NSAIDS

Phospholipids
Phospholipase-A2 --------- Steroids

Arachidonic acid

Cyclooxygenase Lipoxygenase
NSAIDs -------
LOX inhibitors --------

Prostaglandins

PGF2α PGE2 PGI2

Leukotrienes

algesia pyrexia vasodilation

The events of the inflammatory response and mechanisms of anti-Inflammatory

 Introduction
 Vane- M.O.A of Aspirin & NSAID’s.
 NSAIDS- analgesic, antipyretic & anti-inflammatory.

 Like Morphine they don't - suppress the CNS

- abuse liability.
- Physical dependence.
 Non narcotic, Nonopioid or Aspirin like analgesics.
 They act 10 on peripheral & also central in pain mechanism.

 They are available as OTC drugs.

 Salix alba- Salicylic acid- pain & fever

Classification-
I) NON-SELECTIVE COX INHIBITORS-
1.Salicyclic Acid Derivatives-
• Aspirin, sod.salicyclic acid, Difunisal.
2. Para-aminophenol Derivatives-
• Paracetmol.
3.Pyrazolone Derivatives-
• Phenylbutazone, Oxyphenbutazone, Azaprozone.
4. Indole Acetic Acid Derivatives-
• Indomethacin, Sulindac.
5. Aryl acetic Acid Derivatives-
• Diclofenac, Aceclofenac, Tolmetin.
6. Pyrrolo-pyrrole derivatives- Ketorolac
7. Propionic acid derivatives-
• Ibuprofen, Flurbiprofen, Naproxen, Ketoprofen.
8. Anthranilic acid (Fenamtes)-
• Flunamic acid, Mefenamic acid,
9. Oxicams - Piroxicam, Tenoxicam,
II) PREFERENTIAL COX-2 INHIBITORS-
• Nimesulide, Meloxicam, Nabumetone.
III) SELECTIVE COX-2 INHIBITORS-
• Celecoxib, Rofecoxib, Etodolac, Etoricoxib.
I .Salicylates - Aspirin is a proto type.
1.Analgesia-
 M.O.A- by inhibiting PG’s Synthesis.
 Blocks both peripheral & central pain mechanism
 Good analgesic, anti-inflammatory .
 Pain from integumental structures relieved.
 Visceral & Ischaemic pain- less relieved.
 Pain relieved without Euphoria.
 Tolerance & Dependence are not developed.
 Less analgesic when compared to morphine.
2. Antipyretic action-it X PG’s in hypothalamus & rests the
temp to normal level, heat loss-sweating & cutaneous
vasodilation .
3. Anti-inflammatory action-
 Higher dose -3-6gms.
 Reduces the signs & symptoms of inflammation.
 Due to inhibition of PG’s synthesis.
 X Granulocyte infiltration
 Stabilizes lysosmes & movement of WBC to the site of
inflammation.
4.Respiration- ( 4-6gms) .

O2 Co2 + Resp.center Rate & depth of

respiration plasma Co2 Resp. alkalosis.

 Dose dependent
 Inflammatory doses : stimulation
 Toxic doses : respiratory depression & death
 Hyperventilation- Salicylate poisoning
5.Acid base balance-
 Resp + ---- CO2 washed out ----- Resp.alkalosis (alkaline
PH)---compensated by excretion of HCO3- Na, K, H2O
(urine) -----PH returns to normal.
 Toxic doses--- depresses Resp.center---CO2 accumulates----
PH decreases --- HCO3- already excreted-----accumulation
of acidic metabolites------Resp / metabolic acidosis.
(uncompensated)
 Toxic doses--- depress vasomotor centre & kidneys -
acidosis & dehydration.
6.Metabolic effects-
 O2 consumption-- CO2 production(Sk. muscles)--- leads
to heat production.
 Glucose is utilised – mild hypoglycaemia, glycogen
 Toxic doses– fever, -ve N2 balance, FFA’S & Cholesterol.
-hyperglycaemia due to sympathetic stimulation.
7. GIT- irritates GIT mucosa-leads to N,V, epigastric pain, +
CTZ, gastric ulcers & bleeding (malena).
 Haematemesis occurs rarely.
 Ion trapping-
 Soluble aspirin-less ulceration.
8. CVS-larger doses- C.O to meet O2demand, direct
vasodilation.
toxic doses– depress VMC & circulation, BP falls,
Cardiac work with Na & H2O retention- ppt CHF.
9. Immunological effects- High doses suppress Ag-Ab
reactions, inhibits Ab formation & H release.
10. Uric acid excretion-
• <2g/day- uric acid retention & plasma urate levels.
• >5g/day-inhibits reabsorption - urocosuria.
• Not suitable for chronic Gout
11. Blood- Low dose X platelet COX & TXA2 syns.---

interferes with P.aggreation --- prolongs bleeding time.

• A single dose can inhibit TAX2 syn’s (platelets).

• This effects last through out the platelet life span.

• Long term- C.factors - risk of bleeding.

• Prevented by prophylactic Vit.k therapy.

