Presented by:Samya Sayantan Id: 121-29-381 Batch: 7th

Sec: A

Department of Pharmacy

Daffodil International University

non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs stands Non-Steroidal Anti-Inflammatory Drugs.

NSAIDs are a class of drugs that provides analgesic and antipyretic effect & in higher doses anti-inflammatory effects.

NSAIDs are medications other than corticosteroids that relieve pain, swelling , stiffness and inflammation.

NSAIDs

Nonselective COX inhibitors Salicylates: Aspirin.Propionic acid derivatives: Ibuprofen, Ketoprofen,

Flurbiprofen.Fenamate: Mephenamic acid.Enolic acid derivatives: Piroxicam, Tenoxicam.Acetic acid derivatives: Ketorolac, Indomethacin. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone.

Preferential COX-2 inhibitors:Nimesulide, Diclofenac, Aceclofenac, Meloxicam, Etodolac.

Selective COX-2 inhibitors:Celecoxib, Etoricoxib, Parecoxib.Analgesic-antipyretics with poor anti-infammatory action:Paraaminophenol derivative: Paracetamol (Acetaminophen)Pyrazolone derivatives: PropiphenazoneBenzoxazocin derivative: Nefopam

Classification

COX is enzyme responsible for biosynthesis of various prostaglandins

There are two well recognized isoforms COX called COX-I and COX-II

COX-I is constitutive found in most tissues such as blood vessels, stomach and kidneys

PGS have important physiological role in most tissuesCOX-II is induced during inflammation by cytokines and

endotoxins and is responsible for the production of prostanoid mediators of inflammation

Aspirin and most of non steroidal ant inflammatory drugs inhibit both COX-I and COX-II isoforms thereby decrease PG and Thromboxane synthesis

The anti-inflammatory effect of NSAIDs is mainly due to inhibition of COX-II

Aspirin causes irreversible inhibition of COX activity. Rest of the NSAIDs cause reversible inhibition of enzyme.

Mechanism of action

Mechanism of action analgesics:PGE2 and PGI2 are important prostaglandins

involved in pain. Inhibition of this enzyme produce analgesic effect.

Mechanism of action antipyretic:Inhibition of production of prostaglandins induced

by interlukin-1 (IL-1) and interlukin-6 (IL-6) in the hypothalamus and the resetting of the thermoregulatory system, leading to vasodilatation and increased heat loss.

Aspirin is prototype drugSalicylates are used to treat rheumatoid arthritis, juvenile

arthritis, and osteoarthritis as well s other inflammatory disorders. 5-aimino salicylates can be used to treat Crohn disease.

Analgesic effectNSAIDS are mainly used for relieving musculoskeletal

pain and pain associated with inflammation or tissue damage

Analgesic effect is mainly due to peripheral inhibition of PGS production

They also increase pain threshold by acting as sub cortical site

These drugs relieves pain without causing sedation tolerance or drug dependence

Pharmacological actions of aspirin and other NSAIDS:

Antipyretic effectThe thromboregulatory centre is situated in

hypothalamus Fever occurs when there is disturbance in

hypothalamic thermostat NSAIDS reset the hypothalamic thermostat and

reduce the elevated body temperature during fever

They promote heat loss by causing cutaneous vasodilatation and sweating

They do not effect normal body temperature The antipyretic effect is mainly due to inhibition of

PGS in hypothalamus

Anti-inflammatory effect:Anti -inflammatory effect is seen at high

doses(aspirin 4-6 g/day in divided doses )These drugs produce only symptomatic relief They suppress sign and symptoms of inflammation

such as pain , tenderness swelling vasodilatation and leukocyte infiltration but they do not effect the progression underlying disease

The inflammatory action of NSAIDS is mainly due to inhibition of prostaglandins synthesis at the site of injury

They also affect other mediators of inflammation bradykinin , histamine , serotonin and thus inhibit granulocyte adherence to the damaged vasculature

NSAIDS also cause modulation of t cell function stabilization of lysosomal membrane and inhibition of chemo taxis.

Anti-platelets effect:Aspirin in low doses (50-325 mg ) irreversible

inhibits TXA-II synthesis and produces antipalatelet effect which last 8-10 days i.e. the life time of platelets

Aspirin in high doses 2-3 g/day inhibits both PGI 2 and TXA-II synthesis.

Acid base and electrolyte imbalance: In therapeutic doses salicylates causes

respiratory alkalosisIn toxic doses the respiratory centre is depressed

and can lead to respiratory alkalosis In toxic doses the respiratory centre is depressed

and can lead to respiratory acidosis

GITIrritates gastric mucosa and produce nausea

vomiting and dyspepsia  The salicylic acid formed from aspirin also

contributes to these effect Aspirin also stimulates CTZ and produce vomiting

CVSProlonged use of aspirin and other NSAIDS causes

Na and water retention They may precipitate CCF in patients with low

cardiac reserve They may also compromise the effect of

antihypertensive drugs  

Inhibit PG synthesisAdverse effects:

Ibuprofen and all its congeners are better tolerated than aspirin. Gastric erosion and occult blood loss are rare.

Rashes, itching and other hypersensitivity phenomena are infrequent. However, these drugs precipitate aspirin-induced asthma.

