Jack DeRuiter, Principles of Drug Action 2, Fall 2001

HISTAMINE INTRODUCTION
I. Introduction
Histamine is an imidazolylethylamine derivative that is present in essentially all mammalian
tissues. The major physiological actions of histamine are centered on the cardiovascular system,
nonvascular smooth muscle, exocrine glands and the adrenal medulla. In a general sense, histamine
plays an important role as a chemical messenger component of the various pathways that have
evolved in multicellular organisms allowing them to communicate efficiently and effectively. The
involvement of histamine in the mediation of allergic and hypersensitivity reactions as well as in the
regulation of gastric acid secretion has led to the development of important drug classes useful in
the treatment of symptoms associated with allergic and gastric hypersecretory disorders.
Histamine exhibits a wide variety of both physiologic and pathologic functions in different tissues
and cells as described in the Pharmacology Notes. The actions of histamine that are of interest from
both a pharmacologic and therapeutic point of view include (1) its important but limited role as a
chemical mediator of hypersensitivity reactions, (2) a major role in the regulation of gastric acid
secretion and (3) an emerging role as a neurotransmitter in the CNS.
II. Histamine Chemistry and Stereochemistry
Histamine, known trivially as 4(5-)(2-aminoethyl)-imidazole, consists of an imidazole heterocycle
and ethylamine side chain. The methylene groups of the aminoethyl side chain are designated as a
and b. The side chain is attached, via the -CH2 group, to the 4-position of an imidazole ring. The
imidazole N at position 3 is designated as the pros () N whereas the N at position 1 is termed the
tele () N. The side chain N is distinguished as N.

H N
1

NH2

4
N

2
N tautomer

NH2

N H

Ntautomer

Histamine is a basic organic compound (N, pKa1=5.80; N, pKa2=9.40 and N, pKa3=14.0) capable
of existing as a mixture of different ionic and uncharged tautomeric species as shown in the Figure
below. Histamine has been found to exist almost exclusively (96.6%) as the monocationic conjugate
species (N as NH3+) at physiologic pH (7.4). The ratio of the concentrations of the tautomers NH/ N-H has been calculated to be 4.2 indicating that in aqueous solution 80% of the histamine
monocation exists as N-H and 20% as N-H.
Structure-activity relationship studies suggest that the NH3+ monocation is important for
agonist activity at histamine receptors and that transient existence of the more lipophilic uncharged
histamine species may contribute to translocation of cell membranes. Other studies support the
1

Jack DeRuiter, Principles of Drug Action 2, Fall 2001

proposal that the N-H tautomer of the histamine monocation is the pharmacophoric species at the
H1-receptor while a 1,3-tautomer system is important for selective H2-receptor agonism.

NH3

N H
Dication

NH3

H N

NH3

N H

N
-Tautomer (Monocation)

N-Tautomer (Monocation)

NH2

H N

NH2

N H

NH2

Histamine is an achiral molecule, however, histamine receptors are known to exert a high degree
of stereoselectivity toward chiral ligands. Molecular modeling and steric-activity relationship studies
of the influence of conformational isomerism on the activity of histamine suggest the importance of
trans-gauche rotameric structures in the receptor activities of this substance. Studies with
conformationally-restricted histamine analogues suggest that, while the trans rotamer of histamine
possesses affinity for both H1 and H2-histamine receptors, the gauche conformer does not act at H2sites.

Jack DeRuiter, Principles of Drug Action 2, Fall 2001

H

N
N

N
H

H
H

H3N

H
H

H
H

NH3
trans

gauche

III. Histamine Biosynthesis, Storage, Release and Metabolism

Knowledge of the biodisposition of histamine is important to understanding the involvement of this
substance in various pathophysiologies as well as the actions of various ligands that either enhance
or block the actions of histamine. Each of the steps in the life cycle of histamine represents a
potential site for pharmacological intervention.
Histamine is synthesized in cytoplasmic granules of its principle storage cells, mast cells and
basophils. Histamine is formed from the naturally-occurring amino acid, S-histidine via the catalysis
of either the pyridoxal phosphate-dependent enzyme histidine decarboxylase (HDC, EC 4.1.1.22)
or aromatic amino acid decarboxylase as shown below. Substrate specificity is higher for HDC.
Inhibitors of HDC include -fluoromethylhistidine (FMH) and certain flavanoids, however no
HDCIs have proved useful clinically.
NH2
COOH
H N