12. Local effects- Keratolytic, mild antiseptic & fungistatic.

P.K-
 Acidic drugs are absorbed from stomach & S.intestine.
 Not well absorbed, Microfine preparations- absorbed.
 Salicylic acid & methyl Salicylate- well absorbed.
 Extensively bound to plasma Ptns.
 Metabolised in liver & plasma to salicylic acid (active).
 Enters brain slowly and freely crosses placenta.
 T1/2 -3-5hrs, excreted – urine.
 Dose dependent elimination (1 to 0 kinetics).
 Urine alkalinisation- enhances salicylate excretion.
A/E-
• GIT-
• Hypersensitivity & idiosyncrasy.
• G6PD deficiency- Haemolytic anaemias.
• Bleeding on prolonged use
• RYES syndrome- hepatic encephalopathy.
• Pregnancy & infants-
• Nephrotoxicity – Salt & H20 retention, impaired renal function.
• Hepatotoxicity – T.doses - serum transaminases .
Salicylism - Chronic salicylate intoxication syndrome.
 Anti-inflammatory dose- chronic use

 It may be mild to severe.

 Dizziness, tinnitus, vertigo, reversible impairment of

hearing,

 Excitement, mental confusion, hyperventilation &

electrolyte imbalance.

 Symptoms are reversible on withdrawal.

 Tinnitus is a good guide.

 Rx of Acute Salicylate poisoning-(15-30g fatal dose)

• Hospitalization.

• Gastric lavage - activated charcoal

• Fluids & electrolyte balance

• I.V Sod. bicarbonate- corrects metabolic acidosis.

• External cooling

• Haemodialysis-forced alkaline diuresis (NaHCO3).

• VitK1 & blood transfusion – during bleeding.

Precautions & C.I-
 Peptic ulcers, liver diseases, bleeding, child viral fevers,
pregnancy, renal & liver failures.
Dosage-

Analgesic doses- 2-3gms/day in divided doses

Anti-inflammatory- 4-6g/day.

Antiplatelet dose – 50-325mg/day.

Uses of NSAIDS-

1. Analgesic use- 0.3-0.6g/6hrly.

 headache, joint pains, neuralgias, dysmenorrhoea, cancer & bone pain.

2. Antipyretic- symptomatic relief & PCM is preferred.

3. R.A- 3-5gm/day. NSAIDS are 1st line drugs

4. Acute Rheumatic fever- 4-6gms/day/ wk.
- 50mg / kg / day/3wks aspirin is preferred.

5. Osteoarthritis-NSAIDS are preferred.

6. Eclampsia & Pre-eclampsia - low dose aspirin (80-100mg).

7) Post myocardial infarction & Post stroke-
-50-300mg / day (low dose aspirin)
- Reduces the incidence of - Reinfraction.
- Also TIA & stroke
- MI & Post MI (prophylaxis)
8) Closure of patent ductus arteriosus.
9) Colon & rectal cancer- chemoprophylaxis.

10) Alzheimer's disease- retards onset.

11) To control radiation induced diarrhea.

12) To control Pruritus & flushing associated nicotinic acid.

13. Barter’s syndrome

15. Slow down cataract formation

16.Familial colonic polyposis

17. Locally : Keratolytic, fungistatic mild antiseptic

Methyl salicylate : counter irritant

Mesalamine : IBD
 Drug interactions' with NSAID’s
Pharmacodynamics Pharmacokinetics
Diuretics - diuresis Oral anticoagulants
β Blockers - Anti HTN Sulfonylurea's X Metabolism

ACE inhibitors - Anti HTN Phenytoin

Anticoagulants - Bleeding Valproate

Sulfonylurea's - hypoglycaemia Digoxin

Elimination

Cyclosporine - Nephrotoxicity Li & Mtx

Corticosteroids - ulcer bleeding Amino glycosides

 Ibuprofen- 400/600mg- TDS. Pain > inflammation.
 Actions are slightly lower than high dose aspirin.
 Less displacement interactions .
 Short lasting antiplatelet action.
 Aspirin 650mg + codeine 60mg.
 Antagonises L.D Aspirin action.
 Effective in dysmenorrhoea.
 Inflammatory conditions.
 Soft tissue injuries.
 postpartum/ postoperative inflammation.
 Fractures & Tooth extraction.
 Diclofenac – 50mg/TDS/ Oral/I.M.
 Actions & efficacy is similar to naproxen.
 Antiplatelet action short lasting
 Reduces superoxide generation & chemotaxis.
Kinetics:
 Well absorbed
 90% PPB
 Metabolized, excreted in bile & urine
 Good tissue penetrability & concentrated in synovial fluid.
 Available as E.coated / S.Release tab /Gel/TD patch.
Adverse effects:
 Epigastric pain, nausea, headache, dizziness.
 Elevation of serum aminotransferases.

Uses:
 Rheumatoid arthritis, osteoarthritis.
 Bursitis, ankylosing spondylitis.
 Toothache, dysmenorrhoea.
 Post traumatic/ post operative inflammations.
 Quick relief from wound edema.

 Aceclofenac- Chondroprotective property.

