesized
Methyl salicylate is a volatile liqiud derivate.
MOA-aspirin inhibits COX irreversibly by acetylating one of its
serine residue.
Its one of the oldest analgesic-anti inflammatory drug and is still
widely used.

20. PHARMACOLOGICAL ACTIONS
ANALGESIC,ANTIPYRETIC,ANTIINFLAMMTORY ACTION :-
Aspirin is a weaker analgesic than morphine (600 mg ~codeine 60mg),
but effectively relieves, tissue injury related inflammation and
integumental pain.
Relatively ineffective in severe viceral and ischemic pain.
The analgesic action is mainly due to obtunding of peripheral
receptors and prevention of prostoglandin-mediated sensitization of
nerve endings.

21. • Aspirin resets the hypothalamic thermostat and rapidly reduces fever
by promoting heat loss (sweating, cutaneous vasodilatation), but does
not decrease heat production.
• Anti inflammatory action is exerted at high doses(3-5g/day or
100mg/kg/day)
• Signs of inflammation are supressed but progression of underlying
disease in Rh arthritis,Rh fever and osteoarthrirtis are not affected.

22. METABOLIC EFFECTS :-
Significant only at anti-inflammatory doses.
Cellular metabolism is increased, especially in skeletal muscles due
to uncoupling of oxidative phosphorylation increased heat
production.
Increased decrease in blood sugar(specially in diabetics) and liver
glycogen is depleted.
Hyperglycemia is seen at toxic doses due to central sympathetic
stimulation increases release of Adrenal and corticosteroids.

23. ACID BASE AND ELECTROLYTE BALANCE :-
Usual analgesic dose(0.3-1.5g) have no effect.
Anti-inflammatory doses produce significant change in acid balance.
CVS :-
No direct effect in therapeutic dose.
Larger doses increase cardiac output to meet increased peripheral O2
demand and cause vasodilatation.
Toxic doses depress vasomotor centre.
BP may fall.

24. GIT :-
Aspirin and released salicylic acid irritates gastric mucosa cause
epigastric distress, nausea and vomiting.
At high doses it stimulates chemoreceptor trigger zone as well.
Aspirin remains unionized in gastric juice but on entering mucosal
cell it ionises. This ion trapping enhances gastric toxicity.

25. BLOOD :-
Even small doses inhibit TXA2 synthesis irreversibly by platelets this
interferes platelet aggregation thus bleeding time prolonged to twice
the normal value.
This last for 1 week ( turn over time of platelet).
Long term intake of aspirin decrease synthesis of clotting factors in
liver and predisposes to bleeding ( prevented by prophylactic Vit K
therapy).

26. PHARMACOKINETICS
•Well 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.

27. •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.
•Together with released salicylic acid is 3-5hrs.
•Metabolic processes get saturated over therapeutic range.
•t1/2 of anti-inflammatory doses may be 8-12hrs.
•While that during poisoning may be upto 30hrs.
•Thus elimination is dose dependant.

28. ADVERSE EFFECTS
a) Gastrointestinal:-
• Most common side effect that occurs at analgesic dose
(0.3-1.5g/day).
• Epigastric distress, nausea, vomiting.
• Increased occult blood loss in stools.
• Gastric mucosal damage and peptic ulcer.
b) Hypersensitivity and Idiosyncrasy:-
• Though infrequent, these can be serious.
• Reactions include; rashes, urticaria, angioedema, rhinorrhoea,
asthma and anaphylactoid shock.

29. c) Salicylism:-
• High doses(at anti-inflammatory doses) or chronic use of aspirin
may induce a syndrome characterised by tinnitus, hearing defects,
blurring of vision, dizziness, headache, mental confusion,
hyperventilation and electrolyte imbalance.
• Effects are reversible.
d) Rey’s syndrome:-
• Occurs in infants and children.
• Occurs when aspirin given during viral infections(varicella,
influenza).
• Characterized by liver damage and encephalopathy.
• Replaced by acetaminophen in such condition to reduce fever.

