HISTAMINE AND

ANTIHISTAMINES.
AUTACOID PHARMACOLOGY1.
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SYNTHESIS AND METABOLISM OF HISTAMINE.

Histidine.
(From diet)

L histidine decarboxylase

Histamine
Histamine N methyl Diamine Oxidase(DAO)
transferase

N methyl histamine Imidazole acetic acid(IAA)

Monoamine oxidase(MAO)

NMIAA
N methylimidazole acetic acid IAA Riboside
If histamine is over
produced,NMIAA will be the Excreted in urine
diagnostic marker in the urine.
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Distribution , turnover and storage of histamine.

• In the tissues , the histamine concentration can range from less than 1 to over 100ug/g.

• The tissue distribution of histamine is identical to the mast cell distribution (wherever mast cells are,
there will most likely be histamines present).

Mast cells are distributed in :

• Skin
• Bronchial mucosa
• Gut mucosa
• Other mucosal surfaces.

• Mast cells synthesize histamine very slowly and store it in specific granules for a very long time
(until needed).

• Histamine levels in the plasma are normally very low.

• Histamine levels in the CSF are high.
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• Histamine levels in the plasma are normally very low.

• Histamine levels in the CSF are high.

• In the brain, stomach, healing tissues and some cells in the

skin, histamine is not stored in granules.

• It is produced de novo.
• It has a high turnover(made quickly, destroyed quickly)
• Low steady state level.
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Basic mast cell biology.
• An allergic response will occur when an allergen causes cross linking of IgE molecules.

• The cross linking of IgE antibodies will cause the IgE receptors on the surface of the mast
cell to be brought into close proximity to each other.

• The IgE receptor has an intracellular domain which belongs to syk family of kinases.

• The Kinases are tyrosine kinases, of which there are 2 (Lyn and Syk).

• When IgE binds, it causes a conformational change which allows phosphorylation of one
of these tyrosine residues (lets say Lyn – it may be Syk).

• Phosphorylation of the tyrosine activates the tyrosine kinase (Lyn).This activated tyrosine
kinase cross phosphorylates the other tyrosine kinase (Syk) on the other IgE receptors.
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• The phosphorylation of the Syk tyrosine kinase allows phosphorylation of
the enzymes phospholipase C.

– Note that for those who do not get allergic reactions, there is no cross linking
of IgE molecules and so only one IgE receptor is activated.

– The binding of IgE to the receptor will cause phosphorylation of the Lyn
tyrosine kinase but since there is no other IgE nearby, cross phosphorylation of
Syk cannot occur.

– It is the Syk tyrosine kinase which is able to activate phospholipase C .

• Phospholipase C (PLC) breaks down membrane phospholipids and releases
Inositol triphosphate (IP3) as product.
• IP3 causes the release of Ca2+ from intracellular stores.
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• Ca2+ results in the release of granules (Ca2+ dependent exocytosis).
– The stored granules have a pH of 5.5 .
– At this PH histamine is positively charged.It is held inside the granule by ionic interaction
with negatively charged molecules also in the granule.

• This molecules are :

 Heparin.
 Chondroitin sulphate
 Proteases.
• The histamine released can act on the mast cell it came from and inhibit
the further release of histamine(autoinhibition).

• Histamine does this by acting on a H2 receptor on the mast cell.

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• The H2 receptor causes the activation of adenylate cyclase which
increases the amount of cAMP .
• cAMP inhibits the release of histamine.
• The mast cell also has a B2 receptor which also does the same thing
• Therefore, B2 agonists can inhibit the release of histamine from mast cells.
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What triggers the release of histamines?
• Antigen specific, IgE mediated.
Anaphylactoid triggers.
• Organic bases
• Morphine
• Tubocurarine
• Succinylcholine chloride
• Contrast media used in radiography.
• Dextran
• Some neuropeptides
• Venom from insects (e.g mastoparan from wasps).
Diseases associated with increased histamine.
• Urticaria pigmentosa(mastocytosis)
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– Increased mast cells in skin.
– itchy, coloured lesions.

• Systemic mastocytosis.
– mast cells increase in organs.

• Myelogenous leukemia.
– Increased numbers of basophils.
• Basophils are of different origin to mast cells but have similar effects.

• Gastrinoma
– Zollinger-Ellison syndrome.
• Increase in gastrin release resulting in excessive release of histamine from ECL cells in the
gut.
• Get ulcers and diarrhea.
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All of these can be caused by Histamine.

• Urticaria.
• Dermographism
• Pruritis.
• Headaches.
• Weakness.
• Hypotention.
• Flushing of the skin.
• GIT disturbances.
• Ulcers.

• Effects
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Effects of histamine in humans.
• Burning ---- due to sensory nerve stimulation.
• Itching ---- due to sensory nerve stimulation.

• Warmth ---- due to sensory nerve stimulation/vasodilation.

• Skin flush ---- vasodilation.

• Hypotension ---- vasodilation which leads to reduced peripheral resistance.

• Headache ------ vasodilation/stimulation of afferent nerve fibres.
• Skin oedema/hives --- microvascular leakage.

• Colic/nausea ---- GI irritation.

• Acid hypersecretion ---- action of histamine on H2 receptors on parietal cells.
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• Brochospasm ---- effects of histamine on smooth muscle contraction in
bronchi.

