Biosynthesis of Histamine,Storage and release,Histamine H1-Receptor ,Histamine H1-Receptor Antagonists,Differences between first generation & second generation antihistamines,H2 receptor blockers

2. Katzung, Bertram G., Susan B. Masters, and Anthony J. Trevor. Basic & Clinical
Pharmacology. 12th ed. New York: McGraw-Hill Medical, 2012.
Goodman, Louis S, Alfred Gilman, and Laurence L Brunton. Goodman & Gilman's Manual of
Pharmacology and Therapeutics. New York: McGraw-Hill Medical, 2008.
Remington, Joseph P. Remington, the Science and Practice of Pharmacy. Easton, Pa: Mack
Pub. Co., 1995.
Richard Finkel, Michelle A. Clark, Luigi X. Lippincott's Illustrated Reviews: Pharmacology.
6th ed. Baltimore, MD; New Delhi: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2012.
H P Rang, M M Dale, J M Ritter, R J Flower, G Henderson RANG AND DALE’S
Pharmacology. 7th ed. Elsevier Inc. 2007.
Ashutosh Kar. Medicinal Chemistry. 4th ed. New Delhi: New Age International, 2007.

3. Histamine is synthesized in cytoplasmic granules
of its principal storage cells (mast cells & basophil)
from naturally occurring amino acid S-histidine via
catalysis of pyridoxal phosphate dependant
histidine decarboxylase.

4. Allergies and anaphylaxis can also trigger significant release of histamine, where histamine
release is initiated by the interaction of an antigen-antibody (IgE) complex with the membrane
of a histamine storage cell.
Exocytotic release of histamine follows the degranulation of the storage cell.
Histamine is released from mast cells in the gastric mucosa by gastrin & acetylcholine.
Most histamine is synthesized & stored in mast cells
& basophils.
Histamine is also stored in selected neuronal tracts
in the CNS.
Protein-complexed histamine is stored in secretory
granules & released by exocytosis in response to a
wide variety of immune & non-immune stimuli.
The stimuli for release of histamine from tissues may
include destruction of cells as a result of cold, toxins
from organisms, venoms from insects and spiders,
and trauma.

5. Four different histamine receptors have been characterized and are designated H1 –H4 all of
which are G protein-coupled receptors. These different receptors are expressed on different
cell types and work through different intracellular signalling mechanisms, which explain, at
least at a simple level, the diverse effects of histamine in different cells and tissues.
Receptor
Type
Major Tissue Locations Major Biologic Effects
H1
Smooth muscle, Endothelial cells and Nerve
endings.
Acute allergic responses,
vasodilatation, Contraction of most
smooth muscle, except blood vessels.
H2
Gastric parietal cells (gastric mucosa), Cardiac
muscle cells, Mast cells and Brain.
Stimulation of gastric secretion.
H3
Central nervous system (Presynaptic autoreceptors
and heteroreceptors)
Modulating neurotransmission
H4
Intestinal tissue, Spleen, Thymus & Immune active
cells such as- T cells, Neutrophils, Eosinophils.
Regulating immune responses

6. The term antihistamine historically has referred to drugs that antagonize the actions
of histamine at H1-receptors. The H1-antagonists are now commonly subdivided into
two broad groups - the first generation or classical antihistamines and the
second generation or “non-sedating” antihistamines – based primarily on their
general pharmacological profiles.
The first generation or classical antihistamines are related structurally and include a
number of aminoalkyl ethers, ethylenediamines, piperazines, propylamines,
phenothiazines and dibenzocycloheptenes. In addition to H1-receptor antagonism,
these compounds display an array of other pharmacological activities which
contribute toward therapeutic applications and adverse reactions. More recently, a
number of second generation or “non-sedating” antihistamines have been developed
and introduced. The second generation agents bear some structural resemblance to
the first generation agents, but have been modified to be more specific in action and
limited in their distribution profiles.

