Introduction to Antihistaminic Agents pdf

Histamine exerts its effects primarily by binding to G protein-coupled histamine receptors, designated H1, H2, H3, and H4.�
Histaminic receptors are associated with
H1: Allergic Reponses
H2: Gastric acid regulation
H3: Neurotransmitter release modulation
H4: Immune system function
Classification of Antihistaminic Agents

1. By-
Dr. Prerana B. Jadhav
M. Pharm, Ph.D.
Pharmaceutical Chemistry
Assistant Professor,
SanjivaniCollege of Pharmaceutical Education and Research,
Kopargaon.
Antihistaminic agents

2. What is Histamine?
•Histamineconsistsofanimidazoleringattachedto
anethylaminechain;underphysiologicalconditions,theamino
groupoftheside-chainisprotonated.
•Regulatesphysiologicalfunctionsinthegut.
•Ithasbeenconsideredalocalhormone(autocoid)
•Itactsasaneurotransmitterforthebrain,spinalcord,anduterus.
•Histamineisinvolvedintheinflammatoryresponseandhasa
centralroleasamediatorofitching.
•Aspartofanimmuneresponsetoforeignpathogens,histamineis
producedbybasophilsandbymastcellsfoundinnearbyconnective
tissues.
•Histamineincreasesthepermeabilityofthecapillariestowhiteblood
cellsandsomeproteins,toallowthemtoengagepathogensin
theinfectedtissues.

3. Synthesis and metabolism
•Histamine is derived from thedecarboxylationof
theamino acidhistidine, a reactioncatalyzedby
theenzymeL-histidine decarboxylase.
•Rapidly inactivated by its primarydegradative
enzymes,histamine-N-methyltransferaseordiamine
oxidase.

4. Storage andRelease
•StoredinmastcellsinComplexwithHeparin(anticoagulant)
•StoredinbasophilesinComplexwithChondrotin
•Histamineasstoredinmastcellsarefoundalmost
everywhere:skinandthemucosalcellsofthebronchi,
intestine,urinarytract,andtissuesadjacenttothecirculation
andwithinneuronsofCNS
•Itisreleasedinresponsetoawidevarietyofimmune(antigen
andantibody)andnonimmune (bacterialproducts,
xenobiotics,physicaleffects,andcholinergiceffects)stimuli.

5. Mechanism of action
Histamine exerts its effects primarily by binding to G protein-coupled
histamine receptors, designated H
1, H
2, H
3, and H
4.
Histaminic receptors are associated with
•H1: Allergic Reponses
•H2: Gastric acid regulation
•H3: Neurotransmitter release modulation
•H4: Immune system function

6. R Location Function
H
1
•CNS: in the
histaminergictuberomammillary
nucleus, which projects to thedorsal
raphe,locus coeruleus, and additional
structures.
•Periphery:Smooth
muscle,endothelium,mast cells, sensory
nerves
•CNS:Sleep-wake cycle(promotes wakefulness),body,
temperature,nociception,endocrine homeostasis,
regulatesappetite, involved in cognition
•Periphery: Causesbronchoconstriction,
bronchialsmooth musclecontraction, urinary bladder
contractions,vasodilation, promotes hypernociception
(visceral hypersensitivity), involved initch
perceptionandurticaria.
H
2
Periphery: Located onparietal
cells,vascular smooth muscle
cells,neutrophils,mast cells, as well as on
cells in theheartanduterus
•Periphery: Primarily involved in vasodilation and
stimulation ofgastric acidsecretion.
Urinary bladder relaxation.
Modulates gastrointestinal function.
H
3
Located in thecentral nervous systemand
to a lesser extentperipheral nervous
systemtissue
Autoreceptorandheteroreceptorfunctions:
decreasedneurotransmitterrelease of
histamine,acetylcholine,norepinephrine,serotonin.
Modulates nociception, gastric acid secretion, and food
intake.
H
4
Located primarily onbasophilsand in
thebone marrow. It is also expressed in
thethymus,small intestine,spleen,
andcolon.
Plays a role in mast cellchemotaxis, itch perception,
cytokine production and secretion, and visceral
hypersensitivity. Other putative functions (e.g.,
inflammation, allergy, cognition, etc.) have not been fully
characterized.

