- 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.
- 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, PGF2α, PGI2, TXA2.
- No cyclization or reduction for LTs – LTB4, LTC4, LTD4.
Biosynthesis of Eicosanoids
- 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.
- 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.
- 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.
- 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.
- 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
|Organ||Prostaglandin E2 (PGE2)||Prostaglandin F2α (PGF2α)||Prostacyclin (PGI2)||Thromboxane A2 (TXA2)|
|1. Blood vessel||Vasodilatation, ↓ BP||Vasodilation (mostly), larger veins constrict, little effect on BP||Vasodilatation (marked & widespread), ↓ BP||Vasoconstriction|
|2. Heart||Weak inotropic, reflex cardiac stimulation||Weak inotropic||–||–|
|3. Platelets||Variable effect||–||Anti-aggregatory||Aggregation and release reaction|
|4. Uterus||Contraction, softening of cervix||Contraction (in vivo & in vitro), softening of cervix||–||–|
|5. Bronchi||Dilation, inhibit histamine release||Constriction||Dilation (mild), inhibit histamine release||Constriction|
|6. Stomach||↓ acid secretion, ↑ mucus production||–||↓ acid secretion (weak), mucosal vasodilatation||–|
|7. Intestine||Contracts longitudinal & relaxes circular muscles, ↑ peristalsis, ↑ Cl¯ & water secretion||Spasmogenic, ↑ fluid & electrolyte secretion (weak)||Weak spasmogenic, inhibit toxin-induced fluid secretion||Weak Spasmogenic|
|8. Kidney||Natriuresis, ↓ Cl¯ reabsorption, inhibit ADH action, vasodilatation, renin release||–||Natriuresis, vasodilatation, renin release||Vasoconstriction|
|9. CNS||Pyrogenic, variety of effects on i.c.v. inj.||–||–||–|
|10. Release of NA||↑ or ↓||↑ or ↓||–||–|
|11. Afferent nerve||Sensitize to noxious stimuli → tenderness||–||Same as PGE2||–|
|12. Endocrine system||Release of ant. Pituitary hormones, steroids, insulin; TSH-like action||Release of gonadotropins & prolactin, luteolysis (in animals)||–||–|
|13. Metabolism||Antilipolytic, insulin like action, mobilization of bone Ca2+||–||–||–|
- Essential of Medical Pharmacology 7th edition, K D Tripathi