N
L-Histidine

NH2

Histidine
Decarboxylase
Pyridoxal Phosphate

H N

N
Histamine

Histamine is found in almost all mammalian tissues in concentrations ranging from 1 to >100 mg/g.
This substance is in particularly high concentration in skin, bronchial and intestinal mucosa. It is
found in higher concentrations in mammalian cerebrospinal fluid than in plasma and other body
fluids.
Most histamine is synthesized and stored in mast cells and basophil granulocytes. Proteincomplexed histamine is then stored in secretory granules and released by exocytosis in response to
a wide variety of immune (antigen and antibody) and non-immune (bacterial products, xenobiotics,
physical effects and cholinergic effects) stimuli. The release of histamine as one of the mediators
of hypersensitivity reactions is initiated by the interaction of an antigen-IgE complex with the
membrane of a histamine-storage cell. This interaction triggers activation of intracellular
phosphokinase C (PKC) and accumulation of inositol phosphates, diacylglycerols and Ca++.
Exocytotic release of histamine follows the degranulation of histamine storage cells. Histamine is

Jack DeRuiter, Principles of Drug Action 2, Fall 2001

released from mast cells in the gastric mucosa by gastrin and acetylcholine. Neurochemical studies
also suggest that histamine is stored in selected neuronal tracts in the CNS.

Jack DeRuiter, Principles of Drug Action 2, Fall 2001

Histamine Metabolism
NH2

H N

N
Histamine

DAO

N-Methyltransferase
H

NH2

O
H N

CH3

Imidazoleacetaldehyde

N-Methyl-Histamine

Aldehyde
Dehydrogenase

DAO and MAO

H

OH

O
H N

CH3

N-Methyl-Imidazoleacetaldehyde

Imidazoleacetic Acid

Aldehyde
Dehydrogenase

Ribosyl
Transferase
OH
HO

OH

O
O

OH

OH

O
CH3

N-Acetyl-Imidazoleacetic Acid

N-Ribosyl-Imidazoleacetic Acid

Three principle ways exist for terminating the physiological effects of histamine. Cellular
uptake: Na+-dependent process in rabbit gastric glands and the histamine is metabolized once in the
cell. Desensitization of cells; some H1-receptor-containing tissues exhibit a homogeneous loss of
sensitivity to the actions of histamine perhaps as a result of receptor modification. Metabolism, the
most common pathway for terminating histamine action, involves enzymatic inactivation. The
enzyme histamine N-methyltransferase (HMT, EC 2.1.1.8) is widely and ubiquitously distributed
among mammalian tissues and catalyzes the transfer of a methyl group from S-adenosyl-Lmethionine (SAM) to the ring N-nitrogen of histamine producing N-methylhistamine and S5

Jack DeRuiter, Principles of Drug Action 2, Fall 2001

adenosyl-L-homocysteine. Histamine is also subject to oxidative deamination by diamine oxidase
(DAO, EC 1.4.3.6) yielding imidazole acetic acid, a physiologically inactive product, excreted in the
urine. Similarly, N-methylhistamine is converted by both DAO and monoamine oxidase (MAO)
to N-methyl imidazole acetic acid. These metabolites may also be conjugated with ribose. These
pathways are summarized on the previous page.
IV. Histamine receptors
Once released, the physiological effects of histamine are mediated by specific cell-surface
receptors. Extensive pharmacological analysis suggests the existence of three different histaminereceptor subtypes, H1, H2 and H3. Histamine H1-receptors mediate smooth muscle contraction,
increased vascular permeability, pruritus, prostaglandin generation, decreased atrioventricular
conduction time accompanied by tachycardia and activation of vagal reflexes. Histamine H1receptors are Gq/11-proteinlinked receptors which, when activated, give stimualte phospholipase C
(PLC) resulting in a rise intracellularly to the second messengers inositol triphosphate (IP3) and
diacylglcerol (DAG). These actions result in increased intraceulluar calcium and protein kinse C
activities. The structure of the H1-receptor has been determined and shown to display several
important features that distinguish it from the H2-receptor.8 The H1-receptor contains seven
hydrophobic transmembrane domains (TMs) characteristic of most G-protein receptors. Analysis
of the primary structure of this receptor indicates the presence threonine and asparagine residues in
TM5 proposed to serve as the histamine-imidazole binding site and an aspartate reside in TM3
thought to interact ionically with the histamine NH3+ monocation. A structural requirement for
H1-receptor agonism is the presence of an aromatic nitrogen with a nonbonded pair of elections
oriented a to the point of attachment of the ethylamine side chain, i.e, N in the case of histamine.
NH3

