Antihistamine: Encyclopedia II - Antihistamine - First-generation H₁-receptor antagonists

Antihistamine - First-generation H₁-receptor antagonists

These are the oldest antihistaminergic drugs and are relatively inexpensive and widely available. They are effective in the relief of allergic symptoms, but are typically moderately to highly potent muscarinic acetylcholine receptor-antagonists (anticholinergic) agents as well. These agents also commonly have action at α-adrenergic receptors and/or 5-HT receptors. This lack of receptor-selectivity is the basis of the poor tolerability-profile of some of these agents, especially compared with the second-generation H₁-antihistamines. Patient response and occurrence of adverse drug reactions vary greatly between classes and between agents within classes.

The first H₁-antihistamine discovered was piperoxan, by Forneau and Daniel Bovet (1933) in their efforts to develop a guinea pig animal-model for anaphylaxis. Bovet went on to win the 1957 Nobel Prize in Physiology or Medicine for his contribution. Following their discovery, the first-generation H₁-antihistamines were developed in the following decades. They can be classified on the basis of chemical structure, and agents within these groups have similar properties.

Antihistamine - Ethylenediamines

Ethylenediamines were the first group of clinically-effective H₁-antihistamines developed.

• mepyramine (pyrilamine)
• antazoline

Antihistamine - Ethanolamines

Diphenhydramine was the prototypical agent in this group. Significant anticholinergic adverse effects, including sedation, are observed in this group but the incidence of gastrointestnal adverse effects is relatively low. (Nelson, 2002; Rossi, 2004)

• diphenhydramine
• carbinoxamine
• doxylamine
• clemastine
• dimenhydrinate

Antihistamine - Alkylamines

The isomerism is a significant factor in the activity of the agents in this group. E-triprolidine, for example, is 1000-fold more potent than Z-triprolidine. This difference relates to the positioning and fit of the molecules in the histamine H₁-receptor binding site. (Nelson, 2002) Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxical CNS stimulation. (Rossi, 2004)

• pheniramine
• chlorphenamine (chlorpheniramine)
• dexchlorphenamine
• brompheniramine
• triprolidine

Antihistamine - Piperazines

These compounds are structurally-related to the ethylenediamines and the ethanolamines; and produce significant anticholinergic adverse effects. Compounds from this group are often used for motion sickness, vertigo, nausea and vomiting. The second-generation H₁-antihistamine cetirizine also belongs to this chemical group. (Nelson, 2002)

• cyclizine
• hydroxyzine
• meclizine

Antihistamine - Tricyclics

These compounds differ from the phenothiazine antipsychotics in the ring-substitution and chain characteristics. (Nelson, 2002) They are also structurally-related to the tricyclic antidepressants, explaining the antihistaminergic adverse effects of those two drug classes and also the poor tolerability profile of tricyclic H₁-antihistamines. The second-generation H₁-antihistamine loratadine was derived from compounds in this group.

• promethazine
• alimemazine (trimeprazine)
• cyproheptadine
• azatadine

Antihistamine - Common structural features of classical antihistamine

• 2 Aromatic rings
• Connected to a central Carbon, Nitrogen or CO
• Spacer between the central X and the amine
• Usually 2-3 carbons in length
• Linear, ring, branched, saturated or unsaturated
• Amine is substituted with small alkyl groups eg CH3

X = N, R1 = R2 = small alkyl groups
X = C
X = CO

• Chirality at X can increase both the potency and selectivity for H1-receptors
• For maximum potency, the two aromatic rings should be orientated in different planes.
  • for example, tricyclic ring system is slightly puckered and the two aromatic rings lie in different geometrical planes, given the drug a very high potency.

Adapted from the Wikipedia article "First-generation H₁-receptor antagonists", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki