1

ANTIHISTAMINIC AGENTS
INTRODUCTION
Histamine is an important chemical messenger communicating information from one
cell to another, and is involved in a variety of complex biologic actions. It is mainly stored
in an inactive bound form, from which it is released as a result of an antigen-antibody
reaction initiated by different stimuli such as venoms, toxins, proteolytic enzymes,
detergents, food materials, and numerous chemicals. Histamine exerts its biologic function
by interacting with histamine receptors. It is the mediator associated with allergic
manifestations. It binds to and activates specific receptors in the nose, eyes, respiratory tract,
and skin, causing characteristic allergic signs and symptoms. It also causes contraction of
smooth muscles, relaxation of capillaries, and gastric acid secretion.

HISTAMINE STRUCTURE

SAWHORSE AND NEWMAN PROJECTIONS

NH3 NH3 NH3 NH3 N

NH
H H H
A H H
B H H N
NH
H H H
H H H H
H
N N H
N gauche
N
H trans H

1. The trans conformer has less steric hindrance but the gauche conformer is stabilized by
an ion–dipole interaction
2. Both conforms exist is solution
3. It is believed that both the H1 and H2 receptors bind the trans conformer

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4. This is based on the observation that α– and β–methyl histamine are unable to assume
the trans conformation and are weak agonists at both the H1 and H2 receptors. However,
they are strong H3 agonists, thus the H3 receptor must bind Histamine in the gauche
conformation.

Mole Pe rc entage
of Spe cies at
pH 7.4
NH3

HN + NH 3.3
pKa2 = 5.94 Dicatio n
NH3 NH3

HN N N NH 96.2
Mon ocation
pKa1 = 9.75
NH2 NH2
0.4
N HN N N NH N
Unio nized
pKa3 = 14
NH2

N – N ~0
Anion

1. About 80% of histamine monocation exists in aqueous solution that binds receptors
2. The τ tautomer (H on the τ nitrogen) permits binding with the receptors However,
tautomerism does not appear to be important in H1 binding but does appear to be
important in the H2 interaction
3. Electron donating groups on C5 increase the t tautomer while electron withdrawers
increase the π tautomer fraction

BIOSYNTHESIS, STORAGE AND CATABOLISM OF HISTAMINE

The major source of histamine in body appears to be decarboxylation of the naturally
occurring amino acid, histidine, under the influence of L-histidine decarboxylase. It is highly
specific enzyme whose activity is governed by histamine itself, through negative feedback

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inhibition mechanism. This conversion utilizes pyridoxal-5-phosphate as a coenzyme.

Histidine is also converted to histamine by pathway of minor importance that is catalyzed by
non specific enzyme, aromatic-L-amino acid decarboxylase (dopa decarboxylase). Almost
all mammalian tissues contain varying amounts of histidine, L-histidine decarboxylase and
enzymes that metabolize histamine.
NH2 NH2

N COOH N
Histidine decarboxylase
Aromatic aminoacid
N decarboxylase N
H H
Histidine O H Histamine

HO CH2OPO3

H3C N
H
Pyridoxal phosphate

The higher concentration of histamine, however, is found in the skin, intestinal mucosa,
lungs and bone marrow. In brain, histamine is present in significant amount. The tissue fixed
mast cells and blood basophils are the principal cells where histamine is synthesized and is
stored in secretory granules. Besides mast cells, histamine is also present in skin, gastric
mucosa and CNS where it is biosynthesized and stored in non-mast cells. Here histamine
usually undergoes rapid turnover and is released, rather than stored. It is this histamine
which is probably of greater physiological importance.
Some histamine is also synthesized in the gut lumen by bacteria. But most of it is inactivated
during absorption in the gastrointestinal mucosa, liver and lungs to N-acetyl histamine.
Except 2 and 3, rest of the metabolites of histamine retains little or no physiological activity.
In general, conjugation reactions rarely utilize ribose as substrate. Urine serves as principal
vehicle for the excretion of these inactive products.
Specific as well as nonspecific enzymes are involved in the inactivation of liberated
histamine into the body. Imidazole-N-methyl transferase is present in the tissues but not in

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blood whereas diamino oxidase is present in high concentration in intestine, kidney, liver
and thoracic duct lymph.
NH2 NH2

CHO COOH

N N N N
MAO Aldehyde
dehydrogenase
N N N N
H
Histamine (1) CH3 CH3 CH3

Methyl histamine (2) OH Methylimidazole

acetic acid (3)
Diamine oxidase
(Histaminase) N

COOH N
H
N Imidazole
ethanol(5)
NH2
N
H
Imidazole N
aceic acid (4)
N OH

OH

OH

Riboside(6)
O

HISTAMINE RELEASE
1. Tissue injury: Any physical or chemical agent that injures tissue, skin or mucosa is
particularly sensitive to injury and will cause the immediate release of histamine from mast
cells.
2. Allergic reactions: exposure of an antigen to a previously sensitized (exposed) subject
can immediately trigger allergic reactions. If sensitized by IgE antibodies attached to their
surface membranes will degranulate when exposed to the appropriate antigen and release
histamine, ATP and other mediators.
3. Drugs and other foreign compounds: Morphine, dextran, antimalarial drugs, dyes,
antibiotic bases, alkaloids, amides, quaternary ammonium compounds, enzymes

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(phospholipase C), Penicillins, Tetracyclines, Basic drugs- amides, amidines, diamidines,

Toxins, venoms, Proteolytic enzymes, Bradykinin and Kallidin.

