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ANTIHISTAMINES IN DERMATOLOGY

Dr. Retno Indar W, M.Si., SpKK


HISTAMINE
Histamine is a biogenic amine and is synthesized by L-histidine dekarboksilase
(HDC) from the amino acid histidine

Mast cells, basophils, gastricenterochromaffin-like cells and histaminergic


neurons are the best-described cellular sources of histamine

&
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

Phenothiazines Methdilazine, promethazine


Other Doxepin Azelastine, emedastine, epinastine,
olopatadine

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

First-generation H1 antihistamines Second-generation H1 antihistamines

Usually administered in three to four Usually administered once or twice a


daily doses day
Cross the blood-brain barrier Do not cross the blood-brain barrier
(lipophilicity, low molecular weight, lack (lipophobicity, high molecular weight,
of recognition by the P-glycoprotein recognition by the P-glycoprotein efflux
efflux pump pump)

Potentially cause side-effects (sedation/ Do not cause relevant side-effects


hyperactivity/insomnia/convulsions) (sedation/fatigue/hyperactivity/convuls
iew ions),

Carson S, Lee N, dkk. Drug Class Rev.iew Newer Antihistamines. Oregon Health & Science
Univer sity. 2010
H2- Antihistamines

The H2-antihistamines exhibit


competitive inhibition at the parietal cell
H2 receptor and suppress basal and meal-
stimulated acid secretion
CLINICAL COMPARISON OF H2- ANTIHISTAMINES

Katzung BG, Master SB, Trevor AJ. Basic & Clinical


Pharmacology. 2012
H3 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

H4-antihistamines prevent the histamine


binding-activity to histamine 4 receptor in
bone marrow and peripheral hematopoietic
cells

Example of H4- antihistamines are:


Thioperamide, JNJ-39758979, JNJ777120
EFFICACY OF ANTIHISTAMINES IN DERMATOLOGY
EFFICACY OF H1- ANTIHISTAMINES

Condition currently treated with H1-antihistamines


Strong evidence base for second Weak evidence base for (new)- Weak evidence base for first
(new)-generation H1- generation H1-antihistamine use (old) generation H1-
antihistamine use antihistamine use in CNS and
vestibuler disorders
Alergic rhinitis Atopic dermatitis Insomnia
Asthma Conscious sedation
Anaphylaxis Perioperative sedation
Non-allergic angioedema Analgesia
Allergic conjungtivitis Upper respiratory tract Anxiety
Infection(colds) Migraine
Otitis media Vertigo
Sinusitis
Urticaria Nasal polyps
Non-specific cough
Non-allergic, non-specific itching

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.

Cyclosporine is ineffective or side effects Good response with steroid


Insufficient response to steroids
prohibitive Taper dose every 2-3 weeks as
Low dose steroids as note above Cyclosporine-once response is
tolerable. Goal is mild urticaria; rare
Weekly methotrexate angicedema obtained, eliminate corticosteroid
Intravenous gamma globulin
Plasmapheresis for autoimmune
subgroup
EFFICACY OF H3-ANTIHISTAMINE
Clinical data on Antihistamines 3
AH-3 Clinical Observations and Status

BF2.649 (Pitolisant) Efficacy reported in narcoleptic


patients and Parkinsons disease,
sleep disturbances and insomnia

PF-03654746 Sleep disturbance, insomnia


GSK189254 Sleep disturbance, insomnia
GSK239512 Schizophrenia
MK--0249 Sleep disturbance, insomnia
ABT-288 Schizophrenia
JNJ-17216498 narcoleptic patients
Brioni JD, Esbenshade TA, Garrison TR, Bitner SR, Cowart MD. Discovery of Histamine H3
Antagonists for the Treatment of Cognitive Disorders and Alzheimers Disease. 2011
EFFICACY OF H4- ANTIHISTAMINES

Zampeli E, Tiligada E. The role of histamine H4 receptor in


immune and inflammatory disorders. British journal of
Pharmacology. 2009
The contribution of histamine H4 receptor

Condition Function of the H4 receptor


Pruritus & Suppression of late-phase swelling and eosinophil
dermatitis infiltration by H3/H4receptor
antagonist thioperamide in Ag-non-specific dermatitis
in mice
Hirasawaet al.(2008)

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

Thurmond RL, Gelfand EW, Dunford PJ. The role of histamine H1


and H4 receptors in allergic inflammation: the search for new
antihistamines. Nature Publishing Group. 2008
Expression of Histamine, H1R, and H4R in Healthy Donors and
Atopic Dermatitis Patients

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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