NSAIDsDR SHILPA SHIVANAND

1ST YEAR PGDEPT OF PERIODONTICS

CONTENTS • Introduction• History• Definition• Mechanism of action of NSAID’s• Prostaglandins and actions• Classification• Choice of NSAID’s• NSAID’s – periodontal considerations and host modulatory

therapy• NSAID’s – Enzymes combination• Conclusion• References

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 term NSAIDs are chemically diverse class of drugs (>70 NSAIDs in use) that have anti-inflammatory, analgesic, and antipyretic properties.

Prostaglandins,prostacyclins and TXA2 have been associated with gingivitis, periodontitis and alveolar bone resorption. (Goodson et al, 1974, Williams, 1990)

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 at

that time. • The next major advancement was the development of

phenylbutazone in 1949 having anti-inflammatory activity almost comparable to corticosteroids.

• The term Non-Steroidal Anti-Inflammatory Drugs (NSAID) was coined to designate such drugs.

• 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.

• Recently, some selective COX-2 inhibitors (rofecoxib, celecoxib) have been added.

DEFINITION NSAIDs are chemically diverse class of drugs (>70

NSAIDs in use) 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.

MECHANISM OF ACTION OF NSAIDs When a tissue is injured, from any

cause,inflammation results.

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,TNF-alpha etc.

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.

Naturally, a drug that prevents the synthesis of prostaglandin is likely to be effective in relieving pain due to inflammation of any kind.

This is they do 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. 2.COX-2-Inducible (Inflammatory response) Sites-brain, JG cells (constitutive)

FITZGERALD

PROPERTIES OF PROSTAGLANDINS

PROPERTIES OF Prostaglandins Pain: PGI2 and PGE2 sensitize nerve endings to

bradykinin,Histamine and substance P and cause hyperalgesia

Inflammation: PGI2, PGD2 and PGE2 are vasodilators (edema, erythema)

Protection of the gastric mucosa: PGI2 Maintenance of renal blood flow: PGE2

Fever: PGE2

Platelets: PGI2 and PGD2 inhibit platelet aggregation TXA2 stimulates platelet aggregation

Uterus: PGD2 contracts uterus

Beneficial actions due to Prostaglandin synthesis inhibition

Analgesia Antipyresis Antiinflammatory Antithrombotic 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.

Analgesia Prostaglandins 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.

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.

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.(cox-2).

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.

Dysmenorrhea Increase levels of Prostaglandins in

menstrual blood flow, endometrial biopsies, and their metabolites is seen in dysmennorhic women-myometrial ischaemia –menstrual cramps.

NSAIDs-lowers uterine Prostaglandins—relief.

Antiplatelet

Inhibit synthesis of TXA2 by acetylating platelet COX irreversibly

Ductus arteriosus closure Prostaglandins E2, I2-

responsible for maintaining patency in foetal circulation.

Parturition

Sudden increase in Prostaglandin synthesis by uterus triggers labour and facilitate its progression.

NSAIDs –delay and retard labour.

Gastric mucosal damage Inhibition of synthesis of gastro protective

Prostaglandin (E2,I2)- decrease in mucus,HCO3,increases acid secretion, may promote mucosal ischemia.

Ion trapping with NSAIDs also play role.

Renal effects Conditions like hypovolaemia, decrease renal

perfusion, and Na+ loss- induce renal Prostaglandin synthesis –leading to vasodilatation, inhibition of cl – reabsorption.

NSAIDs- 1. Cox dependent impair renal bl.flow.—decrease

in gfr-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 pts ofCHF, Hypovolemia, hepatic cirrhosis renal disease, pts on diuretics and antihypertensive edema.

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.

Prostaglandins And Periodontitis• Prostaglandins - mediators of the cardinal signs of

inflammation: redness, edema, pain, heat, and loss of function. (Weeks 1972, Hinman 1972, Kuehl 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; Mendieta et al, 1985; El Attar et al, 1986; Williams et al, 1988; Dewhirst et al, 1983)

Classification (KD Tripathi 1st ed)A) Nonselective Cox inhibitors (Traditional NSAIDs)

1.Salicylates- Aspirin

2.Pyrazolone derivatives- Phenylbutazone, oxyphenbutazone

3.Indole derivatives- Indomethacin, Sulindac

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

B) Preferential cox-2 inhibitors• Nimesulide, Meloxicam,Nabumetone.

