1

Y.VEDAVATHI

Under the esteemed Guidance of

K.V.S.Santosh Kumar M.Pharm.

Vignan Pharmacy College

Presented By

Affiliated to JNTU Kakinada, (Approved by AICTE, PCI, New Delhi & Govt. of A.P) Vadlamudi, Guntur (Dt.)

ANTIHISTAMINES

(11AB1R0081)

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Introduction BiosynthesisMetabolismReceptorsSARDrugsMechanism of actionUses of antihistaminesConclusionReferences

CONTENTS

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HISTAMINE

• Histamine is a β-imidazolylethylamine derivative present in all

mammalian tissues.

• It was first discovered by SIR HENRY DALE.

• Its synthesis occurs in mast cells,parietal cells of gastric mucosa,

CNS, periphery.

• It functions as an autocoid & one of the mediator involved in the

allergic inflammatory responses.

• It has an important role in the regulation of gastric acid secretion.

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BIOSYNTHESIS OF HISTAMINE

S-HISTIDINE HISTAMINE

HDCHN N

NH2

HCOOH

HN NH

NH2

H

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BIOSYNTHESIS OF HISTAMINE

• Histamine is synthesized in cytoplasmic granules of its storage cells,

mast cells & basophils.

• It is formed from naturally occurring amino acid, S-histidine, via

the catalysis of the pyridoxal phosphate – dependent enzyme

histidine decarboxylase/ aromatic decarboxylase.

INHIBITORS OF HISTIDINE DECARBOXYLASE

α-fluoromethyl histidine

Certain flavonoids

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HN N

NH2

HN N

O

Imidazole acetic acid

Histamine

OH

N N

NH2

CH3 N-Methyl histamine

N N

CH3

OH

O

N-Methylimidazole acetic acid

N NOOH

OHOH

O

OH

Imidazole acetic acidriboside

SAMSAH

DAO

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METABOLISM OF HISTAMINE

• Metabolism of histamine takes by the enzymatic inactivation.• Enzymes that involve in the metabolism are:

1. Histamine N-methyl transferase(HMT)

2. Diamine oxidase.

• Histamine is metabolized as N- methylimidazole acetic acid ,

imidazole acetic acid riboside. Both are excreted through urine.

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IMPORTANCE OF HISTAMINE

It is not used therapeutically but in the past it has been used to test

acid secreting capacity of stomach.

To test bronchial hyperactivity in asthmatics.

For diagnosis of pheochromocytoma , but these pharmacological

tests are risky.

In pulmonary laboratories, histamine aerosol has been used as a

provocative test of bronchial hyperactivity.

To distinguish between real & pseudoanesthesia.

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RECEPTORS

• Histamine receptors are belonging to the family of G-Protein coupled receptors.

• The sub types of histamine receptors are: H1

H2

H3

H4

Myocardial cells,parietal cells

CNS,myentric plexus, gastric mucosa

Spleen,thymus,T-cells, eosinophils.

RECEPTOR

LOCATION

H1 H2 H3H4

Brain,GIT,CVSLymphocytes.

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HISTAMINE ANTAGONISTS

• Drugs that block the action of histamine at H1,H2,H3,H4 receptors

• The development of antihistamines began by the discovery of

PIPEROXAM.

1. Drugs that inhibits the histamine release.

2. Drugs that inhibits the action of released histamine

a. H1 antagonists(first,second&third generations)

b. H2 antagonists

c. H3 antagonists

3.Drugs having dual action7/10/2014

GENERAL STRUCTURE OF ANTIHISTAMINES

STRUCTURAL REQUIREMENTS:

Ar is aryl:Phenyl, substituted phenyl,hetero aryl groups like 2- pyridyl.

Ar1: Second aryl (or) aryl methyl group.

X: Connecting atom of O, C, (or) N.

(CH2)n: Carbon chain usually ethyl.

NRR1: Basic, terminal amine functional group.

X

Ar

Ar1

CH2 N

R

R1

n

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DRUGS THAT BLOCK THE HISTAMINE RELEASE

O

O

O

OCH3

CH3

OCH3

KHELLIN

O

O

COO

OCH2CHCH2O

OH

O

O

COO Na

CROMOLYN SODIUM7/10/2014

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• These drugs act by stabilizing the mast cells & inhibit the

release of histamine & other mediators of inflammation.

