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Published on : Jul 18, 2021 | Views : 2702 | Downloads : 4

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AUTACOIDS (LOCAL HORMONES) AND THEIR PHARMACOLO- GICAL MODULATION Assoc. Prof. Ivan Lambev E-mail: itlambev@mail.bg www.medpharm-sofia.eu (Summary)
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endogenious compounds; play an important role in the physiological and pathological processes; have very short t1/2; have local action. Autacoids
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a) Histamine 1. Monoamines The synthesis and breakdown of histamine
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Histamine is presented in high concentration in the skin, and in the mucous layer of the lung and GIT as an autacoid. At cellular level, it is found largely in mast cells and basophiles. Non-mast-cell histamine occurs as a neurotransmitter in CNS.
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In mast cells and basophiles histamine is located in intracellular granules together with heparin.
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Histamine is released from mast cells by a secretory process during inflammatory or allergic reactions (Ag-Ab reactions). The secretory process is initiated by a raise in intracellular Ca2+. Histamine is released from mast cells during burns too.
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Some drugs (mainly alkaloids atropine, morphine, reserpine, tubocurarine in high doses) release histamine by non-receptor action and can cause bronchoconstriction, arterial hypotension, and other unwanted effects.
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Folia Urticae Naja naja (Leaves of Nettle)
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Spoilt (putrid) fish contains histidine!
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contains potent allergens: can be potentially dangerous. remains allergenic despite cooking. FISH
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Agents which increase cAMP (adrenaline, salbutamol, and others) inhibit histamine secretion and produce bronchodilation (antiasthmatic effect).
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Histamine produces effects by acting on H1, H2, H3, H4, and H5-receptors. Histamine’s receptors are G-protein coupled.
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Stimulation of H1-receptors contraction of endothelium, increasing of vascular permeability and producing type I hypersensitivity reactions (urticaria and hay fever); contraction of smooth muscle of bronchi, GIT, uterus; excitement of CNS.
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Histamine and antagonists of H1-receptors (H1-blockers)
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H1-blockers Used mainly for the treatment of urticaria and hay fever. Some of them (embramine, promethazine) have antiemetic effect too.
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Dimetindene Embramine Chloropyramine Promethazine Cyproheptadine (H1&5-HT2) H1-blockers from 1st generation (with sedative and M-cholinolytic effects) Clemastine (weak sedation)
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Hydroxyzine is an H1-blocker with anxyolitic, antiemetic, antimuscarinic, and spasmolytic effects. It is effective in pruritus and urticaria.
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Astemizole Cetirizine Loratadine Terfenadine H1-blockers from 2nd generation (without sedative and M-cholinolytic effects) prolongation of QT interval and hypokalemia
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H1-blockers from 3…rd… generation Desloratadine (Aerius® – film-tab. 5 mg; t1/2 27 h) Levocitirizine
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cardiac stimulation stimulation of gastric acid secretion Activation of H2-receptors:
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Cimetidine (? …) Famotidine Nizatidine Ranitidine Roxatidine Antagonist of H2-receptors (H2-blockers) – for the treatment of peptic ulcer:
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Cromoglycate – per inh. (Cromolyn – USAN) Ketotifen (p.o.) Nedocromil – per inh. Mast cell stabilizers prevent transmembrane influx of calcium ions, provoked by antigen-IgE antibody reaction on the mast cell membrane. They prevent degranulation and release of histamine and other autacoids from mast cells. Indications: treatment of asthma.
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b) Serotonin (5-Hydroxytryptamine: 5-HT) Indol derivative Rang et al. Pharmacology – 5st Ed. (2003)
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Structures rich in 5-HT GIT (chromaffin cells and enteric neurons) platelets CNS
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Important actions of 5-HT increased GI motility increased platelet aggregation increased microvascular permeability stimulation of nociceptive nerve endings control of appetite, sleep, mood, hallucinations, stereotyped behavior, pain perception, and vomiting
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Clinical conditions in which 5-HT plays a role include: migraine mood disorders (depressive illnesses) anxiety vomiting carcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)
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5-HT1-receptors: 5-HT1A - 5-HT1F All subtypes occur in CNS and cause neural inhibition Act by inhibiting adenylate cyclase
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Buspirone is a selective partial agonsist of presynaptic 5-HT1A-receptors. It is an anxyolitic agent, used in anxiety.
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5-HT1D-receptors are found in some blood vessels (a. carotis externa et interna, meningeal vessels). They produce vasoconstriction. pathophysiology of migraine
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Pathogenesis of migraine and drug treatment Rang et al. Pharmacology – 5st Ed. (2003)
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The agonist of 5-HT1D-receptors are highly effective, but expensive, in acute attacks of migraine: Naratriptan Rizatriptan Sumatriptan Zolmitriptan
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Activation of 5-HT2-receptors in CNS produces excitement in blood vessels - contraction and platelet aggregation act through phospholipase C/ inositol phosphate pathway
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Antagonists of 5-HT2-receptors are used: for prophylaxis of migraine - cyproheptadine - iprazochrome - methysergide - pizotifen as a peripheral vasodilator - Naftidrofuryl (Dusodril®)
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Adverse effects of methysergide: retroperitoneal fibrosis renal failure
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SSRIs (selective serotonin reuptake inhibitors): Fluvoxamine, Citalopram, Fluoxetine, Paroxetine, Sertraline are used in humans to treat: chronic anxiety Depression, bulimia
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Monoamine Reuptake Inhibitors α2-adrenergic blockers Enzime inhibitors Mainly NA-ergic Desipramine Nortriptyline Mainly 5-HT-ergic Amitriptyline Clomipramine Imipramine Selective NARIs Reboxetine Selective 5-HTRIs Citalopram, Fluoxetine Escitalopram, Fluvoxamine Paroxetine, Sertraline Mianserine** Mirtazapine Trazodone Tricyclic antidepressants MAO-AIs Moclobemide - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - DA&NARIs Bupropion
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5-HT3-receptors Located in enteric neurons and in CNS. Act by stimulating adenylate cyclase. Effects are excitatory, causing GI motility and vomiting.
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Dolasetron Granisetron Ondansetron Tropisetron Antagonists of 5-HT3- receptors are very powerful antiemetics:
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Agonists of 5-HT4-receptors Tegaserod (Zelmac®) activates 5-HT4- receptors in the intestine and stimulates peristalsis and secretion. Indication: colon irritable syndrome
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2. EICOSANOIDS (20 carbon atoms!) prostanoids - prostaglandins (PGs) - thromboxanes (Txs) leucotrienes (LTs) lipoxins (eicosi = 20)
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The eicоsanoids are important mediators of inflammation and allergy. The main source of eicosanoids is arachidonic acid. It is a 20-carbon unsaturated fatty acid.
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Phospholipase A2 Phospholipids Arachidonic acid 5-lipoxygenase Leucotrienes Cyclooxygenase (Cox) Endoperoxides PGs TxA2 15-lipoxygenase Lipoxins Inflammatory stimulus
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PGI2 (prostacyclin) is located predominantly in vascular endothelium. Main effects: vasodilatation inhibition of platelet aggregation TxA2 is found in the platelets. Main effects: platelet aggregation vasoconstriction PROSTANOIDS (PGs & Txs)
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Several thromboxane A2-receptor antagonists may be able to restrict further infiltration of inflammatory cells in atherosclerotic vessels, thus stabilizing vulnerable plaques in the related cardiovascular diseases.
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PGE1 alprostadil (prodrug – used to maintain the patency of the ductus arteriosus in neonates with congenital heart defects, and for treatment of erectile dysfunction by injection into the corpus cavernosum of the penis); misoprostol (used for prophylaxis of peptic ulcer associated with NSAIDs); gemeprost used as pessaries to soften the uterine cervix and dilate the cervical canal prior to vacuum aspiration for termination of pregnancy.
