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The term antihistamine historically has referred to drugs that block the actions of histamine at H1-receptors rather than other histamine receptor subtypes. The development of anti-histamine drugs began decades ago with the discovery by Fourneau and Bovet22 that piperoxan could protect animals from the bronchial spasm induced by histamine. This finding was followed by the synthesis of several N-phenylethylene-diamines with antihistamininic activities superior to those of piperoxan.23 Further traditional structure-activity studies in this series, based largely on the principles of isosterism and functional group modification, led to the introduction in the 1940s to 1970s of various ^-antihistamine containing the diarylalkylamine framework.23,24 These antihistamines, referred to now as the first-generation or classical antihista-mines, are related structurally and include several aminoalkyl ethers, ethylenediamines, piperazines, propylamines, phe-nothiazines, and dibenzocycloheptenes. In addition to H1-antihistaminic action, these compounds display an array of other pharmacological activities that contribute either toward additional therapeutic applications, or limit use as adverse reactions. More recently, several second-generation or "nonsedating" antihistamines have been developed and introduced.10,23 The second-generation agents are derivatives of several first-generation agents, but have been modified to be more specific in pharmacologic action and limited in their tissue distribution or accumulation profiles.

Mechanism of Action

It is now known that ^-antihistamines act as inverse agonists that combine with and stabilize the inactive form of the H1-receptor, shifting the equilibrium toward the inactive state.10 Thus, they effectively antagonize the actions of histamine at H1-receptors. Historically, ^-antihistamines have been evaluated in vitro in terms of their ability to inhibit his-tamine-induced spasms in an isolated strip of guinea pig ileum. Antihistamines may be evaluated in vivo in terms of their ability to protect animals against the lethal effects of histamine administered intravenously or by aerosol.

To distinguish antagonism of histamine from other modes of action, the index pA is applied in in vitro assays. The index pA2 is defined as the inverse of the logarithm of the molar concentration of the antagonist that reduces the response of a double dose of the agonist to that of a single one. The more potent ^-antihistamines exhibit a pA2 value significantly higher than 6. Although there are many pitfalls to be avoided in the interpretation of structure-activity relationship (SAR) studies using pA2 values, the following example illustrates distinguishing competitive antagonism. pA2 values for pyrilamine (mepyramine) antagonism range from 9.1 to 9.4 with human bronchi and guinea pig ileum.24,25 By contrast, the pA2 value in guinea pig (H2-receptor) is 5.3. Thus, one may conclude that pyrilamine is a weak, noncompetitive inhibitor of histamine at the H2-receptors and a competitive inhibitor at H1-receptors. The structural features required for effective interaction of these receptors are discussed next. Some ^-antihistamines can also block histamine release. The concentrations, however, are considerably higher than those required to produce significant histamine receptor blockade. The ^-antihistamines do not, however, block antibody production or antigen-antibody interactions.10,26

Figure 23.5 • Metabolism of histamine. (ALD-DH, aldehyde dehydrogenase; PRT, phosphoribosyltransferase.)

Structure-Activity Relationships at Hi-Receptors

The Hi-antihistamines are now commonly subdivided into two broad groups—the first-generation or classical antihistamines and the second-generation or "nonsedating" antihis-tamines—based primarily on their general pharmacological profiles.10'23'27 The differences between these two series are discussed in more detail in the sections that follow. The most detailed published SAR analyses for antihistamines, however, focus on the structural requirements for the firstgeneration agents.22-24 From these studies, the structural requirements for H1-antihistaminic action were identified as shown in Figure 23.6. In this structure, Ar is aryl (including phenyl, substituted phenyl, and heteroaryl groups such as 2-pyridyl); Ar' is a second aryl or arylmethyl group; X is a connecting atom of O, C, or N; (CH2)n represents a carbon chain, usually ethyl; and NRR' represents a basic, terminal amine function. The nature of the connecting atom as well as the diaryl substitution pattern and amine moiety has been used to subclassify the first-generation antihistamines as indicated in the succeeding sections.

This diaryl substitution pattern is present in both the first- and second-generation antihistamines and is essentially a significant H1-receptor affinity.22-24 Furthermore, several SAR studies suggest that the two aryl moieties must be able to adopt a noncoplanar conformation relative to each other for optimal interaction with the H1-receptor.28 The two aromatic systems may be linked, as in the tricyclic antihistamines (phenothiazines, dihenzocycloheptanes, and heptenes), but again they must be noncoplanar for effective receptor interaction. Most ^-antihistamines contain sub-stituents in one of the aryl rings (usually benzene), and these influence histamine potency as well as biodisposition, as discussed for the individual classes of compounds in the succeeding sections.

