Autacoids II

Autacoids IIAutacoids II

Prostaglandins Prostaglandins Other eicosanoids: leukotrienes, TXA, PGIOther eicosanoids: leukotrienes, TXA, PGI History: 1930- 2 GynaecologistsHistory: 1930- 2 Gynaecologists(semen caused (semen caused

uterine contraction & relaxation, Von Euler later named the uterine contraction & relaxation, Von Euler later named the agent PG)agent PG)

1971 – Vane Smith and Willis 1971 – Vane Smith and Willis (inhibition of synthesis by NSAIDs).(inhibition of synthesis by NSAIDs).

Biosynthesis:Biosynthesis: Prostagladin* are 20C unsaturated Prostagladin* are 20C unsaturated

carboxylic acid with cyclo-pentane ring.carboxylic acid with cyclo-pentane ring. Phospholipases C/A2 or ↑Ca2+ results in Phospholipases C/A2 or ↑Ca2+ results in

the release of arachidionate.the release of arachidionate. Precursors membrane derived lipidsPrecursors membrane derived lipids

Biosynthesis:Biosynthesis:

(PLC) (lipase) Lipid membrane →→ DiGlyceride→ Arachidionate→ PGs

? (PLA2)

Arachidionate ? ? ? Prostaglandins*

↓

↓

ProstaglandinsProstaglandins

PG-2 series are derived from PG-2 series are derived from arachidionate arachidionate (in mammals)(in mammals). .

Other PGs – 1 and 3 from linolenic Other PGs – 1 and 3 from linolenic acid and eicosapentanoic acid acid and eicosapentanoic acid precursors respectively. precursors respectively.

*First, PGG *First, PGG →→ PGH and later PGD, E, PGH and later PGD, E, F, PGI, TXAF, PGI, TXA

Other pathways – P450, non-Other pathways – P450, non-enzymaticenzymatic


COX – 2 inducers include: cytokines, COX – 2 inducers include: cytokines, endotoxin, growth factorsendotoxin, growth factors

1,2,3, denotes the number of double 1,2,3, denotes the number of double bonds in the side chainsbonds in the side chains

PG: A, B or C; Not naturally occurringPG: A, B or C; Not naturally occurring Inhibition of pathway:Inhibition of pathway: PLA-2 inhibitor: (drugs that reduce Ca2+ PLA-2 inhibitor: (drugs that reduce Ca2+

and calmodulin)and calmodulin) :Glucocorticoids, through lipocortin.:Glucocorticoids, through lipocortin.


COX inhibitors: COX inhibitors: GlucocorticoidsGlucocorticoids NSAIDsNSAIDs *Selective COX-2: The COXIBS*Selective COX-2: The COXIBSe.g. Celecoxib, Rofecoxib e.g. Celecoxib, Rofecoxib TXA synthase inhibitor: PirmagrelTXA synthase inhibitor: Pirmagrel Ridogrel (+ receptor)Ridogrel (+ receptor) DazoxibenDazoxiben


Lipoxygenase inhibitors;Lipoxygenase inhibitors;• 12-HETE (Platellets)12-HETE (Platellets)• 5-HETE (leukocytes)5-HETE (leukocytes)Selective inhibitors of lipoxygenase:Selective inhibitors of lipoxygenase: Zileuton Zileuton Uses: Uses: Asthma, Asthma, Allergic rhinitis, Allergic rhinitis, Ulcerative colitisUlcerative colitis

ZileutonZileuton

Orally active lipo-oxygenase inhibitorOrally active lipo-oxygenase inhibitor Blocks the synthesis of LTB4, LTC4, Blocks the synthesis of LTB4, LTC4,

LTD4, LTE4LTD4, LTE4 Usual dose: 600 mg 4ce daily Usual dose: 600 mg 4ce daily

{Asthma}, with meals{Asthma}, with meals

ZileutonZileuton

Tmax: 1.7 hoursTmax: 1.7 hours Cmax: 4.98um/mlCmax: 4.98um/ml Vd: 1.2L/kgVd: 1.2L/kg Plasma protein binding: 93% {albumin Plasma protein binding: 93% {albumin

mainly, mainly, αα-acid glycoprotein}-acid glycoprotein} T1/2: 2.5 hoursT1/2: 2.5 hours Metabolism: dehydroxylation by CYP1A2, Metabolism: dehydroxylation by CYP1A2,

CYP2C9 and CYP3A4CYP2C9 and CYP3A4 And GlucuronidationAnd Glucuronidation

ZileutonZileuton

ADR:ADR: Flatulence, Vomiting, ConstipationFlatulence, Vomiting, Constipation Arthalgia, Neck pain, Rigidity Arthalgia, Neck pain, Rigidity ConjuctivitisConjuctivitis Somnolence, Insomnia, DizzinessSomnolence, Insomnia, Dizziness Malaise, feverMalaise, fever LymphadenopathyLymphadenopathy


