2. Eicosanoids and NSAIDs

// NSAIDs and Eicosanoids

02.07.21 | 19:26 tags:


  • Lipid autocoids

Eicosanoids

[[Pasted image 20210702205903.png]] ^fc3b23

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.
EffectsProstaglandin
Fever - Pain and inflammationPGE2
Platelet aggregationTxA2
Inhibition of platelet aggregationPGI2
Ductus Arteriosus (IUL) is kept openPGE2
VasodilationPGI2 (Iloprost), PGE2
Upper Uterine segment contractionPGE2, PGF2alpha
Relaxes Lower segmentPGE2
Inhibits proton pump inhibitor of stomachPGE2
Mucous and Bicarbonates are increased in stomachPGE2
Vasodilation -> Blood flow is increasedPGE2
Uveo-cleral outflow is increasedPGF2alpha (Latanoprost)

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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

  • 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

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  • NSAIDs - Non-Steroidal Anti-Inflammatory Drugs
Cyclooxygenase 1Cyclooxygenase 2
Constitutive enzymeInducible enzyme
Present at most placesInduction at site of inflammation
COX-1 maybe induced at lesser degreeThey may be present in the kidney, endothelium and CNS constitutively
Non-selective COX inhibitorsSelective COX-2 Inhibitors
Increased risk of Peptic Ulcer diseaseLesser risk of PUD as COX-1 will produce PGE2 in the stomach
Examples
DrugEffect
Aspirin
Paracetamol (Acetaminophen)No Anti-inflammatory activity
IbuprofenDOC NSAID in Children
Diclofenac
IndomethacinCauses Sedatiob - contraindication
PiroxicamLong-acting due to enterohepatic cycle
Phenylbutazone

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