antihistamines

1. H1 AND H2 RECEPTOR BLOCKERS
PREPARED BY: ARZOO DHARASANDIA GUIDED BY: UTTAM MORE
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
SHREE DHANVANTARY PHARMACY COLLEGE, KIM

2. HISTAMINE
 Histamine is an organic nitrogenous compound involved in local
immune responses as well as regulating physiological function in the
gut and acting as a neurotransmitter for the brain, spinal cord and
uterus.
 Histamine is involved in the inflammatory response and has a
central role as a mediator of itching. As part of an immune response
to foreign pathogens, histamine is produced by basophils and by
mast cells found in nearby connective tissues.

3. Synthesis and metabolism
 Histamine is derived from the decarboxylation of the amino
acid histidine, a reaction catalyzed by the enzyme L-histidine
decarboxylase. It is a hydrophilic vasoactive amine.
 Once formed, histamine is either stored or rapidly inactivated by its
primary degradative enzymes, histamine-N-
methyltransferase or diamine oxidase. In the central nervous
system, histamine released into the synapses is primarily broken
down by histamine-N-methyltransferase, while in other tissues both
enzymes may play a role.

4. Synthesis and metabolism

5. HISTAMINE AND ITS RECEPTORS
 H1 – Smooth muscle, endothelium, CNS.- Bronchoconstriction,
vasodilation, separation of endothelial cells, pain and itching, allergic
rhinitis, motion sickness.
 H2 – gastric parietal cell, basophils. Regulate gastric acid secretion,
inhibition of IgE-dependent degranulation.
 H3 - CNS cells, and some in peripheral NS. Presynaptic, feedback
inhibition of histamine synthesis and release. They also control
release of DA, GABA, ACh, 5-HT & NE.
 H4 - Highly expressed in bone morrow and white blood cells.
Mediate mast cell chemotaxis..

7. ANTIHISTAMINES
 Histamine has no therapeutic applications, but drugs that block
its effects at H1 and at H2 receptors are very important in
clinical medicine.
 veryless antagonists of H3 or H4 receptors are currently
available for clinical use.
 H1 antihistamines antagonize all actions of histamine except
for those mediated by H2 receptors.

8. CLASSIFICATION OF ANTIHISTAMINES

9. H1 RECEPTOR BLOCKERS
 1st generation h1 blockers
 Aminoalkylethers(ethanolamines): Ex.
Diphenhydramine,dimenhydrinate,doxylamine succinate
 Ethylenediamines: Ex Tripelennamine,pyrilamine
maleate,antazoline phosphate
 Propylamine derivatives: Ex. Chlorpheniramine,pheniramine
maleate.
 Phenothiazine derivatives: Ex. Promethazine,trimeprazine
tartrate.
 Piperazine derivatives: Cyclizine,chlorocyclizine,meclizine
 Debenzocycloheptenes: Cyproheptadine, azatadine
 Miscellaneous drug: Diphenyl pyraline

10. Second-Generation antihistamines.
 The second-generation antihistamines bind only to peripheral H1
receptors, and reduce allergic response with little or no sedation.
 These newer agents are structurally divers, but are derivatives of
first generation drugs.
 The new second generation drugs currently on the market include:
 Acrivastine
 Cetrizine and levocetrizine
 Desloratadine and loratidine
 Fexofenadine
 terfenadine

11. SAR OF 1ST GENERATION H1 BLOCKERS
A protonatable amine
A connecting atom X which can be O, C or N
A carbon chain, usually ethyl
Variations in the diaryl groups, connecting moiety, substituents
on the connecting moiety, and substituents on the terminal
nitrogen account for the differences observed in potency as well
as pharmacologic, metabolic, and adverse reaction profiles.

12. SAR OF 1ST GENERATION H1 BLOCKERS
 The nitrogen should be 3° in nature for maximum antihistaminic activity. The
‘N’ may also form a part of heterocyclic moieties like piperidine, or
piperazine or diazocine.
 Generally two aromatic rings - phenyl, benzyl, or an isostere such as pyridyl;
Pyridyl generally results in more potent compounds than phenyl.
 The group present between nitrogen atom and group X may be saturated or
unsaturated or substituted.
 The Ar group may be aryl or heteroaryl, which may be substituted.

