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platelets, dendritic cells (DCs), and T cells, can also express HDC after
stimulation
HDC expression is influenced by cytokines, including IL-1, IL-3, IL-12, IL-18, GM-
CSF,macrophage colony-stimulating factor, and TNF-
Mast cells and basophils store large quantities of histamine, which is released
on degranulation in response to immunologic and nonimmunologic stimuli
Characteristics of the Histamine Receptor Subtype
Characteristics H1-Receptor H2-Receptor H3-Receptor H4-Receptor
Receptor described, 1966, 1993 1972, 1991 1983, 1999 1994, 2000
human gene cloned
Receptor proteins in 487 amino acids, 359 amino acids, 445 amino acids, 390 amino acids
human 56 kD 40 kD 70 kD
Chromosomal 3p25, 3p14-21 5, 5q35.3 20, 20q13.33 18q11.2
location in human
Equilibrium ~10 mol/L ~ 30 mol/L ~ 10 nmol/L 20-40 nmol/L
constant for
dissociation (Kd)
Receptor expression Widespread, Widespread, High expression in High expression in
including neurons, including histaminergic bone marrow and
smooth muscle gastric mucosa neurons, low peripheral
(e.g., parietal expression hematopoietic cells,
airways, vascular), cells, smooth- elsewhere low
and other muscle, heart, expression
types of cells. and other types of elsewhere
cells
H4 receptor have higher affinity for histamine compare with H1-receptor
Shahid M, tripathi T, Sobia F, dkk. Histamine, Histamine Receptors, and their Role in Immunomodulation An
Update Systematic Review. The Open Immunology Journal.. 2009
The predominant histamine receptors,
designated H1,H2,H3,H4 eliciting the effects.
H1:
H2:
H3:
H4:
Antihistamines H1 Antihistamines
Functional class
Chemical class First (old) generation Second (new) generation
Alkylamines Brompheniramine, chlorpheniramine, Acrivastine
dexchlorpheniramine, dimethindene,
pheniramine, triprolidine
Piperazines Buclizine, cyclizine, hydroxyzine, Cetirizine, levocetirizine
meclizine, oxatomide
Piperidines Azatadine, cyproheptadine, Astemizole, bepotastine, bilastine,
diphenylpyraline, ketotifen desloratadine, ebastine, fexofenadine,
levocabastine, loratadine, mizolastine,
rupatadine, terfenadine, alcaftadine
Ethanolamines Carbinoxamine, clemastine,
dimenhydrinate, diphenhydramine,
doxylamine, phenyltoloxamine
Ethylenediamines Antazoline, pyrilamine, tripelennamine
Simons F. Estelle R, MD, FRCPC, Simons Keith J, PhD. Histamine and H1-antihistamines :
Celebrating a century of progess. Journal Allergy Clin Immunol. 2011
Differences between first and second-generation H1 antihistamines
Carson S, Lee N, dkk. Drug Class Rev.iew Newer Antihistamines. Oregon Health & Science
Univer sity. 2010
H2- Antihistamines
H3-antihistamines prevent
the histamine binding-
activity to histamine 3
receptor in neurons
Example of H3-
antihistamines are:
Betahistine, ciproxifan, PF-
03654746, MK0249, JNJ-
17216498, GSK189254.
H4- Antihistamines
Simons F. Estelle R, MD, FRCPC, Simons Keith J, PhD. Histamine and H1-antihistamines :
Celebrating a century of progess. Journal Allergy Clin Immunol. 2011
EFFICACY OF H2- ANTIHISTAMINES
:
The use of systemic glucocorticoids in dermatology
disorders is associated with gastrointestinal side
effects including gastritis, peptic ulceration, and
gastrointestinal hemorrhage
Use of H2- antihistamines (ex: ranitidine) for
gastrointestinal protection in systemic corticosteroid
users
TREATMENT OF CHRONIC IDIOPATHIC OR AUTOIMMUNE URTICARIA ANGIOEDEMA
Non-Sedating Antihistaminics :
Response One agent or combinations at 2-4 times the dose recommended for
rhinitis
Inadequate response
1. Other antihistamines to maximal dose e.g. Hydroxazine
Response
or Diphenhydramine 25-50 mg q.i.d.
Maintain at dose where urticaria is
"mild"-need not be eliminated
2. Addition of H2 antagonist + leucotriene antagonist
Insufficient response
Presents with history of taking considerable 1. Low dose daily (10 mg prednisone or equivalent)
corticosteroid or has hypertension, diabetes, steroid or alternate day steroid (20-25 mg q.o.d.)
osteoporosis, severe stria, morbid obesity with slow taper employing 5 mg and 1 mg
prednisone tablets
2. Cyclosporine as an alternative to #1
Cyclosporine-concomitant steroid is maximum
of 15 mg/day-taper gradually with goal of
eliminating it.
Zampeli E, Tiligada E. The role of histamine H4 receptor in immune and inclammatory disorders.
British journal of Pharmacology. 2009
MELANOMA:
H4R was expressed in 42% of human melanoma
biopsies, suggesting a potential therapeutic
application of H4R ligands.
PSORIASIS:
Plasmacytoid dendritic cells (pDC) are present in
inflammatory skin lesions
In psoriasis, the expression of the H4R is detected
on pDC in the blood and in lesional psoriasis skin
HRH4 mRNA levels are higher in the blood samples of patients with
systemic lupus erythematosus (SLE) compared with controls.
Yu B, Shao Y, Li P, Zhang J, dkk. Copy number variations of the human histamine H4 receptor
gene are associated with systemic lupus erythematosus. British Association of
Dematologists. 2010
Proposed role of histamine H1and H4 receptors in peripheral and central
transmission of itch responses.
H1 H4
histamine
Ohsawa Yusuke, Hirasawa Noriyasu. The Role of Histamine H1 and H4 Receptors in Atopic
Dematitis: From Basic Research to Clinical Study. Allergology International Vol 63, No4. 2014
VIDEO: mechanism release histamine
and antihistamine in allergy
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