Histamine & antihistamines

4THCOFFEE
1 5 t h M a y 2 0 2 0
N a t t a s a s i S u c h a m a l a w o n g , M D .
Pediatric Allergy and Immunology Unit, King Chulalongkorn Memorial Hospital
Histamine
& Antihistamine

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outline
• Histamine receptors
• Antihistamine
• Historical of antihistamine
• Molecular basis of action of histamine and antihistamine
• Pharmacokinetics and pharmacodynamics of H1 antihistamines
• Efficacy & Adverse effect of H1 antihistamines
• H1-antihistamine in allergic disease
• H1-antihistamines in special situations
• H1 antihistamines in KCMH

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Histamine
Thomas Eiwegger, F. Estelle R. Simons.Middleton's Allergy, 9th Edition
• A natural body constituent
• Low-molecular-weight amine synthesized from L-histidine exclusively
by histidine decarboxylase
• Histamine is produced by various cells
- central nervous system neurons - gastric mucosa parietal cells
- mast cells - basophils - lymphocytes
• Mast cells and basophils are the major source of granule-stored
histamine
• Myeloid and lymphoid cell types (e.g., dendritic, T cells) that
do not store histamine show high HDC activity and are capable
of production of high amounts of histamine (HDC)
•
HDC

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histidine decarboxylase
Synthesis &
Catabolism of histamine
2% to 3% of histamine is excreted unchanged
N-methyltransferase
pathway in
CNS
small intestine mucosa
liver and kidneys
42- 47%
4- 8%
Diamine oxidase
small intestine mucosa, liver, kidneys, placenta, skin
not in CNS
9- 11%
16- 23%
metabolites in the urine for 12 hours

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Function of histamine
• The pleiotropic effects of histamine
• Histamine plays an important role in immune modulation and allergic
inflammation through at least 4 histamine receptors ,All these receptors
belong to the G protein–coupled receptor (GPCR) family
• These heptahelical transmembrane molecules transduce extracellular
signal by using G proteins and intracellular second-messenger systems
• Mast cells and basophils are not the only cellular sources of histamine.
In addition to gastric enterochromaffin like cells, platelets, and
histaminergic neurons
• The active and inactive states of HRs exist in equilibrium
Thomas Eiwegger, F. Estelle R. Simons.Middleton's Allergy, 9th Edition.2020

4THCOFFEE Histamine receptor subtypes
short arm chr. 3p25b
chr. 5
chr. 20
chr. 18q11.2

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NONCONVENTIONAL BINDING SITES OF HISTAMINE
Histamine can bind to non-classic binding sites that include
cytochrome P-450 (CYP) and histamine transporters.

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Histamine receptor subtypes & function
subtype expression function
H1 (HR1) - Immune cells: neutrophils, eosinophils, monocyte,
macrophage, DCs, T cells, B cells
- CNS
- CVS, endothelial cells, smooth muscle cells, epithelial cells
Pruritus, pain,vasodilation,
hypotension, tachycardia, headache,
bronchoconstriction
H2 (HR2) - GI
- CNS
- Immune cells: neutrophils, eosinophils, monocyte,
macrophage, DCs, T cells, B cells
- CVS, endothelial cells, smooth muscle cells, epithelial cells
Gastric acid secretion, vasodilation,
hypotension, tachycardia, headache,
bronchodilation, mucus production
(airway)
H3 (HR3) - CNS, peripheral neurons
- CVS, endothelial cells, monocytes, eosinophils, Lungs
- Decrease serotonin, dopamine,
histamine, NorE, Ach releases useful in
Alzheimer, ADHD, schizophrenia,
epilepsy, narcolepsy
- Prevent excessive bronchoconstriction
H4 (HR4) - CNS, Endocrine cells, Bone marrow
- Immune cells: neutrophils, eosinophils, monocyte,
basophil, mast cells, DCs, T cells
Differentiation of myeloblasts,promyelocyte

4THCOFFEE Immunologic events during the sensitization
phase against allergens.
1
2
3
4

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Regulation of the immune system through histamine receptors(HRs)
Induce tolerance
IL-3 , GM-CSF regulated
histamine production and
its receptor expression

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Induction and regulation of immune tolerance to allergens by histamine
VIA HR2
+

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Conclusion : histamine receptor
Simons and Simons ,WAO Journal & September 2008

4THCOFFEE Historical of histamine

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Ekaterini Tiligada et al. British Journal of Pharmacology (2020) 177 469–489