Catabolism: Catabolism: (1) {Fast} dehydrogenase, (1) {Fast} dehydrogenase, (2) [Slow] reductase(2) [Slow] reductase (3) Oxidation of side chain to give (3) Oxidation of side chain to give

polar dicarboxylic acid derivatives.polar dicarboxylic acid derivatives.* * In the case of PGIIn the case of PGI22 is hydrolysed to 6-keto PGF1α is hydrolysed to 6-keto PGF1α

thereafter as above. thereafter as above.


Receptors: DP1, EP1-3, FP, IP, TPReceptors: DP1, EP1-3, FP, IP, TP *EP, FP, TP: increase smooth muscle tone *EP, FP, TP: increase smooth muscle tone

Platelet aggregation – TP1 + EP3Platelet aggregation – TP1 + EP3

Pharmacologic effects:Pharmacologic effects: CVS: PGD, E – Generally dilating and lower BPCVS: PGD, E – Generally dilating and lower BP PGFPGF2α2α – vasoconstriction; no effect on B.P. – vasoconstriction; no effect on B.P. PGIPGI22 - vasodilatation - vasodilatation TXATXA22 - vasoconstriction - vasoconstriction LTC4, LTD4 – Vasodilatation, ↓B.P, LTC4, LTD4 – Vasodilatation, ↓B.P,

vasopermeability. vasopermeability.

ProstaglandinsProstaglandins Platelet aggregation: enhanced by TXA2Platelet aggregation: enhanced by TXA2 PGI prevents/inhibits platelet aggregationPGI prevents/inhibits platelet aggregation Chemotaxis (of eosinophils, neutrophils, Chemotaxis (of eosinophils, neutrophils,

monocytes) - LTB4, PAF monocytes) - LTB4, PAF Lymphocyte: PG inhibits proliferation and Lymphocyte: PG inhibits proliferation and

reduces antibody synthesisreduces antibody synthesis *Smooth muscle – Contraction or *Smooth muscle – Contraction or

relaxation relaxation * Predominant effect of PGs on bronchial * Predominant effect of PGs on bronchial

smooth muscle is constriction smooth muscle is constriction But PGI2, PGE2 cause bronchodilatation But PGI2, PGE2 cause bronchodilatation


Renals:Renals: PGE2, PGI2, PGD2 stimulate release of PGE2, PGI2, PGD2 stimulate release of

renin. renin. Promote blood flow and water Na+ K+ Promote blood flow and water Na+ K+

excretion. excretion. GIT: GIT: PGE & PGF inhibit gastric acid secretion, PGE & PGF inhibit gastric acid secretion,

↑mucus secretion blood flow, ↑motility.↑mucus secretion blood flow, ↑motility.CNS: CNS: Both stimulant and depressant effects Both stimulant and depressant effects

noticed when injected into ventricles.noticed when injected into ventricles.


Afferent nerves: Afferent nerves: pain when injected intradermally.pain when injected intradermally.Endocrine:Endocrine: - ↑secretion of ACTH, GH, prolactin - ↑secretion of ACTH, GH, prolactin

gonadotropinsgonadotropins - ↑Insulin release- ↑Insulin release - Progesterone release from corpus - Progesterone release from corpus

luteumluteumMetabolic:Metabolic:

↓↓rate of lipolysis from adipopse tissue, rate of lipolysis from adipopse tissue, ↓↓blood glucose blood glucose ↑↑circulating Ca2+circulating Ca2+


Therapeutic uses:Therapeutic uses: Gastric cytoprotection - Gastric cytoprotection - e.g. misoprostol e.g. misoprostol

(E1), enprostol (E2) analogs(E1), enprostol (E2) analogs.. Tx or prevention of Ischaemia (vasoclusive Tx or prevention of Ischaemia (vasoclusive

disorders): disorders): analogs of PGI2 (Carbacyclin, analogs of PGI2 (Carbacyclin, Iloprost)Iloprost)

Platelet storage – Platelet storage – PGE, PGI2 to improve PGE, PGI2 to improve harvest of platelet.harvest of platelet.

Impotence – Impotence – PGE (alprostadil), PGE (alprostadil), intracarvenosal injectionintracarvenosal injection..

Abortion – Abortion – eg. dinoprost, dinoprostone, eg. dinoprost, dinoprostone, misoprostol + methotrexate (in 1misoprostol + methotrexate (in 1stst trim.) trim.)

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Autacoids II