Pharmacology of the H1 Histamine Receptor

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By: Elaine Lai, Jia Hui Zhao, Melissa Wing San Choi, Wei-Hsin Tang . PHM142 Fall 2016. Instructor: Dr. Jeffrey Henderson. Presentation overview. Structure of the H1 histamine receptor. Location of the receptor. ID: 525881 Download Presentation

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Pharmacology of the H1 Histamine Receptor

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Presentations text content in Pharmacology of the H1 Histamine Receptor


Pharmacology of the H1 Histamine Receptor

By: Elaine Lai, Jia Hui Zhao, Melissa Wing San Choi, Wei-Hsin Tang

PHM142 Fall 2016

Instructor: Dr. Jeffrey Henderson


Presentation overview

Structure of the H1 histamine receptor

Location of the receptor

Signaling pathway

Drugs that target the H1 histamine receptor

Diseases and treatments


Crystallized structure of the H1 histamine receptor



Mechanism Overview


Gq signaling pathway

Signals through Gaq protein pathwayGaq protein activate PLC PLC then cleaves PIP2 into DAG and IP3IP3 then diffuse through the cytosol to bind to IP3 receptors in cytosolAllow calcium through Channels


Mechanism overview


Downstream effects of Histamine- Smooth Muscle Contraction


Downstream effects of Histamine-Neural activity

Histaminergic neuron


Drugs Targeting H1 Histamine Receptor

Histamine receptors are extremely important in mediating allergic reactions, thus drugs targeting H1 histamine receptors are involved in treating allergies

These drugs are known as H1 anti-histamines

1st generation

→ sedating



Diphenhydramine (Benadryl)

2nd generation

→ non-sedating

Loratadine (Claritin)

Cetirizine (Zyrtec)

3rd generation

→ active metabolites of 2nd generation parent drugs

Fexofenadine (Allegra)


H1 Anti-histamine Mechanism

2 Mechanisms:

Acts as

inverse agonists

by binding with the H1 Histamine receptor and stabilizing the inactive form

Inverse agonist because it prevents constitutive activity of H1 Histamine receptor

Anti-histamines prevent allergic symptoms by preventing release of allergic reaction mediators from basophils and mast cells through inhibiting Calcium Channels

Helps prevent hives + itching + rhinitis + other allergy symptoms


H1 Anti-histamine Mechanism

Choi, Y. S., Park, Y. M., Rha, Y. H., & Choi, S. H. (2013). An overview and considerations in prescribing H1-antihistamine. Journal of the Korean Medical Association, 56(3), 231-239.


Side Effects of H1-antihistamines

Cardiac Effects:

Older H1-antihistamines cause

arrhythmias and prolonged QT intervals

due to inhibition of

HERG1 K+ channels

in heart

Terfenadine and Astemizole

have been taken off the market

CNS Effects:

1st generation: Drowsiness

In the brain, histamine receptors are involved in

sleep-wake cycle and memory formation

Since 1st generation H1-antihistamines are highly lipophilic, they can cross the BBB

Block histamine receptors in the brain which causes

drowsiness, fatigue, and impaired memory

Other sites:

Block muscarinic, alpha-adrenergic, and serotonin receptors

Pupillary dilation, dry eyes, dry mouth, peripheral vasodilation


H1 Antihistamines for Motion Sickness

H1 Histamine receptors located at the

emetic center of brain H1 Antihistamines can be used to decrease severity of motion sickness symptoms such as vomiting and nauseaBlocks the final processes in motion sicknessPrevents histaminergic signals from reaching emetic centerExamples:Dimenhydrinate (Gravol)Meclizine Cyclizine

Takeda, N., Morita, M., Hasegawa, S., Horii, A., Kubo, T., & Matsunaga, T. (1993). Neuropharmacology of motion sickness and emesis: a review.

Acta Oto-Laryngologica



(sup501), 10-15.