 Piroxicam – 20mg / BD followed by OD.
 Long acting & potent NSAID.
 Inhibits reversibly COX-1.
 Prolongs bleeding time.
 Reduces leucocyte chemotaxis & IgM RA factor.
Kinetics:
 Rapid & complete absorption.
 99% PPB.
 Metabolized in liver & undergoes E.H.C.
 Long t1/2 – 2days. Cpss - 1wk.
 Excreted in urine & bile.
EHC- Entero hepatic circulation
Uses-
 Short term analgesic & long term anti-inflammatory.
 R.A & O.A.
 Acute gout, Musculoskeletal injuries.
 Dentistry & episiotomy.
Adverse effects-
 Edema & reversible azotaemia.
 Less ulcerogenic.
 Ketorolac- 10-20 mg/6hrly/ oral. 30mg/1ml amp.
 Potent analgesic.
 Modest anti-inflammatory action.
 Oral/ I.M/I.V route.
 Combined with morphine.
 Free of opioid side effects.
Uses:
 Post operative, musculoskeletal pain- 15-30mg.
 Renal colic, migraine, dental.
 Pain due to bony metastasis.
 Avoided continuous use for 5 days.
 Short term management of moderate pain.
 Superior to aspirin, PCM & Ibuprofen.
 Indomethacin- 25/50/75mg/ BD cap, Suppository.
 Potent anti inflammatory.
 Potent X of P.G syn's & chemotaxis.
 Relieves only inflammatory/ tissue injury related pain.
 Toxic dose - uncouples oxidative phosphorylation.
Uses:
 Rheumatoid/ Psoriatic arthritis
 Acute gout & Ankylosing spondylitis.
 Bartter syndrome.
 Malignancy associated fever.
 Closure of PDA- 0.1-0.2mg/kg.
 Nimesulide – 100mg/BD.
 Selectively inhibits COX-2 over COX-1.
 Reduces superoxide generation.
 X PAF synthesis & TNF- release.
 Free radical scavenging effect.
 Inhibition of metalloproteinase activity.
Uses:
 Headache, Toothache, Myalgia.
 Dysmenorrhoea, Sinusitis, ENT disorders.
 Arthritis, Post operative pain
 Short lasting painful injuries.
 Aspirin induced asthma patients.
 Paracetamol- Acetaminophen 0.5 – 1gm TDS/ 125,150mg- child.
 Active metabolite of phenacetin
 Poorly inhibits P.G syn’s peripherally.
 More active in brain - COX-3 inhibitor.
 Good antipyretic action.
 Central analgesic & weak peripheral anti-inflammatory action.
 Analgesic action of PCM + aspirin- additive.
 Contrast pharmacological actions to aspirin.
 Less ulcerogenic, no bleeding.
 preferred in pregnancy & lactating women.
Kinetics:
 Well absorbed, t1/2- 3hrs.
 Conjugation with glucuronic acid & sulfate.
 Excreted in urine.
Adverse effects:
 Nausea, Rashes, Leucopenia
 Analgesic nephropathy.
 Acute paracetamol poisoning-
 Common in children due less hepatic conjugation ability.
 Toxic dose > 10g in adult.
 Nausea, Vomiting, abdominal pain, tenderness.
 Centrilobular hepatic necrosis, renal necrosis.
  Jaundice starts after 2 days.
 Fulminating hepatic failure & death.
 Plasma levels > 200μg/ml at 4hrs & 30 μg/ml at 15hrs.
Mechanism of toxicity:
 N-acetyl-p- benzoquinoneimine – glutathione.
 Large doses – glutathione is depleted.
 Metabolite binds covalently to ptn’s in liver/ renal cells.
 Causes necrosis.
 In chr. alcoholics even 5-6g/day- hepatotoxic.
 Alcohol induces CYP2E1.
 Not recommended in premature infants.
Treatment: Hospitalization
 Gastric lavage / induction of vomiting.
 Activated charcoal
 Supportive measures
 N-acetyl cysteine -150mg/kg / i.v 15min.
- 75mg/kg / orally/6hrly/3days.
 Glutathione stores are replete.
Note-
Rx is ineffective after 15hrs of PCM ingestion.
Uses:
 Analgesic – Headache, Dysmenorrhoea
 Choice of analgesic – Osteoarthritis
 Best antipyretic – Children.
 Selective COX2 inhibitors (coxibs) -
 Don’t affect COX 1.
 Less chance of P.U & ulcer bleeding.
 More suitable to P.U pt’s.
 Lowest dose & for a short period should be used.
 Don’t X TXA2 synthesis, P.A/ prolong bleeding.
 Rofecoxib & Valdecoxib - C.V risk.
 Should be avoided in IHD/HT/cardiac failure.
 May not ve broad range efficacy-traditional NSAID’s.
• May delay ulcer healing.

• X of Renal COX 2 – salt & H2O retention, edema, ppt CHF

& B.P rise.

Celecoxib/ Rofecoxib-
 Analgesic, anti-inflammatory & antipyretic actions
Uses-
 Osteo/ Rheumatoid arthritis.
 Acute gout
 Dysmenorrhoea.
 Lumiracoxib - newer drug.
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