7. (i) Aminoalkylethers : Examples-Diphenhydramine
Hydrochloride ; Bromodiphenhydramine Hydrochloride ;
Dimenhydrinate ; Doxylamine Succinate ;
Diphenylpyraline Hydrochloride.
(ii) Ethylenediamines : Examples-Mepyramine Maleate
; Tripelennamine Hydrochloride, Thonzylamine
Hydrochloride ; Zolamine Hydrochloride.
(iii) Thiophene Derivatives: Examples-Methapyrilene
Hydrochloride; Methaphenilene Hydrochloride,
Thenyldiamine Hydrochloride; Chlorothen Citrate.
(iv) Alkylamine derivative: Chlorpheniramine
Maleate

8. (v) Cyclic Basic Chain Analogues: Examples-
(a) Imidazoline Derivatives, e.g., Antazoline Hydrochloride
(b) Piperazine Derivatives, e.g., Cyclizine Hydrochloride ;
Chlorcyclizine Hydrochloride ; Meclizine Hydrochloride ;
Buclizine Hydrochloride ;
(c) Piperidine Derivativs, e.g., Thenalidine Tartrate.
(vi) Phenothiazine Derivatives: Examples-Promethazine
Hydrochoride ; Promethazine Teoclate ; Trimeprazine
Tartrate ; Methdilazine Hydrochloride.
(vii) Second-generation Non-Sedating Antihistamines:
Examples: Terfenadine ; Astemizole ; Loratadine ;
Acrivastine ;Fexofenadine
(viii) Miscellaneous Agents: Examples-Phenindamine
Tartrate; Triprolidine Hydrochloride;
Cyproheptadine Hydrochloride.

9. The diaryl substitution pattern is present in both
the first and second generation antihistamines
and is essential for significant H1-receptor
affinity. Most H1-antagonists contain substituents
in one of the aryl rings (usually benzene), and
these influence antihistamine potency, as well as
bio disposition.
In many of the first generation antihistamines the terminal nitrogen atom is a simple dimethyl
amino moiety. However, the amine may also be part of a heterocyclic structure, as illustrated by
the piperazine, some propylamines (pyrrolidines and piperdines), some phenothiazines, the
dibenzocycloheptenes and the second generation antihistamines. In all cases the amino moiety
is basic with pKas ranging from 8.5 to 10 and thus presumed to be protonated when bound on
the receptor.
X is a connecting atom of O, C or N. The X connecting moiety of typical H1-antagonists may be a
saturated carbon-oxygen moiety or simply a carbon or nitrogen atom. This group along with the
carbon chain appears to serve primarily as a spacer group for the key pharmacophoric moieties.

10. Many of the anthistamines containing a carbon
atom in the connecting moiety are chiral, and
exhibit stereoselective receptor binding. For
example, in the pheniramine series and
carbinoxamine, this atom is chiral and in vitro
analysis indicates that those enantiomers with the
S-configuration have higher H1-receptor affinity.
The (CH2)n group and connecting atom results in a distance between the central point of the
diaryl ring system and the terminal nitrogen atom in the extended conformation of the
antihistamines ranging from 5 to 6 angstroms (a "spacer" group). In some series branching of the
carbon chain results in a reduction of antihistaminic activity. However, there are exceptions as
evidence by promethazine which has a greater activity than its non-branched counterpart.
When the carbon adjacent to the terminal nitrogen atom is branched, the possibility of asymmetry
exists. However, stereoselective H1-receptor antagonism typically is not observed when chirality
exists at this site. Also, in those compounds which possess an asymmetrically substituted
unsaturated carbon chain (pyrrobutamine and triprolidine) one geometric isomer typically displays
higher receptor affinity than the other.