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Molecular basis of action of histamine and antihistamines
(antihistamine – inverse agonists)
• (A) The inactive state of histamine H1 receptor is in
equilibrium with the active state
• (B) The agonist, histamine, has preferential affinity for
the active state, stabilizes the receptor in this
conformation, and shifts the equilibrium toward the
active state
• (C) An H1 antihistamine(inverse agonist) has
preferential affinity for the inactive state, stabilizes the
receptor in this conformation, and shifts the
equilibrium toward the inactive state
Equilibrium
Agonist
Histamine
Inverse agonist
Anti-histamine

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Chemical structures of H1 antihistamine
Cetirizine: metabolite of Hydroxyzine
Levocetirizine: enantiomer of Cetirizine
Desloratadine: metabolite of Loratadine
Fexofenadine: metabolite of Terfenadine
1st generation H1 antihistamine
2nd generation H1 antihistamine

4THCOFFEE H1 Antihistamines: Chemical and Functional Classification
The original 2nd-generation agents were terfenadine and astemizole; both were removed from the market
after case reports of prolonged QT interval resulting in torsade de pointes. Both of these drugs exhibited
K+ blocking properties in cardiac conducting tissues, and had Cytochrome P450 (CYP450) isoenzyme
CYP3A4-dependent metabolism
Doxepin potent H1- and H2-antihistamine (classified as both H1 antihistamine and a tricyclic antidepressant).
6 groups
Antihistamine&Mast cell stabilizer
Both H1&TCA effect

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Different Development Objectives
• General trend: improve tolerability and safety
(less to no sedation; reduce the cholinergic effects)
PK, lower drug-drug
interactions
Receptor affinity
and selectivity,
efficacy
Safety, lower
cardiotoxicity
Targeted
Molecules for
improvement
Type of
Improvement
Loratadine
Hydroxyzin
e
Terfenadin
e
ObjectiveClass
Piperidine
Piperazine
Piperidine
Piperidine
Isomer
Purification
Levocetirizin
e
Desloratadine
Cetirizine
Fexofenadine
No possible
improvement

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Differences between 1st & 2nd generation H1 antihistamine
An Bras Dermatol. 2010;85(2):195-210.

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Benefits of H1 antihistamines
interfere with histamine action
at H1 receptors
In addition to acting directly to interfere with histamine action at H1 receptors on sensory neurons and small blood vessels, mainly postcapillary
venules, H1 antihistamines also downregulate allergic inflammation indirectly through nuclear factor-κB and through calcium ion channels

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Adverse effect 1st generation H1 antihistamine effects
More common in 1st generation H1 antihistamine
Minimal or no adverse effect in 2nd generation H1 antihistamine
Simons FER. Histamine and H1-antihistamines: celebrating a century of progress. J Allergy Clin Immunol 2011;128:1139-50

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potential adverse effects
System 1st generation H1 antihistamine 2nd generation antihistamine
CNS Impairment of alertness, cognition, learning,
memory,
performance with or without drowsiness
- Minimal or no adverse effect
- Esp fexofenadine
Cardiac Sinus tachycardia, SVT
Prolongation of QTC interval, Ventricular arrhythmia
- Minimal Concern in some countries
Others Anti muscarinic, anti serotonin, anti ⍶ adrenergic effect None
Toxicity
after
overdose
- CNS > Cardiac
- Adult: depress CNS
- Children: paradoxical excitation
- Prolongation of QTC interval, Ventricular arrhythmia
Up to 30 overdoses of cetirizine,
loratadine, fexofenadine  not associate
with serious events or fatality
Drug
abuse
Euphoria, hallucination None

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The sedative effect
• Standard/low dose:
• 1st generation H1 antihistamines
• cross BBB 50-70%
Standard/low dose:
1st generation H1 antihistamines
cross BBB 50-70%
Less-sedatingNon-sedating sedating
1st gen ATH

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Central nervous system effect

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Pharmacokinetics
• After usual doses, H1 antihistamine concentrations can be detected in picogram to
nanogram amounts in plasma, urine, and tissue
• Less pharmacokinetics of the first (old)–generation H1 antihistamines comparable
with new generation antihistamine
• Oral Administration
• Well absorb
• Peak plasma concentrations within 0.7 - 2.6 hours
• Bioavailability is influenced by several types of drug transporters, including ATP-
binding cassette (ABC transporters) such as organic anion transport protein
(OATP) and P-glycoprotein expression on the luminal surfaces of intestinal
endothelial cells

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Middleton's Allergy, 9th Edition
J ALLERGY CLIN IMMUNOL OCTOBER 2003
pharmacodynamic
significantly suppressed from 1 to 28 hours
Before and after ingestion of levocetirizine 5 mg
by children age 6 to 11 years

4THCOFFEE H1-antihistamines: pharmacokinetics and
pharmacodynamics in healthy adults

4THCOFFEEH1-antihistamines: pharmacokinetics and pharmacodynamics in healthy adults
F. Estelle R. Simons, M.D.,N Engl J Med 2004;351:2203-17.