HISTAMINE ACTIONS
1. Cardiovascular: Drop in blood pressure, tachycardia, cutaneous flush, headache, rise in
skin temperature, permeability increase
2. Respiration: Bronchoconstriction, prostaglandin release. Asthmatics may experience
marked bronchial constriction compared with normal subjects.
3. Glandular tissue: potent stimulator of gastric secretion (HCl & pepsin), enhances
salivary and lacrimal gland secretion (minimal unless large doses are given), stimulates
chromaffin cells in adrenal medulla to secrete catecholamines.
4. Skin: Lewis triple reflex (reddening at injection site due to vasodilatation, wheal or disk
of edema within 1 to 2 min, a large, bright crimson flare or halo surrounding the wheal)
(flush, flare, wheal); itching; leukocyte recruitment
Axon reflex
vasodilation

Bronchospasm Direct
vasodilation

Bronchial Increased
secretion Histamine vascular
permeability

Gastric Pain
secretion
Immunosupression
Physiological actions of histamine

TYPES OF RECEPTORS
Histamine receptors are G protein-coupled receptors. There are four different types
of receptors H1, H2 and H3 and H4

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H1 receptors:
Histamine H1 receptors are metabotrophic G-protein-coupled receptors present in
brain, smooth muscle from airways, gastrointestinal (GI) tract, genitourinary system, the
cardiovascular system, adrenal medulla, and endothelial cells, and lymphocytes. The H 1
receptor is linked to an intracellular G-protein (Gq) that activates phospholipase-C and the
phosphatidylinositol (PIP2) signaling pathway. Activation of H1 causes contraction of
smooth muscles in gut, the uterus, and the bronchi (nonvascular smooth muscles).
Contraction of the bronchi leads to asthma. Stimulation of H1 receptors on smooth muscles
in fine blood vessels causes increased vascular permeability and muscle relaxation, and the
resulting vasodilatation may result in severe fall in blood pressure.
This receptor contains 7 hydrophobic transmembrane domains (TMs), Possessing N-
terminal glycosylation sites characteristic of most G-protein receptors. Structural analysis of
the receptor indicates presence of threonine and asparagine in TM 5 proposed to serve as the
histamine – imidazole binding site and an aspartate reside in TM 3 thought to interact with
the histamine α-NH3+ monocation. Lysine residue interacts with the Nπ-nitrogen of histamine
and is important for the activation of the H1-receptor by histamine and the non-imidazole
agonist, 2-pyridylethylamine.

H2 receptors:
These are located on the cell membrane of the acid secreting cell of the gastric
mucosa and mediate the gastric acid secretary actions of histamine and may involved in
cardiac stimulation. They activate adenylate cyclase ( AC) as secondary messenger to
produce physiological effects. These are present in CNS, H 1 and H2 receptors
predominantly localized on postsynaptic membranes.
This receptor contains 7 hydrophobic transmembrane domains (TMs), Possessing N-
terminal glycosylation sites characteristic of most G-protein receptors. Structural analysis of
the receptor indicates presence of threonine and asparagine in TM 5 proposed to serve as the
histamine – imidazole binding site and an aspartate reside in TM 3 thought to interact with
the histamine α-NH3+ monocation.

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H3 receptors:
Neural autoreceptor serving to modulate histamine synthesis and release in the CNS.
H3 receptors appear to function predominantly as presynaptic receptors, and also been
detected in some peripheral organs like gastrointestinal tract, lung and heart.
Like all histamine receptors, the H3 receptor is a G-protein coupled receptor. The H3
receptor is coupled to the Gi G-protein, so it leads to inhibition of the formation of Camp.
Also, the β and γ subunits interact with N-type voltage-gated calcium channels, to reduce
action potential mediated influx of calcium and, hence, reduce neurotransmitter release.

H4 receptors:
H4 receptor exhibits very restricted locations in intestinal tissue, spleen, thymus and
immune active cells (such as T cells, neutrophils, and eosinophils), suggesting a role of H 4-
receptors in the regulation of immune function and in allergic and inflammatory diseases.

HISTAMINE AGONIST STRUCTURE ACTIVITY RELATIONSHIP

1. Side chain N–methyl and dimethyl are active but weaker. Larger alkyls are not well
tolerated. The activity decreases in the order NH2>NHMe>NMe2>N+Me3
2. Branching the side chain decreases potency, optical isomers are equipotent
3. Ring modifications produce variable activities. For example:
a) 1-Methyl derivatives are inactive
b) 2-methyl substitution makes H1 selective
c) 3-Methyl derivatives are very weak at H1 & H2
d) 4-Substitution causes H2 selective, electron withdrawer favor τ tautomer
e) 5-Substitution causes H2 selective where electron donor favor τ tautomer

NH2 NH2 H3C NH2 NH2

S
N HN N
HN N HN N CH3
CH3
H1 Agonists H2 Agonist H3 Agonist

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RECEPTOR BINDING
+
NH3 -OOC Asp107
H
207Asn N HN N
HN
Lys200