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PGE2 causes: contraction of pregnant uterus inhibition of gastric acid secretion contraction of GI smooth muscles PGF2α – main effects: contraction of bronchi contraction of myometrium
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PGF2α (dinoprost) PGE2 (dinoprostone) are given for: induction of labour termination of pregnancy PGE1 (gemeprost) Dorland’s Illustrated Medical Dictionary (2003, 2004)
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Main actions of the eicosanoids Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
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Cyclooxygenase (COX) is found bound to the endoplasmatic reticulum. COX exists in 3 isoforms: COX-1 (constitutive) acts in physiological conditions. COX-2 (inducible) is induced in inflammatory cells by pathological stimulus. COX-3 (in brain)
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Aspirin-like drugs inhibit mainly COX-1 and can cause peptic ulcer, GI bleeding, bronchial asthma, and nephrotoxicity.
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Inhibiting activity rate (COX-2/COX-1) Aspirin Indometacin Meloxicam 155 60 0,8 (Preferential COX-2 inhibitor) Classical NSAIDs
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Arachidonic acid Cyclooxygenase (Cox) Endoperoxides PGs TxA2 (-) Aspirin Thromboxane A2 synthase (-) 100 mg/24 h >1 g/24 h
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COX-2 inhibitors Selective (coxibs) Preferential Selective COX-3 inhibitors Antipyretic analgesics Nonselective (Aspirin-like) COX-1/COX-2 inhibitors NSAIDs COX INHIBITORS
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Coxibs are selective COX-2 inhibitors. They exert anti-inflammatory, analgesic and antipyretic action with low ulcerogenic potential. Coxibs can cause infertility. They have prothrombotic cardiovascular risk. The ulcerogenic potential of preferential COX-2 inhibitors Meloxicam, Nabumetone, and Nimesulide (Aulin®) is significant. Pfizer $2.3 billions penalty
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Inflammatory stimulus (+) Phospholipase A2 Phospholipids Arachidonic acid (-) Lipocortin Glucocorticoids (+)
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INFLAMMATION alteration exudation proliferation NSAIDs (-) Gluco- corticoids (-) (-)
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Arachidonic acid 5-Lipoxygenase Leukotrienes (LTs) LTC4- receptor LTD4- receptor LTE4- receptor Montelukast, Zafirlukast (-) (-)
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3. Platelet activating factor (PAF) PLA2 releases PAF in inflammation. PAF causes vasodilatation, increases vascular permeability, activates platelet aggregation.
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3. Peptides a) Vasoconstrictors
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Endothelins (ET-1, -2, -3)
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Blockers of ET-1 receptors are indicated for the treatment of PAH (pulmunary arterial hypertension): AMBRISENTAN BOSENTAN MACITENTAN
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ANP CGRP SP NPY (with NA) VIP (with ACh) Kinins (kallikrein, bradykinin Cholecystokinin (CCK) b) Vasodilators: c) Neuripeptide involved in pathogenesis of panic reactions
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soluble proteins and glycoproteins that interact with specific cellular receptors. Cytokines are involved in inflammatory and immune response. 5. Cytokines –
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Cytokines act together (“as a team”) on: endothelium, leucocytes, mastocytes, fibroblasts, stem cells and osteoclasts. Cytokines control their proliferation, differentiation and/or activation by receptor mechanism.
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IL-1 participates in the pathogenesis of rheumatoid arthritis. Glucocorticosteroids and glucosamine depress the synthesis of IL–1. IL-2: used i.v. in renal carcinoma but has ADRs! IL-11 stimulates thrombocytopoesis. INTERLEUKINES (ILs)
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IL-18: Upregulated INF production Enhenced NK cell cytotoxicity IL-23: Anti-viral activity Stimulates T-cell, macrophage, and NK cell activity. Direct anti-tumor effects Used therapeuticaly in viral and autoimmune conditions
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Interferon alpha-2b (Intron©): - in chronic hepatitis B and C - lymphomas, melanomas, etc. Interferon beta-1b (Betaferon©) s.c. in multiple sclerosis. Interferon gamma – in the regulation of the immune system. INTERFERONS (INFs)
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Colony-stimulating factors (rHuCSFs): - Filgrastim, Molgramustim, Lenograstim (to treat agronulocytosis and leukopenia) TNF-alpha (alfa) TNF-beta VEGF PDGF, EGF, etc.
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Colorectal cancer