Pharmacology

Eicosanoids (Prostaglandins)

Eicosanoids

  • Prostaglandin (PGs) and leukotrienes (LTs) are derived from polyunsaturated essential fatty acids with 20 carbon atoms.
  • 1930: Human semen – contracts uterus and other smooth muscles (SM) to cause fall in BP.
  • The prostaglandin was derived from the prostate.
  • 1970: Aspirin like drugs inhibit PG synthesis
    • Thromboxanes (TX) and Prostacyclin (PGI)
  • Bergstrom, Samuelsson and Vane got the Nobel Prize in 1982 for their work on PGs and LTs.

Chemistry

  • Chemically, PGs may be considered to be derivatives of prostanoic acid, though prostanoic acid does not naturally occur in the body.
  • PGs are designated in series as – A, B, C ….I etc. depending on ring structure and substitution
    • Each series is named 1,2,3 indicating no. of double bonds
  • LTs are also similarly – A, B, C …..F and 1, 2, 3, 4.

Chemistry of Eicosanoids

  • In the body PGs, TXs and LTs are all derived from eicosa (referring to 20 C atoms) tri/tetra/ Penta enoic acids. Therefore, they can be collectively called eicosanoids.
  • In human tissue – derived from 5,8,11,14 eicosa tetra eonic acid (arachidonic acid).
  • During the synthesis of PG, TX, and LT – 2 double bonds get saturated due to cyclization – only 2 double bonds in the side chain – so, subscript 2 PGs are important e.g. PGE2, PGF, PGI2, TXA2.
  • No cyclization or reduction for LTs – LTB4, LTC4, LTD4.

Biosynthesis of Eicosanoids

Cyclooxygenases (Cox)

  1. Cox-1
    • COX-1 is a constitutive enzyme in most cells.
    • Synthesized in basal states – not changed even if the cell is fully grown.
    • It serves as ‘house-keeping functions’ functions – secretion of mucus in Gastric mucosa, Haemostasis, and Renal function.
  2. Cox-2
    • COX-2 normally present in insignificant amounts.
    • Inducible by inflammatory mediators (cytokines, interleukin-1, tumor necrosis factor (TNF) – Induction inhibited by corticosteroids.
    • it supports inflammation / pain / fever .
    • Exception: Kidney, brain, and fetus.

3.   Cox-3

  • Found in the dog brain (recent discovery).
  • A Splice variant of Cox-1 – it develops fever
  • This iso-enzyme is inhibited by paracetamol.
  • The exact role in humans is not known.

Synthesis inhibitors

  • NSAIDS – Mostly non-selective (both COX-1 and COX-2)
    • Aspirin – acetylates COX at serine site – irreversible inhibition
    • Other NSAIDs – competitive and reversible inhibition
    • Selective Cox 1 inhibitors – celecoxib, etoricoxib
  • Zileuton – Inhibits LOX – was used in asthma
  • Glucocorticoids – inhibit release of arachidonic acid – produces protein annexin – inhibits Phospholipase A2
    • Also inhibits induction of COX-2.

Degradation

  • Biotransformation of arachidonates occurs rapidly in most tissues, but fastest in the lungs.
  • The plasma t ½ of most PGs, TXA2, and prostacyclin have a few seconds to few minutes.
  • Uptake is carried out by a specific carrier into the cells. The side chains are then oxidized and double bonds are breakdown to yield inactive metabolites.
  • Metabolites are excreted in the urine.

Action of Prostaglandins, Thromboxanes, and Prostacyclin

OrganProstaglandin E2 (PGE2)Prostaglandin F2α (PGF2α)Prostacyclin (PGI2)Thromboxane A2 (TXA2)
1. Blood vesselVasodilatation, ↓ BPVasodilation (mostly), larger veins constrict, little effect on BPVasodilatation (marked & widespread), ↓ BPVasoconstriction
2. HeartWeak inotropic, reflex cardiac stimulationWeak inotropic
3. PlateletsVariable effectAnti-aggregatoryAggregation and release reaction
4. UterusContraction, softening of cervixContraction (in vivo & in vitro), softening of cervix
5. BronchiDilation, inhibit histamine releaseConstrictionDilation (mild), inhibit histamine releaseConstriction
6. Stomach↓ acid secretion, ↑ mucus production↓ acid secretion (weak), mucosal vasodilatation
7. IntestineContracts longitudinal & relaxes circular muscles, ↑ peristalsis, ↑ Cl¯ & water secretionSpasmogenic, ↑ fluid & electrolyte secretion (weak)Weak spasmogenic, inhibit toxin-induced fluid secretionWeak Spasmogenic
8. KidneyNatriuresis, ↓ Cl¯ reabsorption, inhibit ADH action, vasodilatation, renin releaseNatriuresis, vasodilatation, renin releaseVasoconstriction
9. CNSPyrogenic, variety of effects on i.c.v. inj.
10. Release of NA↑ or ↓↑ or ↓
11. Afferent nerveSensitize to noxious stimuli → tendernessSame as PGE2
12. Endocrine systemRelease of ant. Pituitary hormones, steroids, insulin; TSH-like actionRelease of gonadotropins & prolactin, luteolysis (in animals)
13. MetabolismAntilipolytic, insulin like action, mobilization of bone Ca2+

Reference

  1. Essential of Medical Pharmacology 7th edition, K D Tripathi

Hello! My name is Smrutiranjan Dash, a pharmacy professional. belonging from, Bargarh, Odisha. I have acquired Master degree in Pharmacy (Pharmacology) form B.P.U.T, Rourkela, Odisha. Currently I am working as an Assistant Professor at The pharmaceutical college, Barpali.

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