Autacoids: eicosanoids, angiotensin, neurotensin, NO, kinins, histamine, serotonin, endothelins, etc.
They are local hormones. “Paracrine effect”.
The eicosanoids
Prostaglandins
Thromboxanes
Leukotrienes
are eicosanoids.
They are oxygenation products of polyunsaturated long chain fatty acids.
They have a wide range of therapeutic usefullness with the enzyme inhibitors, receptor agonists or inhibitors. They are involved in many pathological and physiological processes.
Arachidonic acid is the most abundant and the most important precursor of eicosanoids.
Arachidonic acid is the most abundant and the most important precursor of eicosanoids.
It has 20 C atoms and contains 4 double bonds. “Eicosotetraenoic acid”.
Arachidonic acid is liberated from the cell membrane phospholipids.
Phospholipase A is the enzyme responsible for generation of arachidonic acid from the cell membrane.
Phospholipase A (PLA) has various forms: cardiac, cytosolic and secretory.
Phospholipase A (PLA) has various forms: cardiac, cytosolic and secretory.
Secretory and cytosolic isoforms are Calcium dependent and involved in arachidonic acid liberation more frequently.
PLC can also liberate arachidonic acid with diglyceride lipase.
According to cell type various eicosanoids are synthesized.
Arachidonic acid pathways
Cyclooxygenase pathway: cyclooxygenase (COX) is the enzyme that converts arachidonic acid to PGG2 and then eicosanoids are produced successivelly.
Cyclooxygenase has three isoforms:
COX –1, COX-2 and COX-3 (neuronal)
COX-1 is secreted during physiological processes and helps the maintenance of various functions.
COX-2 is an inducible enzyme, synthesized and secreted during inflammatory and pathological processes.
Inhibitors of COX isoenzymes
Most of non-steroidal antiinflammatory drugs inhibit both isoforms non selectively. E.g. Aspirin, indomethacin, naproxen, etc.
Rofecoxib, celecoxib are COX-2 inhibitors.
Nimesulide is more potent on COX-2.
COX-1 is responsible for inhibition of gastric acid secretion and helps the synthesis of protective mucus in the stomach.
Gastric side effects are common with COX-1 inhibitors and non-selective inhibitors.
Both COX enzymes convert arachidonic acid to prostaglandin G2.
Both COX enzymes convert arachidonic acid to prostaglandin G2.
It is an unstable cyclic endoperoxide.
PGG2 is then converted into PGH2.
PGH2 is also unstable and yields the formation of various prostoglandins and thromboxanes.
PGI2 (prostocycline), PGE2, PGF2, PGD2 are prostoglandins.
Thromboxane A2 and ThrombaxeB2 are thromboxanes.
Arachidonic acid
PGG2
PGH2
Membrane phospholipids
PGI2
PGE2
PGD2
TXA2
PLA
COX1 or COX2
COX or COX2
Prostacycline
synthase
PGF2
TXB2
Thromboxane synthase
Steroids are potent anti-inflammatory agents. They induce the formation of lipocortin that inhibits PLA.
Steroids are potent anti-inflammatory agents. They induce the formation of lipocortin that inhibits PLA.
They can also inhibit COX-2 gene expression.
PGI2, PGE2, PGD2, PGF2, TXA2 are the important products of arachidonic acid metabolism and they have their own receptors. They act on these receptors and exert their effects.
PGE2 receptors: EP1, EP2, EP3 (stimulate adenylate cyclase and cAMP is released).
PGE2 receptors: EP1, EP2, EP3 (stimulate adenylate cyclase and cAMP is released).
PGI2, PGE1,PGD2 bind to platelet receptors and inhibit platelet aggregation by acting on specific receptors and they inhibit the adenylate cyclase enzyme.
TXA2 binds to specific receptors and increase phosphatidylinositol metabolism and IP3 mobilizes Ca2+.
Effects of eicosonoids
They have effects on vascular, airway, reproductive and GI smooth muscles.
Vascular smooth muscle:
TXA2 is a potent smooth muscle mitogen, and a vasoconstrictor.
PGF2 is also another vasoconstrictor.
PGI2 and PGE2 are vasodilator prostaglandins.
Gastointestinal smooth muscles:
Gastointestinal smooth muscles:
PGs and TXA2 are contractors. Administration of PGE2 or PGF2 produce colicky pain.