C) Selective cox- 2 inhibitors• Celecoxib, Rofecoxib,Valdecoxib,Parecoxib.

D) Analgesics- Antipyretics with poor anti inflammatory action

• Para amino phenol derivatives : Paracetamol (Acetaminophen).

• Pyrazolone derivatives : Metamizol (Dypirone), Propifenazone.

• Benzoxazocine derivative : Nefopam.

SALICYLATES• Prototype : 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-antiinflammatory drug and is

still widely used.

PHARMACOLOGICAL ACTIONS

I .ANALGESIC,ANTIPYRETIC,ANTIINFLAMMTORY ACTION:

-Aspirin is a weaker analgesic than morphine (600 mg ~codeine60mg), but effectively relieves inflammatory,tissue injury related,CT 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 PG-mediated sensitization of nerve endings .

• Aspirin resets the hypothalamic thermostat and rapidly reduces fever by promoting heat loss (sweating, cutaneous vasodilatation), but does not decrease heat production.

• Antiinflammatory 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.

II. METABOLIC EFFECTS

• Significant only at antiinflammatory doses• Cellular metabolism is increased,especially in sk

muscles due to uncoupling of oxidative phosphorylation->increased heat production

• ->decrease in blood sugar(specially in diabetics) and liver glycogen is depleted

• Hyperglycemia is seen at toxic doses due to central sympathetic stimulation -> release of Adr and corticosteroids.

III . RESPIRATION• Effects are dose dependant• At antiinflammatory doses,respiration is

stimulated by : i.peripherally-increased CO2 production ii.centrally-increased sensitivity of respiratory centre to CO2

• Hyperventilation is prominent in salicylate poisoning

• Further rise in salicylate level causes respiratory depression and death due to respiratory failure.

IV . ACID BASE AND ELECTROLYTE BALANCE

• Usual analgesic dose(0.3-1.5g)have no effect• Antiinflammatory doses produce significant

change in acid balance balance• Initially respiratory stimulation predominates and

washes out CO2( respiratory alkalosis);compensated by increased renal excretion of HCO3-

• Adults treated with 4-6g/day stays in state of compensated respiratory alkalosis

• Higher doses cause respiratory depression with CO2 retention (respiratory acidosis)

V . 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• CHF maybe precipited in patients with low cardiac

reserve(because of increased cardiac work and Na+ –water retention).

VI . 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.

• Aspirin particle coming in contact with gastric mucosa promotes local back diffusion of acids focal necrosis of mucosal cells and capillariesa/c ulcer, erosive gastritis, congestion and microscopic hemorrhages.

VII . URATE EXCRETION

• Dose related effect • <2g/day urate retention and antagonism of all

uricosuric drugs• 2-5 g/day variable effects, often no change• >5 g /day increased urate excretion• Aspirin is not suitable for use in chronic gout

VIII . BLOOD

• Even small doses inhibit TXA2 synthesis irreversibly by platelets interferes platelet aggregation bleeding time prolonged to twice 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).

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

• 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 antiinflammatory doses may be 8-12hrs• While that during poisoning may be upto 30hrs• Thus elimination is dose dependant

ADVERSE EFFECTSa) 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

c) 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, 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

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, petechial hemorrhages, restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death due to respiratory and cardiovascular failure

Treatment:

• Symptomatic and supportive• Most imp 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

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

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.

• It blunts diuretic action of furosemide or thiazides and reduces K+ conserving action of spironolactone.

USES

1.As analgesic (0.3g-0.6g /day6-8hrly;max at 1000mg)

2. As antipyretic- in various infections, PUO3. Acute rheumatic fever4. Rheumatoid arthritis (3-5g/day)5. Osteoarthritis6. Postmyocardial infraction & poststroke patients

(60-100mg/day). In such patients aspirin reduces TIA and incidence of stroke.

7. Other less well established uses are : -pregnancy induced hypertension -pre-eclampsia -to delay labour -patent ductus arteriosus in new born -familial colonic polyposis -prevention of colon cancer -prevent flushing attending nicotinic acid

ingestion,which is due to PG release in skin.

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/day

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 inj prepration

(Lysine acetylsalicylate 900mg+Glycine 100mg/5ml water)

OTHER CLINICALLY USED SALICYLATES

a) Sodium salicylate:• Aspirin alternative in rheumatic fever• But now is obsolete

b) Methylsalicylate (Topical):• Used topically as a counterirritant in muscle and

joint pain, in the form of liniments and ointments• Systemic absorption can lead to toxicity

c) Salicylic acid (Topical):• Used as keratolytic• Combined with benzoic acid (Whitefield ointment)

for local use in epidermophytosis

PROPIONIC ACID DERIVATIVES

• 1st member – IBUPROFEN (1969) better tolerated alternative to aspirin

• MOA- inhibit PG synthesis• Most potent- naproxen• Others – ketoprofen,flurbiprofen• Antiinflammatory efficacy is rated somewhat

lower to that of high dose of aspirin• Inhibit platelet aggregation reversibly and cause

short lasting prolongation of bleeding time.

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

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.

DOSAGE AND PREPARATIONS OF PROPIONIC ACID DERIVATIVES

DRUG PLASMA t1/2

DOSAGE PREPERATIONS

1 IBUPROFEN 2 hr 400-600mg(5-10mg/kg) TDS

BRUFEN,EMFLAM,IBUSYNTH 200,400,600 mg T,IBUGESIC also 100mg/5ml suspension

2 NAPROXEN 12-16hr 250mg BD-TDS NAPROSYN,NAXID,ARTAGEN,XENOBID 250mg T,NAPROSYN also 500mg T

3 KETOPROFEN 2-3hr 50-100mg BD-TDS

KETOFEN 50,100mg T,OSTOFEN 50mg C,RHOFENID 100mg,200mg SR T, T,100mg/200ml amp

4 FLURBIPROFEN 4-6hr 50mg BD-QID ARFLUR 50,100mg T,200mg SR T,FLUROFEN 100mg T.

DOSAGE

USES• ‘over the counter’ drug as analgesic and antipyretic

in low dose as aspirin• Rh arthritis, osteoarthritis , other musculoskeletal

disorders specially when pain is more prominent than inflammation

• Soft tissue injury, tooth extraction, fractures, vasectomy, post partum and post op : supress swelling and inflammation-VERY POPULAR IN DENTISTRY

• NAPROXEN is more efficacious and better tolerated in antiinflammatory doses (long acting and BD dose )

ANTHRANILIC ACID DERIVATIVE(FENAMATE) MEPHENAMIC ACID It is an analgesic, antipyretic and

antiinflammatory 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.

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

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 ~2 hrs.

• Good tissue penetrability & concentration in synovial fluid is maintained for three times longer than plasma.

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 inj.

Diclofenac potassium: VOLTAFLAM 25,50 mg T, VOVERAN 1% topical gel.

• ACECLOFENAC : relatively selective COX2 congener of diclofenac sod

• 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.

ADVERSE EFFECTS

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

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.

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• Piroxicam – short term analgesic and long term

antiinflammatory drug in Rh and osteoarthritis, ankylosing spondylitis, acute gout, musculoskeletal injuries and in dentistry.

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.

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 pain2. Acute musculoskeletal pain (15-30mg im or iv)3. Renal colic4. Migraine5. Pain due to bony metastasis.

• 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

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.

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

CONTRAINDICATIONS Machinery operators Drivers Psychiatric patients Epileptics Kidney disease Pregnant women and in children

Dose: 25-50 mg BD-QID

INDICIN, INDOCAP 25mg C,75mg SR C, ARTICID 25,50mg C,INDOFLAM 25,75mg C,1% eye drop

USES

Rheumatoid arthritis

Ankylosing spondylitis

Acute exacerbations of destructive artropathies

Psoriatic arthritis

Acute gout

Closure of patent ductus arteiosus dose; 0.1-0.2 mg/kg

PYRAZOLONE

• 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.

