NSAIDS-IIDr. R. Jamuna Rani MD,

Professor & HOD,Department of Pharmacology.

CLASSIFICATION OF NSAIDs

Nonselective COX inhibitors(COX1&2)(conventional)

1.SALICYLATES:Aspirin2.PARA AMINOPHENOL DERIVATIVES:

Paracetamol (acetaminophen), phenacetin3.PYRAZOLONE DERIVATIVES: Phenylbutazone,

oxyphenbutazone, metimazole,propiphenazone4.ACETIC ACID DERIVATIVES: Indomethacin, sulindac5.PROPIONIC ACID DERIVATIVES: Ibuprofen,

naproxen, ketoprofen and flurbipropen

CLASSIFICATION6.PHENYL ACETIC ACID DERVATIVES: Diclofenac7.FENAMATES: Flufenamic acid, mefenamic acid8.OXICAM DERVATIEVS: Piroxicam, Tenoxicam,9.HETERO ARYL ACETIC ACID DERIVATIVES:

Ketorolac 10.BENZOXAZOCINE: nefopam

COX-2 selective – Nimeusulide, Etodolac, Meloxicam, NabumetoneCOX-2 Selective (absolute)- Celecoxib, Rofecoxib, Valdecoxib

MECHANISM OF ANALGESIC-ANTIPYRETICS

During pain, fever, inflammation AA – is liberated from phospholipid of cell membrane

AACOX1 & COX2

PGS and TXA2COX1 – Constitutive formCOX2 – Inducible (except in brain and kidney) Induced by cytokines and other signal molecules at site of inflammation. NSAIDs inhibit COX1 and COX2 either selectively or nonselectively blocking the synthesis of PGS

PARA AMINO PHENOL DERIVATIVES

PARACETAMOL (Acetaminophen)Has analgesic and antipyretic effect similar to aspirin.Effective alternative to aspirin but anti inflammatory action-weak.Useful in pain relief in non inflammatory OA.Well tolerated GI S/E low.No gastric irritation, erosion or bleeding.No effect on platelet functionAvailable as OTC drug and common house hold analgesic

PARACETAMOL

Excellent bioavailability, t1/2 2 hoursConjugated with glucoronic acid, sulfuric acid or cysteine.90 - 100% is excreted in urine Children have less capacity for glucoronidation A small amount undergo N hydroxylation to form N acetyl-P-benzoquinoneimine (NAPQI) a highly reactive intermediate normally it reacts with sulfhydryl groups in glutathione and excreted. (no harmful effect).

continued

Oral – 325-1000mgRectal 650mg total daily dose should not exceed 2000mg dose children-10mg/kgSide effects: Rashes, neutropenia, thrombocytopenia & pancytopenia.Fatal hepatic necrosis occurs with toxic doses (10-15gm)- NAPQI binds to macro molecules disrupting enzymatic system.If concentration is 300mcg/ml at 4hrs and 45mcg/ml at 15 hrs condition is serious

TREATMENT OF PARACETAMOL POISONING

Activated charcoal within 4hrsN acetyl cysteine – specific antidote -detoxify NAPQI by repleting glutathione sulfhydryl stores S/E of N acetyl cysteine rash, nausea, vomiting, diarrhoeaGiven as IV infusion in 5% dextrose Loading dose 150mg/kg in 100ml – 15 mts

50mg/kg in 250ml – 4 hrs100mg/kg in 500ml – 16 hrs

Continued

Oral dose 140mg/kg – loading dose 70mg/kg every 4 hrs X 17

dosesMonitor liver and renal function Intubate if respiratory distressTreat hypoglycemiaLiver transplantation if fulminant hepatic failure ensues

PROPIONIC ACID DERIVATIVE

Ibuprofen: Non selective COX inhibitors available as OTC drug rapid absorption; high protein binding 90% metabolised and excreted in urineLonger half life; once or twice daily.S/E Better tolerated than aspirin and indomethacin GI S/E,rashes, thrombocytopenia, head ache, dizziness, blurred vision, fluid retention and edema

CONTINUED

D/I Decrease the action of antihypertensives and diuretics; increased bleeding with warfarin; BM suppression with methotrexateUSES: Mild - moderate pain, in RA, OA,Juvenile arthritis, musculoskeletal disorders and dysmenorrea.Can be used in pregnant, lactating mothers( Risk benefit ratio) and children. no beneficial effects in myocardial infarction DOSE: 400 – 800 mg

NAPROXEN

Absorbed completely, enhanced by sodium bi carbonate and delayed by magnesium oxide and aluminium hydroxide, also absorbed rectally99% bound to plasma protein, metabolised and excreted entirely in urine.Have inhibitory action on leucocyte functionS/E:GI, CNS, Blood, ototoxicity and dermatitisUSES: RA, OA, Dysmenorrhoea

FENOPROFEN,KETOPROFEN,FLURBIPROFEN

Fenoprofen: Similar to ibuprofenKetoprofen: COX inhibitor; stabilise lysosomal membrane, antagonize actions of bradykinin; renal function should be monitoredFlurbiprofen: Non selective; used in RA, AS, OA and gout; topical opthalmic preparation for inhibition of intraoperative miosis S/E: Similar to ibuprofen, cogwheel rigidity, tremor and ataxia.