H N

OOCAsp

HOThr

(Asn)
H1 Receptor
H2-receptors are located on the cell membrane of acid-secreting cells (parietal) of the gastric
mucosa and mediate the gastric acid secretory actions of histamine. The physiologic and
pharmacologic effects of H2-receptor ligands are mediated by a stimulatory Gs-protein coupled
receptor which, in turn, activates the adenylate cyclase/cyclic adenosine monophosphate (AMP)
intracellular second messenger system. The H2-receptor has been cloned and, similar to the H1-site,
found to consist of seven hydrophobic TMs. Examination of the primary structure of the H2-receptor
has led to the proposal that an aspartate residue in TM3 is the primary biding site for the cationic
nitrogen of histamine and that a threonine and an aspartate residue in TM5 may be important for
hydrogen bonding with the nitrogen atoms of the imidazole ring of histamine. It has been further
proposed that tautomerism of the imidazole ring of histamine or isosteric structural features of other

Jack DeRuiter, Principles of Drug Action 2, Fall 2001

H2-agonists is an important component of the ability of agonist ligands to activate this receptor
system as shown below:
NH3

NH3
Tautomerism
B

H N

H A

B H

H2 Receptor

N H

H2 Receptor

The most recently described receptor for histamine, the H3-receptor, is proposed to function as
a neural autoreceptor (presynaptic) serving to modulate histamine synthesis and release in the CNS.
Subsequent studies have also located H3-sites in peripheral tissue including the gastric mucosa where
this receptor may negatively control gastric acid secretion and on the cardiac sympathetic terminals
in the myocardium. Isolation and characterization of the H3-receptor protein as well as identification
of transmembrane signaling are just beginning. It appears this receptor is linked to G proteins that
may be coupled to adenylate cyclase and inhibit this enzyme resulting in decreased cyclic AMP
levels and decreased histamine release.
V. Inhibitors of Histamine Release
The discovery of the bronchodilating activity of the natural product khellin led to the
development of the bis(chromones) as compounds that inhibit the release of histamine and other
mediators of inflammation. The first therapeutically significant member of this class was cromolyn
sodium. Further research targeting more effective agents resulting in the introduction of nedocromil
more recently. The structures, chemical properties and pharmacologic profiles are provided in the
monographs that follow.
OCH3
CH3

OCH3
Khellin

Cromolyn Sodium, USP. Disodium 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane

(Intal). The pKa of cromolyn is 2.0. Cromolyn belongs to a completely novel class of
compounds and bears no structural relationship to other commonly used antiasthmatic
compounds. Unlike its naturally occurring predecessor (khellin), cromolyn is not a
smooth-muscle relaxant or a bronchodilator. It has no intrinsic bronchodilator,
antihistaminic, or antiinflammatory action.

Jack DeRuiter, Principles of Drug Action 2, Fall 2001

Cromolyn inhibits release of histamine, leukotrienes, and other potent substances from mast cells
during allergic responses. Apparently, its action is on the mast cell after the sensitization stage
but before the antigen challenge. It does not seem to interfere with the antigen-antibody reaction,
but it seems to suppress the responses to this reaction.
Na+OOC

OCH2CHCH2O

COO -Na+

OH
Cromolyn Sodium

Although growing evidence indicates that the mechanism of action is not all mast cell related,
the benefits of the drug in asthma are exclusively prophylactic. It is of no value after an asthmatic
attack has begun (status asthmaticus). Cromolyn is also indicated for the prevention and
treatment of the symptoms of allergic rhinitis. In order for cromolyn to be effective it must be
administered at least 30 minutes prior to antigen challenge, and administered at regular intervals
(see dosing information below). Overuse of cromolyn results in tolerance. It is not orally
effective.

Nedocromil Sodium, USP. Disodium 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2g]quinoline-2,8-dicarboxylate (Tilade).

Nedocromil is structurally related to cromolyn and displays similar, but broader

pharmacological actions. This drug prevents the release of inflammatory, chemotactic and
smooth muscle contracting mediators from the inflammatory cells implicated in asthma
including neutrophils, eosinophils, monocytes, platelets and mast cells. Nedocromil also
suppresses neuronal reflexes, including C-fiber response in the lung implicated with
bronchoconstriction and blocks the immunologic and non-immunologic activation of mast
cells. As a result of these actions, this drug inhibits not only the acute bronchoconstrictor
response to inhaled irritants, but also the delayed asthmatic or inflammatory response. The
superiority of nedocromil over cromolyn in the treatment of asthma has been established in
a number of comparative clinical trials.
CH3CH2
+

Na OOC

CH2CH2CH3

COO Na

Nedocromil sodium