Antihistamines and Autacoids

LECTURE NO-10
UNIT- I 10 Hours
Antihistaminic agents and autacoids
a) Antihistaminic agents: Histamine, receptors and their distribution in the human body
b) H1-antagonists: Diphenhydramine hydrochloride, Dimenhydrinate, Doxylamine ssuccinate,
Clemastine fumarate, Tripelenamine hydrochloride, Chlorcyclizine hydrochloride, Meclizine
hydrochloride, Buclizine hydrochloride, Chlorpheniramine maleate, Triprolidine hydrochloride,
Phenindamine tartarate, Promethazine hydrochloride, Trimeprazine tartrate, Fexofenadine, Astemizole,
Loratadine, Cetirizine, Cromolyn sodium
c) H2-antagonists: Cimetidine, Famotidine, Ranitidine
d) Gastric Proton pump inhibitors: Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole
e) Autacoids: Prostaglandins, Prostanoids, Leucotriene antagonists
[Diphenhydramine hydrochloride, Cetirizine, Promethazine hydrochloride, Ranitidine]
Antihistaminic agents S D Magar PRCOP
October 14, 2021 1

Antihistaminic agents and autacoids
MC2.pdf
Antihistaminic agents S D Magar
PRCOP
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• .
N N
NH2
H
1
2
3
4
5
Histamine
Sir Henry Dale,
discovered histamine
2-Imidazole-4-yl-ethylamine

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 Histamine is biogenic amine involved in a local immune response
as well as regulating physiological function in the gut and acting as
neurotransmitter.
 Biosynthesis- histamine synthesized in golgi apparatus of mast cell
and basophiles. histamine is derived from histidine by enzyme L-
histidine decarboxylase.
Histidine histamine
N
H
N
N
H2
OH
O
L-histidine
decarboxylase

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Metabolism: it is metabolised by N -methylation and oxidation.
 Histamine exist in equilibrium mixture of tautomeric cation at
physiological pH.
 Histamine exist in dication form and in monocation form .
 Mostly exist in monocation form at physiological pH.
N
N
H
NH2
NH
N
NH2
+ +

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Receptor
The Binding site of Drug “Which is ultimately responsible for the
biological effect” is known as Receptor
Receptors are mostly membrane-bound proteins that interact
with ligands (small molecules)
Introduction
Receptor Drug interaction

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There are four types of histamine receptors
1. H1 histamine receptor

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Location-The histamine H1 receptor has been reported
to be expressed in brain, kidney, lung, nasal cavity,
placenta, skeletal and smooth muscle, and vessel
H1 receptor:
http://en.wikipedia.org/wiki/Histamine

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Function-
 Mediate smooth muscle contraction ,increase vascular
permiability,prostaglandin generation, decrease atrioventricular
conduction time accompanied by tachycardia and activation of
vagal refluxes.
 H1 when activated give rise intracellularly two second messengers
inositol triphosphate(IP3) and diacyl glycerol.
H1 receptor contain seven hydrophobic transmembrane domain
(TMS) characteristic of most G-PCRS.
Antagonist-
 Diphenhydramine
 Loratadine
 Cetrizine

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H2 receptor:
Location:
 Located on parietal cells
Function:
 Primarily stimulate gastric acid secretion .
 Smooth muscle relaxation.
 Speed up sinus rhythum.
 Inhibit antibody synthesis, T-cell proliferation and cytokines
production.
Antagonist:
 Ranitidine
 Cimetidine

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Figure: H3 Receptor 3D Homology
H3 receptor
www.cnsforum.com

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Location:
 Located in peripheral tissues, including gastric mucosa
Function:
 Decreases neurotransmitter release like Histamine, Ach,
Norepinephrine, Serotonin.
Antagonist:
 Thioperamide
 Ciproxifan

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H4 receptor:
Location:
 Found primarily in the thymus, small intestine, spleen and
colon also found in basophiles and in the bone marrow.
http://en.wikipedia.org/wiki/Histamine

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Structure is similar to H1 receptor (G-PCR)
Function:
 No physiological role.
 It is activated not only by histamine but also
R-(alpha) methyl histamine (H3 agonist)
Clonazepine (neuroleptic)
Antagonist:
 Thioperamide

CLASSIFICATION OF ANTIHISTAMINES
a) H1-antagonists: Diphenhydramine hydrochloride, Dimenhydrinate,
Doxylamine ssuccinate, Clemastine fumarate, Tripelenamine hydrochloride,
Chlorcyclizine hydrochloride, Meclizine hydrochloride, Buclizine hydrochloride,
Chlorpheniramine maleate, Triprolidine hydrochloride, Phenindamine tartarate,
Promethazine hydrochloride, Trimeprazine tartrate, Fexofenadine, Astemizole,
Loratadine, Cetirizine, Cromolyn sodium
b) H2-antagonists: Cimetidine, Famotidine, Ranitidine
c) Gastric Proton pump inhibitors: Omeprazole, Lansoprazole, Rabeprazole,
Pantoprazole
d) Autacoids: Prostaglandins, Prostanoids, Leucotriene antagonists
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H1 Antagonist
• Promethazine hydrochloride
Promethazine Hydrochloride is the hydrochloride salt form of promethazine, a phenothiazine
derivative with antihistaminic, sedative and antiemetic properties.
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N,N-dimethyl-1-phenothiazin-10-ylpropan-2-amine;hydrochloride
C17H21ClN2S
Mol Wt-
320.9