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F. Estelle R. Simons, M.D.,N Engl J Med 2004;351:2203-17.
H1-antihistamines: pharmacokinetics and pharmacodynamics in healthy adults

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Simons FER, Silver NA, Gu X, et al. J Allergy Clin Immunol 2001;107:526-30
Fexofenadine
120 mg/day
Diphenhydram
ine 50 mg/day

4THCOFFEE H1-antihistamines: pharmacokinetics and
pharmacodynamics in healthy adults

4THCOFFEEH1-antihistamines:
Intranasal Antihistamines
Seidman, et al. Clinical Practice Guideline: Allergic Rhinitis. Otolaryngol Head Neck Surg. 2015; 152(1S):S1-S43

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Metabolite ,Absorption ,Excretion
• All 1st gen H1 antihistamines, and some 2nd gen H1 antihistamines (desloratadine
and loratadine) are metabolized by the hepatic cytochrome P450 (CYP450) system
• Drug–drug interactions
• interference with absorption through active transport mechanisms (e.g., P-
glycoprotein, organic-anion transporters, and other ATP-binding cassette transporters)
in the mucosa of GI tract
• inhibition or induction of metabolism in the hepatic CYP450 system.
↓ H1-antihistamine plasma
concentrations
• diminished efficacy
• P450 inducers: benzodiazepines
↑H1-antihistamine plasma
concentrations
• adverse effects
• P450 inhibitors: macrolides, antifungals,
calcium antagonists

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Metabolite ,Absorption ,Excretion
• Cetirizine, levocetirizine, fexofenadine
avoid metabolic passage through the liver
• Fexofenadine
• Excretion by biliary tract, elimination by stool without metabolic changes
• Substate of P glycoprotein
• clearance of toxic elements from the CNS
• P glycoprotein inducer ↓ absorption Grapefruit juice, rifampin , St. John’s wort
• P glycoprotein inhibitor↑ absorption Erythromycin, ketoconazole
• Organic acid
• Bind to aluminum/magnesium containing antacids

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H1 antihistamines : recommend dose
SIMONS AND SIMONS, J ALLERGY CLIN IMMUNOL VOLUME 128, NUMBER 6, 2011

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H1 antihistamines : recommend dose
SIMONS AND SIMONS, J ALLERGY CLIN IMMUNOL VOLUME 128, NUMBER 6, 2011
Nasal sprays
Ophthalmic

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H1-antihistamines : potential adverse effects

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Antihistamine
in KCMH

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H1 antihistamine in KCMH
Chlorpheniramine
• CHLORPHENIRAMINE 4 mg /tab
CHLORPHENIRAMINE (GPO) syr 2 mg/5 ml
CHLORPHENIRAMINE (GPO) inj 10 mg/ml
Hydroxyzine
• HYDROX-10 10 mg/tab
ATARAX, HIZIN LIQUID 10 mg/5ml
Diphenhydramine
• BENADRYL 25 mg/cap
Cyproheptadine
• PERIACTIN 4 mg/tab
Ketotifen
• KETEN 1mg/tab
POLITIFEN 1 mg/5m
Phenylephrine HCL & Brompheniramine maleate
• NASOTAPP 4 mg/tab , 10 mg/tab

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H1 antihistamine in KCMH
Cetirizine
• CETRIZIN(G) 10 mg/tab
ZYRTEC syr 5 mg/5ml
ORMIST syr 1 mg/ml
Loratadine
• LORSEDIN 10 mg/tab
CLARITYNE syr 5 mg/5ml
Desloratadine
• AERIUS syr 2.5 mg/5ml
Desloratadine SANDOZ 5mg/tab
Fexofenadine HCL
• VIFAS(G) 60 mg/tab,
FENAFEX 180 mg/tab
TELFAST oral susp 6 mg/ml
Levocetirizine
• XYZAL , LEVOCET 5mg/tab
Bilastine
• BILAXTEN 20 mg/tab
Rupatadine Fumarate
• RUPAFIN 10 mg/tab