1. An anionic center to provide the initial interaction and to bind with the protonated amine
(Asp107); the area surrounding the ionic site is small or nonexistent compared to the
Muscarinic receptor, for N–methyl decrease potency
2. Next is a flat region probably another aromatic ring on an amino acid residue to interact
with the imidazole ring (Asp207 possibly interacting with the N t-nitrogen of imidazole
ring)
3. Lys200 interacts with the nucleophilic Nπ-nitrogen
4. Between the two there is no stereoselectivity, no Chirality

H1 RECPTOR ANTAGONIST
Allergic illnesses are a complex collection of disturbances with chronic and severe effects
ranging from slight reddening, rashes, and runny nose to severe and even fatal anaphylaxis.
It has been shown that around 10 % of the population may be prone to some form of allergy.
Therapy directed towards removing the source of allergen is not always successful. In a
number of cases, the allergen itself is never found. Therefore, symptomatic treatment using
H1 antihistamines is carried out.
H1 antihistamines are clinically used in the treatment of histamine-mediated allergic
conditions. Specifically, these indications may include allergic rhinitis, allergic
conjunctivitis, allergic dermatological conditions (contact dermatitis), pruritis (atopic
dermatitis, insect bites), anaphylactic reactions.
The H1 receptor blockade results in decreased vascular permeability, reduction of pruritis,
and relaxation of smooth muscle in the respiratory and gastrointestinal tracts. H 1 receptor
antagonists have been used clinically to treat various allergic disorders such as seasonal or
perennial allergic rhinitis and chronic urticaria.
The most common adverse effect of the first-generation anti-histamines is sedation; this is
due to their relative lack of selectivity for the peripheral H 1 receptor.

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MECHANISM OF ACTION
H1 receptor antagonists act by competitively antagonizing the effects of histamine at
receptor sites; they do not block the release of histamine.
pA2 Index: Inverse of the logarithm of the molar concentration of the antagonist which
reduces the response of a double dose of the agonist to that of a single one. The more potent
H1-antagonists exhibit a pA2 value significantly higher than 6.

RECEPTOR INTERACTION
 The H1 antagonists do not occupy the same area or space as the natural receptor substrate
 Only the protonated nitrogen binds the same anionic site as Histamine
 The aromatic tail binds adjacent to the Histamine binding site thus produces the
nonspecific conformational perturbation of the receptor. This changes the shape of the
receptor decreasing the affinity for Histamine
 It seems that sites outside may be chiral because stereoselectivity is observed with some
H1 antagonists
 As previously discussed the optical isomers of α-Methyl histamine are equipotent as
agonists

FIRST GENERATION / CLASSICAL ANTIHISTAMINICS

STRUCTURE ACTIVITY RELATIONSHIP
The basic structural requirements for H1- receptor antagonism is as follows
Ar' R

X (CH2)n N

Ar R'
In this structure Ar is aryl (including phenyl, substituted phenyl, and heteroaryl groups such
as 2-pyridyl), Ar’ is a second aryl or arylmethyl group, X is a connecting atom of O, C, or
N, (-CH2)n represents a carbon chain, and NRR’ represents a basic, terminal amine function.
The nature of connecting atom, as well as the diaryl substitution pattern and amine moiety
has been used to sub classify the first generation antihistamines. This diaryl substitution
pattern is present in both first and second generation antihistamines and is essential for

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significant H1-receptor affinity. Two aryl moieties must be capable of adopting a non-
coplanar confirmation relative to each other for optimal interaction with the H 1-receptor.
The two aromatic systems may be linked (e.g. Phenothiazine), but again they must be non-
coplanar for effective receptor interaction. Most H1 antagonists contain substituents in one
of the aryl rings (usually benzene), and these influence antihistaminic potency and
biodisposition.
In many of the first generation or classical antihistamines, the terminal nitrogen atom is a
simple dimethylamino moiety. However, the amine may also be part of a heterocyclic
structure (e.g. Cyclizine, Triprolidine, Methdilazine, Cetirizine etc). In all cases, the amino
moiety is basic, with pKa ranging from 8.5 to 10 and thus presumed to be protonated when
bound on the receptor. The moiety is also important in the development of stable, solid
dosage forms through salt formation.
The carbon chain consists of two or three atoms. As a result, the distance between the
central point of the diaryl ring system and the terminal nitrogen atom in the extended
conformation of these compounds ranges from 5 to 6 A0. A similar distance between these
key moieties is observed for those antihistamines with less conformational freedom (e.g.
Cyclizine). In some series, branching of the carbon chain results in a reduction of
antihistaminic activity. (Exception - promethazine, which has greater activity than its
nonbranched counterpart).
The X connecting moiety of typical H1-antagonists may be 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.
Antihistamines containing the carbon atom in the connecting moiety are chiral and exhibit
steroselective receptor binding (e.g. Carbinoxamine - S-configuration have higher H1-
receptor affinity). Generally, the first and second generation antihistamines are substantially
more lipophilic than the endogenous agonist histamine (or the H 2-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.
Adverse effects:

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 CNS depression and Drowsiness; additive with alcohol, accidents with first generation
of H1 blockers
 Lessened effect after chronic administration: induction of microsomal enzymes in liver,
increased metabolism.
 Drying salivary bronchial secretion (antichloinergic; antimuscarinic)
 GIT disturbances: Loss of appetite, nausea, vomiting
The classes of first generation antihistamines are as follows
1) Ethylenediamine derivatives
2) Aminoalkyl ether analogues
3) Cyclic basic chain analogues / Piperazine derivatives
4) Monoaminopropyl analogues / Propylamine derivatives
5) Tricyclic ring systems / Phenothiazine analogues
6) Dibenzocycloheptanes / Dibenzocycloheptenes

ETHYLENEDIAMINE DERIVATIVES
The Ethylenediamine antihistamines are characterized by the presence of nitrogen
connecting atom (X) and a two carbon atom chain as the linking moiety between the key
diaryl and tertiary amino moieties.All compounds in this series are simple diaryl
ethylenediamines except for Antazoline, in which the terminal amine and the portion of the
carbon chain are included as part of an imidazoline ring system.
Phenbenzamine was the first clinically useful member of this class and served as the
prototype for the development of more effective derivatives. Replacement of the phenyl
moiety of the Phenbenzamine with a 2-pyridyl system yielded Tripelennamine, a
significantly more effective histamine receptor blocker. Substitution of a p-methoxy
(Pyrilamine or mepyramine), chloro (chloropyramine), or bromo (bromtriplennamine)
results in a further enhancement in activity. Replacement of benzyl group of Tripelennamine
with a 2-thienylmethyl group provided Methapyrilene, and replacement of tripelennamine’s
2-pyridyl group with a pyrimidinyl moiety (along with p-methoxy substitution) yielded
Thonzylamine, both of which function as potent H1 receptor antagonists.
In these compounds, the aliphatic terminal amino group is more basic than nitrogen
bonded to diaryl moiety, thus amino group is useful for formation of salts.

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Pharmacokinetics: They are well absorbed orally, bound moderately to plasma proteins,
metabolized by oxidation at aromatic ring, N-demethylation followed by glucuronide
conjugation, excreted through kidney.
STRUCTURE OF ETHYLENEDIAMINE DERIVATIVES
Ar' CH3
H2 H2
N C C N

Ar CH3
Name Ar’ Ar
Phenbenzamine

Tripelenamine

Pyrilamine
OCH3

Methapyrilene

S
N

Thonzylamine
N
OCH3

Antazoline
N

NH

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AMINOALKYL ETHER / ETHANOLAMINES

These are characterized by the presence of a CHO connecting moiety (X) and a two
or three carbon atom chain as the linking moiety between the key diaryl and tertiary amino
groups. Compounds in this series are simple N, N-dimethylethanolamine derivatives except
Clemastine and Diphenylpyraline.
Diphenhydramine was the first clinically useful member of the ethanolamine series
and serves as the prototype. It is when substituted by methoxy (Medrylamine), bromo
(Bromodiphenhydramine) group gives agents with superior therapeutic profiles.
Replacement of one of the phenyl ring of the diphenhydramine with a 2-pyridyl group
(Doxylamine and Carbinoxamine) give more active compounds. In case optically active
antihistamines the activity resides predominantly in S-enantiomer.
The diaryl tertiary Aminoalkyl ether structure that characterizes these compounds
also serves as a pharmacophore for Muscarinic receptors. Hence, they posses antichloinergic
activity.
Pharmacokinetics: They are well absorbed orally, bound moderately to plasma proteins,
metabolized by N-oxidation, N-dealkylation followed by amino acid conjugation, excreted
through kidney.

STRUCTURE OF AMINOALKYL ETHER DERIVATIVES

R CH3
H2 H2
Ar' C O C C N

Ar CH3

Name Ar’ Ar R
Diphenhydramine H

Medrylamine H3CO H

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Bromodiphenhydramine Br H

Doxylamine CH3

Carbinoxamine Cl H

Diphenylpyraline

CHO N CH3

Clemastine
CH3
O
C

N
H3C

PIPERAZINES / CYCLIZINES
These can also be considered to be ethylenediamine derivatives however, in this
series connecting moiety (X) is a CHN group and the carbon chain , terminal amine
functionality as well as the nitrogen atom of the connecting group are all part of a piperazine
moiety . The both nitrogen atoms in these compounds are aliphatic and thus display
comparable basicities.
The activity is characterized by slow onset and long duration of action. These agents
exhibit peripheral and central antimuscarinic activity, and this may be responsible for the
antiemetic and antivertigo effects. The agents diminish vestibular stimulation and may act
on the medullary chemoreceptor trigger zone. Thus, as a group, these agents are probably
more useful as antiemetic and antinauseants and in the treatement of motion sickness.