7. H1 Receptors
H1 receptors throughout your body, including in neurons (brain cells), smooth
muscle cells of airways and blood vessels
•Itchy skin (pruritus).
•Expanding of blood vessels (vasodilation).
•Low blood pressure (hypotension).
•Increased heart rate (tachycardia).
•Flushing.
•Narrowing of airways (bronchoconstriction).
•Pain.
•Movement of fluids through blood vessel walls (vascular permeability).
•Some of these bodily changes result in sneezing,nasal congestionandrunny
nose(rhinorrhea).
•Outside of allergic reactions, H1 receptors also help to regulate:
•Sleep-wake cycles.
•Food intake.
•Body temperature.
•Emotions.
•Memory.
•Learning.

8. H2 Receptors
•Stomach acid secretion, which helps with digestion.
•Stimulation of mucous glands in your airways.
•Vascular permeability.
•Hypotension.
•Flushing.
•Headache
•Tachycardia.
•Bronchoconstriction.

9. H3Receptors
•H3receptorsaremainlyinvolvedinblood-brainbarrierfunction.
They’refoundinneuronsincentralnervoussystem.H3receptors
regulate the release of histamine
andneurotransmitterslikedopamine,norepinephrineandacetylcholine.
•ResearchersarecurrentlystudyingH3receptorantagonistmedications
forpotentialuseinthetreatmentofneurodegenerativediseases.
H4Receptors
•H4receptorsarepresentinbonemarrowandhematopoieticcells
(immaturecellsthatcandevelopintoalltypesofbloodcells).Theyplay
aroleintheformationofcertainbloodcells.
•Theyalsoplayimportantrolesininflammatorydisorders
andautoimmunediseases.

10. Classification of Antihistaminic Agents
1. H1 Antagonist
a)First generation
•Amino-alkyl ether –diphenhydramine, dimenhydrinate, doxylamine
succinate, clemastinefumarate
•Ethylenediamine-TripelennamineHCl, pyrilamine
•Mono-amino propyl–chlorpheniraminemaleate, triprolidine
•Tricyclicring system-PromethazineHCl, TrimeprazineTartarate
•Miscellaneous-Phenindamine
b) Second Generation
Astemizole, Loratadine, Cetirizine, Levocetrazine, Cromolyn sodium,
fexofenadine
2. H2 Antagonist
Cimetidine, Famotidine, Ranitidine
3. Gastric Proton Pump Inhibitors
Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole

11. SAR of H1 Antihistaminics
1.Nature of Aryl group
2.Nature of X group
3.Nature of Alkyl Chain
4.Nature of terminal nitrogen

12. 1.NatureofArylgroup
•Diarylsubstitutionisessential
•-Cl,-Br,-OCH
3substitutiononarylgroupincreases
activity
•Replacementofoneofthearomaticringswith2-pyridylgroup
increaseshistaminicselectivity
•AlkylSubstitutioninthesearomaticringsinfluenceselectivity
•IncreasingalkylsubstituionsatC2increasesanticholinergic
activityanddecreasesantihistaminicactivity
•IncreasingalkylsubstituionsatC4decreasesanticholinergic
activityandmodestlyincreasesantihistaminicactivity

13. 2.NatureofXgroup
•ThenatureofXprovidesbasisforchemicalclassification
ofantihistaminic.
When,X-Oxygen(Aminoalkyletheranalogue)
X-Nitrogen(Ethylenediaminederivative)
X-Carbon(Monoaminopropylanalogue)
3.Natureofalkylchain
•Ethylenechainisimportant
•Extensionorbranchingwillresultinlessactivecompound

14. MOA
•H
1antagonistsactbycompetitivelyinhibitingtheeffectsof
histamineatH
1receptor.
•H
1receptorblockaderesultsindecreasedvascular
permeability,reductionofpruritus,relaxationofsmooth
muscleintherespiratory,GIT.

