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"Pharmacology

Eicosanoids
Lecture
.

Eicosanoids

Eicosanoids
They are oxygenated products of polyunsaturated fatty acid (PUFA). They are a large family of compounds highly potent with a wide spectrum of biological actions. *They have a very short t1/2 (half life seconds to minutes ). Most important of these compounds are prostaglandins (PGs), Leukotriens (LTs) and thromboxanes (TXs). They are produced in minute (small) amounts by all cells except RBCs and they act locally i.e. at the same site of synthesis . Their inactivation is rapid (also local) i.e. they don't circulate in blood in significant concentration. So they have low blood concentration because they are synthesized, released, act and inactivated locally by the same tissues, so they don't need to circulate.

Eicosanoids are not found preformed in tissues. They are generated de novo from phospholipids. They are implicated in the control of many physiological processes [e.g. mediators and modulators of inflammatory reactions] Many stimuli liberate arachidonic acid (AA), (vary with cell type). (i.e. thrombin in the platelets, bradykinin in fibroblasts, and antigen-antibody [Ag-Ab] reaction on the mast cells). General cell damage also starts the process of liberating AA. Arachidonic acid is the source of Eicosanoids.

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Prostaglandins (PGs):

Synthesis: Arachidonic acid, which is a 20 carbon F.A., is the primary source of PGs & related compounds (LTs, TXs ); it is present in the phospholipids of cell membrane. Arachidonic acid is released from tissue phospholipids by the action of phospholipase A2. 1. Cyclo oxygenase pathway: Eicosanoids with ring structure (i.e. PGs, TXs and prostacyclines) are synthesized by this pathway. Two cyclo-oxygenase (2 enzymes) have been identified: COX-1 & COX-2. COX-1 is ubiquitous and constitutive (i.e. housekeeping function). COX-2 is induced in response to inflammatory stimuli. 2. Lipoxygenase pathway: Several lipoxygenase can act on the A.A (5-, 12-, &15- lipoxygenase) to form unstable peroxidated derivatives converted into LTs or LXs (lipoxins) depending on the tissue.

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Eicosanoids DIAGRAM

Mediators derived from phospholipids & their action & their sites:

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Eicosanoids Prostanoids (PGs and TXs): COX enzyme acts on arachidonate to produce cyclic endoperoxides (PGG2, PGH2), these give rise to:
PGI2 (prostacyclin): from vascular endothelium, act on IP receptors. The main effects: 1) Vasodilatation and 2) Inhibition of platelets aggregations. TXA2: mainly from platelets, is acts on TP receptors, the main effect are: 1) Vasoconstriction and 2) Platelets aggregation (opposite to PGI2). PGE2: the main effects: On EP1 receptors contraction of the bronchial and GIT smooth muscles. On EP2 receptors relaxation of bronchial, vascular and GIT muscles. On EP3 receptors 1) Inhibition of gastric acid secretion. 2) Increase in gastric mucous secretion. 3) Contraction of pregnant uterus and GIT smooth muscles. PGE2 is a mediator of fever. PGF2 : act on FP-receptors (found in smooth muscle and corpus luteum, main effect is contraction of uterus).

PGD2: from mast cell mainly, acts on DP receptor, the main effect is:
vasodilatation and inhibition of platelet aggregation.

Basic pharmacology of Eicosanoids:

Mechanism of action:

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PGI inhibits platelets aggregation through a mechanism by binding to receptor activation of adenylate cyclase intracellular cAMP activation of protein kinase phosphorylation of internal Ca ++ pump Ca++ sequestration that enter the cell (RBCs) so platelet will NOT aggregate. contractile effect (especially on smooth muscle) is mediated by the release of Ca++. Relaxation effect of Eicosanoids is mediated by generation of cAMP.

Effect of PGs & TXs:

1. smooth muscle:
a) Vascular smooth m.: PGE2 & PGI2 relax the human smooth muscle. PGE 2, PGI2 and other PGs promote vasdilation through activation of adenylate cylclase. TXA2 & PGF2 act mostly as vasoconstrictor (especially in veins). b) GIT smooth m.: Longitudinal muscles of GIT (intestine) are contracted by PGI2 & PGF2. The circular muscles are contracted by PGI2 & PGF2 and are relaxed by PGE2. c) Airways: Respiratory smooth mm. are relaxed by PGE1, PGE2 and PGI2, & they are contracted by TXA2 and PGF2. d) Genito-urinary tract: The smooth mm. (especially in uterus) are contracted by PGE2 and PGF2, so these are used in labour & abortion.