In many of the first-generation, or classical, antihista-mines, the terminal nitrogen atom is a simple dimethyl moiety. The amine may also be part of a heteroyclic structure, however, as illustrated by the piperazines, some propylamines (pyrrolidines and piperidines), some phenthiazines, the dibenzocycloheptenes, and the second-generation antihistamines. In all cases, the amino moiety is basic, with pKas ranging from 8.5 to 10, and thus is presumed to be protonated when bound on the receptor. The amine moiety is also important in the development of stable, solid dosage forms through salt formation.

The carbon chain of typical ^-antihistamines consists of two or three atoms.22-24 As a result, the distance between the central point of the diaryl ring system and the terminal nitrogen atom in the extended conformation of these compounds ranges from 5 to 6 angstroms (A). A similar distance between these key moieties is observed for those antihista-mines with less conformational freedom. In some structural series, branching of the carbon chain results in reduced

Figure 23.6 • General antihistamine structure.

antihistaminic activity. There are exceptions, however, as evidenced by promethazine, which has greater activity than its nonbranched counterpart. When the carbon adjacent to the terminal nitrogen atom is branched, the possibility of asymmetry exists. Stereoselective Hi-receptor binding is typically not observed, however, when chirality exists at this site.29 Also, in compounds with an asymmetrically substituted unsaturated carbon chain (pyrrobutamine and triprolidine), one geometric isomer typically displays higher receptor affinity than the other.

The X connecting moiety of typical ^-antihistamines may be a saturated carbon-oxygen moiety or simply a carbon atom. This group, along with the carbon chain, appears to serve primarily as a spacer group for the key pharmacophore moieties. Many antihistamines containing a carbon atom in the connecting moiety are chiral and exhibit stereoselective receptor binding. For example, in the pheniramine series and carbinoxamine, this atom is chiral, and in vitro analyses indicate that enantiomers with the S configuration have higher H1-receptor affinity.30

Generally, the first- and second-generation antihista-mines are substantially more lipophilic than the endogenous agonist, histamine (or the H2-antagonists).31 This lipophilic-ity difference results primarily from the presence of the two aryl rings and the substituted amino moieties and thus may simply reflect the different structural requirements for antagonist versus agonist action at H1-receptors.

The nature of the connecting moiety and the structural nature of the aryl moieties have been used to classify the antihistamines as indicated in the sections that follow. Furthermore, variations in the diaryl groups, X-connecting moieties, and the nature of substitution in the alkyl side chain or terminal nitrogen among the various drugs account for differences observed in antihistaminic potency as well as pharmacological, biodisposition, and adverse reaction profiles. The ability of these drugs to display an array of pharmacological activities is largely because they can interact with H1-receptors throughout the body, and that they contain the basic pharmacophore required for binding to muscarinic as well as adrenergic and serotonergic receptors (Table 23.2). The relationships of antihistamine structure to these overlapping actions (H1-anthistaminic, anticholinergic, and local anesthetic) have been analyzed.

General Pharmacological and Therapeutic Considerations

The classical antihistamines have been used extensively for the symptomatic treatment (sneezing, rhinorrhea, and itching of eyes, nose, and throat) of allergic rhinitis (hay fever, polli-nosis), chronic idiopathic urticaria, and several other hista-mine-related diseases.10 These uses are clearly attributed to their ability to counter the action of histamine at peripheral H1-receptors, which mediate the immune and inflammatory processes characteristic of these pathologies. These drugs best relieve the symptoms of allergic diseases at the beginning of the season when pollen counts are low. The antihista-mines also reduce the number, size, and duration of wheals and itching in chronic urticaria when used promptly. Most clinical evidence suggests that there is no significant difference in therapeutic efficacy for first- and second-generation agents in the treatment of these conditions. The antihista-mines have been widely used to relieve the symptoms of

TABLE 23.2 General Pharmacologic Properties of Selected "Antihistamines"

Dosing Int. Sedative Anti-H1 Anti-M

Antihistamine Dose (mg) (hrs) Effects Activity Activity Antiemetic

TABLE 23.2 General Pharmacologic Properties of Selected "Antihistamines"

Dosing Int. Sedative Anti-H1 Anti-M

Antihistamine Dose (mg) (hrs) Effects Activity Activity Antiemetic

First Generation: Propylamines

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