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

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.

MONOAMINE (HISTAMINE )

Storage Sites

Highest amounts in mast cells

Basophils Skin Lung Intestinal mucosa Stomach Brain

RELEASE

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)

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

SYNTHESIS & INACTIVATIONTION

H 2

H 1

H 3

H

istamine Mediator

NeurotransmitterCNSANS

H 3

+

+

+

H 1

-ve presynaptic autoregulation

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

Histamine receptors antagonists

What is the physiological Antagonist of Histamine?

First generation Diphenhydramin, Promethazine etc

(Sedating and Pass Blood Brain Barriers)

Clinical uses :Antinausia and VomitingInsomniaCough Motion sicknessAllergy

H1 antagonists

Second generation.Loratadine

Non-sedatingClinical uses Allergic conditions Allergic rhinitis ConjunctivitisUrticaria

H1 antagonists

Ranitidine

Inhibitor of gastric acid secretion Used in the treatment of peptic ulcers

H2 antagonists

BETAHISTINE (Betaserc)

Used in treatment of vertigo in middle ear

H3 antagonists

EICOSANOIDS (PROSTAGLANDINS)

INHIBITORS OF EICOSANOIDS

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

ACTIONS

Vascular smooth muscles:

Potent vasoconstrictor.

PGE2 and PGI2

Thromboxane A2

Potent vasodilators.

Blood:

PGE2 and PGI2

inhibit platelet aggregation

TXA2 a potent

inducer of platelet aggregation.

One of the chemical mediators in inflammatory reactions.

Inflammation:

-PGF2

-LTs and thromboxane are potent bronchoconstrictors in man → allergic bronchospasm .

Bronchial smooth muscle:

-PGE2 cause dilatation.

Uterine smooth muscle:

PGE2 and PGF2 → Menstruation/ Dysmenorrhea/ Labor contractions

- PGE2 and PGF2

GIT smooth muscle:

­GITmotility

GIT secretions:

PGE2 , PGE1 PGI2

↓acid and pepsinogen secretion .

­ mucin, water and bicarbonate & Blood flow.

Thus, it is cytoprotective

PGE2 and PGI2 increase renal blood flow and diuresis.

Kideny

Central and peripheral nervous systems

Fever: PGE1 and PGE2 increase body temperature.

CLINICAL USES OF PGS ANALOGS

Carboprost

PGF2α ( analog)

1) Abortifacient:

Trigger abortion in first trimester.

2) For postpartum haemorrhage

vasoconstriction

(PGF2α analog )

eye drops in open angle glaucoma.

↓ IOP by enhancing outflow of the aqueous humar.

Latanoprost

Alprostadil

(PGE1analog)

1 -Injected in corpus cavernosum of the penis for some forms of male impotence.

2 -In congenital heart anomalies

to keep the patent ductus arteriosus until

surgery .

Misoprostol

(PGE1 analog)

Peptic ulcer

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)

Thank you & Good Luck