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COX-1- Constitutive form, serve housekeeping functions

COX-2– Inducible form, inducible by cytokines and other signal molecules at site of inflammation

Non-Selective COX-1/2 vs. Selective COX-2: No antiplatelet aggregatory, gastric mucosal damage, Aspirin sensitive asthma precipitation in selective COX-2 inhibitors


Effects of NSAIDS


PGs induce hyperalgesia, NSAIDs block pain sensitizing mechanism induced by

bradykinin, TNF alpha, IL by primarily inhibiting COX-2


Decrease PGE2- in hypothalamus- decrease set point- reduces fever by promoting heat loss (sweating, cutaneous vasodilation but does not decrease heat production), COX-2 mediated



Inhibition of COX-2 mediated suppression of




Inhibit synthesis of TXA2 which is

proaggregatory, COX-1 mediated


arteriosus closure

PGE2 inhibition ,COX-2 mediated, if NSAID

given in pregnancy premature closure occurs, so avoid NSAIDs near term


Delay labor due to inhibition of PGs

Gastric mucosa


Inhibit COX-1 mediated protective PGs synthesis, decreased bicarbonate secretion,

enhance acid secretion

Renal effect

In hypovolemia, decreased renal perfusion and Sodium loss-> PGs-> vasodilation, NSAIDs can:

  • Impair blood flow and reduce GFR


In dysmenorrhea, PG elevated, NSAID lower

uterine level of PG- Provide relief

Anaphylactoid reactions

Precipitate asthma, Angioneurotic swellings, urticarial: Immunologically mediated

Salicylates (Aspirin- Prototype)


  • Acetylation of COX
  • Analgesic, antipyretic, anti-inflammatory action– Weaker analgesic than morphine; good anti-inflammatory action; anti-inflammatory action at high dose
  • Metabolic effect– cellular metabolism increased, esp. in skeletal muscle due to uncoupling of oxidative phosphorylation-> increase heat production; increased utilization of glucose-> blood sugar may deplete; liver glycogen is depleted; hyperglycemia at higher dose due to sympathetic stimulation
  • Respiration- dose dependent, at anti-inflammatory dose respiration is stimulated by peripheral as well as central action- Hyperventilation; further increase in salicylate level causes respiratory depression causing death
  • Acid-base and electrolyte balance- usual analgesic dose has no effect; anti-inflammatory doses produce significant change in AB balance and electrolyte composition; initially respiratory stimulation-> CO2 wash out-> respiratory alkalosis; which is compensated by renal excretion of HCO3 with accompanying Na+, K+ and water; still higher dose cause respiratory depression-> CO2 retention-> respiratory acidosis; dehydration occur in poisoning due to water loss in urine
  • Gastric mucosa damage- Inhibit COX-1 mediated protective PGs synthesis, decreased bicarbonate secretion, enhance acid secretion
  • GIT- aspirin and released salicylic acid irritates gastric mucosa-> causes epigastric distress, N, V, stimulates CTZ: vomiting; aspirin remains unionized and diffusible in gastric juice but on entering mucosal cell it ionizes and becomes in diffusible; this ion trapping in gastric mucosal cell enhances gastric toxicity further aspirin particle coming in contact with gastric mucosa promote local back diffusion of acid-> focal necrosis of mucosal cells-> acute ulcers, erosive gastritis, congestion and microscopic hemorrhages
  • Urate excretion- retention at low dose and increased excretion at high dose
  • Blood- Aspirin even in small doses, irreversibly inhibits TXA2 synthesis by platelets. Thus it interfere with platelet aggregation and bleeding time is prolonged to nearly twice the normal value. This effect lasts for about a week (turnover time of platelet); long term intake of large dose decrease synthesis of clotting factors in liver and predisposes to bleeding; prevented by giving prophylactic vit K


Side effects- at analgesic dose

N, V, Epigastric distress, increased occult blood in stool, gastric mucosal alteration and peptic ulcer

Hypersensitivity and idiosyncrasy

Rashes, FDE, Urticaria, Rhinorrhea, Asthma, Anaphylactoid reaction

Anti-inflammatory dose (3-5 g/day)

Salicylism- Dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement, hyperventilation

Children with RA- Liver damage

Children with viral infection- influenza, varicella- Reye’s syndrome- a rare form of hepatic encephalopathy

Acute salicylate poisoning

At fatal dose– Vomiting, diarrhea, acidotic breath, hyper/ hypoglycemia, restlessness, delirium, hyperpyrexia, convulsion, coma and death due to RF+ CVS collapse