30. 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
Vomiting, dehydration, electrolyte imbalance, acidotic breathing,
hyper/hypoglycemia, petechial hemorrhages, restlessness, delirium,
hallucinations, hyperpyrexia, convulsions, coma and death due to
respiratory and cardiovascular failure.

31. TREATMENT
• Symptomatic and supportive.
• Most important is external cooling.
• Gastric lavage.
• I.V. infusion of Na+ , K+ , HCO3 and glucose(dextrose-5%).
• Vitamin K 10mg I.V.
• Peritoneal dialysis or hemodialysis.

32. PRECAUTIONS AND CONTRAINDICATIONS
• Peptic ulcer.
• Sensitive patients.
• 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.

33. INTERACTIONS
• Aspirin displaces warfarin, naproxen, sulfonylurease & phenytoin
from its plasma protein binding sites-toxicity of these drugs may occur
• Its anti-platelet action increases risk of bleeding in patients on oral
anticoagulant.
• Inhibits tubular secretion of uric acid and antagonizes action of
uricosuric agents.

34. USES AND DOSES
• 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/days- in various infections.

35. VARIOUS PREPERATIONS AVAILABLE
• Aspirin 350mg T
• Colsprin 100,325,625mg T
• Ecospirin 75,150,325mg T
• Disprin 350mg T
• Loprin 75,162.5mg T
• Biosprin : recently available injection prepration (Lysine
acetylsalicylate 900mg+Glycine100mg/5ml water)

36. PROPIONIC ACID DERIVATIVES
• IBUPROFEN (1969) better tolerated alternative to aspirin
• MOA- inhibit PG synthesis
• Most potent- naproxen
• Others – ketoprofen, flurbiprofen
• Anti inflammatory efficacy is rated somewhat lower to that of high
dose of aspirin
• Inhibit platelet aggregation reversibly and cause short lasting
prolongation of bleeding time.

37. ADVERSE EFFECTS
• Most common-nausea, gastric discomfort and vomiting (less than
aspirin or indomethacin).
• Gastric erosion and occult blood loss-rare.
• CNS-headache, dizziness, blurring of vision, tinnitus, depression.
• Rashes, itching and other hypersensitivity phenomenon are
infrequent.
CONTRAINDICATED
• In pregnant woman and peptic ulcer patient.

38. PHARMACOKINETICS AND INTERACTIONS
• Better tolerated orally and the incidences of adverse reactions are
low.
• Highly bound to plasma proteins (90-99%).
• Because they interact with platelet function, SHOULD NEVER BE
USED with anticoagulants.
• Enter brain, synovial fluid and cross placenta.
• Metabolized in liver by hydroxylation and glucuronide conjugation.
• Excreted in urine as well as bile.

39. DOSAGE AND PREPARATIONS OF PROPIONIC ACID
DERIVATIVES
DRUG PLASMA
t1/2
DOSAGE PREPERATIONS
IBUPROFEN 2 hr 400-600mg
(5-10mg/kg) TDS
BRUFEN,EMFLAM,IBUSYNTH 200,
400,600mg T, IBUGESIC
also 100mg/5ml suspension
NAPROXEN 12-16hr 250mg BD-TDS NAPROSYN,NAXID,
ARTAGEN,XENOBID 250mg T,NAP
ROSYN also 500mg T
KETOPROFEN 2-3hr 50-100mg BD-TDS KETOFEN 50,100mg T,
OSTOFEN 50mg C,RHOFENID
100mg,200mg SRT,100mg/200ml amp
FLURBIPROFEN 4-6hr 50mg BD-QID ARFLUR 50,100mg T,200mg SR T,
FLUROFEN 100mg T.