11. Generally, the first and second generation anthistamines are substantially more lipophilic than the
endogenous agonist histamine (or the H2-antagonists). This lipophilicity difference results
primarily from the presence of the two aryl rings, and the substituted amino moieties, and thus
may simply reflect the different structural requirements for antagonist versus agonist action at
H1-receptors.
Features
First generation
H1 receptor blocker
Second generation
H1 receptor blocker
Daily Doses Usually three to four daily doses Usually once or twice a day
Blood-brain
barrier
Cross the BBB Don’t cross the BBB
Side effects Potentially occurs Do not cause relevant side effects
Common side
effects
sedation/hyperactivity/insomnia/
convulsions
sedation/fatigue/hyperactivity/
convulsions
Toxicity Case reports regularly published No reports of serious toxicity
Lethal dose
Lethal dose identified for infants/young
children
Do not cause fatality in overdose

12. Gastric acid is secreted from parietal cells
located mainly in the upper portion of the
stomach and is stimulated by three
endogenous substances: gastrin, acetylch
oline, and histamine. The parietal cell
contains receptors for gastrin, acetylcholine
(muscarinic, M3), and histamine (H2). When
acetylcholine or gastrin binds to the parietal
cell receptors, they cause an increase in
cytosolic calcium, which in turn stimulates
protein kinases that stimulate acid secretion
from an H+/K+ ATPase (the proton
pump) on the canalicular surface

13. In close proximity to the parietal cells are gut endocrine cells called
enterochromaffin-like (ECL) cells. ECL cells have receptors for gastrin and
acetylcholine. It is thought that gastrin and acetylcholine act on ECL cells to
release histamine. Histamine then binds to the H2 receptor on the parietal cell,
resulting in activation of adenylyl cyclase, which increases intracellular cyclic
adenosine monophosphate (cAMP), cAMP activates protein kinases that stimulate acid
secretion by the H+/K+ ATPase.
Figure: Schematic diagram of one model of the
physiologic control of hydrogen Ion secretion by
the gastric parietal cell. EC cell, enterochromaffin-
like cell; G(CCK-B>, gastrih-chdlecystokinin-B
receptor; H, histamine; H2. histamine Ha receptor;
M1, M3, muscarinic receptors; ST2 somatostatin
receptor; ATPase,Kf/Ht ATPase proton pump.
Some investigators place histamine receptors—and
possibly cholinoceptors—on nearby tissue cells
rather than on the parietal cell Itself.
(Modified and redrawn from Sachs 6,Prinz C:Gast
ric enterochromaffin-like cells and the regulation of
acid secret.on.News Physiol Set 1996eU:S7,and ot
her sources)

14. The H2 receptor antagonists in
clinical use are histamine congeners
that contain a bulky side chain in
place of the ethylamine moiety.
Early representatives of the group,
such as burimamide and cimetidine
(the first compound released for
general use) retain the imidazole
ring of histamine. This ring is
replaced in more recently developed
compounds by a furan (ranitidine) or
a thiazole (famotidine, nizatidine).
HN N
CH2CH2NH2
Histamine
HN N
H2
CH3C
S
H2
C
C
H2
H
N C NH CH3
N C N
Cimetidine
O
H2CN
H3C
H3C
H2
C
S
H2
C
C
H2
H
N
C
H
N
CH3
CH NO2
Ranitidine
N
S
N
H2
C
S
H2
C
C
H2
Famotidine
C
H2N
H2N
C
N SO2NH2
NH2

15. The H2 receptor antagonists exhibit competitive inhibition at the parietal cell
H2 receptor, and suppress basal (fasting), nocturnal and meal stimulated acid
secretion in a linear dose-dependent manner. They are highly selective and
do not affect H1 or H3 receptors
H2 antagonists reduce acid secretion stimulated by histamine as well as by
gastrin and cholinomimetic agents through two mechanisms:
First, histamine released from ECL cells by gastrin or vagal stimulation is
blocked from binding to the parietal cell H2 receptor.
Second, direct stimulation of the parietal cell by gastrin or acetylcholine
results in diminished acid secretion in the presence of H2 receptor blockade.
It appears that reduced parietal cell cAMP levels attenuate the intracellular
activation of protein kinases by gastrin or acetylcholine.