• Natural product KHELLIN led to the development of bis

compounds.

• CROMOLYN nasal solution used for the prevention &

treatment of allergic rhinitis.

• Oral concentrate used to treat the histaminic symptoms of

mastocytosis.

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DRUGS THAT BLOCK THE RELEASED HISTAMINE

a) H1 ANTAGONISTS(FIRST GENERATION DRUGS):

• These are classical antihistamines.

• These are clinically used in the treatment of histamine mediated

allergic conditions like allergic rhinitis, allergic conjuctivitis etc.,

CLASSIFICATION:a) Amino alkyl ethers.

b) Ethylenediamine derivatives.

c) Propyl amine derivatives.

d) Phenothiazine derivatives.

e) Piperazine derivatives.7/10/2014

a) AMINO ALKYL ETHERS (ETHANOLAMINES)

General structure:R

Ar

Ar1

O (CH2)2 N CH32

DIPHENHYDRAMINE

DRUG Ar Ar1 R CHEMICAL NAME

HN,N-Dimethylethanamine.

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2-[α-[2-(dimethylamino)ethoxy]-α-methylbenzyl pyridine.

N

DOXYLAMINE.

CLEMASTINE.

Cl

2-[2-[1-(4-ChloRo phenyl)-1-Phenyl-ethoxy]Ethyl]1-Methyl pyrrolIdine.

CH3

CH3

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STRUCTURE ACTIVITY RELATIONSHIP

These are characterized by presence of OXYGEN connecting moiety.

Most compounds in this series are simple N,N-dimethyl ethanolamine

derivatives.

CLEMASTINE differs from basic structural pattern.

Most amino alkyl ethers are optically active.

The drugs in this group possess significant anticholinergic activity,

which may enhance the H1 blocking action on exocrine secretion.

This amino alkyl ethers have to penetrate the BBB and occupy central

H1 receptor resulting the DROWSINESS.

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b) ETHYLENEDIAMINE DERIVATIVES:

GENERAL STRUCTURE:

N CH2 CH2 N

R

R1

Ar

Ar1

DRUG Ar Ar1CHEMICAL NAME

TRIPELENNAMINE

CH2

N

2-[Benzyl[2-(dimeThylamino)ethyl]-Amino]pyridine

METHAPYRILENE S

CH2 N

2-[2-(DimethylAmino)ethyl]2-Thienylamino Pyridine.

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THONZYLAMINE

CH2H3CO

N

N 2-[2-DimethylaminoEthyl](p-methoxyBenzyl amino]pyrimidine

SAR:

These are characterized by NITROGEN connecting atom.

Phenbenzamine was first clinically useful member.

Replacement of phenyl moiety of Phenbenzamine with a 2-pyridyl system

yielded “tripelennamine”

Replacement of benzyl group of tripelennamine with a 2-thienylmethyl

group provided methapyriline.

Replacement of tripelennamine with -2-pyridyl group with a pyrimidinyl

moiety yields thonzylamine.

The anticholinergic & antiemetic action of these compounds are low.7/10/201419

C) PROPYLAMINE DERIVATIVES:

1. SATURATED ANALOGUES:

GENERAL STRUCTURE:

Ar

Ar1

CH2CH2 N CH3 2

DRUG Ar Ar1 CHEMICAL NAME

PHENIRAMINE

N

2-[α-[2-DimethylAmine ethyl]Benzyl]pyridine.

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CHLORPHERINAMINE Cl

N

2-[P-Chloro-α[2-Dimethyl amino)Ethyl]benzyl]-pyridine

SAR:

Phenyl substituent at P-position replaces with “Cl” is chlorpheniramine &

“Br” is bromopheniramine.

These halogenated pheniramines are more potent & have a longer duration

of action.

The agents in this class produce less sedation than the other classical

antihistamines.

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2) UNSATURATED ANALOGUES:

N

Ar

Ar1

PYRROBUTAMINE

TRIPROLIDINE

DRUG Ar Ar1

Cl CH2 N

CH3

N 7/10/201422

d) PHENOTHIAZINE DERIVATIVES:

GENERAL STRUCTURE:

N

S

R

CHEMICAL NAME

(±)10-[2-(Dimethylamino)propyl]phenothiazine

TRIMEPRAZINE

(±)10-[3-(Dimethylamino)-2-methylpropyl]phenothiazine.