Treatment– Symptomatic and supportive, Gastric lavage, IV fluids with Na, K, HCO3, Glucose


  • Aspirin sensitivity
  • Peptic ulcer
  • Bleeding tendency
  • Chicken pox, influenza
  • Diabetics
  • CLD- can cause hepatic necrosis
  • 1 week before surgery
  • 3rd trimester- can cause prolonged labor, premature closure of DA
  • G6PD- can cause hemolysis


  • Analgesic– headache, backache, myalgia, joint pain, pulled muscle , toothache, neuralgia, dysmenorrhea
  • Antipyretics– PCM is safer
  • Acute rheumatic fever
  • Rheumatoid arthritis
  • Osteoarthritis
  • Post myocardial infarction and Post stroke Pts.
  • Patent ductus arteriosus







Paracetamol (acetaminophen)

  • Central analgesic action of PCM is like aspirin i.e. it raises pain threshold
  • Good and promptly acting antipyretic
  • But has weak peripheral anti- inflammatory component
  • Poor inhibitor of PG synthesis in peripheral tissue, but more active on COX in the brain
  • Inability to inhibit COX in the presence of peroxides generated at site of inflammation, but are not present in brain
  • Does not stimulate respiration or affect AB balance; does not increase cellular metabolism
  • GI irritation is insignificant- occur only in overdose
  • Does not affect platelet function or clotting factor and not uricosuric
  • In isolated antipyretic dose PCM is safe and well tolerated
  • N and Rashes occur occasionally, leucopenia is rare

Acute PCM poisoning

  • Esp. in small children who have low hepatic glurorinide conjugating ability or if large dose (>150 mg/kg or >10 g in adult) is taken; fatality common with > 250 mg/kg
  • Early manifestation– N, V, Abdominal pain, Liver tenderness with impairment of consciousness
  • Followed by (12-24 hr.)– Centrilobular hepatic necrosis, Renal tubular necrosis, hypoglycemia that may progress to coma
  • Mechanism of toxicity- N-acetyl-p- benzoquinoneimine (NAPQI) is a highly reactive arylating minor metabolite of paracetamol which is detoxified by conjugation with glutathione. When a very large dose of paracetamol is taken, glucuronidation capacity is saturated, more of the minor metabolite is formed—hepatic glutathione is depleted and this metabolite binds covalently to proteins in liver cells (and renal tubules) causing necrosis. Toxicity thus shows a threshold effect manifesting only when glutathione is depleted to a critical point.
  • Treatment- gastric lavage, N-acetylcysteine
  • Headache
  • Mild migraine
  • MSK pain
  • Dysmenorrhea
  • Osteoarthritis- DOC
  • Best drug to use as antipyretic– no risk of Reye’s syndrome


  • 15-30 mg IM or IV every 4- 6 hours
  • Potent analgesic but modest anti-inflammatory activity
  • In PO pain it has equaled the efficacy of morphine but is free of opioid side effects
  • Like other NSAIDs it inhibits PG synthesis and relieves pain primarily by peripheral


  • Nausea, abdominal pain, dyspepsia, ulceration, loose stool
  • Drowsiness, headache, dizziness, nervousness
  • Pruritus
  • Pain at injection site
  • Raised serum transaminases
  • Fluid retention
  • POP pain
  • Dental pain
  • MSK pain
  • Renal colic
  • Migraine
  • Pain due to bony metastasis
  • Orally (10-20 mg 6 hrly.) for short term management of moderate pain
  • Topical ketorolac in ocular condition


  • Weaker anti-inflammatory
  • Same as other NSAID
  • Analgesic, Antipyretic- as aspirin
  • Dysmenorrhea– due to PG synthesis inhibition
  • Rheumatoid arthritis
  • OA
  • MSK disorder
  • Soft tissue injuries
  • Fracture, vasectomy, tooth extraction
  • Postpartum and postoperatively


  • Relatively weak inhibitor of PG synthesis and moderately COX-2 selective
  • GI– Epigastralgia, Heart burn, N, loose motions
  • Dermatological– Rash, pruritus
  • Central– somnolence, dizziness
  • Ulcer can occur
  • Fulminant hepatic failure can occur- withdrawn in spain, ireland
  • Short acting painful inflammatory conditions like:
  • Sports injury, dental surgery, sinusitis, ENT disorders, bursitis, low backache, dysmenorrhea, POP pain, OA and fever
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