40. USES
• Rh arthritis, osteoarthritis , other musculoskeletal disorders specially
when pain is more prominent than inflammation.
• Soft tissue injury, tooth extraction, fractures, post partum and post
op, supress swelling and inflammation-VERY POPULAR IN
DENTISTRY.
• NAPROXEN is more efficacious and better tolerated in anti
inflammatory doses (long acting and BD dose).

41. ANTHRANILIC ACID DERIVATIVE(FENAMATE)
MEPHENAMIC ACID
•It is an analgesic, antipyretic and anti inflammatory agent which inhibits COX as
well as antagonises certain actions of PGs.
• Mephenamic acid exerts peripheral as well as central analgesic action.
ADVERSE EFFECTS
Diarrhoea is the most important dose related side effect.
PHARMACOKINETICS
•Oral absorption is slow but almost complete.
•It is highly bound to plasma proteins.
•Partly metabolized and excreted in urine as well as bile.
•Plasma t ½ is 2-4 hours.

42. USES
•It is indicated as analgesic in muscle, joint and soft tissue pain
•It effective in dysmenorrhoea.
•It may be useful in cases of rheumatoid and osteoarthritis.
DOSE
•250-500mg TDS
•MEDOL 250,500mg T
•MEFTAL 250,500mg T;100mg/5ml susp.
•PONSTAN 125,250,500mg T,50mg/ml syrup.

43. ARYL-ACETIC ACID DERIVATIVE
DICLOFENAC SODIUM
•Along with prostaglandin inhibition, it also reduces nuetrophil
chemotaxis
• Inhibits the lipooxygenase pathways, thus reducing formation of the
leukotrienes
• May inhibit phospholipase A2.
• Used commonly to treat mild to moderate post-operative or
post-traumatic pain, particular when inflammation is also present, and
is effective against menstrual pain.
•Well absorbed orally, plasma half life is ~2hrs.
• Good tissue penetrability & concentration in synovial fluid is
maintained for three times longer than plasma.

44. Dose: 50mg TDS, then BD oral,75mg deep im VOVERAN,
DICLONAC, MOVONAC 50mg enteric coated T,100mg SRT,25mg/
ml in 3ml amp for im injection.
Diclofenac potassium: VOLTAFLAM 25,50mg T,
VOVERAN 1% topical gel.
ACECLOFENAC
Relatively selective COX2 congener of diclofenac sodium
Dose : 100mg BD
ACECLO,DOLOKIND 100mg T,200 mg SRT.
USES
•Toothache, Rh and osteoarthritis, bursitis, ankylosing spondylitis,
dysmenorrhoea,post traumatic and post op inflammatory conditions
affords quick relief of pain and wound oedma.

45. ADVERSE EFFECTS
• Epigastric pain
• Nausea
• Headache
• Dizziness
• Rashes
• Gastric ulceration & bleeding are less common
• Reversible increase in serum aminotransferases
• Kidney damage is rare.

46. OXICAM DERIVATIVES
PIROXICAM
Long acting, potent NSAID with good antiinflammatory action.
MOA
• Reversible inhibitor of COX.
• Lowers concentration of prostaglandin in synovial fluid.
• Decreases production of IgM Rheumatoid factor.
• Chemotaxis of leucocytes is inhibited.
PHARMACOKINETICS
•Well absorbed orally, 99% is plasma bound.
• Single daily dose is sufficient.
• Used for short and long term antiinflammatory conditions.

47. ADVERSE EFFECTS
• Heartburn, nausea, anorexia are common
• Better tolerated and less ulcerogenic than indomethacin
• Cause less faecal blood loss than aspirin
• Rashes and pruritis are seen in < 1 % cases
• Edema and reversible azotaemia (abnormally high levels of nitrogen
containing compounds in blood) have been observed.
USES
Short term analgesic and long term anti inflammatory drug in Rh and
osteoarthritis, ankylosing spondylitis, acute gout, musculoskeletal
injuries and in dentistry.