• Mechanism of Action
Promethazine hydrochloride selectively blocks peripheral H1 receptors thereby diminishing the effects
of histamine on effector cells. Promethazine hydrochloride also blocks the central histaminergic receptors,
thereby depressing the reticular system causing sedative and hypnotic effects. In addition, promethazine
hydrochloride also has centrally acting anticholinergic properties and probably mediates nausea and
vomiting by acting on the medullary chemoreceptive trigger zone.
Properties
Promethazine hydrochloride is an odorless white to faint yellow crystalline powder. Bitter taste. A 10%
solution in water has a pH of 3.5-5.0.
Uses
October 14, 2021 Antihistaminic agents S D Magar PRCOP
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Promethazine hydrochloride is the hydrochloride salt of promethazine It has a role as an antipruritic
drug, a H1-receptor antagonist, a local anaesthetic, an antiemetic, a sedative, an anti-allergic agent and
an anti corona viral agent.

H1 Antagonist
• Trimeprazine tartrate
October 14, 2021 Antihistaminic agents S D Magar PRCOP 18
(2R,3R)-2,3-dihydroxybutanedioic acid;N,N,2-trimethyl-3-phenothiazin-10-ylpropan-1-amine
Molecular
Formula
C40H50N4O6S2
Molecular
Weight
747.0

Drugs that selectively bind to but do not activate histamine H1 receptors, thereby blocking the actions
of endogenous histamine. Included here are the classical antihistaminics that antagonize or prevent
the action of histamine mainly in immediate hypersensitivity. They act in the bronchi, capillaries, and
some other smooth muscles,
Mechanism of Action
used to prevent or allay motion sickness, seasonal rhinitis, and allergic dermatitis and to induce
somnolence.
Uses

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Fexofenadine
H1 Antagonist
Fexofenadine is a second generation, long-lasting selective histamine H1 receptor antagonist with anti-
inflammatory property.
2-[4-[1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butyl]phenyl]-2-methylpropanoic acid
Molecular
Formula
C32H39NO4
Molecular
Weight
501.7

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Mechanism of Action
Fexofenadine is a highly selective and reversible competitor at peripheral H1 histamine receptors in the
gastrointestinal (GI) tract, blood vessels, and bronchial smooth muscle. This agent interferes with
mediators release from mast cells either by inhibiting calcium ion influx across mast cell/basophil plasma
membrane or by inhibiting intracellular calcium ion release within the cells. In addition fexofenadine may
also inhibit the late-phase allergic reaction by acting on leukotrienes or prostaglandins, or by producing
an anti-platelet activating factor effect. Overall, this agent blocks the actions of endogenous histamine,
thereby leads to temporary relief of the negative symptoms associated with histamine and achieve effects
such as decreased vascular permeability, reduction of pruritus and localized smooth muscle relaxation.
Uses
Fexofenadine is a second generation antihistamine that is used for the treatment of allergic rhinitis,
angioedema and chronic urticaria. Fexofenadine has not been linked to serum enzyme elevations
during therapy or to instances of clinically apparent acute liver injury.
Symptoms of overdosage are consistent with fexofenadine's adverse effect profile and are likely to
include dizziness, drowsiness, and dry mouth.
Toxicity

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H1 Antagonist
Astemizole
Astemizole is a piperidine compound having a 2-(4-methoxyphenyl)ethyl group at the 1-position and an
N-[(4-fluorobenzyl)benzimidazol-2-yl]amino group at the 4-position. It has a role as a H1-receptor
antagonist, an anti-allergic agent and an anticoronaviral agent. It is a member of benzimidazoles and a
member of piperidines.
1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl]benzimidazol-2-amine
Molecular
Formula
C28H31FN4O
Molecular Weight 458.6

Astemizole is a synthetic piperidinyl-benzimidazol derivative with antiallergic properties, Astemizole
acts as a reversible competitive inhibitor of histamine H1 receptors, with less anticholinergic effects
compared to related agents. It is a long-acting, non-sedative antihistaminic used in the treatment of
seasonal allergic rhinitis, asthma, allergic conjunctivitis, and chronic idiopathic urticaria.
Mechanism of Action
Astemizole is a long-acting, non-sedating second generation antihistamine used in the treatment of
allergy symptoms.
Toxicity
It was withdrawn from market by the manufacturer in 1999 due to the potential to cause arrhythmias at
high doses, especially when taken with CYP inhibitors or grapefruit juice
Uses