DRUG R

PROMETHAZINE

CH2

CH3

N(CH3)2

CH2 CH2N(CH3)2

CH3 7/10/201423

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SAR

Phenothiazine derivatives that contain a 2/3 carbon branched alkyl chain

between alkyl chain between the ring system and terminal nitrogen atom.

This differs the phenothiazine’s from antipsychotic series in which an

unbranched propyl chain is required.

PROMETHAZINE, the parent member of this series is moderately potent &

with prolonged action & pronounced sedative side effects.

The combination of lengthening of side chain & substitution of lipophilic

groups in 2nd position of aromatic ring results in compounds with decreased

antihistaminic activity & increased psychotherapeutic properties.

These compounds undergo mono-di & N-dealkylation,sulfur oxidation, aromatic oxidation at 3rd position to yield phenol & N-oxidation.

METABOLISM:

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DIBENZOCYCLOHEPTANES & DIBENZOCYCLOHEPTENES

N

CH3

CYPROHEPTADINE

.HCl

X

N

RAZATIDINE

These are the phenothiazine analogues in which sulfur atom is replaced

by an isosteric vinyl group (cyproheptadine) or saturated ethyl bridge

(AZATIDINE). 7/10/201425

e) PIPERAZINE DERIVATIVES:

GENERAL STRUCTURE:

N N

R

R1

CHEMICAL NAME

CYCLIZINE 1-(Diphenylmethyl)-4-methyl piperazine.

DRUG R R1

H CH3

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CHLORCYCLINE 1-(P-Chloro-α-phenylbenzyl)-4-methyl piperazineCl CH3

MECLIZINE ClCH3

1-(P-Chloro-α-Phenyl benzyl)-4-(m-methylBenzyl)piperazine.

SAR:These are ETHYLENE DIAMINE derivatives.

Connecting moiety(X) is CHN group.

These are moderatly potent, with low incidence of drowsiness. slow onset

of action & exhibit peripheral & central antimuscarnic activity.

Primary structural difference is nature of para aromatic ring substituent.7/10/201427

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MECHANISM OF ACTION

• H1 antagonists act by competitively inhibiting the effects of histamine

at H1 receptor.

• H1 receptor blockade results in decreased vascular permeability,

reduction of pruritus, relaxation of smooth muscle in the respiratory,

GIT.

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H1 ANTAGONISTS (FIRST GENERATION)

These are classical antihistamines.

These are clinically used in the treatment of histamine mediated

allergic conditions.

These are mainly used in allergic rhinitis, allergic conjunctivitis,

allergic dermatological conditions.

ADVERSE EFFECTS:

The main adverse effect of H1 antagonists first generation is SEDATION.

This is evidenced by drowsiness, diminished alertness.

This is due to their relative lack of selectivity for the PERIPHERAL H1

RECEPTOR,.

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SECOND GENERATION H1 ANTAGONISTS(NON-SEDATIVE)

C N CH2CH2CH2CH

OHOH

TERFENADINE

C N CH2CH2CH2CH

OH

C

COOH

OH

FEXOFENADINE

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CH N NO OH

O

CETIRIZINE

Cl

• These have a relative low affinity for central H1 receptors & largely free

from sedation.

• The 2nd generation drugs have little affinity for muscarnic,adrenergic

receptors.

• TERFENADINE is a long acting H1 antagonist.

• FEXOFENADINE is a primary oxidative metabolite of TERFENADINE&

does not cross the BBB. 7/10/201431

THIRD GENERATION H1 ANTIHISTAMINES

These are active metabolite derivatives of second generation drugs

intended to have increased efficacy with fewer adverse drug reactions.

N

Cl

N

COOC2H5

LORATIDINE

N

NH

H COOH

CH3

ACRIVASTINE

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H2 ANTAGONISTS

HN N

CH2SCH2CH2NH C NHCH3CH3

NCH

CIMETIDINE

N

SN

CH2SCH2CH2NH C NH2

NH2

NH2

NSO2NH2

FAMOTIDINE

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O

CH2SCH2CH2NH C NHCH3

N CHNO2

CH3

CH3

RANITIDINE

S N

N

CH3

CH3

CH2SCH2CH2NH NHCH3C

CHNO2

NIZATIDINE

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SAR & STRUCTURAL REQUIREMENTS:GENERAL FORMULA FOR H2 ANTAGONISTS:

BASIC HETEROCYCLE

GROUP

FLEXIBLE CHAIN/

AROMATIC RINGPOLAR GROUP

The imidazole ring of histamine is not required for competitive antagonism

of histamine at H2

Separation of ring & nitrogen group with the equivalent of 4 carbon chain

is necessary for optimum antagonist activity.