48. DOSE
• 20 mg BD for 2 days followed by 20mg OD
• DOLONEX,PIROX 10,20 mg C , 20mg disp T, 20mg/ml inj in 1 and
2 ml amp
• PIRICAM 10,20 mg C
• TENOXICAM : congener of piroxicam ; TOBITIL 20 mg T, dose
20 mg OD.

49. PYROLLO-PYROLLE 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 ,dental pain
2. Acute musculoskeletal pain (15-30mg IM or IV)
3. Renal colic
4. Migraine
5. Pain due to bony metastasis

50. •One of the few NSAIDs that can be used for parenteral
administration.
• Continous use for more than 5 days is not recommended.
• Cause Dizziness, Dyspepsia, Nausea and pain at site of injection
• Should not be given to patients on oral anticoagulants.
• Not indicated for preaesthetic medication or for obstetric analgesia.
• KETOROL, ZOROVON, KETANOV,TOROLAC 10mg T, 30mg in
1 ml amp.

51. INDOLE DERIVATIVES
•It is a potent analgesic anti-inflammatory & antipyretic
•It relives only inflammatory or tissue related pain.
•It is highly potent inhibitor of PG synthesis and suppresses neutrophil
motility.
PHARMACOKINETICS
•It is well absorbed orally, rectal absorption is slow but dependable.
•It is 90% bound to plasma proteins, partly metabolized in liver to
inactivate products and excreted by kidney.
•Plasma t1/2 is 2-5 hours.

52. ADVERSE EFFECTS
•A high incidence of gastrointestinal and CNS side effects is produced.
•Increased risk of bleeding due to decreased platelet aggregation.
•Gastric irritation, nausea, anorexia, gastric bleeding and diarrhoea are
prominent
•Frontal headache(very common), dizziness, ataxia, mental confusion,
hallucination ,depression, pschycosis
•Leucopenia ,rashes and other hypersensitivity reactions are also
reported.

53. CONTRAINDICATIONS
•Machinery operators
•Drivers
•Psychiatric patients
•Epileptics
•Kidney disease
•Pregnant women and in children
DOSE
25-50 mg BD INDICIN, INDOCAP 25mg C,75mg SR C, ARTICID
25,50mg C, INDOFLAM 25,75mg C,1% eye drop.

54. USES
•Rheumatoid arthritis
•Ankylosing spondylitis
•Acute exacerbations of destructive artropathies
•Psoriatic arthritis
•Acute gout
•Closure of patent ductus arteiosus dose; 0.1-0.2mg/kg

55. PYRAZOLONE DERIVATIVES
•ANTIPYRINE AND AMIDOPYRINE were introduced in 1884 as
antipyretics and analgesics.
•Their use was associated with agranulocytosis.
•PHENYLBUTAZONE was introduced in 1949 but are rarely used
now due to risk of bone marrow depression.
•Two other pyrazolone-METAMIZOL and PROPIPHENAZONE.
METAMIZOL (DIPYRONE)
• It is a derivative of amidopyrine which continues to be widely used.
• In contrast to phenylbutazone, it is a potent and promptly acting
analgesic.
• It can be given orally, I.M. as well as I.V but gastric irritation and
pain at injection site occurs.

56. .
DOSE
0.5-1.5 g oral/IM/IV
ANALGIN 0.5g tab
NOVALGIN, BARALGAN 0.5g tab,0.5gm/ml in 2ml and 5ml amps,
ULTRAGIN 0.5gm/ml injection in 2ml amp and 30ml vial.
PROPIPHENAZONE
Another pyrazolone, similar in properties to metamizol; claimed to be
better tolerated.
DOSE
300-600 mg TDS, SARIDON,ANAFEBRIN: Propiphenazone 150 mg
+ Paracetamol 250 mg., DART: propiphenazone 150mg + paracetamol
300mg + caffeine 50mg T.