Diseases + Possible Treatments

•Examples: Allergic Rhinitis and Asthma•Allergic rhinitisO Inflammation => nasal mucosa•Mechanism:Increased number of H1 receptors => nasal mucosaO Increased levels of H1R mRNA (in allergic rhinitis patients)Higher responsiveness to histamine by H1 receptorsO Lower concentration of histamine (required => immune responses)

(Iriyoshi, Takeuchi, Yuta, Ukai, Sakakura,1996)


Diseases + Possible Treatments

•Allergic Rhinitis-Immune responsesO Nasal mucosaO Allergen (eg. Pollen) => IgE antibody (mast cells and basophils) => histamine => H1 receptors => immune responsesO Symptoms: sneezing, vasodilation, swelling, rhinorrhea (running nose)•Allergic Rhinitis-TreatmentsO Mechanism of Action: Block H1 receptorsDrug Examples:O Cetirizine (Zyrtec); Azelastine (Astelin)



Summary Slide

H1 histamine receptor is a GPCR protein (metabotropic)

Phosphate group and tryptophan at active site important for ligand - receptor interaction

H1 receptor primarily found in smooth muscle, endothelial cells, the CNS, and the Heart

H1 histamine receptor mediates the cellular effects of histamine Gq signaling cascade. Gq pathways increases intracellular Ca2+ level and NF-KB pathways

Downstream effects of histamine (1) smooth muscle cell contraction due to increased intracellular Ca2+ (2)increased neural activity via histaminergic neurons in hypothalamus


Summary continued

Drugs Targeting H1 Histamine Receptor

H1-antihistamines are inverse agonists used to treat allergies and motion sickness



generation (sedating), 2


generation (non-sedating), “3


generation” (2


generation active metabolites)


Bind to and stabilize inactive form of the histamine receptor → decreased DAG, IP3, PKC → decreased Nuclear Factor KappaB (transcription factor involved in inflammation) + intracellular calcium release (inhibits allergic mediator release)

Side effects


Arrhythmias and prolonged QT intervals due to inhibition of HERG1 K+ channels in heart. In CNS, ability of 1


generation to cross BBB leads to drowsiness, fatigue, and impaired memory formation. Also acts on muscarinic, serotonin, and alpha adrenergic receptors to produce side-effects of dry mouth, dry eyes, peripheral vasodilation, dilation of pupils

Treats motion sickness by inhibiting histaminergic signals from reaching emetic center of brain, leading to decreased vomiting and nausea

Diseases associated with H1 histamine receptor => examples: allergic rhinitis and asthma



Iriyoshi, N., Takeuchi, K., Yuta, A., Ukai, K., & Sakakura, Y. (1996). Increased expression of histamine H1 receptor mRNA in allergic rhinitis. Clin Exp Allergy Clinical Experimental Allergy, 26(4), 379-385. doi:10.1046/j.1365-2222.1996.d01-323.x

Centanni, S., & Santus, P. (2003). The Role of Antihistamine Drugs in Allergic Disorders. Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents CMCAIAA, 2(3), 284-295. doi:10.2174/1568014033483743

Mizuguchi, H., Das, A. K., Maeyama, K., Dev, S., Shahriar, M., Kitamura, Y., . . . Fukui, H. (2016). Antihistamines suppress upregulation of histidine decarboxylase gene expression with potencies different from their binding affinities for histamine H1 receptor in toluene 2,4-diisocyanate-sensitized rats. Journal of Pharmacological Sciences, 130(4), 212-218. doi:10.1016/j.jphs.2016.02.002

Gq mechanism: G protein coupled receptors

[Video file]. (2013, September 4). In

. Retrieved November 17, 2016, from


References cont’d

Leurs, R., Church, M. K., & Taglialatela, M. (2002). H1

antihistamines: inverse agonism, anti

inflammatory actions and cardiac effects.

Clinical & Experimental Allergy



(4), 489-498.

Church, M. K., & Church, D. S. (2013). Pharmacology of antihistamines.

Indian journal of dermatology



(3), 219.

Baroody, F. M., & Naclerio, R. M. (2000). Antiallergic effects of H1

receptor antagonists.




(s64), 17-27.

Simon, F. E. R., & Simons, K. J. (2008). H 1 antihistamines: Current status and future directions.

World Allergy Organization Journal



(9), 1.

Bakker, R. A., Schoonus, S. B., Smit, M. J., Timmerman, H., & Leurs, R. (2001). Histamine H1-receptor activation of nuclear factor-κB: roles for Gβγ-and Gαq/11-subunits in constitutive and agonist-mediated signaling.

Molecular pharmacology



(5), 1133-1142.

Simons, F. E. R., & Simons, K. J. (1994). The pharmacology and use of H1-receptor-antagonist drugs.

New England Journal of Medicine



(23), 1663-1670.

Simons, F. E. R. (2004). Advances in H1-Antihistamines.

N Engl J Med



, 2203-17.

Takeda, N., Morita, M., Hasegawa, S., Horii, A., Kubo, T., & Matsunaga, T. (1993). Neuropharmacology of motion sickness and emesis: a review.

Acta Oto-Laryngologica



(sup501), 10-15.






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