13. SAR OF 1ST GENERATION H1 BLOCKERS
 X
 Atom X can be an oxygen, nitrogen, or carbon, which links the side chain to an
“aromatic tail.” The nature of atom X is the basis for the structural classification
of H1 antagonists. The classical H1 antagonists are divided into six classes based
on what X equals:
 X =C–O: (Aminoalkyl Ethers)
 1. Ethanolamines
 X = C:
 2. Propanolamines (clemastine, diphenylpyraline)
 3. Propylamines (Saturated and Unsaturated)
 X = N:
 4. Ethylenediamines
 5. Piperazines (Cyclizines) and Tricyclics.

14. chlorpheniramine dhiphenhydramine
pyrilamine

15. AMINOALKYL ETHERS
 Derivatives of N,N-dimethyl ethanolamines.
 Characterised by the CHO connecting Moiety between the key diaryl
and tertiary amino groups and a two or three carbon moiety.
 The simple diphenyl derivative diphenhydramine was the firt clinically
useful member of the ethanolamines series and serves as a prototype.

16. AMINOALKY ETHERS
 Replacement of one of the phenyl rings of the
diphenhydramine with a 2-pyridyl group, as in doxylamine
enhances the antihistaminic activity.
 The diaryl tertiary aminoalkyl ether structure serves as a
pharmacophore for the muscarinic receptors.
 Drowsiness ,as well as other CNS effects, is a common side
effect of tertiary amino alkyl ethers because of the ability
of these compounds to penetrate BBB and bind to the
central H1 receptors.
 Conversion to a quaternary ammonium salt does not alter
the antihistaminic activity but does increases in
anticholinergic action.

17. AMINOALKYL ETHERS
Diphenhydramine HCL
Doxylamine
carbinoxamine bromodiphenhydramine

18. Bromodiphenhydramine synthesis

19. ETHELENDIAMINES
 R1 and R2 should be small (CH3) for maximum H1-antagonist activity.
 Ar1 and Ar2 can be benzene ring or any other isosteric rings such as
heterocycles.
 One of the aromatic should be benzyl for better activity which has P-
substitution.
Isosteric rings to benzen

20. ETHELENDIAMINE
methapyrilene

21. Piperazines
 Are derivatives of the piperazine nucleus
 They are the cyclic analogues of ethelendiamines.

22. USES
 They have mainly CNS depressant effects.
 Main uses:
 In allergy.
 As antiemetic agents.
 In motion sickness.
CYLIZINE
1-(diphenylmethyl)-4-methyl piperazine.

23. PIPERAZINES

24. Phenothiazines
 Possess a tricyclic system
 Phenothiazine derivatives possess two or three carbon chain bridge between
basic phenothiazine nucleus and terminal nitrogen.

25. promethazine
 10-(2- dimethylaminopropyl) phenothiazine

26. 2nd generation h1 blockers
 Piperazine derivative
 CETIRIZINE and levocetrizine
 Piperidine derivative
 FEXOFENADINE
 TERFENADINE
 dibenzepines
 LORATADINE
 DESLORATADINE
 AZELASTIN
USES:
ALLERGY
URTICARIA
COMMON COLD

27. 2nd generation drugs
 The second generation antihistamines are more similar pharmacologically than
structurally.
 Structurally they are all diaryl substituted piperazines (cetirizine) or piperidines
(all others).
 As discussed earlier in this module, these compounds were developed as selective
H1-receptor antagonists with relatively high potency.
 Most of these compounds also produce prolonged antihistaminic effects as a
result of slow dissociation from H1-receptors, and the formation of active
metabolites with similar receptor binding profiles.
TERFENADINE
FEXOFENDINE

28.  The second generation agents have little affinity for muscarinic, adrenergic or
serotonergic receptors and therefore display a lower degree of side effects
associated with antagonism at these receptors, but their affinities for these
receptors is somewhat variable.
 Generally, the large aralkyl groups or polar groups linked to the
piperidine/piperazine rings of these compounds reduces their affinity for
muscarinic or adrenergic receptors.
CETRIZINE

29. loratadine
 Loratadine is a non–sedating H1 antagonist with no anticholinergic side effects
 Introduction of a Cl and carboxyethyl increases potency
 Since carbamate nitrogen is neutral rapidly absorbed and quick acting
 Metabolized by CYP3A4 and 2D6 directly to Desloratadine via an oxidative
process without hydrolysis
 Prodrug??