57. PREFERENTIAL COX-2 INHIBITORS
NIMESULIDE
• Weak inhibitor of prostaglandin synthesis.
• Anti inflammatory action may be exerted by other mechanisms like
reduced generation of superoxide by nuetrophils, inhibition of platelet
activating factor synthesis & TNF release, free radical scavenging,
inhibition of metalloproteinase activity in cartilage.
USES
Short lasting inflammatory conditions like sports injuries, sinusitis,
other ENT disorders, dental surgery, bursitis, low back ache,
dysmmenorrhea, post op pain, osteoarthritis and fever.

58. PHARMACOKINETICS
• Completely absorbed orally.
• 99% plasma protein bound.
• Extensively metabolized and excreted mainly in urine.
• Plasma t1/2 2-5hrs.
ADVERSE EFFECTS
• GI-epigastralgia, heart burn, nausea, loose motion
• Dermatological- rashes, pruritis
• Central- somnolence, dizziness
• Haematuria in children.
Used in asthmatics who cannot tolerate ASPIRIN.

59. DOSE
100mg BD; NIMULID,NIMEGESIC,NIMODOL,100mg T,50mg/ml
susp.
MELOXICAM
• Newer congener of piroxicam has COX2:COX1 selectivity ratio 10.
• Since measurable inhibition of platelet TXA2 occurs at therapeutic
dose it has been labelled pref.COX2.
DOSE
7.5-15mg OD,MELFLAM,MEL-OD,MUVIK,M-CAM 7.5mg,15mg T

60. NABUMETONE
• Prodrug with analgesic, antipyretic and antiinflammatory activity.
• Effective in Rh, osteoarthritis and soft tissue injury.
DOSE
NABUFLAM 500mg T ,1tab OD

61. SELECTIVE COX-2 INHIBITORS(COXIBS)
Celecoxib, Etoricoxib, Parecoxib, Rofecoxib, Valdecoxib,Lumiracoxib
• Directly targets COX-2.
• Reduces the risk of peptic ulceration.
• These drugs should be avoided in presence of severe hepatic/renal
disease & in those receiving rifampin, warfarin, methotrexate.
• Increased risk of myocardial infarction and stroke.
DOSE
Rofecoxib 12.5-25 mg OD, ROFACT, ROFEGESIC, RIFIBAX,
ROFLAM, Celecoxib 100-200 mg BD, CELACT, REVIBRA,
COLCIBRA, Etoricoxib 60-120mg OD, ETODY,TOROCOXIA,
ETOXIB,NUCOXIA,60,90,120mg T, Parecoxib 40mg oral IM/IV
repeated after 6-12hrs, REVALDO,VALTO-P 40mg/vial injection,

62. PARAAMINO PHENOL DERIVATIVES
PHENACETIN
• Was introduced in 1887.
PARACETAMOL
• The deethylated active metabolite of phenacetin but came into common use
since 1950.
• The central analgesic action of paracetamol is like aspirin, it raises pain
threshold.
• Paracetamol is a good and promptly acting antipyretic, it is a poor inhibitor of
PG synthesis in peripheral tissues, but more active on COX in brain (poor ability
to inhibit COX in presence of peroxides generated at site of inflammation)
• Gastric irritation is insignificant; Mucosal erosion and bleeding occur rarely
only in overdose.
• It does not affect platelet function or clotting factors.

63. PHARMACOKINETICS
• Well absorbed orally; only 1/4th is plasma bound ; uniform
distribution in body
• T1/2 2-3hrs;effect of an oral dose lasts for 3-5hrs.
ADVERSE EFFECTS
• Nausea and rashes are occasional.
• Leukopenia is rare.
• Acetaminophen overdose can cause hepatotoxicity, severe
hepatotoxicity has been reported even after
therapeutic doses.
• ANALGESIC NEUROPATHY: occurs after years of heavy ingestion
of analgesics; such persons have some personality defect.

