// NSAIDs and Eicosanoids

02.07.21 | 19:26 tags:

• Lipid autocoids

Eicosanoids

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PA Integration:

• AA - 20C FA - 4 Double bonds
• LT - 4Double bonds
• PG - Cyclization occurs thus only 2 double bonds (endogenous)
  • Synthetic PGs like Misoprostol and Alprostadil (PGE1) have 1 double bond ^da623c
• Cyclooxygenase enzyme converts the straight chain fatty acid -> cycIe in which 2 double bonds break andform Prostaglandins with 2 doubie bonds.

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			Ductus arterious is a connection in the intrauterine life connecting Pulmonary Trunk to Aorta

PDA - condition where ductus arteriosus hasn’t regressed

• Treatment involves inhibition of production of PGE2

  • Aspirin
  • Indomethacin
  • Ibuprofen

• During treatment of Transposition of Great Vessels, ductus arteriosus is needed to be kept open for the surgery

  • This is done by giving PGE1 (PGE2 analogue) synthetic prostaglandins like Alprostadil

• Abortion uses PGE2, PGF2 to contract upper part and relax the lower part Misoprostol - PGE1 (PGE2 analogue)

  • Similarly Misoprostol is also used for cervical ripening in induction of labor for relaxation of lower segment of the uterus and cervic

• Postpartum bleeding usually stops due to uterine contractions

  • In some cases the contractions are weak -> Postpartum hemorrhage
  • Carboprost PGF2 alpha - DOC is Oxytocin

• Cox Inhibitors induce peptic ulcers due to p

  • For ulcer, most specific drug caused by NSAID-induced peptic ulcer - Misoprostol
  • However DOC -> Proton Pump Inhibitors

• For primary open angle glaucoma, latanoprost a PGF2alpha analogue is given -DOC

  • Side effects
    • P: Pigmentation of iris (Heterochroma iridis)
    • G: Growth of eye lashes (Hypertrichosis)
    • F2 alpha: Fluid in Macula (Macular Edema)

NSAIDS

• NSAIDs - Non-Steroidal Anti-Inflammatory Drugs

Paracetamol

• Peroxide theory

  • At site of inflammation, ROS like H202 are formed
  • In presence of H202, Acetaminophen does not exhibit activity
  • Thus anti-inflammatory effect is absent

• To explain lesser PUD risk

  • COX-3 inhibition theory
  • COX-3 is present mainly in the CNS
  • As pain and fever is a central effect and inflammation is peripheral
  • Since it’s not anti-inflammatory, it’s antipyretic and analgesic (thus not a DOC NSAID for children)

• Paracetomol’s metabolite acts on vanilloid receptors (TRPV) -> responsible for Analgesic action

Post-metabolism, 99% of paracetamol is inactive

• Acetaminophen -> [CYP] ->N-Acetyl para-amino benzo quinone imine (NAPQI) NAPQI has high affinity for -SH groups
• The glutathione produced by liver binds with NAPQI and neutralizes it

• Thus paracetamol toxicity can occur when
  • Overdosage
  • Liver disease
  • Chronic Alcholism
• N-Acetyl Cysteine is given as a DOC for Paracetamol toxicity -> contains -SH groups

Asprin

• Irreversible COX Non-selective inhibitor

Aspirin prevents formation of PGH2 by irreversibly binding

• Because TxA2 is produced by activated platelets - that do not have a nucleus thus there’s no transcription -> COX enzyme production is not renewed
• However PGI2 synthesis occurs in endothelial cells, which do have a nucleas and upregulate the production of Cyclooxygenase
• This thus causes the anti-platelet-aggregatory effect of Aspirin

• It is contraindicated in children with viral infection due to risk of Reye’s syndrome

• Can cause hyperuricemia at therapeutic doses -> Avoided in gout

• Salicylism - OD of aspirin

  • Stimulation of respiratory center
  • -> Hyperventiltion -> decreased CO2
  • -> Respiratory Alkalosis - Reversible till here
  • Metabolic Acidosis - Irreversible step
    • Due to compensation -> removal of bicarbonate
    • Due to hyperventilation -> Lactic acid metabolites
    • Aspirin itself is an acidic drug
  • Treatment
    • Sodium Bicarbonate
      • Alkalizes urine
      • Reverses metabolic acidosis
      • Helps in aspirin excretion