Airways: TXA2 and PGF2 are contractors of bronchial smooth muscles. PGI2 and PGE1 and PGE2 are bronchodilators.
Platelets:
Platelets:
PGE1 and PGI2 inhibit aggregation. TXA2 enhances platelet aggregation potently. TXA2 is also increased during myocardial infarction.
Aspirin at low doses inhibit TXA2 formation only in platelets.
Aspirin at high doses can inhibit vasodilator PGI2 formation as well.
So it is administered at low doses as an antiaggregant.
Kidneys:
Kidneys:
Both the renal medulla and the cortex synthesize PGs, modifying the renal hemodynamics.
They are important in maintenence of normal kidney functions.
PGE1, PGE2 and PGD2 are required for glomerular filtration due to their vasodilator effects.
Kidney functions are affected in the elderly using PG inhibitors (non steroidal anti-inflammatory agents: COX inhibitors) for osteoarthritis.
TXA2 appears to increase water retention. Beware of use of NSAIDs in hypertension.
Reproductive system:
Reproductive system:
Effects of PGs in uterine functions are extremely important. PGE2 and PGF2 are oxytocic molecules. They are also important in normal delivery.
They can be used for the termination of pregnancy (abortion) and initiation of labor.
Seminal vessicles, prostate and testes produce PGs and men having low PGs in their ejaculate are usually sterile.
PGE1 also helps erection.
CNS:
CNS:
Fever:
PGE1 and PGE2 are involved in the fever generation. Pyrogens release interleukin-1 that lead PG formation and this may help the thermoregulatory center in hypothalamus to increase the body temperature.
Sleep: PGD2 induces natural sleep.
Neurotransmission: modulatory effects.
Neuroendocrine organs: affect the secretion of neurohormones.
Eye: PGE and PGF decrease the intraocular pressure.
Clinical pharmacology
Abortion: PGE2 and PGF2 used for the induction of abortion and initiation of labor. They are superior to oxytocin.
Dinoprostone, a synthetic analogue of PGE2 can be administered vaginally.
It produces contraction of uterine muscles.
PGF2 is not commonly used. Since it may produce severe pulmonary hypertension.
Dysmenorrhea is attributed to increased PGE2 and PGF2 production. NSAIDs are used for the treatment of pain during menses.
Dysmenorrhea is attributed to increased PGE2 and PGF2 production. NSAIDs are used for the treatment of pain during menses.
Alprostadil, a PGE1 analogue may be used for the treatment of erectile dysfunction in men. Prolonged erection and priapism may occur and penile pain is usually observed.
Cardiovascular uses:
Cardiovascular uses:
pulmonary hypertension: epoprostenol (PGI2 analogue) is used for pulmonary hypertension.
Raynaud disease and atherosclerosis are the that result due to an imbalance of PGs with opposite effects.
Patent ductus arteriosus: Patency of ductus arteriosus in some neonates depend on PGE2 and PGI2. NSAIDs are used for the duct closure. If the duct should remain open alprostadil is administered.
Misoprostol (PGE1 analogue) used for the ulcer treatment. It can be administered with NSAIDs, so that COX-1 effects are minimized. Expensive!!
Misoprostol (PGE1 analogue) used for the ulcer treatment. It can be administered with NSAIDs, so that COX-1 effects are minimized. Expensive!!
Inhibition of prostaglandin synthesis produce analgesia. Since prostaglandins increase the sensitivity of nerve endings to bradykinin and other pain producing substances.
Lipooxygenase pathway
Arachidonic acid can also be metabolised by lipooxygenase (5-LOASE).
Arachidonic acid leukotriene A4
Leukotriene B4
Leukotriene C4
Leukotriene D4
Leukotriene E4
LTA4 is an unstable molecule.
LTA4 is an unstable molecule.
LTB4 is not very active.
LTC4 and LTD4 are potent bronchoconstrictors. They are also known as slow-reacting substances of anaphylaxis those are secreted in asthma and anaphylactic shock.
Zileuton, an inhibitor of LOASE can be used in asthma.
Zileuton, an inhibitor of LOASE can be used in asthma.
Zafirkulast, a receptor antagonist of LTs can also be used in asthma.
