Autocrine & Paracrine Pharmacology (Part II)

Prof. AlhaiderDepartment of PharmacologyCollege of Medicine

OBJECTIVES

At the end of lecture the Students should be able to :

1 -Specify storage sites of histamine2 -Explain the synthesis, release &

inactivation of histamine3-List histamine receptors regarding:

Type, major location, major biologic effects4-Explain the clinical uses of histamine

receptors antagonists.

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5 -Describe the synthesis of Eicosanoids6 -Classify drugs that inhibit synthesis of

eicosanoids7 -Enumerate the pharmacological actions

of eicosanoids8-Enumerate the clinical uses of PGs

analogs

H

istamine

H

istamine

NeurotransmitterNeurotransmitterAllergic & Inflammatory reactions

Allergic & Inflammatory reactions

Gastric acid secretionGastric acid secretion

Storage Sites

Biosynthesis

Inactivation

Histamine

Methyl histamine (Oxidation)

Methyl imidazole acetic acid

Imidazole N-methyltransferase

Diamine oxidase

H H

22

H H

11

H H

33

H H

33+

+

+

H H

11

-ve presynaptic autoregulation

RELEASE

Primary mechanism, during allergic reactions on sensitizing [ IgE antibody interacts with antigen on the surface of mast cells ]

Mast cells are degranulated and release histamine and leads to allergic reactions.

It also has some role in acute inflammation ,on injury it causes local vasodialtion and leakage of plasma, anti bodies and inflammatory cells.

Its release is modulated by binding to H3 presynaptic receptors

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Enzymes as trypsin or drugs as morphine or other chemicals can liberate histamine

Tissue injury by trauma or burn

ReceptorType

Major Tissue Locations

Major Biologic Effects

H1smooth muscle, endothelial cells

acute allergic responses

H2gastric parietal

cellssecretion of gastric

acid

H3central nervous

systemneurotransmission

H4

mast cells, eosinophils, T

cellsregulating immune responses

Histamine receptorsHistamine receptors

Effects Of Histamine

Pain, itching, hives الجلدي الطفحHypotension, tachycardia, flushing and

bronchoconstriction فرط حاالت في تحصلالحساسية

Headache, visual disturbances, increase skin temperature

Excessive secretion of gastric acids and diarrhea

Bronchoconstriction, dyspnea,

Histamine receptors antagonists

Physiologic antagonists: Histamine effects can be reduced by physiologic antagonism such as epinephrine which acts on different receptors but produces effects opposite to histamine especially in anaphylaxis. Therefoe, Epinephrine is the drug of choice for Anaphylaxis ( الحساسية (فرط

Specific receptor blockage:Of Blocking of histamine receptors.But in most of the cases these blockers specific in

their binding and blocking activity.

First generation H1 receptor Blockers (CNS).

Diphenhydramine,

cyclizine,

promathazineSecond generation H1 receptor blockers (PeroLoratidineCitrizine

DiphenhydraminDiphenhydramin

(First (First generation) generation)

Has a Sedating effect

Clinical uses :

Insomnia

Motion sickness

Cold medication

Allergy

H1 antagonists ( Blockers )

H1 antagonists ( Blockers )

Loratadine Loratadine (Second (Second

generation)generation)H1 antagonistsH1 antagonists

CimetidineCimetidine

Inhibitor of gastric acid secretion

Used in the treatment of

peptic ulcers

H2 antagonistsH2 antagonists

BETAHISTINEBETAHISTINE

Used in treatment of

vertigo in middle ear

H3 antagonistsH3 antagonists

EICOSANOIDS

INHIBITORS OF EICOSANOIDS

Phospholipids Phospholipase A2

Arachidonic Acid

Prostaglandins

Thromboxane (TXA2)

Prostacyclin

Cyclooxygenase

Leukotrienes

Lipoxygenase

Drugs

NSAIDs

Corticosteroids

Zileuton

Actions of prostaglandins (Very Important)

Causes vasodilatation of vascular smooth muscle cells

Causes inhibition of platelets aggregation

Sensitize neurons to cause pain

Induce labor

Decrease intraocular pressure

Acts on thermoregulatory center of hypothalamus

Acts on kidney to increase glomerular filtration

Acts on parital cells of stomach to prevent gastric mucosa

Comparison in actions between

Prostaglandins

Thromboxane A2

Vascular smooth muscles:

Potent vasoconstrictor.

Prostaglandins Thromboxane A2

Potent vasodilators.

Blood:

Prostaglandins

inhibit platelet aggregation

TXA2 a potent inducer of platelet aggregation.

Both play important role in inflammatory reactions.

Inflammation:

-Thromboxane

( bronchoconstriction)

Bronchial smooth muscle:

-Prostaglandins ( bronchorelaxation )

Uterine smooth muscle:

Prostaglandins increase uterine contractions → Menstruation/ Dysmenorrhea الطمث Labor /آالمcontractions

- Prostaglandins

GIT smooth muscle:

GITmotility

GIT secretions:

Prostaglandins

↓acid secretion

Mucin secretion

Prostaglandins increase renal blood

flow and diuresis.

Kideny

Central and peripheral nervous systems

Fever

Clinical uses of prostaglandins analogs

( Synthetic prostaglandins )

Carboprost

1) Abortion

Induce abortion in first trimester.

2) Treatment of postpartum haemorrhage

( vasoconstriction + uterine muscle contraction)

Carboprost cont.

PGF “less used nowadays “

eye drops /in treatment of open angle glaucoma.

(↓ IOP by enhancing outflow of the aqueous humar)

Latanoprost

Misoprostol

Treatment of Peptic ulcer

Prostaglandin Antagonists have very important clinical uses e.g: NSADS (Aspirin; Paracetamol; Brufen). Also, Leukotriene antagonists have an important value for treating asthma الربو

Thank you

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