The terminal nitrogen group should be polar,non-basic substituents for

maximal activity.

These are the result of modification of histamine structure.

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SAR STRUCTURE

HN N

NH2

HISTAMINE:H1=H2 Agonism

5-Methylhistamine:H2>H1 Agonism

HN N

NH2CH3

N-Guanylhistamine:Partial H2 agonist (weak – antagonist)

HN N

NH C NH2

NH

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Burimamide:Full H2 Antagonist. low potency HN N

CH2CH2 NH C NHCH3

S

Metiamide:Full H2 antagonist. Higher potency HN N

SCH2CH2 NH C NHCH3

S

CH3

Cimetidine:Full H2 antagonist Higher potency HN N

SCH2CH2 NH C NHCH3CH3

N

CN7/10/201437

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H3 ANTAGONISTSGeneral structure:

Hetero cycle A chain B chain Lipophilicgroup

Polar group

DRUGS:

This THIOPERAMIDE was first potent H3 antagonist used to treat sleep disorders.

HN

NN C

S

NH

THIOPERAMIDE

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H4 ANTAGONISTS

O

(CH3)2N(H2C)2HC

DOXEPINE

N

S

(CH2)3 N (CH3)2

Cl

CHLORPROMAZINE

This DOXEPINE, CHLORPROMAZINE are bind to the H4 receptor

with high affinity.

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DRUGS HAVING DUAL ACTION

N

H3C

NN

Cl

O

AZELASTINE

OO

HO

NH3C

CH3

OLOPATIDINE

• Both the drugs having the action of antihistaminic & mast cell

stabilization.

• Both are used in allergic conjunctivitis. 7/10/201440

DRUG CHEMICAL STRUCTURE

OMEPRAZOLE

LANSOPRAZOLE

USES OF ANTIHISTAMINES

ALLERGIC DISORDERS:

They effectively control certain immediate type of allergies like itching,

urticaria, seasonal hay fever, allergic conjunctivitis & angioedema of lips

eyelids etc.,

CETIRIZINE have adjuvant role in seasonal asthma.

PRURITIS:

Antihistamines are first choice of drugs for idiopathic pruritus.

COMMON COLD:

They donot effect the illness but may afford sympatomatic relief by

anticholinergic & sedative actions.

As hypnotics eg: diphenhydramine & promethazine. 7/10/201441

PANTAPRAZOLE

RABEPRAZOLE

As “anti-tussives” Eg: diphenhydramine.

As “anti-emetic” Eg: meclizine

In “parkinsonism” Eg: promethazine , diphenhydramine.

In drug induced “acute dystonias” Eg: diphenhydramine,

promethazine.

To treat “motion & morning sickness” Eg: cyclizine,

promethazine.

To treat “vertigo” conditions Eg: cinnarizine.

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CONCLUSION

Histamine is an important chemical messenger that

exhibits significant physiological effects mediated

through its receptor. A thorough knowledge of drugs

is very much useful to treat the clinical conditions

arising due to imbalance of histamine in the body.

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REFERENCES

JOHN H.BLOCK & JOHN M WILSON& GISVOLD’S

Organic Medicinal & Pharmaceutical chemistry.

(Pg): 698 – 728

D.SRIRAM & P.YOGEESWARI -Medicinal chemistry.

(Pg): 278 – 302

BERTRAM G.KATZUNG, SUSAN B.MARTERS

ANTHONY J.TREVOR Basic & Clinical pharmacology

(Pg) : 277

K.D TRIPATHI Essentials of medical pharmacology.

(Pg): 159 – 160.7/10/2014

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FOYE’S Principles of medicinal chemistry.

(Pg) NO: 1045.

KATZUNG- Basic & clinical pharmacology.

(Pg) NO: 277.

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ACKNOWLEDGEMENT

• I would like to thank my guide

Mr. K.V.S. Santosh Kumar for his valuable support and guidance.

• I also like thank our Principal Dr. P. Srinivasa Babu and the seminar committee for their valuable suggestions.

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