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Pharmacokinetics: They are well absorbed orally, bound moderately to plasma proteins,
metabolized by N-oxidation, N-dealkylation followed by conjugation, excreted through
kidney.
Adverse effects: Less CNS depression compared to ethylenediamines and Aminoalkyl
ethers
STRUCTURES OF PIPERAZINES / CYCLIZINES

N N R2

R1

Name R1 R2
Cyclizine H CH3
Chlorcyclizine Cl CH3
Meclizine Cl

CH3

Buclizine Cl CH3

CH3

CH3

Hydroxyzine Cl O
OH

Cinnarizine H

MONOAMINOPROPYLS / PROPYLAMINES

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These are characterized by sp3 or sp2 carbon connecting atom with a carbon chain 2
additional carbons linking the key tertiary amino and diaryl pharmacophore moieties.
Those propylamine with a saturated carbon connecting moiety are commonly
referred as pheniramines. All of the pheniramines consist of a phenyl and 2-pyridyl aryl
groups, and a terminal dimethylamino moiety. All pheniramines are chiral molecules and
activity resides exclusively in the S-stereoisomers.
Those propylamine with an unsaturated connecting moiety include the open
derivatives pyrrobutamine and triprolidine, and cyclic analogs Dimethindene and
Phenindamine. In the open chain propylamine. It appears that a coplanar aromatic double
bond system is an important factor for antihistaminic activity, the pyrrolidino group of these
compounds is the side chain tertiary amine that imparts greatest antihistaminic activity.
Pharmacokinetics: They absorbed orally, bound moderately to plasma proteins, undergo
first pass effect and metabolized by N-dealkylation followed by glycine conjugation,
excreted through kidney.
Adverse effects: Less CNS depression compared to ethylenediamines and Aminoalkyl
ethers
STRUCTURES OF SATURATED MONOAMINOPROPYLS / PROPYLAMINES
Ar' CH3
H2 H2
CH C C N
Ar CH3
Name Ar’ Ar
Pheniramine

Chlorpheniramine Cl

Brompheniramine Br

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STRUCTURES OF UNSATURATED MONOAMINOPROPYLS / PROPYLAMINES

Ar'
H2
C C C N
H
Ar
Name Ar’ Ar
Triprolidine
CH3

Pyrrobutamine
Cl

Phenindamine
N
CH3

Dimethindene
CH3
N

CH3

CH3

PHENOTHIAZINES
This class is result of bridging the aryl units of the ethylenediamines. It contain a 2 or 3
carbon atom, branched alkyl chain between ring system and terminal nitrogen atom (where
as antipsychotic agents requires unbranched propyl chain). The asymmetry appears to be of
less influence on antihistaminic activity when chiral centre lies near the positively charges
side chain nitrogen.

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Prototype of this class promethazine is with prolonged action and pronounced sedative side
effects. In addition to its antihistaminic action, it is potent antiemetic, antichloinergic and
sedating agent. In general, lengthening of the side chain and substitution of lipophilic groups
in the 2-position of the aromatic ring results in compounds with decreased antihistaminic
activity and increased psychotherapeutic properties.
Pharmacokinetics: They absorbed orally. Metabolized by N-dealkylation, Sulphur
oxidation, aromatic oxidation at 3-positionand N-oxidation followed by glucuronide
conjugation, excreted through kidney.

STRUCTURES OF PHENOTHIAZINES
S

Name R
Promethazine CH3
H2 H
C C N

CH3 CH3

Trimeprazine CH3
H2 H H2
C C C N

CH3 CH3

Methdilazine H2
C

N CH3

DIBENZOCYCLOHEPTANES / DIBENZOCYCLOHEPTENES
These are regarded as phenothiazine analogues in which the sulphur atom has been replaced
by an isosteric vinyl group (Cyproheptadine) or a saturated ethyl bridge (Azatadine), and the
ring nitrogen replaced by a sp2 carbon atom. The Azatadine is an aza (pyridyl) isostere of
Cyproheptadine in which the 10, 11-double bond is reduced.

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N
N
CH3
CH3
Cyproheptadine
(Periactin) Azatadine

SECOND GENERATION ANTIHISTAMINES

The goal of designing antihistamines with reduced ability to penetrate the CNS and
decreased affinity for central histamine receptors leads to second generation antihistamines.
Generally they do not cross the blood-brain barrier readily hence do not cause the sedation
and drying like in first generation antihistamines

THREE APPROACHES USED TO REDUCE BBB ABSORPTION

1. The most obvious is to add polar or highly ionized groups to decrease the LWPC, thus
decreasing ability to pass through lipid barriers.
2. The second approach is to create a very high lipid soluble compound. High LWPC. This
has three effects:
a) Low water solubility results in low concentrations in the blood, thus low
concentration gradient results in low passage of BBB.
b) Increase in protein binding, which further decreases the concentration gradient by
decreasing the amount of free unbound drug.
c) Once the drug diffuses into the lipid bilayer it sequesters itself in the lipid
environment. It will not pass out into the cell.
3. Create a zwitterion that has low ability to pass through the BBB's lipid barriers.
These drugs produce prolonged action as a result of slow dissociation from H1 receptors and
the formation of active metabolites with similar receptor binding profiles. They have little
affinity for Muscarinic, adrenergic or serotonergic receptors and therefore display a lower
degree of side effects.

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The terfenadine and astemizole has significant drug–drug interactions with Ketoconazole,
Itraconazole, Fluconazole, Erythromycin, Clarithromycin and Troleandomycin. All three are
metabolized by the same enzyme. However, these are inhibitors of CYP3A4. They slow the
metabolism of Terfenadine and astemizole allowing blood levels to increase significantly.
These high levels produce a cardiotoxicity (QT interval prolongation and arrhythmias)
which can prove fatal. This led to its removal from the market.

