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AUTACOIDS (LOCAL HORMONES) PHARMACOLOGY BY: Dr. Marwa Shaalan PHARM-D
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Autacoids endogenous compounds; play an important role
in the physiological and pathological processes; have very short t1/2; have local action. 2
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1. Monoamines a) Histamine The synthesis and breakdown of histamine 3
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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 .
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Histamine Releasers: 1- drugs (mainly alkaloids atropine, morphine, reserpine, tubocurarine in high doses) release histamine can cause bronchoconstriction, hypotension, itching and skin rash 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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FISH contains potent allergens: can be potentially dangerous. remains
allergenic despite cooking.
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Physiological antagonists:
*adrenaline, salbutamol, and others----inhibit histamine secretion and produce bronchodilation (antiasthmatic effect).
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Histamine Receptors H1, H2, H3, H4, and H5 Histamine’s receptors are G-protein coupled.
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1-Stimulation of H1-receptors
Pharmacological actions: 1-Contraction of smooth muscles (bronchi, uterus and GIT). 2- CVS - Vasodilatation of BV - Increased capillary permeability (oedema) -Tachycardia : Cardiac stimulation -- 3-Dilatation of cerebral vessels ( headache, histamine cephalgia) 4-Exocrine glands: stimulates gastric secretion. -Stimulation of sensory nerve endings (pain & itching) 5-Skin : Triple response Skin: A-Reddness (vasodilatation of capillaries) B-Wheal (oedema) C-Flare (stimulation of sensory nerve endings). 6-Release of catecholamines from adrenal medulla so HISTAMINE AGONISTS For diagnosis of phaeochromocytoma.
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ANTIHISTAMINIC H1-receptors (H1-blockers)
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H1-blockers Used in treatment of urticaria and hay fever.
Some of them (Mepyramine, promethazine) have antiemetic effect too.
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1st generation H1-blockers
(with sedative and Atropine-LIKE effects) Didimetindene Embramine Chlorpyramine Promethazine Cyproheptadine (H1&5-HT2) Clemastine (weak sedation)
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effects. It is effective in pruritus and urticaria.
Hydroxyzine is an H1-blocker with anxiolytic, antiemetic,antimuscarinic, and spasmolytic effects. It is effective in pruritus and urticaria.
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Fexofenadine , Loratadine Cetirizine 2nd generation H1-blockers
(without sedative and M-cholinolytic effects Astemizole Fexofenadine , Loratadine Terfenadine Cetirizine 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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stimulation of gastric acid secretion
Activation of H2-receptors: cardiac stimulation stimulation of gastric acid secretion
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Antagonist of H2-receptors (H2-blockers) – for the treatment
of peptic ulcer: Cimetidine (? …) Famotidine Nizatidine Ranitidine Roxatidine
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Indications: prophylactic treatment of asthma.
Mast cell stabilizers They prevent degranulation and release of histamine and other autacoids from mast cells. They also inhibit leukocyte activation and chemotaxis. Indications: prophylactic treatment of asthma. Cromoglycate – per inh. (Cromolyn – USAN) Ketotifen (p.o.) Nedocromil – per inh.
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b) Serotonin Indol derivative (5-Hydroxytryptamine: 5-HT) Rang et al.
Pharmacology – 5st Ed. (2003) b) Serotonin (5-Hydroxytryptamine: 5-HT) Indol derivative
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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) 28
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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 anxiolytic agent partial agonist of the 5-HT1A-receptors
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) Pathogenesis of migraine and drug treatment
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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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5-HT2-receptors are used:
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 38
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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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powerful antiemetics:
Antagonists of 5-HT3- receptors are very powerful antiemetics: Dolasetron Granisetron Ondansetron Tropisetron 40
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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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(eicosi = 20) 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. 43
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Arachidonic acid Inflammatory stimulus Leucotrienes Lipoxins PGs TxA2
Phospholipids Phospholipase A2 Arachidonic acid 5-lipoxygenase Cyclooxygenase (Cox) 15-lipoxygenase Endoperoxides Leucotrienes Lipoxins PGs TxA2
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PROSTANOIDS (PGs & Txs) 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
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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: PGF2α – main effects: 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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Dorland’s Illustrated
Medical Dictionary (2003, 2004) PGE1 (gemeprost) PGF2α (dinoprost) PGE2 (dinoprostone) are given for: induction of labour termination of pregnancy
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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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inhibit mainly COX-1 This has relevance for the mechanism of action of
NSAIDs. Most of them inhibit mainly COX-1 and can cause peptic ulcer, GI bleeding, bronchial asthma, and nephrotoxicity.
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Aspirin Arachidonic acid Cyclooxygenase (Cox) (-) >1 g/24 h
Endoperoxides (-) 100 mg/24 h Thromboxane A2 synthase PGs TxA2
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COX INHIBITORS NSAIDs Nonselective COX-1/COX-2 inhibitors Selective
IL® Nonselective COX-1/COX-2 inhibitors NSAIDs Selective COX-3 inhibitors Antipyretic analgesics COX-2 inhibitors Selective (coxibs) Preferential
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Pfizer $2.3 billions penalty
Coxibs are selective COX-2 inhibitors. They exert anti-inflammatory, analgesic and antipyretic action with low ulcerogenic potential. SIDE EFFECTS: Coxibs can cause infertility. They have prothrombotic cardiovascular risk.
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Montelukast, Zafirlukast
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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4. Peptides A-Endothelins: ET-1, ET-2, RT-3
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B-Kinins (kallikrein, Cholecystokinin (CCK) – bradykinin
neuripeptide involved in pathogenesis of panic reactions
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5. Cytokines – soluble proteins and glycoproteins
that interact with specific cellular receptors. Cytokines are involved in inflammatory and immune response.
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(“as a team”) on: Cytokines act together endothelium, leucocytes,
mastocytes, fibroblasts, stem cells and osteoclasts. Cytokines control their proliferation, differentiation and/or activation by receptor mechanism.
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INTERLEUKINES (ILs) 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.
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IL-18: IL-23: Upregulated INF production Enhenced NK cell cytotoxicity
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©):
INTERFERONS (INFs) 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.
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Colony-stimulating factors
- Filgrastim, Molgramustim, Lenograstim TNF-alpha (alfa) TNF-beta VEGF PDGF, TGF, etc.
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ANY QUESTIONS??? THANK YOU
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