Antihistaminic agents

Histamine [4-(2-aminoethyl)imidazole]occurs in mast cell , blood basophiles and acid secreting

parietal cells. Antigens derived from food products, pollens, dust and human hair releases histamine
and causes serious allergic reaction. The physiological action of histamine is due to their action on
histamine receptors (H1, H2 and H3).

Histamine
Antihistaminic agents (Histamine H1 receptor antagonist/ Classical antihistaminics):
These are drugs which competitively antagonise the action of histamine at H1 receptor.
Classification of antihistaminic agents (Histamine H1 receptor antagonist/ Classical
antihistaminics):
Antihistaminic agents are classified chemically into different classes.
(i) Aminoalkyl ether derivatives:

Diphenhydramine Bromodiphenhydramine

(ii) Ethylenediamine derivatives:

Mepyramine (pyrilamine) Tripelennamine

(iii) Piperazine derivatives:

Cyclizine Chlorcyclizine

(iv) Phenothizine derivatives:

Promethazine Trimeprazine

(v) Propylamine derivatives:

a) Saturated analogs:

Pheniramine Chlorpheniramine

b) Unsaturated derivatives:

Triprolidine
 1. Synthesis of Diphenhydramine

Uses:
 diphenhydramine is used in allergic disorders like itching, utricaria, sesonal hay fever and
allergic conjunctivitis.
 Used in motion sickness.
2. Synthesis of Mepyramine (pyrilamine)

 Mepyramine is used in allergic disorders like itching, utricaria, sesonal hay fever and allergic
conjunctivitis.
3. Synthesis of Cyclizine

 cyclizine is used in allergic disorders like itching, utricaria, sesonal hay fever and allergic
conjunctivitis.
 4. Synthesis of Chlorpheniramine

 They are used in allergic disorders like itching, utricaria, sesonal hay fever and allergic
conjunctivitis.
5. Synthesis of Promethazine

Uses:
 Promethazine is used in motion sickness.
 Used especially as preanaesthetic medication.
 Used for mild symptomatic relief in early parkinsonism.
 They are used in allergic disorders like itching, utricaria, sesonal hay fever and allergic
conjunctivitis.
 6. Synthesis of Cetrizine

Uses:
 They are used in allergic disorders like itching, utricaria, sesonal hay fever and allergic
conjunctivitis.

Mode of action of antihistaminics:

 Antihistaminics usually block the agonist to bind with their receptors. The classical
antihistamine competitively inhibits the binding of histamine to their receptor. While the other
occupy the minimal area (allosteric site) of the receptor cite thereby prevents the access of
histamine through steric hindrance.
 Some antihistaminics also anatagonise the action of serotonin and bradykinin which are
released along with histamine during anaphylaxis reaction.

SAR of antihistaminics:

The basic structural requirements for the first generation antihistaminics is

 In the above structure Ar is aryl (phenyl, substituted phenyl, 2-pyridyl). Ar2 is a second aryl or
arylmethyl group; X is a connecting atom of O,C, or N; (CH2)n represents a carbon chain and
NRR1 represents a basic amino function.
 Diaryl groups:
 The aryl groups are essential for significant H1-receptor affinity. The two aryl moieties must be
able to adopt a nonplanar conformation for interaction with H1-receptor.
 Introduction of a halogen atom (Cl, Br) at para position of the aromatic group increases the
antihistaminic activity e.g. chlorpheniramine is more active than pheniramine.
 For enhanced activity one aromatic moiety should be 2-pyridyl while the other aromatic group
could be benzyl e.g. pyrilamine.
 The two aromatic ring may be linked to form a tricyclic ring e.g. promethazine.
Carbon chain:
 The carbon chain primarily serves as a spacer group. For maximum activity the carbon chain
between the X atom and basic amino group must be ethylene.
 Branching of the carbon chain results in reduced antihistaminic activity, however in case of
promethazine having isopropyl chain is more active than its nonbranched counterpart.
 The carbon chain may be unsaturated leading to formation of E and Z isomer. e.g. E-
pyrrobutamine is more potent than its Z-isomer.
Basic amino group:
 The amino group is important for the development of solid dosage form through salt formation.
 The amino group should be tertiary to exhibit maximum activity.
 The amino group may also be the part of heterocyclic ring e.g. piperazine in cyclizine.
Nature of X atom:
 The connecting atom X may be O/N/C.
 The nature of X atom provides the basis of classification
e.g. when X= oxygen (aminoalkyl ether derivatives)
X= nitrogen (ethylenediamines derivatives)
X= carbon (Propylamine derivatives)

H2 receptor antagonist

Drugs that antagonise of the action of histamine at its H2 receptor are called H2 receptor antagonist.

Examples of H2 receptor antagonist are

Cimetidine Ranitidine

Famotidine Roxatidine
Ranitidine

Mode of action H2 antagonist (Ranitidine):

 Rantidine inhibits secretion of HCl from the gastric parietal cells by acting as an antagonist on
H2 receptor.
 They block the H2 receptor and prevent binding of histamine to the same.

Uses:

 Rantidine is used in the treatment of duodenal ulcer, gastric ulcer, gastroesophageal reflux
disease (GERD) and acid indigestion.
 Rantidine is also used in multi drug treatment protocol for eradication of H. pyroli in treatment
of peptic ulcer.
Omeprazole

Synthesis

Mode of action

Omperazole belongs to the category of protein pump inhibitors. It inhibits secretion of acid from the
gastric parietal cells by irreversibly inhibiting the enzyme H+-K+ ATPase.

Uses

 Omeprazole is used in the treatment of duodenal ulcer, gastric ulcer, gastroesophageal reflux
disease (GERD) and acid indigestion.
 Omeprazole is also used in multi drug treatment protocol for eradication of H. pyroli in
treatment of peptic ulcer.