• Few cases of agranulocytosis were reported and Metemizol was banned in USA.

• It has been extensively used in India

and some European countries.• Dose: 0.5-1.5 g oral/i.m/i.v• ANALGIN 0.5g tab• NOVALGIN, BARALGAN 0.5g tab,0.5gm/ml

in 2ml and 5ml amps,ULTRAGIN 0.5gm/ml inj in 2ml amp and 30ml vial

PROPIPHENAZONE

• Another pyrazolone, similar in properties to metamizol ; claimed to be better tolerated.

• Agranulocytosis has not been reported• Dose : 300-600 mg TDS• SARIDON,ANAFEBRIN : Propiphenazone

150 mg + Paracetamol 250 mg.• DART : propiphenazone 150mg +

paracetamol 300mg + caffeine 50mg T.

PREFERENTIAL COX-2 INHIBITORS

• NIMESULIDE : • Weak inhibitor of prostaglandin synthesis.• Antiinflammatory 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

PHARMACOKINETICS• Completely absorbed orally• 99% plasma protein bound• Extensively metabolized and excreted mainly in urine• Plasma t1/2 2-5hrsADVERSE EFFECTS• GI-epigastralgia, heart burn, nausea, loose motion• Dermatological- rashes, pruritis• Central- somnolence, dizziness• Haematuria in children.• Recently several instances of fulminant hepatic failure have

been associated and hence banned in Spain, Finland, & Turkey and not marketed in UK,USA,Australia,Canada

• Used in asthmatics who cannot tolerate ASPIRIN.• DOSE : 100mg BD; NIMULID,NIMEGESIC,NIMODOL,100mg

T,50mg/ml susp• MELOXICAM• newer congener of piroxicam• has COX2:COX1 selectivity ratio 10• Since mesurable inhibition of platelet TXA2 occurs at

therapeutuc dose it has been labelled pref.COX2 • DOSE: 7.5-15mg OD,MELFLAM,MEL-OD,MUVIK,M-CAM

7.5mg,15mg T• NABUMETONE• Prodrug with analgesic, antipyretic and antiinflammatory

activity• Effective in Rh, osteoarthritis and soft tissue injury• DOSE : NABUFLAM 500mg T ,1tab OD

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• Doses: 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 inj,PAROXIB 40mg T

PARA AMINO PHENOL DERIVATIVES• PHENACETIN• Was introduced in 1887. It was extensively used but is now

banned in many countries-analgesic abuse nephropathy• 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• Paracetamol 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.

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 3-5hrsADVERSE 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 analgesic s; such persons have some personality defect

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

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

hepatotoxicityUSES• Headache• Musculoskeletal pain• Toothache• Dysmenorrhea• Pregnant women & lactating mothers• Much safer than aspirin in terms of GI manifestations• Does not prolong bleeding time ; so less chance of post

extraction haemorrhage• Can be used in all age groups

DOSE• 0.5- 1gTDS• infants 50mg• children 1-3yrs 80-160mg• 4-8yrs 240-320mg• 9-12yrs 300-600mg• CROCIN 0.5,1.0mg T, METACIN, PARACIN 500mg

T 125mg/5ml syrup, 150mg/ml paed.drops• ULTRAGIN,PYRIGESIC,CALPOL 500mg

T,125mg/5ml syrup• NEOMOL,FEVASTIN,FEBRINIL 300mg/2 ml inj• CROCIN PAIN RELIEF: paracetamol

650mg+caffeine 50mg T

CHOICE OF NSAIDs1. 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 derivative4.Gastric intolerence to conventional NSAIDs-etoricoxib, paracetamol5. h/o asthma, anaphylactic reaction to aspirin or other NSAIDs- nimesulide,COX2 inhibitor6. Pregnancy-paracetamol best preferred, second best low dose aspirin7. Paediatric- paracetamol ,aspirin, ibuprofen, naproxen

NSAID’s as HOST MODULATORY AGENTS

• 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)

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

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 dent res 1991)

• 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)

Author Purpose Host MAgent

Parameters Subjects Results

Ishihara y,nishihara tet al(1991)

demonstrate thelipopolysaccharide isolated from a.a comitans strain induced bone resorption

Indomethacindexamethasone

PGE2 and IL-1levels

Mouse PGE2 and IL-1participate in LPSinduced boneresorption in vitro.