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H1-antihistamine
in allergic disease

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Conditions Currently Treated with H1 Antihistamines
Simons FER, Simons KJ. Histamine and H1-antihistamines: celebrating
a century of progress; J Allergy Clin Immunol 2011;128:1139-50.)
Strong evidence
base
for 2nd generation
H1
antihistamine use
Level IA
Weak evidence
base for 2nd
generation H1
antihistamine use
Level II-IV, B,C,D
Weak evidence base
for
1st generation H1
antihistamine use
Level II-IV, B,C,D

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BOUSQUET ET AL. J ALLERGY CLIN IMMUNOL. 2019 VOLUME 145, NUMBER 1
Allergic rhinitis
2016 2019

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Demoly P et al. Phenotypes and endotypes of
rhinitis and their impact on management. a
PRACTALL report. Allergy 2015;70,474-94

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British Society for Allergy and Clinical Immunology (BSACI) guideline for the diagnosis and management of
allergic and non-allergic rhinitis (Revised Edition 2017

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Allergic rhinitis (PAR, SAR)

4THCOFFEE Effect of azelastine and fluticasone in combination (MP29-02) versus
fluticasone propionate (FLU), azelastine (AZE), and placebo (PLA)
Carr W, Bernstein J, Lieberman P, et al. J Allergy Clin Immunol 2012;129:1282-9

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BOUSQUET ET AL. J ALLERGY CLIN IMMUNOL PRACTICE VOLUME 6,2018
single-device azelastine-fluticasone formulation is effective within 5 minutes and the
effect persists over the 4-hour study period.
A free combination of intranasal fluticasone propionate and oral loratadine is effective
after 2 hours.
Change from baseline in VAS (0-
100) for 4 h postdosing (FAS).

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BOUSQUET ET AL. J ALLERGY CLIN IMMUNOL PRACTICE VOLUME 6,2018
single-device azelastine-fluticasone formulation is effective within
5 minutes and the effect persists over the 4-hour study period.

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ARIA 2019
Maintenance of INS
- Symptomatic but VAS < 5
- Congestion
- Exposed to allergen  OAH +INS

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Recto et al. Clin Mol Allergy (2017) 15:19
International guidelines This study serves as a consensus of experts from several
countries in APAC (Hong Kong, Malaysia, Philippines, Singapore, Thailand, Vietnam)
Second-generation antihistamines are the first-line treatment option in the management
of allergic rhinitis and urticaria)
Selection of optimal second-generation antihistamines depends on many factors,
particularly drug safety and efficacy, impact on psychomotor abilities, and sedation.
Country-specific considerations include drug availability and cost-effectiveness. Survey
results reveal bilastine as a preferred choice due to its high efficacy and safety, suitability
for special patient populations, and the lack of sedative effects.

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Recto et al. Clin Mol Allergy (2017) 15:19

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Int. J. Mol. Sci. 2019, 20,2-13

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Drugs Dermatol. 2020;19(2)145-154

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Chronic urticaria
ZUBERBIER ET AL , EAACI Allergy. 2018;73:1393–1414

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Indian Journal of Dermatology 2016; 61(3)

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Staevska M, et al. JACI 2010;125:676-82.

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• Bilastine, a second-generation antihistamine,is approvedin Europefor the
treatment of allergic rhinoconjunctivitis and urticaria in adults (20 mg)and
children aged≥6years (10 mg).
• PK,PD data for children 6–11 years were extracted post hoc from a study in which
children (2–11 years) with allergic rhino-conjunctivitis or urticaria received oral
bilastine (10 mg/day) safety same adult dose
adverse effect in children (6–11 years) receiving bilastine 10 mg same placebo.
• Conclusion: Pharmacokinetic and safety analyses in children aged 6–11 years
support the suitability of the pediatric dose of bilastine 10 mg and confirm that
the safety profiles of bilastine and placebo are similar.
Eur J Pediatr (2020) 179:801–805

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Eur J Pediatr (2020) 179:801–805
Summary statistics for bilastine pharmacokinetic parameters AUC0–24 and Cmax calculated in adults (bilastine 20 mg
once daily) in seven clinical studies and in children aged 6–11 years (bilastine 10 mg once daily) (n=12)