CH3
HO C N CH3
HO CH3

Terfenadine

HN N

F N OCH3

Astemizole

FEXOFENADINE

CH3
HO C N COOH
HO CH3
Fexofenadine

Fexofenadine (as a racemate) is an active metabolite of Terfenadine with no drug–drug

interactions because it is not metabolized through the same pathway. Even though a
carboxylic acid it exists as a zwitterion in aqueous media at physiological pH, which
decreases its solubility. This drug does not produce cardiotoxicity like terfenadine and
Astemizole.

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LORATADINE

Cl

N
Loratidine

O O CH3

Loratadine is non–sedating H1 antagonist with no antichloinergic side effects, which is

structurally related to the antihistamine Azatadine and Cyproheptadine. It differs from
Azatadine in that a neutral carbamate group has replaced the basic tertiary amino moiety,
and the phenyl group has been substituted with the chlorine atom (which increases potency).
The replacement of the basic group with a neutral functionality is believed to preserve
antihistaminic action while reducing CNS effects. It has more antiserotonergic activity than
other agents from class. It is metabolized by CYP3A4 and 2D6 directly to Desloratadine
(active metabolite) via an oxidative process without hydrolysis. This drug does not produce
cardiotoxicity like terfenadine and Astemizole.
CETIRIZINE
Cl

O O

N N

OH

Cetirizine

Cetirizine is acid analog of Hydroxyzine. It has 6.5 times lower receptor affinity and being a
zwitterion (polar) lower CNS effects. Thus less sedating but not non–sedating agent.
Advantages of this compound appear to be once daily dosing, a rapid onset of activity and

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minimized CNS effects. This drug does not produce cardiotoxicity like terfenadine and
Astemizole.
The most common adverse effect is dose related somnolence and thus patient should be
advised that Cetirizine may interfere with the performance of certain psychomotor /
psychophysical activities.
ACRIVASTINE

H COOH

N
H

H3C
Acrivastine
Acrivastine is a modern non–sedating agent. It is related to Triprolidine and is slightly more
potent. The unsaturated carboxylic acid substituent (carboxyethylene moiety) is responsible
for the lack of sedation. Non–sedating agents have difficulty in crossing the BBB.
USES OF H1 ANTIHISTAMINICS
1) Effective in perennial and seasonal allergic rhinitis, vasomotor rhinitis, allergic
conjunctivitis, urticaria and angioedema, allergic reaction to blood and plasma, and as
adjuncts to conventional therapy in anaphylactic reactions.
2) A few antihistamines are effective in mild, local allergic reaction to insect bites.
3) Selected antihistamines (e. g. diphenhydramine) reduce rigidity and tremors in
Parkinson’s disease, and in drug-induced extra-pyramidal symptoms.
4) Some antihistamines (e. g. buclizine, cyclizine and diphenhydramine) are also effective
in the active and prophylactic management of motion sickness.
5) The phenothiazine antihistaminics (e. g. promethazine) are useful for pre-operative and
postoperative vomiting and obstetric sedation.
INHIBITION OF HISTAMINE RELEASE
Nedocromil sodium and cromolyn sodium seem to act by phosphorylating a mast cell
protein and there by stabilized the mast cell, preventing its disruption to release histamine.

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CROMOLYN SODIUM

O O O O

OH

NaOOC O O COONa
Cromolyn sodium
It does not seem to be interfere with the antigen-antibody reaction but it seems to suppress
the responses to this reaction. It is used prophylactically in asthma and for treatement of
allergic rhinitis.

NEDOCROMIL SODIUM
O

NaOOC N COONa

C3H7
Nedocromil

It displays similar, but broader pharmacological actions than cromolyn sodium.

DUAL ACTING ANTIHISTAMINES

These are novel antihistaminic compounds with dual mechanisms of action including H 1-
receptor antagonism and mast cell stabilization. e. g. Azelastine and Ketotifen. These
compounds contains basic pharmacophore to produce relatively selective histamine H 1
antagonism (diarylalkylamines) as well as inhibition of the release of histamine and other
mediators (e. g. leukotrines and PAF) from mast cells involved in the allergic response. In-
vitro studies suggest that these compounds also decrease chemotaxis and activation of
eosinophils. Azelastine and Ketotifen currently are indicated for the treatment of itching of
the eye associated with allergic conjunctivitis. Their antiallergy actions occur within minutes
after administration and persist for upto 8 hours.