• Triple response .

– Red spot ---- vasodilation

– Wheal ----- leakage of vessels.
– Flare ----- axon reflex. Stimulation of sensory afferents signals
itchy pain.
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Histamine receptors.
• 3 types ------------ H1, H2, H3.
• All are 7 transmembrane spanning G protein coupled receptors.
• When histamine binds, it causes a conformational change which exposes a
region on the intracellular tail of the receptor which allows G proteins to
bind.

Receptor location Prototype Signalling

subtype blocker molecule

H1 Smooth muscle diphenhydra PLC, IP3, DAG

Microvessels
Endothelium
mine
Sensory nerves

H2 Stomach,heart, cimetidine Increase in

Mast cAMP.
cells(autoinhibit
ion),endotheliu
m(smooth
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H3 Nerves,brain,gut,h impromidine G couple
eart Ca2+ entry
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Signal transduction
H1 RECEPTOR
• G protein

• Activates phospholipase C which causes release of IP3 .

• IP3 stimulates release of intracellular Ca2+ stores.

• Free intracellular Ca2+may also activate Ca2+ dependent protein kinases.

– e.g. myosin light chain kinase in smooth muscle(causing contraction).
– May also activate phospholipase A2 which causes production of eicosanoids.
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H2 receptor
• G protein
• Activates adenylate cyclase
• Increase in cAMP.
H3 receptor
• G protein mediated Ca2+ entry from the extracellular compartment into
the cell(note the difference to H1 receptors where the increase in
cytosolic Ca2+ is from intracellular stores.)
. Histamine in the brain.
• Histamine is synthesised and degraded by enzymes in synaptosomes.
• H1 receptors in the brain.
– Found in hypothalamus
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– Affect wakefulness(many antihistamines cause drowsiness)
– Appetite suppression.

• H1/H2 receptors involved in :

– Drinking
– Thermoregulation
– Secretion of ADH
– Blood pressure regulation

• H3 receptors
• Poorly understood.Modulate H1 effects.
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Histamine in the heart.
• Increase in atrial and ventricular force via H2 receptors(increase in Ca2+).

• Increase in heart rate by reducing the diastolic depolarisation time at the

SA node (H2 receptors).
• Decrease in the AV conduction time (H1 receptors)

• Arrhythmias (only in high doses)

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Histamine in smooth muscles.
• Bronchial smooth muscle. H1: contraction is the dominant pathway
• Gut smooth muscle. H2: relaxation (via increase in cAMP ) is a
weak minor compensation(modulates
• H1effects of constriction)

• Histamine in the vessels.

• H1 activates endothelial relaxation via NO(+PG12) .
• H2 activates a slower onset of direct relaxation.(some microcirculations
are very sensitive to histamine,so that a H1 spasm may dominate.)
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Agonists and antagonists.
• Agonists
– No therapeutic use
– Only used in specialties such as in bronchial hypereactivity testing for asthmatics
– Used by dermatologists as a positive control to test for allergen reactivity.
• Antagonists
• H1 antagonists are used to treat mild allergies
– Hay fever
– Allergic conjunctivitis
– Rhinitis
– Some skin disorders
• Other potential uses of H1 antagonists
– Colds (useless,may even be harmful due to their sedative effect)
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– Asthma (never used any more even though the air ways of the asthmatic are
filled with mast cells.)
– Useful in histamine overproduction diseases
– Motion sickness(not as effective as scopolamine)
– Vomiting(not as good as ondansetron)
• H2 antagonists are often used to treat:
– Peptic ulcers
– Dyspepsia/heart burn.
– Gastric reflux.
Classic H1 antagonists.
• Are sedative
• Often short acting(3 – 6 hours)
• May have significant anti-cholinergic action.
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Non sedating(new generation) H1 antagonists.
• Low or zero CNS penetration.
• Long acting
• Little anticholinergic effects

 An important point about some of the new generation drugs:

– Polymorphic Ventricular Tachycardia (PVT) may occur with astemizole and Terfenadine if
these drugs are taken in high doses or in conjunction with certain macrolide antibiotics
(erythromycin and clarithromycin) and/or certain anti-fungals (ketaconazole and
itraconazole).

– These other drugs inhibit a hepatic cytochrome p450 enzyme which is required for the
metabolism of these 2 H1 antagonists.
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H2 antagonists.
• Cimetidine
• Ranitidine
• Famotidine
• Nizatidine
How H2 receptors mediate acid secretion
Gastrin
G
ECL cell parietal cell
Cl-
K+
Histamine H2 H+
cAMP

M K+
Proton pump
Ach from vagus
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What we are expected to know.
• H1 involved in allergy.
• H2 involved in acid.
• H3 involved in alertness
Also to know :
• Synthesis and degradation pathway of histamine.
• The distribution of histamine and mast cells.
• Effects of histamine in humans.
• Biology of mast cell degradation.
• Histamine receptor subtypes
– G proteins
– Transduction mechanisms.
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• Biology of acid secretion
• Uses of H1 blockers in allergy.
• Differences between classical antagonists and the new generation
antagonists.
• Why H2 blockers are used to treat ulcers.
• Be able to give the names of the drugs in the lecture.
• The basis of PVT.