30. H2 receptor blockers
 -Cimetidine ( Tagamet)
 -Ranitidine ( Zantac)
 -Famotidine (Pepcid , Pepcid AC) - Nizatidine ( Axid)
 These products have been approved for the relief of
“heartburn associated with acid indigestion, and sour
stomach.” They should not be taken for longer than 2
weeks and are not recommended for children < 12 years
of age.

31. What conditions are they used to treat?
 -To reduce acid reflux which may cause heartburn or inflammation of the
gullet (esophagitis). These conditions are sometimes called
gastroesophageal reflux disease (GERD).
 -To treat ulcers in the stomach and in part of the gut (the duodenum).
 -To help heal ulcers associated with anti-inflammatory medication called
non-steroidal anti-inflammatory drugs (NSAIDs).
 -In other conditions where it is helpful to reduce acid in the stomach.
 Also :
 -Damage to the stomach and/or intestines due to stress or
trauma, Hives
 -Pancreatic problems
 -Stomach or intestinal ulcers (sores) resulting from damage caused by
medication used to treat rheumatoid arthritis.

33. MOA of h2 blockers
 The H2 antagonists are competitive antagonists of histamine at parietal cell
H2 receptor .
 They suppress the normal secretion of acid by parietal cells and the meal –
stimulated secretion of acid .
 They accomplish this by two mechanism : Histamine released by ECL
(enterochromaffin – like) cells in the stomach is blocked from binding on
parietal cell H2 receptor , which stimulate acid secretion : therefore other
substances that promote acid secretion ( such as gastrin and acetylcholine )
have a reduce effect on parietal cell when the H2 receptors are blocked

34. Side effects of h2 blockers
 Some of the side effects that may occur with H2 receptor blockers include:
 -constipation
 -diarrhea
 -difficulty sleeping
 -dry mouth
 -dry skin
 -headaches
 -ringing in the ears
 -a runny nose
 -trouble urinating

35. SAR
 The First approach in synthesizing H2-antagonists was the use of Histamine as
the lead compound to produce antagonist activity.
 Can be done by:
 Adding extra hydrophobic group to the structure.
 Varying the polar amino group.
 Make extension to the ethyl linker between the amino and the imidazole ring.

36. SAR

37. SAR
 The next approach was to vary the polar groups in histamine with other polar
functional groups.
 The first derivative was N-guanylhistamine:
 Has a weak H2-antagonist (partial agonist).
 The guanidine moiety has a positive charge at physiological pH which will be
distributed over the three nitrogen atoms.

38. N-guanylhistamine as a lead

39.  * The imidazole ring proofed to be important for both agonist and antagonist
binding. So the pka of this ring should be closer to the histamine one (5.74).
 * The pka of imidazole from burimamide is 7.25 which means that around 40%
of the imidazole ring is ionized.
 * The side chain of burimamide should be electron withdrawing to make the
pka of the ring close to 5.74.

40.  Guanylhistamine provided the lead.
 Extension of the side chain increased anti H2 potency
but some agonist activity remained.
 Replacing the basic guanidino group with the neutral
thiourea yielded effective H2 antagonists.
 Burimamide lacked agonist action but was not orally
absorbed
 In Metiamide (1) reduce the pKa of the ring N,
reduced ionization, increased membrane permeability
and absorption and 10X more potent than
Burimamide,
 (2) cause the tautomer to predominate which
interact with H2 But caused kidney damage and
granulocytopenia, possibly due to the thiourea so was
replaced by the isosteric guanidine.
 This compound being highly basic was 20 times less
potentReplacement of this group with strong electron
withdrawer but more lipophilic cyano derivative
yielded Cimetidine.

42. references
 1) https://en.wikipedia.org/wiki/H2_antagonist
 2) Wilson and gisvold’s textbook of organic medicinal and pharmaceutical
chemistry.

43. THANK YOU