64. ACUTE PARACETAMOL POISONING
• Occurs specially in small children who have low hepatic glucuronide
conjugating ability.
• If large dose is taken (>150mg/kg or >10g in an adult) serious
toxicity can occur ; fatality common with>250mg/kg.
• Early manifestation : nausea, vomiting, abdominal pain, liver
tenderness.
• After 12-18hrs: hepatic, renal tubular necrosis, hypoglycemia
progressing to coma.
• After 2days: jaundice.
• Further fulminating hepatic failure and death.

65. TREATMENT
• If patient is bought early:vomiting is induced, gastric lavage done,
activated charcoal given to prevent further absorption.
• ANTIDOTE : N-acetylcysteine infused IV /orally
• Paracetamol is not recommended in premature infants for fear of
hepatotoxicity.
USES
• Headache
• Musculoskeletal pain
• Toothache
• Dysmenorrhea
• Much safer than aspirin in terms of GI manifestations
• Does not prolong bleeding time ; so less chance of post extraction

66. DOSE
0.5- 1gTDS, infants 50mg, children 1-3yrs 80-160mg, 4-8yrs 240-320
mg, 9-12yrs 300-600mg, CROCIN 0.5,1.0mg T, METACIN,
PARACIN 500mg T 125mg/5ml syrup, 150mg/ml paed.drops,
ULTRAGIN, PYRIGESIC, CALPOL 500mgT, 125mg/5ml syrup
NEOMOL,FEVASTIN,FEBRINIL 300mg/2 ml injection, CROCIN
PAIN RELIEF: paracetamol 650mg+caffeine 50mg T.

67. CHOICE OF NSAIDs
1.Mild to moderate pain with little inflammation paracetamol or low
dose ibuprofen.
2. Acute musculoskeletal, osteoarthritic, injury associated
inflammation-a propionic acid derivative, diclofenac or rofecoxib.
3. Postextraction or other acute short lasting pain-ketorolac,diclofenac,
nimesulide, a propionic acid derivative.
4.Gastric intolerence to conventional NSAIDs-etoricoxib, paracetamol
5. H/O asthma, anaphylactic reaction to aspirin or other NSAIDs-
nimesulide,COX2 inhibitor.
6. Pregnancy-paracetamol best preferred, second best low dose aspirin.
7. Paediatric-paracetamol ,aspirin, ibuprofen, naproxen.

68. NSAID’s as HOST MODULATORYAGENTS
• Concept of host modulation was 1st introduced by Williams (1990)
and Golub et al (1992).
• To modify or reduce destructive aspects of host response: so that
immune-inflammatory response to plaque is less damaging; host
modulation therapies has been developed.
• Treatment concept that aims to reduce tissue destruction and stabilize
or even regenerate the periodontium by modifying or downregulating
destructive aspects of host response and upregulating protective or
regenerative responses.(CARRANZA)

69. ACTIONS
• Inhibits prostaglandins
• Reduce inflammation
– Used to treat pain, acute inflammation, and chronic inflammatory
conditions.
– Inhibits osteoclastic activity in periodontitis(Howell TH in oral
bio med 1993)
• NSAIDs such as indomethacin(Williams RC 1987) flurbiprofen
(Jeffcoat MK JP 1989) and naproxen(Howell TH 1993) administered
daily for up to 3 years, significantly slowed the rate of alveolar bone
loss compared with placebo.

70. DISADVANTAGES
• Administration for extended periods is necessary for periodontal
benefits to become apparent, and are associated with significant side
effects:
– gastrointestinal problems,
– hemorrhage (from decreased platelet aggregation),
– and renal and hepatic impairment.
• Research shows that the periodontal benefits of taking long-term
NSAIDs are lost when patients stop taking the drugs, with a return to
or even an acceleration of the rate of bone loss seen before NSAID
therapy, often referred to as a “rebound effect.”(William RC j dentres
1991).