15. Chemical Classification of H1 Antagonist
A) EthylenediamineDerivative
Example: TripelennamineHClN CH
2
CH
2
N
CH
3
CH
3N

16. •MOA:
BindswithH1receptor.Blockstheactionofendogenous
histaminewhichleadstotemporaryreliefofnegative
symptomsassociatedwithhistaminerelease.
Uses:
Antiprurtic,asthama,rhinitis,urticaria.
Sideeffects:
Sedation,irritation,drymouth,dizziness

17. B) Aminoalkylether analogue
•Example
Diphenhydramine
•MOA: Blocks H1 receptor. Rapidly cross BBB acts as
anticholinergic, produces sedation. Acts as antimuscarinic
used in treatment of Parkinsonism.O CH
2
CH
2
N
CH
3
CH
3
H

18. •Doxylaminesuccinate
•Used in allergy, used as an antitussive, antiemetic and
hypnoticO CH
2
CH
2
N
CH
3
CH
3
CH
3
N

19. ClemastineFumarateO CH
2
CH
2
CH
3
N
Cl
N
CH
3
HHOOC
H COOH

21. C) Cyclic basic chain analoguesCHN NR
2
X
Example:
ChlorcyclizineCHN NCH
3
Cl
Uses: Urticaria, Rhinitis,
pruritus, and other allergic
symptoms

22. •Meclizine
•BuclizineCHN N
Cl
CH
3
MOA: H1 antagonist with anti
emetic, anticholinergicactivity
Uses: Used to treat motion
sicknessCHN N
Cl
CH
3
CH
3
CH
3
Uses: prevention and
treatment of nausea,
vomiting, and dizziness
associated with motion
sickness.

23. D) Monoaminopropylanalogue

24. •Use: Symptomatic relief of hypersensitivity reaction,
cough and common cold.

25. E) Tricyclicring system

26. F) Miscellaneous

31. Cromolynsodium

32. Adverseeffectsof Antihistaminic
agents

33. Fig:EffectsofH
1antihistaminesathistamine,adrenergic,cholinergic,andserotonin-binding
receptors.Manysecondgenerationantihistaminesdonotenterthebrainand,therefore,
showminimalCNSeffects.

35. SAR& STRUCTURALREQUIREMENTS:
GENERAL FORMULA FOR H
2ANTAGONISTS:
BASIC
HETEROCYCLE
GROUP
FLEXIBLE
CHAIN/
AROMATIC RING
Thesearetheresultofmodificationofhistaminestructure.
Theimidazoleringofhistamineisnotrequiredforcompetitiveantagonism
ofhistamineatH
2
Separationofring&nitrogengroupwiththeequivalentof4carbonchain
isnecessaryforoptimumantagonistactivity.
Theterminalnitrogengroupshouldbepolar,non-basicsubstituentsformaximal
activity.
35

36. H
2ANTAGONISTS
FAMOTIDINE
33

37. H
2ANTAGONISTS
CIMETIDINE
33

38. 34
RANITIDINE

39. USES OFANTIHISTAMINES
ALLERGIC DISORDERS:
They effectively control certain immediate type of allergies like itching,
urticaria, seasonal hay fever, allergic conjunctivitis & angioedemaof lips
eyelids etc.,
CETIRIZINE have adjuvant role in seasonal asthma.
PRURITIS:
Antihistamines are first choice of drugs for idiopathic pruritus.
COMMON COLD:
They do not effect the illness but may afford sympatomaticrelief by
anticholinergic& sedative actions.
As hypnotics eg: diphenhydramine & promethazine.
41

40. Synthesis of Diphenhydramine

41. PromethazineHydrochloride

42. Ranitidine
Ranitidine,issynthesizedfromfurfurylalcohol,whichundergoes
aminomethylationreactionusingdimethylamineandformaldehyde,which
form5-(dimethylaminomethyl)furfurylalcohol.Furtherreactionwith2-
mercaptoethylaminehydrochloridegivesaproductofsubstitutionofthe
hydroxylgroup,5-dimethylaminomethyl-2-(2′-aminoethyl)thiomethylfurane.
ReactingthiswithN-methyl-1-methylthio-2-nitroethenaaminegives
ranitidine.

43. O
CH
2
OH+
HCHO+
NH
CH
3
CH
3
Furfuryl alcohol FormaldehydeDimethylamine
SH CH
2
CH
2
NH
22 - mercaptoethyl amine
O
CH
2
OHCH
2
N
CH
3
CH
3
(5 - dimethylaminomethyl) furfuryl alcohol
O
CH
2
N
CH
3
CH
3
CH
2
SCH
2
CH
2
NH
2
5 - dimethylaminomethyl -2 -(2 - aminoethyl) thiomethylfurane
CH
SH
3
C
HNH
3
C
NO
2
N -methyl -1 - methylthio -2 - nitroethanamine
O
CH
2
N
CH
3
CH
3
CH
2
SCH
2
CH
2
NHCNHCH
3
CH
NO
2Ranitidine