Loratadine
H1 Antagonist
Molecular
Formula
C22H23ClN2O2
Molecular
Weight
382.9
ethyl 4-(13-chloro-4-azatricyclopentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene)piperidine-1-carboxylate

Loratadine is a piperidine histamine H1-receptor antagonist with anti-allergic properties and without sedative
effects. Loratadine blocks the H1 histamine receptor and prevents the symptoms that are caused by histamine
activity on capillaries, bronchial smooth muscle, and gastrointestinal smooth muscle, including vasodilatation,
increased capillary permeability, bronchoconstriction, and spasmodic contraction of gastrointestinal smooth
muscle. Loratadine does not cross the blood-brain barrier and does not cause central nervous system effects.

Autacoids: Prostaglandins, Prostanoids, Leucotriene antagonists.
[Diphenhydramine hydrochloride, Cetirizine, Promethazine hydrochloride, Ranitidine]

Prostanoid
Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators
of inflammatory and anaphylactic reactions), the thromboxanes (mediators
of vasoconstriction), and the prostacyclins (active in the resolution phase of inflammation.)
The prostanoids are part of the oxylipin family of biologically active lipids derived
from the action of cyclooxygenases or prostaglandin synthases upon the twenty-
carbon essential fatty acids or eicosanoids, primarily arachidonic acid.
They can be further subdivided by structure into two main groups, the
prostacyclopentanes, comprising the prostaglandins and prostacyclins, and
the thromboxanes with a 6-membered ether-containing ring, each of which is
involved in some aspect of signalling and especially the inflammatory response.

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The prostaglandins were first isolated from semen and named from the prostate gland,
thought to be their source, as long ago as the 1930s, but it was the 1960s before the
biosynthetic relationship to specific essential fatty acids was described and intensive
research into their biological properties began.
The Nobel Prize for Medicine for 1982 was awarded to Professors Bengt Samuelsson,
John Vane and Sune Bergström for their discoveries in this field (see Samuelsson, B.,
2012; DOI).
In general, prostaglandins occur at very low levels in tissues, of the order of
nanomolar concentrations, but they have profound biological activities as short-lived
autocrine and paracrine signalling molecules.
While most studies have been concerned with their occurrence and function in
mammals, they have also been detected in birds, ray-finned fishes, marine
invertebrates, trypanosomes, blood flukes, and some algae and yeasts.

Biosynthesis
Cyclooxygenase (COX) catalyzes the conversion of the free essential fatty acids to prostanoids by a two-
step process. In the first step, two molecules of O2 are added as two peroxide linkages and a 5-member
carbon ring is forged near the middle of the fatty acid chain.
This forms the short-lived, unstable intermediate Prostaglandin G (PGG). One of the peroxide linkages
sheds a single oxygen, forming PGH.
All other prostanoids originate from PGH (as PGH1, PGH2, or PGH3).

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Prostaglandin H2
Thromboxane-A
synthase
Prostacyclin synthase
PGD synthase
PGEsynthase
PGE 9-
ketoreductase
TXA
6-keto-PGFα PGF2
PGJ2
PGD2
PGE2
PGA2
PGB2
PGI2

The Functions of Prostanoids
Prostanoids are ubiquitous lipids in animal tissues that coordinate a multitude of physiological and pathological
processes at concentrations down to 10-9g per g of tissue, either within the cells in which they are formed (autocrine)
or in closely adjacent cells (paracrine) (they are deactivated too readily to be transported far) in response to specific
stimuli.
They are transported out of cells mainly by members of the ABC transporter superfamily.
Under normal physiological conditions, they have essential homeostatic functions in the cytoprotection of gastric
mucosa, renal physiology, gestation, and parturition, but they are also implicated in a number of pathological
conditions, such as inflammation, cardiovascular disease and cancer.
Different prostanoids can have complementary or opposing functions depending on tissue or physiological conditions
and the correct balance between them can often be crucial.
Receptors
Inflammation and immune responses

Gastrointestinal system: COX-1 is always present throughout the human gastrointestinal tract, and produces
PGI2 and PGE2, which have protective effects on the gastrointestinal mucosa. Both of these prostanoids reduce
acid secretion from parietal cells, while increasing blood flow and stimulating the secretion of mucus.
Cardiovascular effects: Two prostanoids are especially important and have essential but opposing functions in
the maintenance of vascular homeostasis.
Kidney function: Prostaglandins generated by both COX-1 and COX-2, especially PGE2, assist in the regulation
of kidney function by maintaining vascular tone, blood flow, and salt and water excretion.
Reproductive system: Prostaglandins produced both by COX-1 and COX-2 are involved in many aspects of
reproduction in females, from ovulation and fertilization through to labour.
Cancer: COX-2 is over-expressed in many cancers, including those of the breast, colon and prostate.

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