71. • Inhibition of COX-1 by nonselective NSAIDs causes side effects
– gastrointestinal ulceration
– and impaired hemostasis
• Use of selective COX-2 inhibitors reduce periodontal inflammation
without the side effects typically observed after long-term
(nonselective) NSAID.
• Selective COX-2 inhibitors slowed alveolar bone loss in animal
models(Bezerra MM J Periodontol 1993) and modified prostaglandin
production in human periodontal tissues (Vardar S J Periodontol 2003)

72. Risk vs Benefits of NSAIDs for Periodontal Disease Treatment
• NSAIDs - harmful side effects.
• Gastrointestinal upset.
• Haemorrhage.
• Renal and hepatic impairment.
• Induction of aseptic meningitis in previously healthy patients.
• Ibuprofen in high doses impairs wound healing(Proper et al, 1988).
• It is not clear whether NSAIDs promote or hinder the overall
mineralization process in contemporary periodontal regenerative
therapy (McAllister et al,1995).

73. NSAID’s – Enzymes Combinations
• Enzyme combination of NSAIDs helps in reduction of unwanted
drug effects while maintaining the anti-inflammatory/analgesic
efficacy.
• Protease enzymes belonging to family metalloprotease, have been
successfully tested for their anti inflammatory properties, which
include trypsin, chymotrypsin and serratiopeptidse(Miyata et al., 1971;
McQuade and Crewther, 1969; Lyerly and Kreger, 1981; Aiyappa and
Harris, 1976; Decedue et al 1979).
• Proteolytic enzymes are large protein molecules and they will be
absorbed in an active form from GIT. To overcome their destruction in
stomach by hydrolysis, these tablets are given in enteric coated dosage
form and in combinations.

74. Commercially Available Combinations
• Aceclofenac, Paracetamol, Serratiopeptidase-Acecloren, Acekem-SP
• Diclofenac Potassium, Serratiopeptidase- Acfast d, Aldase D (50mg)
• Diclofenac Sodium, Serratiopeptidase- Actimol S, Alnec-S
• Diclofenac Potassium, Chymotrypsin- Alfapsin-D, Alzibit-D
• Diclofenac Potassium, Trypsin,Chymotripsin-Chemofast-D,
Chymobel Plus

75. NSAID’s And Periodontitis Review
According to Anusha Etikala et al, the influence of administration of
NSAID drugs on outcomes following periodontal treatments (nine
clinical studies) and dental implant placement (four animal studies and
two human clinical studies). Conflicting results were found on the
effects of NSAIDs during periodontal wound healing. NSAID
administration, specifically COX-2 inhibitors could inhibit bone
formation around orthopedic implants and concluded within the
limitations of this review, NSAIDs negatively affected
osseointegration titanium implants.
According to Maracella Morro et al in the study they compared the
effects of the selective COX-2 inhibitor etoricoxib with those of the
classical non-selective NSAID diclofenac on the inflammatory process
and alveolar bone loss in an experimental model of periodontitis in rats.

76. CONCLUSION
• NSAIDs have an extremely safe profile when used for acute dental
pain.
• Within a group they tend to have similar characteristics and
tolerability. There is little difference in clinical efficacy among the
NSAIDs when used at equivalent doses.
• Rather, differences among compounds usually relate to dosing
regimens (related to the compound's elimination half-life), route of
administration, and tolerability profile.
• So a clinician should have a thorough knowledge of mechanism of
action, pharmacokinetics, pharmacodynamics, dosage and adverse
effects of each drug before prescribing the same.

77. REFERENCES
•Essentials of pharmacology for dentistry K D Tripathi – 2nd edition.
•Carranza’s Clinical Periodontology - 11th edition.
•Periobasics – 2nd edition.
•Pharmacology and therapeutics for dentistry John AYagiela,Enid A
Neidle,Frank J Dowd-4th edition.
• Effects of NSAIDS on Periodontal and Dental Implant Therapy;
Compendium- 2019.
•Host modulation therapy with anti-inflammatory agents
Periodontology 2000, Vol. 10, 2017.