Lipoxins
Lipoxins are derived enzymatically from arachidonic acid, an ω-6 fatty acid. There are 2 types of lipoxins LXA and LXB.
They are formed by platelets but platelets cannot synthesize them alone. Platelets depend upon neutrophils for LTA4, which is converted to LXA4 and LXB4 by the action of platelet 12-lipoxygenase. LTC4, LTD4, and LTE4 are also synthesized in platelets from LTA4.
Similarly to the leukotrienes, LXA4 will form the cysteinyl-lipoxins LXC4, LXD4 and LXE4.
Similarly to the leukotrienes, LXA4 will form the cysteinyl-lipoxins LXC4, LXD4 and LXE4.
Lipoxins act on LXA4R receptor and inhibit chemotaxis, transmigration, superoxide generation and NF-κB activation.
Lipoxins also antagonize the receptors of cysteinyl leukotrienes, so that inflammation can stop.
Lipoxins are important during resolution of inflammation.
Lipoxins are important during resolution of inflammation.
As part of resolution, lipoxins signal macrophages to phagocytose the remains of these cells.
During the acute inflammatory process, the proinflammatory cytokines such as IFN-γ and IL-1β can induce the expression of anti-inflammatory mediators such as lipoxins and IL-4, which promote the resolution phase of inflammation
Histamine
-imidazoleethylamine= histamine
Histidine histamine
histidine decarboxylase
Alpha-fluoromethyl histidine and tritocaline inhibits the conversion of histidine to histamine.
Histamine is present in:
Mast cells, as a complex with heparin
Mast cells contain IgE as receptors on their surface. As the antigen interacts with IgE, histamine is liberated.
Histamine can be absorbed but the microorganisms in the GIT metabolise histamine.
Histamine can be absorbed but the microorganisms in the GIT metabolise histamine.
Histamine is metabolised by histamine N-methyl transferase or diamine oxidase.
The end product is methyl imidazole acetic acid.
Histamine receptors
H1, H2 and H3.
H1 and H2 are G-protein coupled receptors. H1 receptor stimulation produces phosphoinositidyl hydrolysis (IP3 and DAG are formed) and H2 receptor stimulation produces inhibition of adenylate cyclase activity.
H3 receptors are located presynaptically and inhibits Acetyl choline release.
Agonists: H1: 2-methyl histamine
Agonists: H1: 2-methyl histamine
H2: 4 methyl histamine
H3: -methyl histamine
Betazole (betahistidine HCl) H1 analogue used as a drug in Meniére’s disease.
Pharmacological effects of histamine
CVS (H1 mediated):
Decrease in blood pressure, vasodilatation. Sometimes vasoconstriction may occur. Vasodilator effect is NO mediated.
Increases PGI2 secretion as well.
Increase in capillary permeability.
Lewis’ triple response: oedema, flare and urticaria.
Increases leukocyte infiltration to the tissues during inflammation.
It may produce (-) inotropic effect and (-) chronotropic effect, but reflex mechanisms usually mask this.
It may produce (-) inotropic effect and (-) chronotropic effect, but reflex mechanisms usually mask this.
Increases gastric acid secretion via H2 receptor stimulation. H2 receptor blockers are used in the treatment of peptic ulcer.
Role of histamine in endogeneous pathological situations
Systemic or local anaphylactic reaction (IgE mediated)
Allergic reactions due to physical factors.
Drug mediated allergic reactions
Histamine mediated headache
Mast cell or basophill tumors
Peptic ulcer
Pruritus, flare, pain sensation
Tissue proliferation and repair
CNS, H1 receptors are involved in awakefullness, so anti histaminics produce sedation.
Serotonin
Serotonin: 5-OH tryptamine (5-HT).
Present in: enteric nervous system
thrombocytes
enterokromaffin cells (APUD cells)
Pharmacological effects of serotonine
Produces severe vasoconstriction in all vascular beds, except the vessels in the skeletal muscle (5-HT1 and 5-HT2 receptors).
Involved in migraine (5-HT1D agonist sumatriptan is used in migraine, pizotifen a 5-HT2 antagonist is also used for the treatment of migraine).
Renal vessels are sensitive to serotonine, even necrosis may occur.
Decreases cardiac rate suddenly.
Stimulates respiration but the bronchi are not sensitive to serotonine.