Use:Ibuprofen is used as a simple analgesic and

antipyretic in the same wav as low dose of aspirin.Dose of ibuprofen is 200- 400 mg, ketoprofen 50-

100 mg

Propionic acid derivatives (Ibuprofen)

Potent anti-inflammatory drug with prompt antipyretic action.

Highly potent inhibitor of PG synthesis and suppress neutrophil.

Well absorbed orally; 90% protein bind nature, metabolized by liver and excreted by kidney; plasma t1/2 is 2-5 hours

ADR: high incidence of (up to 50%) GIT and CNS side effects. Increase bleeding due to decrease platelet aggregability.

Use: arthropathies, psoriatic arthritis and acute gout

Dose: 25 mg cap, 75 mg cap, 1% eye drop

Acetic acid derivatives (Indomethacin)

Potent analgesic but moderate anti-inflammatory agent

Efficacy is similar to morphine; inhibits PG synthesis Rapidly absorbed; 60% protein bind nature,

metabolized by liver (glucuronidation); plasma t1/2 is 5-7 hours

ADR: nausea, abdominal pain, loose stools, pain in injection site.

Use: used in postoperative (concurrently with morphine); continuous use for more than 5 days is not recommended. Topical preparation used for non-infective ocular conditions.

Dose: 10 mg tab, 30 mg inj. 0.5% eye drops

Acetic acid derivatives (Ketorolac)

An analgesic-antipyretic-anti- inflammatory drugInhibits PG and some what COX-2 selectiveWell absorbed orally, 99% protein bound, metabolized

and excreted through urine and bile, plasma t1/2 is approx. 2 hr.

ADR: mild ADRs. Epigastric pain, nausea, headache, dizziness, rashes. Diclofenac can increase the risk of heart ach and stroke. Kidney damage is rare.

Use: most extensively used NSAIDs. Rheumatoid, and osteo-arthritis, ankylosing spondylitis, renal colic, post-traumatic and post-operative inflammatory condition.

Dose: 50 mg entrecoted tab, 100 mg SR, 1% topical ointment, 1% eye drops.

Preferential COX-2 inhibitors (Diclofenac)

Selective COX-2 inhibitorIts exerts with anti-inflammatory, analgesic and

antipyretic actions with low ulcerogenic potential. ADR: Tolerability of celecoxib is better than

traditional NSAIDs. Still abdominal pain, dyspepsia and mild diarrhea are common side effects.

Slow absorbed, 97% plasma protein bound and metabolized primarily by CYP2C9 with t1/2 of approx. 10 hr.

Dose: 100 and 200 mg cap.

Selective COX-2 inhibitors (Celecoxib)

Central analgesics, Paracetamol has negligible anti-inflammatory action.

Poor inhibitor of PG synthesis and more active on COX in brain.

PK: 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 half life is 2-3 hr. Effects after an oral dose last for 3-5 hr.

ADR: Safe and well tolerated. Nausea and rashes occur occasionally. Leukopenia is rare.

Paraaminophenol derivative (paracetamol)

Uses:Antipyretic: reduce body temperature during feverAnalgesic: to relieve headache, toothache,

myelgia, dysmenorrhoeaPreferred analgesic and antipyretic in patients

with peptic ulcer hemophilia, bronchial asthma and children

Adverse effects: Skin rashes, Nausea, Hepatotoxicity,

NephrotoxicityAcute Paracetamol PoisoningHepatotoxicity: Nausea, vomiting, diarrhea,

abdominal pain, hypotension, hypoprothrombinemia coma, death

Toxic metabolite is detoxified by conjugation with glutathione and gets eliminated

High doses of paracetamol causes depletion of glutathione levels

In absence of glutathione toxic metabolites binds with protein in liver ,kidney and cause necrosis

Alcoholics and premature infants are more prone to hepatotoxicity

Activated charcoal is administered to decrease the absorption of paracetamol from gut.

Charcoal heamoperfusion is effective in severe liver failure

Hemodialysis is required in cases with acute renal failure  

Mechanism of toxicity and treatment

Useful in chronic and dull aching painsNo advantages over other NSAIDsWeaker analgesic than aspirinAdverse reactions include gastric upset,

diarrhoea, dizziness, headache, skin rashes, hemolytic anemia

Dose is 500mg 2-3 times a dayUsed in Dysmenorrhoea

Anthranilic acid Derivatives (Fenamates)

Piroxicam:Structurally different from other NSAIDsGiven orally, well absorbed, has long t1/2 (38-45hrs)

and that permits once-daily administration.The parent drug as well as its metabolites are

renally excreted in the urine.Commonly causes GI and CNS disturbancesHas been used to treat rheumatoid arthritis,

ankylosing spondylitis, osteoarthritis and acute gout

Oxicam Derivatives

It is indicated for treatment of rheumatoid arthritis and osteoarthritis.

It is associated with a low incidence of adverse effects.

Nabumetone is metabolized by the liver to an active metabolite that displays anti inflammatory, antipyretic and analgesic activities.

Cautious use of this agents patients with hepatic impairment is warrented.

The dose should be adjusted in those with creatinine clearance of less than 50ml/min

Nabumetone