Nonsedative H1-antihistamines (H1-antagonists)

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Chapter: Medicinal Chemistry : Antihistamines

Antihistamines - > Nonsedative H1-antihistamines (H1-antagonists) - > 1. Cetirizine (Zirtin, Cetin, Cetzine) 2. Loratadine (Alaspan, Lorfast) 3. Epinastine 4. Rocastine - Synthesis and Drug Profile


Nonsedative H1-antihistamines (H1-antagonists)


1. Cetirizine (Zirtin, Cetin, Cetzine)


Route I. From: 1-[4-Chlorophenyl (1-phenylmethyl)]-piperazine

Route II. From: hydroxyzine

Cetirizine is an acid metabolite formed by the oxidation of primary alcohol of antihistamine hydroxyzine.

Properties and uses: Cetirizine hydrochloride is a white powder, soluble in water, practically insoluble in acetone and methylene chloride. This is the principal metabolic product of hydroxyzine, the polar acid group prevents its penetration into the CNS. It is used as an antihistamine to treat various allergic conditions. Cetrizine is one of the most widely prescribed H1-antihistamines. It is highly selective in its interaction with various hormonal binding sites and highly potent as well. Other effects of this drug include fatigue, dry mouth, pharyngitis, and dizziness.

Assay: Dissolve the sample in a mixture of water and acetone (1:7) and titrate against 0.1 M sodium hydroxide to the second point of inflexion and determine the end point potentiometrically.

Dose: Usual dose is 5–10 mg thrice/day.


2. Loratadine (Alaspan, Lorfast)

4-(8-Chlor-5,6-dihydro-benzocyclohepta pyridine-11-ylidene)-1-piperidine carboxylic acid ethylester


Metabolism: It is a nonsedative antihistaminic drug. The metabolite is desloratidine (descarboethoxy loratidine) is associated with potentially cardiotoxic effect.

The metabolic conversion of loratidine to descarboethoxy loratidine occurs via oxidative process and not via hydrolysis, and both CYP2D6 and CYP3A4 are to be the isoenzyme catalyzing this oxidative metabolism.

Properties and uses: Loratadine is a white crystalline powder, practically insoluble in water, soluble in acetone and methanol. Loratadine is an azo isomer of cyproheptadine. The replacement of methyl group of azatadine (piperidine nitrogen) by corresponding carbomate and introduction of 8-chloro substitution preserve the antihistaminic action and reduces the CNS effect. The potency of loratidine is comparable with that of astemizole and greater than of terfenadine.

Assay: Dissolve the sample in glacial acetic acid and titrate against 0.1 M perchloric acid. Determine the end point potentiometrically.


3. Epinastine

Properties and uses: This is structurally related to the antidepressant and nonsedative H1-receptor antagonist mianserin. Introduction of an amidine moiety preserve the antihistamine action and reduce the CNS effect (sedation).


4. Rocastine

Properties and uses: It is a rapid acting, nonsedating H1-antagonist. The R-enantiomer was at least 300 times more potent than S-enantiomer.

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