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.E Tiligada and M Ennis .British Journal of Pharmacology (2020) 177 469–489
Update
Drugs
targeting

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Drugs targeting the histamine H3 receptor
INN (year approved) ATC code Comments-indicative brand names
(see text for further details)
pitolisant
(EMA 2016)
N07XX11 First-in-class drug acting on histamine H3 receptors as
antagonist/inverse agonist; N-piperidyl derivative
developed by the groups of Jean-Charles Schwartz and
Walter Schunack and introduced by Bioprojet, France
FDA in 2010; first authorized in the EU for the treatment
of narcolepsy with or without cataplexy marketed as
Wakix®; Breakthrough Therapy and Fast Track designations
granted by the FDA in august 2019.

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Drugs targeting the histamine H4 receptor
INN (year approved) ATC code Comments-indicative brand names
(see text for further details)
• Seliforant
(a)
NA Investigational histamine H4 receptor antagonist originally
developed by Palau Pharma in Spain as UR-63325;
first in man histamine H4 receptor antagonist that entered
clinical trials in 2010 for seasonal allergic rhinitis; subsequently
licensed by the French biotech granted in 2018; currently
tested in Phase II
clinical trials for treatment of acute unilateral vestibulopathy
• Adriforant
Proposed INN:
List 199
(a)
NA Investigational histamine H4 receptor antagonist originally
developed by Pfizer UK as PF-3893787
and subsequently licensed by the British biopharmaceutical
firm Ziarco as ZPL-389; currently tested in Phase II proof of
concept clinical trials for the treatment of moderate to
severe atopic dermatitis

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Werfel T, et al. Efficacy and safety of the histamine H4 receptor antagonist ZPL-3893787 in atopic dermatitis. J Allergy Clin Immunol2018
A randomized, double-blind, placebo-
controlled, parallel-group study was
conducted to evaluate ZPL-3893787 (30 mg)
once-daily oral therapy in adults with
moderate-to-severe AD.
Patients were randomized (2:1) to ZPL-
3893787 (n = 65) or placebo (n = 33) for
8 weeks. Patients had a history of AD for
more than 12 months
Efficacy parameters included
EASI (Eczema Area and Severity Index (EASI),
IGA (Investigator's Global Assessment ),
SCORAD, and pruritus assessment.
Werfel T et al. Novel systemic drugs in treatment of atopic dermatitis: results from phase II and phase III studies published in 2018. Curr Opin Allergy Clin Immunol

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Treatment with oral ZPL-3893787 showed a 50% reduction
in EASI score compared with 27% for placebo (P=0.01).
improved inflammatory skin lesions in patients with AD,
confirming H4 receptor antagonism as a novel therapeutic option.
SCORAD scores exhibited 41% reduction with ZPL-3893787
versus 26% with placebo (P = .004).

4THCOFFEEIncidence of treatment-emergent adverse events
Werfel T et al. Novel systemic drugs in treatment of atopic dermatitis: results from phase II and phase III studies published in 2018. Curr Opin Allergy Clin Immunol
Somnolence
migraine

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H1 antihistamines in
special situations

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Potential adverse effect in vulnerable patients
Populations 1st generation H1 antihistamine 2nd generation H1 antihistamine
Neonates If mothers give immediately prior to deliver
• irritability, seizure, drowsiness,
respiratory depression
No CNS adverse effect
Infant & young
children
• Often associate with adverse effects,
occasionally fatalities
Long term safety
• cetirizine, levocetirizine, desloratadine
loratadine, fexofenadine
Pregnant & lactating
women
• Category B: Chlorpheniramine,
diphenhydramine
• Category C: Hydroxyzine, ketotifen
• Potentially cause irritability and
drowsiness in nursing infants
• Category B: Cetirizine, loratadine
• Category C: Fexofenadine,
desloratadine
• No CNS effects in nursing infants

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J Investig Allergol Clin Immunol 2013; Vol. 23, Suppl. 1: 1-16
Routes of excretion of the principal second generation antihistamines and their use
in kidney failure (RI)

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Liver metabolism of the principal second generation antihistamines and
possible interactions through this mechanism

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Patients with impaired
hepatic/renal function
Kulthanan K et al.Asian Pac J Allergy
Immunol 2016;34:190-200
First-generation (sedating) antihistamines

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Patients with impaired
hepatic/renal function
Kulthanan K et al.Asian Pac J Allergy
Immunol 2016;34:190-200

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Aspects to take into account in the use of antihistamines in the elderly

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