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O
N CH3
S

N
Azelastine Ketotifen
Cl CH3

AZELASTINE
Azelastine is used for ocular administration only and not for injection or oral. Absorbed drug
undergoes extensive oxidative N-demethylation by cytochrome P-450, and the parent drug
and metabolite are eliminated primarily in the feces.
Adverse effects: Transient eye burning or stinging, headaches, and bitter taste.
KETOTIFEN
Ketotifen is a ketothiophene isostere analogue of the dibenzocycloheptane antihistamines.
This drug product is for ocular administration only and not for injection or oral use.
Adverse effects: Conjuctival injection, headaches and rhinitis.
H2 RECEPTOR ANTAGONIST
Gastric acid is secreted from parietal cells located mainly in the upper portion of the
stomach and is stimulated by three endogenous substances: gastrin, acetylcholine, and
histamine. It is thought that gastrin and acetylcholine act on mast cells to release histamine
then acts on the H2 receptors on parietal cells to stimulate acid secretion.
MECHANISM OF ACTION
The H2 antagonists are competitive inhibitors of the histamine at the parietal cell H 2
receptor. They suppress the normal secretion of acid by parietal cells and the meal-
stimulated secretion of acid. They accomplish this by two mechanisms: histamine released
by ECL cells in the stomach is blocked from binding on parietal cell H 2 receptors that
stimulate acid secretion (by activation of cAMP and concomitant increase in Ca++) and
other substances that promote acid secretion (such as gastrin and acetylcholine) have a
reduced effect on parietal cells when the H2 receptors are blocked.

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Mechanism of HCl Secretion

HOW IT WORKS AT THE RECEPTOR LEVEL

Combined neurocrine, endocrine and paracrine

Acetylcholine events in the activation of gastric HCl secretion
neural input
neurocrine
ACh
receptor
PARIETAL cell
histamine
receptor

H/K
ECL cell P
histamine- transduction- HCl
secreting cell activation events
secretion
H/K
P

gastrin
receptor
paracrine
release of
Gastrin histamine
hormonal input ECL cell =
endocrine enterochromaffin-like cell
G cell =
gastrin-secreting cell
G cell

ACh PGE2
Gastrin
Histamine

M3 _ Adenyl H2
PGE cyclase
+ Gastrin
+ receptor + receptor

Ca++ ATP cAMP Ca++

+ + +

Protein Kinase
(Activated)

K+ + H+
Parietal cell
Proton pump
Lumen of stomach
Gastric acid

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Integration of Gastric Secretion

+ + -
- -
+ + + +

+ +

THERAPEUTIC USES
1) Treatment of gastric and duodenal ulcer
2) The management of hypersecretory conditions, such as Zollinger-Ellison syndrome,
systemic mastocytes, and multiple endocrine adenomas
3) Gastroesophageal reflux diseases

ADVERSE EFFECTS
1. Diarrhea
2. Dizziness
3. Somnolence
4. Headache
5. Rash
6. Constipation
7. Vomiting
8. Arthralgia

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HISTAMINE H2 RECEPTOR INTERACTION

 Cationic Histamine binds to the receptor via the formation of three hydrogen bonds
 The cationic nitrogen and τ–nitrogen of the imidazole ring are hydrogen donors and the
π–nitrogen acts as a proton acceptor
 Participation of the ammonium group in the hydrogen bonding inevitably leads to a
decrease of the positive charge on the ammonium group
 This decrease in positive charge induces a tautomeric change in the imidazole ring
resulting in a stronger binding of the π–nitrogen and proton release by the τ–nitrogen
 The net result is a proton shift at the receptor surface which is believed to trigger the H2
stimulating effect
 This mechanism calls for the presence of a hydrogen atom in position 3 of histamine,
and recall that 3–methylhistamine is unable to stimulate the receptor.
STRUCTURAL DRIVATION
Methylation of the 5-position of imidazole in histamine produces agonist 5-methyl histamine
where as guanidine analogue possesses a small degree of H 2 antagonistic activity
NH2
NH2 NH2 HN C
H3C NH

HN N HN N HN N

Histamine 5-Methyl Histamine N-Guanyl Histamine

Extension of the side chain from 2 to 4 carbons increased anti H 2 potency but some agonist
activity remained. Replacing the basic guanidine group with the neutral thiourea yielded
effective H2 antagonists. Burimamide is lacked agonist action but was not orally absorbed
hence poor bioavailability and less potent.
HN CH3
HN C

S
HN N Burimamide

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Insertion of thioether function in place of methylene group favors the N τ-tautomer and
introduction of the 5-methyl group favors H2 receptor selectivity leads to metiamide, a H2
blocker of higher potency and oral bioavailability compared to Burimamide.
In Metiamide reduce the pKa of the ring N, reduced ionization, increased membrane
permeability and absorption and 10X more potent than Burimamide.
HN CH3
H3C S
HN C

S
HN N
Metiamide
Metiamide causes kidney damage and granulocytopenia, possibly due to the thiourea so was
replaced by the isosteric electron withdrawer but more lipophilic cyano derivative yielded
Cimetidine.
HN CH3
H3C S
HN C

N C N
HN N
Cimetidine

Cimetidine has antiandrogenic activity, which leads to gynecomastia, and it also inhibits the
cytochrome p450 enzyme (increased concentrations of drugs metabolized by this enzyme).

STRUCTURE ACTIVITY RELATIONSHIP

HN CH3
H3C S
HN C

N C N
HN N
Cimetidine

1. Need an aromatic ring with n electrons next to the side chain. The imidazole ring is not
required (the other H2 antagonist don’t have it) but if it is present the t tautomer should
predominate. The t tautomer is promoted by electron donors at position 5 and electron
withdrawers at position 4.
2. The terminal nitrogen group should be polar but not basic for maximal potency

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3. Separation of the ring from the nitrogen group by 4 atoms gives maximal potency.
4. Cimetidine is an extremely successful drug in the treatment of ulcers.
5. Note the electron donor methyl at C5 and electron withdrawing side chain at C4 Also the
non basic cyanoguanidine terminal nitrogen group.