2. Platelet aggregation:
PGE1 and PGI2 inhibit platelet aggregation while TXA 2 promotes platelet aggregation.

3. Reproductive organs:
a) reproductive system: will discussed later. b) reproductive system:
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Semen from a fertile man contain about 400 mg/ml of PGE2 and PGF2. (PGE2 20:1 PGF2). If the ration is different, then there is something wrong in fertility. Testosterone promotes PG production. TXs and LTs are not found in seminal plasma. Men with relatively low seminal contents of PG are relatively infertile. PGs were first isolated from prostate gland, hence they are called Prostaglandins. large doses of Aspirin (NSAIDs) decease the PG content of seminal plasma affect fertility.

4. Nervous system:
a) fever: PGE1 & PGE2 increase the body temperature. Pyogens release IL-1 which promotes synthesis & release of PGE 2, this is blocked by NSAIDs e.g. Aspirin . b) sleep: PGD2, when infused into cerebral ventricles, induces natural sleep in primates. c) Neurotransmission: PGE compound inhibit the release of NA from sympathetic presynaptic nerve endings.

5.Neuro endocrinology:
Eicosanoids in general, affect secretion of neurohormones . PG compounds promote the release of GH, prolactin, TSH, ACTH, FSH, and LH. LTC4 and LTD4 stimulate LH and LHBH secretion.

Effects of LTs
1. Heart & smooth m.: LTC4 or LTD4 decrease myocardial contractility & decrease coronary blood flow. 2. GIT: epithelium of the colon synthesize LTB 4 which is a chemoattractant for neutrophils. It increases in cases of inflammatory bowel disease.

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3. Airway: LTC4, LTD4 and LTE4 are powerful bronchoconstrictors and they cause in microvascular permeability, plasma exudation, and the mucous secretion of the airways. 4. Blood cells: LTB4 is a powerful chemoattractant for neutrophils while LTC4 and LTD4 are powerful chemoattractants for eosinophils.

Inhibition of Eicosanoids synthesis:

1. Corticosteroids: these block all the known pathway of Eicosanoids by stimulating the formation of lipocortin (a protein which inhibits the activity of phospholipase A2. i.e. prevent the release of A.A). 2. NSAIDs: such as aspirin, paracetamol (acetaminophen), indomethacin, ibuprofen, they block the formation of PGs and TXs i.e. inhibit the activity of COX.

Clinical Pharmacology of Eicosanoids:

1. reproductive system:
a) abortion: PGE2 & PGF2 are well known for their oxytocic action and when these two are given I.V they cause abortion in 85 % of cases. b) facilitation of labour: PGE2 & PGF2 effectively initiate & stimulate labour. c) dysmenorrhea: this condition is attributed to increase in the synthesis of PGE2 and PGF2 during menstruation (in this case continue for more than 5 days while normally, it takes 3 days).

2. CVS: Eicosanoids are involved in thrombosis mainly because TXA 2

promotes platelet aggregation, while PGI2 inhibits it.

2. Respiratory system:
a) PGE2 is known to be a powerful bronchodilator, so it is given to asthmatic persons in the form of aerosol but in this condition it induces
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coughing (considered as a disadvantage). b) PGF2 and TXA 2 are strong bronchoconstrictors (mediators of asthma but they are not the main mediators, they are secondary mediators). They main mediators are leukatrienes C 4, D4 and E4 in asthma and other immune responses.

3. Renal system:
a) PGE1, PGE2, and PGI2 increase the glomerular filtration through their vasodilatory effect. b) They also increase water & Na + excretion.

4. GIT: PGs have a protective effect against gastric ulcer (cytoprotection), the
synthetic analogue 10, 16, dimethyl PGE 4 is available for use against gastric ulcer produced by either steroids or NSAIDs.

Therapeutic uses of PGs:

1. Abortion: Several of the natural occurring PGs as dinoproston and carboproston are used as abortifcients (causing abortion). Misoprostol, in combination with methotrexate are effective in termination of pregnancy within the first trimester (1 st 3 months). 2. Peptic ulcer: Misoprostol (a synthetic analogue of PGE 1) is *used to inhibit the secretion of HCl. In stomach it *inhibits gastric acid & pepsin secretion and *increase mucosal resistance to injury. *It is useful in patient with gastric ulcer due to chronic use of NSAID. Misoporstol produce or cause *uterine contraction so it is contraindicated during pregnancy. Also it causes a *dose related diarrhea & *nausea & these are the most common adverse effect.
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Eicosanoids 3. Erectile dysfunction: Alprostadil injected into the corpus c. penis effectively treat some forms of male impotence. Alprostadil the arterial inflow through vasodilation or out flow by relaxation of the corporal smooth m. that occludes drainage. Side effects: Pain at site of injection and rarely prolonged erection (short duration of action).

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