Professor Martin K Church

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Antihistamines, Corticosteroids and Urticaria
Professor Martin K Church
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Human Skin Mast Cell Activation
Urticaria is caused principally by mast cell
degranulation
Human skin mast cells, unlike those of the
airways, may be activated stimuli in addition to
allergen
Activation by complement C5a and neuropeptides
generates principally histamine with little
eicosanoid synthesis
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Histamine and the Wheal and Flare Response
Mast cell derived histamine acts on local blood
vessels to cause
- Local vasodilatation
- Local oedema (wheal)
Mast cell derived histamine causes antidromic
stimulation of sensory nerves to release sensory
neuropeptides, particularly CGRP. The
neuropeptides cause
- Surrounding vasodilatation (flare)
- Itching (pruritus)
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Why do we Need High Doses of the Most Effective
Antihistamines to Treat Urticaria?
Unlike loose tissues such as those found at
mucosal surfaces, the skin is a very tightly
structured tissue. Consequently, histamine
diffuses very poorly in the skin and reaches high
local concentrations
Dermal microdialysis studies have shown that
histamine diffuses only 1 mm from its site of
release
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The Effects of Three Doses of a Drug on a
Supra-Maximal Effect of Histamine (As Seen in
Urticaria)
The concentration/response curve is shown in
orange in the graph. The effects of three doses
of an antihistamine are shown
As you can see, the first dose of the drug shifts
the graph to the left (red horizontal line) but
has no impact on the response
If the dose is doubled, then the shift of the
graph to the left (red horizontal line) is
greater and a small reduction of the response
(vertical green line) is seen
Response
If the dose is trebled, then the shift of the
graph to the left (red horizontal line) is even
greater a large reduction of the response
(vertical green line) is seen
Histamine Concentration
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Relative Inhibition Skin Responses from Placebo
Induced by Levocetirizine
The histogram shows the effectiveness of a second
generation antihistamine against the wheal and
flare response to intradermal histamine
Note that the wheal is less well inhibited than
the flare and itch
Both the flare and itch result from stimulation
of sensory nerves by histamine. In this study,
there was a highly significant (P lt 0.0001)
correlation between the effects of the
antihistamine on flare and itch
Denham et al Inflam Res 200352424-7
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Inflammation and Mast Cell Production
Inflammatory stimulation of many cells leads to
the activation of transcription factors such as
NF-?B and AP-1
These transcription factors stimulate DNA to
transcribe messenger RNA for cytokines and
adhesion molecules which cause inflammation
E-Selectin ICAM-1 VCAM-1 IL-8 GM-CSF TNF?
These transcription factors also stimulate DNA to
transcribe messenger RNA for stem cell factor
(SCF) an important mast cell growth factor
Stem cell factor
Eosinophils Neutrophils
Mast Cells
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Inflammation and Mast Cell Production
Glucocorticoid inhibit the transcription of
inflammatory cytokines, adhesion molecules and
stem cell factor
Corticosteroids
- Reduce the number of mast cells
- Reduce mast cell histamine content
- Do NOT inhibit histamine release
E-Selectin ICAM-1 VCAM-1 IL-8 GM-CSF TNF?
- Do NOT inhibit the effects of histamine
- Reduce eosinophil migration
Stem cell factor
- Reduce eosinophil activation
- Reduce eosinophilic inflammation
Corticosteroids take several weeks to reach
maximum efficacy
Eosinophils
Mast Cells
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Conclusions
Both antihistamines and corticosteroids are used
to relieve the symptoms of urticaria. Neither
will cure the condition

• The choice of drug and dose should be based on
• Evidence based medicine about the effectiveness
  of the drug
• Expert opinion about the unwanted effects of the
  drugs
• Patient acceptability