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PARACRINE MEDIATORS
AUTOCRINE MEDIATORS
Secreted by one cell & acts upon adjacent cells or surrounding extracellular matrix [ECM]
Secreted from a cell and acts on the same cell
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Paracrine Autocrine Mediators Chemically they are classified into
MONOAMINESHistamineSerotonin …etc
PEPTIDESContractants Angiotensin EndothelinNPYVasopressin
Relaxants Kinines ANPTachykinins [SP]VIP ….etc
EICOSANOIDSProstaglandinsProstacyclinesThromboxane A2
Leukotrienes …etc
PURINESATP / ADPAdenosine
NO OTHERSCytokinesChemokineGrowth Factors….etc.
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MONOAMINE (HISTAMINE )
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Storage Sites
Highest amounts in mast cells
Basophils Skin Lung Intestinal mucosa Stomach Brain
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Storage and release:
Histamine is usually found in storage granules as complex with sulfated polysacharides, heparin and released (locally) by:
a) immunologicl Mechanism (During Allergic Reaction (see Fig 56-5)
b) Tissue injury Mast cell degranulation
c) Chemical and physical Conditions ( see table 51-2)
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Chemical and Physical Agents that Release HistaminePhysical Agents Chemical Agents
Mechanical trauma, Radiant energy, Thermal energy
Chymotrypsin, Compound 48/80, Detergents, Dextran, DMSO (dimethyl- sulfoxide), Morphine and other Opiods, Pentamidine , Polymyxin B, Polyvinyl pyrrolidine, Propamidine, eserpine, Surface active agents, Stilbamidine, Toxins, Tubocurarine, venoms, X-ray contrast media
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SYNTHESIS & INACTIVATIONTION
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H 2
H 1
H 3
H
istamine Mediator
NeurotransmitterCNSANS
H 3
+
+
+
H 1
-ve presynaptic autoregulation
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ReceptorType
Major Tissue Locations Major Biologic Effects
H1smooth muscle, endothelial cells
acute allergic responses
H2gastric parietal
cellssecretion of gastric acid
H3central nervous
systemmodulating neurotransmission
H4
mast cells, eosinophils, T
cellsregulating immune responses
Histamine receptors
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Histamine receptors antagonists
What is the physiological Antagonist of Histamine?
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First generation Diphenhydramin, Promethazine etc
(Sedating and Pass Blood Brain Barriers)
Clinical uses :Antinausia and VomitingInsomniaCough Motion sicknessAllergy
H1 antagonists
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Second generation.Loratadine
Non-sedatingClinical uses Allergic conditions Allergic rhinitis ConjunctivitisUrticaria
H1 antagonists
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Ranitidine
Inhibitor of gastric acid secretion Used in the treatment of peptic ulcers
H2 antagonists
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BETAHISTINE (Betaserc)
Used in treatment of vertigo in middle ear
H3 antagonists
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EICOSANOIDS (PROSTAGLANDINS)
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INHIBITORS OF EICOSANOIDS
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Phospholipids Phospholipase A2
Arachidonic Acid
Prostaglandins PGE2, PGD2, PGF2
Thromboxane (TXA2)
Prostacyclin (PGI2)
COX1 & COX2
LeukotrienesLTA4, B4, D4, C4 (Zafirlukast as Antagonist)
Lipoxygenase
Drugs
NSAIDs
Corticosteroids
Zileuton
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ACTIONS
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Vascular smooth muscles:
Potent vasoconstrictor.
PGE2 and PGI2
Thromboxane A2
Potent vasodilators.
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Blood:
PGE2 and PGI2
inhibit platelet aggregation
TXA2 a potent
inducer of platelet aggregation.
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One of the chemical mediators in inflammatory reactions.
Inflammation:
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-PGF2
-LTs and thromboxane are potent bronchoconstrictors in man → allergic bronchospasm .
Bronchial smooth muscle:
-PGE2 cause dilatation.
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Uterine smooth muscle:
PGE2 and PGF2 → Menstruation/ Dysmenorrhea/ Labor contractions
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- PGE2 and PGF2
GIT smooth muscle:
GITmotility
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GIT secretions:
PGE2 , PGE1 PGI2
↓acid and pepsinogen secretion .
mucin, water and bicarbonate & Blood flow.
Thus, it is cytoprotective
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PGE2 and PGI2 increase renal blood flow and diuresis.
Kideny
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Central and peripheral nervous systems
Fever: PGE1 and PGE2 increase body temperature.
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CLINICAL USES OF PGS ANALOGS
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Carboprost
PGF2α ( analog)
1) Abortifacient:
Trigger abortion in first trimester.
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2) For postpartum haemorrhage
vasoconstriction
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(PGF2α analog )
eye drops in open angle glaucoma.
↓ IOP by enhancing outflow of the aqueous humar.
Latanoprost
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Alprostadil
(PGE1analog)
1 -Injected in corpus cavernosum of the penis for some forms of male impotence.
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2 -In congenital heart anomalies
to keep the patent ductus arteriosus until
surgery .
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Misoprostol
(PGE1 analog)
Peptic ulcer
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Clinical Uses:
Oxytocis agents: (e.g.: Dinoprostone PGE2)
Asthma: Leukotrien antagonists (Zafirleukast; Montelukast); Zileuton
Impotance: Alprostadil PGE2
Glaucoma: Latanoprost PGF2
Anti-inflammatory and RA (NSAIDs) Antiplatelet action (Aspirin) Peptic Ulcer (Minoprostol PGE1)(Cytotec)
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Thank you & Good Luck