FAMOTIDINE
O
NH2 O
S N
S
S
H2N
N NH2
N NH2

Famotidine
Famotidine, a thiazole derivative, is 9–15 X potent than Ranitidine or 40–60 X than
Cimetidine. No cases of gynecomastia have been reported. It is a weak inhibitor of CYP.
Like Ranitidine salts can easily be prepared for this compound. But its absorption is
incomplete with only 40 to 50% bioavailability.
RANITIDINE
HN CH3
S
HN C

HC NO2
O

Ranitidine
CH3
N

CH3

Ranitidine is a furan derivative, an isostere of the imidazole with n electrons on the oxygen,
with 50% bioavailability. It is 4 - 10 X potent than Cimetidine with a longer duration of
action. Further, it is a weaker CYP inhibitor. The tertiary amine side chain allows the
formation of salts.

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NIZATIDINE

NO2
S HN

HN CH3
S N

CH3
Nizatidine

CH3

Nizatidine is also a thiazole derivative similar to Ranitidine (5–18 X Cimetidine), but more
bioavailable, 90%, with no antiandrogenic or enzyme inhibition.

OTHER H2 ANTAGONISTS
O

OCH3
N

N N N N CH3
H H
Icotidine

N
O N N
H
Zolantidine

N C O CH3
O N
H
Roxatidine O

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H
N N CH3

CH3

HN
Mifentidine
N
N
CH3

NH
NH2
N
Zaltidine
H2N
N
S

PROTON PUMP INHIBITORS

In 1977 the proton pump was discovered to be the final step in acid secretion
1) In the early 80s it was shown that the substituted benzimidazole blocked the proton
pump
2) Since weak bases accumulate in the acidic compartment, substituents were added to the
pyridine ring to obtain a pKa that maximized the accumulation in the parietal cell
The resulting compound was called Omeprazole
O
H
N S

N H3C
H3CO

Omeprazole
H3CO CH3

Omeprazole is prodrug and need activation to the active species

 The higher pKa also increases the rate of acid mediated conversion to the active species
 The methoxy substitution in the benzimidazole ring made the compound more stable to
conversion at neutral pH.

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R3 R3 R3 R3 R3
R2 R4 R2 R4 R2 R4 R2 R4 R2 R4
H – H2 O
N N N N N
H2 O S AT Pase
S O S OH S OH S S S AT Pase
H N H N N N NH
H N H N
NH NH NH

R1 R1 R1
Benzimidazole PPI Spiro intemediate Sulfenic acid R1 Sulfenamide R1 Disulfide adduct

 Intramolecular transfer of a proton occurs prior to the nucleophilic attack

 Electron donor (OCH3) to the pyridine ring enhanced the rate of attack of the C 2 thereby
promoting formation of the active species (Sulfenamide).
MECHANISM OF ACTION
 Inhibiting the gastric H+/K+–ATPase located in the secretory membranes of the parietal
cells, responsible for gastric acid production
 Omeprazole is a prodrug and is transformed within the acidic canaliculi of the parietal
cells into the active form, a Sulfenamide
 This Sulfenamide reacts with thiol groups of cysteine at critical sites in the extracellular
domain of the enzyme, forming a disulfide link which irreversibly inhibits the enzyme
thereby blocks gastric acid secretion. The high specificity of action is due to several
factors.
1. Omeprazole is a weak base (pKa 4.0), therefore concentrates in acidic canaliculi of
the parietal cells
2. The low pH causes the conversion into the active species close to the target enzyme
3. The active species is a permanent cation which cannot escape the canaliculi
4. At the higher pHs found in the body, Omeprazole has good stability. Commercial
products are enteric coated to prevent gastric decomposition
The pKa and the hydrophobicity of the PPIs determine the extent to which it accumulates in
the canalicular lumen. The rate of enzyme inhibition corresponds to the rate of Sulfenamide
formation.
The PPI s inhibits both basal and stimulated gastric acid secretion. Unlike the H2 blockers
PPIs inhibit daytime and nocturnal acid secretion regardless of time of administration and

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presence of food. The benzimidazole PPIs have antimicrobial activity so can be used to treat
infections caused by H. pylori.
STRUCTURES OF PPIs

CH3 O CF3
O O
CH3 CH3

N N

N S N S
O O
NH NH

Rabeprazole Lansoprazole

CH3 O COOCH3
N

N
H CH3

N Picoprazole
All PPIs have similar potencies and undergoes first pass metabolism primarily by CYP3A4
and CYP2C19. All the PPIs are chiral because of the sulfur. Both isomers are converted into
the nonchiral active species at the same rate. In in-vivo, the S omeprazole (esomeprazole)
produced higher plasma concentrations because it undergoes less metabolism by CYP 2C19
and thus produces 70% higher AUC than Omeprazole

THERAPEUTIC USES
1) Treatment of gastric and duodenal ulcer
2) In oesophagitis and gastroesophageal reflux

Antihistaminic Agents / Dr. Ranjit Gadhave