Increases peristaltic movements in the small intestines (5-HT4 agonist cisapride is used for the treatment of constipation).
Increases peristaltic movements in the small intestines (5-HT4 agonist cisapride is used for the treatment of constipation).
Stimulates the primary afferent nerve endings so mediates pain sensation (5-HT3).
Serotonine secreted from enteric nerves can stimulate the vagal afferent nerves and initiates emesis ( 5-HT3 antagonist ondancetron is used as an anti-emetic agent).
Thrombocytes contain serotonine and helps aggregation and adhesion to the endothelium.
Serotonine is involved in Dumping syndrome that occurs after gastrectomy (sudden gastric emptying produces hypotension and sweating) .
Serotonine is involved in Dumping syndrome that occurs after gastrectomy (sudden gastric emptying produces hypotension and sweating) .
Vasospasm in pulmonary emboli.
Sudden infant death during pregnancy, deformities.
5-HT1A receptors in the CNS are involved in anxiety, 5-HT1A partial agonist buspirone is used as an anxiolytic agent.
Kinins
Activated Haegeman factor converts Prekallikrein to kallikrein
Kallikrein converts kininogens to kinins.
There are high and low molecular weight kalikreins in the plasma.
There is also a tissue kininogen system.
Kallidin converts tissue kininogens to kinins.
Pharmacological effects of kinins
Dilatation of arterioles
Constriction of venules.
Contracts intestinal muscles. Kinin means “moving” in Greek.
Tachykinins and bradykinins.
Stimulate the pain receptor in the tissues.
B1 and B2 receptors. Experimental compounds are available.
Aprotinin inhibits kallikrein and used in diseases where kallikrein overproduction is present.
Endothelins
Endothelin-1 is secreted from vascular endothelium.
It is synthesized as pre-pro-endothelin (big endothelin)
Endothelin-1 is converted to Endothelin-2 and endothelin-3 by endothelin converting enzyme.
Endothelins have ETa and Etb receptors.
Endothelins have ETa and Etb receptors.
Bosentan is non-selective antagonist. It is currently registered for use in pulmonary hypertension.
Pharmacological effects of endothelins
Vasoconstriction (the most potent vasoconstrictor molecule).
However, ET1 receptor antagonists do not decrease the vascular tonus!
Nitric oxide (NO)
Furchgott discoverd NO in 1980.
It is also known as endotheliun derived relaxating factor.
Acetyl choline dilates the phenylephrine contracted vessels.
No dilatation occurs in de-endothelized tissues.
Synthesized from L-arginine by nitric oxide synthase.
NOS has various forms: nNOS (neuronal), eNOS . nNOS and eNOS are constituve.
NOS has various forms: nNOS (neuronal), eNOS . nNOS and eNOS are constituve.
iNOS is inducable NOS.
L-NAME is a NOS inhbitor.
NO is a free radical and interacts with superoxide generating peroxinitrite (ONOO-) that reacts with sulphydryl groups of enzymes.
NO, binds to guanylate cyclase and cGMP is formed. cGMP deactivates myosine light chain kinase (MLCK) is and MLCK cannot phosphoryllate MLC so myosin and aktin cannot combine to form the contracted muscle filaments. Eventually vasodilatation occurs in vascular smooth muscles.
NO, binds to guanylate cyclase and cGMP is formed. cGMP deactivates myosine light chain kinase (MLCK) is and MLCK cannot phosphoryllate MLC so myosin and aktin cannot combine to form the contracted muscle filaments. Eventually vasodilatation occurs in vascular smooth muscles.
Nitroprusside, and other organic nitrates are NO donors, that produce vasodilatation. They are used as vasodilator agents.
Clinical implications of NO system
Hypertension
Atherosclerosis
Immune system
Excitotoxicity, ischemia.
Neurotransmitter release
Impotence (sildenafil: viagra)
Neurotensin
Neurotensin is tridecapeptide which was isolated in the CNS but it was found in the GIT and circulation as well.
It is synthesized as a part of larger molecule that contains neuromedin N.
It acts as a neuromodulator or neurotransmitter in the brain.
It also produces vasodilatation, increased vascular permeability, anterior pituitary hormones, hyperglycemia, inhibiton of gastric acid.
It has 3 types of receptors.
Has therapeutic potential in parkinson’s disease and schizophrenia.
