Both neutral H1 antagonists and inverse H1 agonists reduce or block the actions of histamine by reversible competitive binding to the H1 receptor. Several have been clearly shown to be inverse agonists, and it is possible that all act by this mechanism. They have negligible potency at the H2 receptor and little at the H3 receptor. For example, histamine-induced contraction of bronchiolar or gastrointestinal smooth muscle can be completely blocked by
X is: C or N Y is: C, O, or omitted X Y C C N CH OCH2 Diphenhydramine or dimenhydrinate NCH2 CH3 CH3 Alkylamine derivative Chlorpheniramine CH2 CH2CH Piperidine derivative N N CH3 CH3 Fexofenadine C OH N OH CH3 CH2 CH2 CH2 CH C
FIGURE 16–1 General structure of H1-antagonist drugs and examples of the major subgroups. Subgroup names are based on the shaded moieties.
these agents, but histamine-stimulated gastric acid secretion and the stimulation of the heart are unaffected.
The first-generation H1-receptor antagonists have many actions in addition to blockade of the actions of histamine. The large number of these actions probably results from the similarity of the general structure (Figure 16–1) to the structure of drugs that have effects at muscarinic cholinoceptor, α adrenoceptor, serotonin, and local anesthetic receptor sites. Some of these actions are of therapeutic value and some are undesirable.
1. Sedation—A common effect of first-generation H1 antagonists is sedation, but the intensity of this effect varies among chemical subgroups (Table 16–2) and among patients as well. The effect is sufficiently prominent with some agents to make them useful as “sleep aids” (see Chapter 63) and unsuitable for daytime use. The effect resembles that of some antimuscarinic drugs and is considered very different from the disinhibited sedation produced by sedative-hypnotic drugs. Compulsive use has not been reported. At ordinary dosages, children occasionally (and adults rarely) manifest excitation rather than sedation. At very high toxic dose levels, marked stimulation, agitation, and even seizures may precede coma. Second-generation H1 antagonists have little or no sedative or stimulant actions. These drugs (or their active metabolites) also have far fewer autonomic effects than the first-generation antihistamines.
2.Antinausea and antiemetic actions—Several first-generation H1 antagonists have significant activity in preventing motion sickness (Table 16–2). They are less effective against an episode of motion sickness already present. Certain H1 antagonists, notably doxylamine (in Bendectin), were used widely in the past in the treatment of nausea and vomiting of pregnancy (see below). Although Bendectin was withdrawn in 1983, a similar formulation, combining doxylamine and pyridoxine (Diclegis), was approved by the US Food and Drug Administration (FDA) in 2013.
3.
Antiparkinsonism effects—Some of the H1 antagonists, especially diphenhydramine, have significant acute suppressant effects on the extrapyramidal symptoms associated with certain antipsychotic drugs. This drug is given parenterally for acute dystonic reactions to antipsychotics.
4.
Antimuscarinic actions—Many first-generation agents, especially those of the ethanolamine and ethylenediamine subgroups, have significant atropine-like effects on peripheral muscarinic receptors. This action may be responsible for some of the (uncertain) benefits reported for nonallergic rhinorrhea but may also cause urinary retention and blurred vision.
5.