By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 6

HISTAMINE AND ANTIHISTAMINES

Synthesis and metabolism of histamine

Histidine
(From diet)

L histidine decarboxylase

Histamine N Histamine
methyl transferase Diamine oxidase
(DAO)

N methyl histamine Imidazole acetic

acid (IAA)
Monoamine oxidase
(MAO)

N methylimidazole acetic
IAA Riboside
acid (NMAA)
If histamine is
overproduced, NMAA
will be the diagnostic
Excreted in urine
marker in the urine

Distribution, turnover and storage of histmine

• In the tissues, the histamine concentration can range from less than 1 to over 100µg/g
• The tissue distribution of histamine is identical to the mast cell distribution (wherever mast cells are, there
will most likeley be histamine present).
• Mast cells are distributed in:
• Skin
• Bronchial mucosa
• Gut mucosa
• Other mucosal surfaces
• Mast cells synthesis 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.
• 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 levels

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 (Fcε R1) on the surface of the mast cell to be
brought into close proximity to each other.
• The Fcε R1 receptor has an intracellular domain which belongs to the src family of kinases. The kinases are tyrosine
kinases, of which there are 2 (lyn and syk). When IgE binds, it casues 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 Fcε R1 receptor.
• The phosphorylation of the syk tyrosine kinases allows phosphorylates 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 Fcε R1 receptor is activated. The binding of IgE to the receptor will cause phosphorylation of the lyn
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 6

tyrosine kinase but since there is no other Fcε R1 nearby, cross phosphorylation of syk cannot occur. It is
the syk tyrosine kinase which is able to activate phospholipase C.
• PLC breaks down membrane phospholipids and releases IP3 as a product.
• IP3 causes the release of Ca2+ from intracellular stores.
• 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.
• These 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.
• 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 β2 receptor which also does the same thing. Therefore, β2 antagonists can inhibit the
release of histamine from mast cells.

What triggeres the release of histamine?

• Anaphylactic triggers
• Antigen specific, IgE mediated
• Anaphylactoid triggers
• Organic bases Many drugs used in therapy
• Morphine can trigger mast cells to
• Tubocuravine release histamine
Neuromuscular blockers
• Succinylchloride
• Contrast media used in radiography
• Dextran
• Vancomycin (an antibiotic)
• Complement (C5a, C3a)
• Some neuropeptides
• Venom from insects (e.g. mastoparan from wasps)

Diseases associated with increased histamine

• Urticaria pigmentosa (mastocytosis)
• Increased mast cells in skin
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 6

• 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.
• Urticaria
• Dermographism
• Puritis
• Headaches
• Weakness All these can be caused by histamine
• Hypotension
• Flushing of the skin
• GIT disturbances
• Ulcers

Effects of histamine in humans

• Burning Due to sensory nerve stimulation
• Itching Due to senosry nerve stimulation
• Warmth Due to sensory nerve stimulation/vasodilation
• Skin flush Vasodilation
• Hypotension Vasodilaton which leads to reduced peripheral resistance
• Increased HR Reflex tachycardia to compensate for the reduction in blood pressure.
• 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 partietal cells
• Bronchospasm 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. Antidromic impulses from
branches of the axon cause release of chemicals causing nearby flare.

Histamine receptors
• 3 types (H1, H2 and H3)
• All are 7 transmembrane spanning G 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 subtype Location Prototype blocker Signalling molecule

H1 Smooth muscle Diphenhydramine PLC, IP3, DAG
Microvessels
Endothelium
Sensory nerves
H2 Stomach Cimetidine Increase in cAMP
Heart
Mast cells (autoinhibition)
Endothelium
(smooth muscle)
By Duy Thai, 1997 Pharmacology Semester 1 page 4 of 6

(lymphocytes)
H3 Nerves Impromidine G coupled
Brain Ca2+ entry
(gut)
(heart)

You must know the drugs listed on the handout

Signal transduction
• H1 receptor
• G protein
• Activates phospholipase C which causes release of IP3 and DAG
• IP3 stimulates release of intracellular Ca2+ stores
• DAG (in conjunction with Ca2+) activates protein kinase C
• 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
• H2 receptor
• G protein
• Activates adenylate cyclase
• Incrrease 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 brain
• Found in hypothalamus
• 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?

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 is the SA node (H2 receptors)
• Decrease in the AV conduction time (H1 receptors)
• Arrhythmias (only in high doses)

• The above effects of histamine on the heart are only in experimental conditions. In the body, these effects do not
show any significance since they are overshadowed by the baroreflex, which is a more powerful controller of heart
rate and contractility.

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 H1 effects of constriction)
Histamine in the vessels
• H1 activates endothelial relaxation via NO (+PGI2)
By Duy Thai, 1997 Pharmacology Semester 1 page 5 of 6

• H2 activates a slower onset of direct relaxation. (some micorcirculations are very sensitive to histamine, so that a
H1 spasm may dominate)

Histmaine on the microvasculature

• Contrary to popular belief, histamine does NOT increase capillary permeability.
• Histamine works on the post capillary venule to increase the gap formation between endothelial cells, causing
plasma leakage. (Especially in acute inflammation)
• Histamine may increase the gap formation in 2 possible ways:
• Active contraction of the actin filaments in the endothelial cells.
• Transient de-adhesion
• The endothelial cells are attached to each other via tight junctions. There are also tiny elastic
filaments which are tonically active and will tend to pull the cells apart if there is no physical
connection between the cells. Histamine may cause a loss of adhesion of the tight junctions,
allowing the elastic filaments to cause tiny openings between the endothelial cells.

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 conjunctavitis
• Rhinitis
• Some skin disorders
• Other “potential” uses of H1 antagonists
• Colds (useless, may even be harmful due to their sedative effect)]
• Asthma (never used any more, even though the airways of the asthmatic are filled with mast
cells)
• Useful in histamine overproduction diseases
• Motion sickness (not as effective as ascopolamine)
• Vomiting (not as good as ondansetron)
• H2 antagonists are often used to treat:
• Peptic ulcers
• Dyspepsia/heart burn
• Gastric reflux

Classic H1 antagonists
• Are seadtive
• Often short acting (3 – 6 hours)
• May have significant anti-cholinergic action
• See the handout for the names of the drugs (need to know!)

Non sedating (new generation) H1 antagonists

• Low or zero CNS penetration
• Long acting
• Little anticholinergic effects
• See the handout for the names of the drugs (need to know!)
• An important points 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-fungal drugs (ketaconazole and
By Duy Thai, 1997 Pharmacology Semester 1 page 6 of 6

itraconazole). These other drugs inhibit a hepatic cytochrome p450 enzyme which is required
for the metabolism of these 2 H1 antagonists.

H2 antagonists
• Also on the handout, but I will put them here anyway since there are not many
• Cimetidine
• Ranitidine
• Famotidine
• Nizatidine

How H2 receptors mediate acid secretion

Gastrin

G Parietal cell
Cl-
K+

ECL cell Histamine H2

↑ cAMP
H+
K+
M

Ach from Vagus

Proton pump

What we are expected to know

• H1 involved in allergy
• H2 involved in acid
• H3 involved in alertness
• Know:
• Synthesis and degradation pathway of histamine
• The distribution of histamine and mast cells
• Effects of histmine in humans
• Biology of mast cell degranulation
• Histamine receptor subtypes
• G proteins
• Transduction mechanisms
• Biology of acid secretion
• Uses of H1 blockers in allergy
• Differences between classical antagonists and the new generation
• Why H2 blockers are used to treat ulcers
• Be able to give the names of the drugs in the handout
• The basis of PVT