Howell th,fiorellini i,weber hp etal (1991)

To study the effects of piroxicam inpreventing gingival inflammationand plaque formation

Piroxicam

Gingivalinflammationplaque index

Beagle dogs

Significantly inhibitthe development ofgingival inflammation

Roy S,Feldman,Szeto B et al(1983)

To evaluate the effect on boneresorption: A retrospective study

Aspirin (asp) oraspirin plusindomethcin

Radiographs

Humans Percentage bone lossfor the entiredentition was lower inasp group

OffenbacherS, Odle BMet al (1989)

metabolites of cyclooxygenase(co) during the progression of periodontitis

Flurbiprofen

Crevicular fluidlevels of PGE2and TXB2

Rhesus monkey

prevented rise inTXB2, but did notaffect increase in PGE2.

HeasmanPA, et al(1993)

efficacy offlurbiprofen (50mg) on bothdeveloping and establishedgingivitis

Flurbiprofen

GCFconcentrationof PGE2, TXB2and LTB4,Bleeding index

Human control gingivalinflammation with bothpreventive and therapeuticproperties

Risk versus 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)

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 antiinflammatory 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.

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• Diclofenac Potassium, Trypsin

WHAT’S NEW ?

• NO-releasing nonsteroidal antiinflammatory drugs (NO-NSAIDs) are a recently described class of NSAID derivatives generated by adding a nitroxybutyl moiety through an ether linkage to the parental NSAID (Elliott, McKnight, Cirino,J. L. Wallace. 1995)

• These compounds exhibit a markedly reduced gastrointestinal toxicity, while retaining the antiinflammatory and antipyretic activity of parent NSAID.

• Although NO-NSAIDs spare the gastric mucosa, they inhibit prostaglandin generation and exert powerful antiapoptotic and antiinflammatory effects.

• Preliminary animal studies indicate that NO-NSAIDs are more effective than conventional NSAIDs in reducing inflammation and pain in arthritic rats (Fiorucci,Antonelli, Santucci, O. Morelli, M. Miglietti, B. Federici,A. Morelli. 1999)

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.

REFERENCES Lippincott’s illustrated reviews-Pharmacology Williams and Wilkins- 2nd edition. Essentials of pharmacology for dentistry K D Tripathi – 2nd edition. Pharmacology and therapeutics for dentistry John A Yagiela,Enid A Neidle,Frank J Dowd-4th edition. A turbulent decade for NSAIDs: update on current concepts of

classification, epidemiology, comparative efficacy, and toxicity – review article

Rheumatol Int (2012) 32:1491–1502 DOI 10.1007/s00296-011-2263-6. Association between long-term aspirin use and periodontal

attachment level in humans: a cross-sectional investigation, Australian Dental Journal 2012; 57: 45–50.

An Overview of Clinical Pharmacology of Ibuprofen-Rabia Bushra,Nousheen Aslam (Ziauddin College of Pharmacy, Ziauddin University, Kaarchi, Sindh, Pakistan)

Prostaglandins and bone : potential risks and benefits related to use of NSAIDs in clinical dentistry,journal of oral science,vol 50,no3,247-252,2008

Effects of NSAIDs on beagle crevicular cyclooxygenase metabolites and periodontal bone loss, Journal of Periodontal Research:vol 27,issue3,pages 207–213, May 1992

The Effects of Non-Steroidal Anti-Inflammatory Drugs (Selective and Non-Selective) on the Treatment of Periodontal Diseases, Current Pharmaceutical Design, Volume 11, Number 14, May 2005, pp. 1757-1769(13).