PHENYL ACETIC ACID DERIVATIVE

Diclofenac: Non selective COX Inhibitor;COX2 inhibition greater; free AA in leucocytes decreased; rapidly absorbed; extensive protein binding; accumulates in synovial fluid S/E: GI, CNS, increase hepatic transaminases allergic reactions, fluid retention and edema Uses: RA, OA, AS, musculoskeletal pain, post operative pain and dysmenorrhoea available as extended release tablets, injections and rectal preparations

ACETIC ACID DERIVATIVEIndomethacin: non selective COX inhibitor prominent antiinflammatory action; intolerance limits its use to short term other actions inhibits motility of leucocytes, decrease synthesis ofmucopolysaccharides Excellent bio availability; more in synovial fluid D/I: Indomethacin with probenecid, warfarin, antihypertensives (beta blockers, ACE Inhibitors) and diuretics Uses: RA, AS, OA and acute GOUTIV administration – closure of PDA In refractive fever (Hodgkins disease) S/E: Diarrhoea, ulceration of the bowel, peptic ulcer, acute pancreatitis, CNS, Blood

FENAMATES

Mephenamic acid: Central and peripheral actions; directly antagonise effects of PGs, more GI side effects, enhances oral anticoagulants, serious hemolytic anemia (rare) Stop if diarrhoea or rash appearsNot to be used more than one week C/I: Pregnancy and young children Use: Dysmenorrhoea, RA & OA

OXICAM DERVATIVES

Piroxicam: Non selective COX inhibitor, inhibits leucocytes migration, decreases oxygen radical production, inhibits lymphocytes functionLong half life; once daily dosing, extensively metabolized, can be used in renal impairment Uses: RA, OA, AS, Gout, musculo skeletal pain and dysmennorhoeaS/E: GI, CNS, Available as capsules, dispersible tablets and injections

PYRROLO PYRROLE DERIVATIVE

Ketorolac: Only analgesic minimal antiinflammatory action, highly protein bound used in place of morphine in mild to moderate post surgical pain Available for IM, IV and oral use. An opthalmic preparation is also available Side effects: GI, CNSShould not be used more than 5 days Not recommended for preanesthetic medication and obstetric analgesia

PYRAZOLONES

Phenylbutazone: COX inhibitor potent antiinflmmatory, poor analgesic antipyretic, has uricosuric effect 99% protein bound, long half life S/E: Serious agranulocytosis and steven Johnson syndrome, GI and renal symptoms Use: RA, AS & Gout Withdrawn from USA

METAMIZOLE & PROPHIPHENAZONE

Metamizole (Dipyrone) analgesic antipyretic, poor antiinflammatory, not uricosuric Available for oral IM, IVS/E: Less agranulocytosis, allergic reactions Prophiphenazone: Similar to metamizole available in combinations with paracetamol

COX-2 SELECTIVE INHIBITOR (PARTIAL)

Nimesulide: COX-2 Selectivity similar to celecoxib, inhibition of neutrophil activation, decrease in cytokine and degradative enzyme production Has analgesic, antipyretic, antiinflammatory activity Use: sinusitis, sports injuries, dysmenorrhoea, OA and feverS/E: GI side effects, allergic rash, recently withdrawn from European countries because of hepatic failureShould not be used in children

COX-2 SELECTIVE INHIBITOR (PARTIAL)

Meloxicam: Congener of piroxicam Tenfold selective for COX-2 Dose: 7.5 – 15mgUse: OsteoarthritisSafety: Similar to other NSAIDs Nabumetone: Analgesic anti inflammatory agent, prodrugUse: RA, OA and soft tissue injuryS/E: GI, CNS

SELECTIVE COX-2 INHIBITORS

Celecoxib: COX-2 selective, analgesic, antipyretic, anti inflammatory, less ulcerogenicUSE: OA, RADose: 100-200mg/dayHas potential cardio vascular hazard;less dose for shortest time

SELECTIVE COX-2 INHIBITORS

Valdecoxib: Rapidly absorbed, presence of food delays absorption, enzyme inhibitor, interacts with warfarin, glyburide, ethinyl estradiol, dextromethorphanUse: RA, OA, DysmennorhoeaDose: 10-20mg twice dailyRofecoxib: Withdrawn from market due to risk of MI and stroke

SELECTIVE COX-2 INHIBITORSEtoricoxib: Long half life, extensively metabolized, hepatic impairment leads to drug accumulation, renal insufficiency does not affectUse: OA, RA, acute GOUT, post operative pain and dysmenorrhoea Other Coxibs: Parecoxib, lumiracoxibParecoxib: is available as injection

APAZONE

NSAIDs, antiinflammatory, analgesic antipyretic activity, potent uricosuric agent Use: RA, OA, AS and GOUTDose: Acute – 600mg thrice daily later 300mg thrice dailyS/E: GI side effects