Histamine in health and disease.

TLDR: The realization that first-generation antihistamines often had mixed pharmacological properties and crossed the blood-brain barrier led to the development of the second-generation drugs, which are more selective for H1-receptors, have less access to the central nervous system, and, therefore, a more favorable benefit-to-risk ratio (therapeutic index).

Abstract: Histamine is a potent vasoactive agent, bronchial smooth muscle constrictor, and stimulant of nociceptive itch nerves. Activation of H1-receptors plays a central role in the immediate allergic reaction, but has less of an impact in chronic allergic disorders where inflammatory infiltrates, additional mediators such as LTC4/D4/E4 and cytokines, and structural remodeling occur. Histamine, through its H1-receptor-mediated activities, appears to be primarily a proinflammatory agent, yet it does have some homeostatic functions in gastric acid production (H2-receptors) and the central nervous system (predominantly H3-receptors) (97, 98). The realization that first-generation antihistamines often had mixed pharmacological properties (e.g., anticholinergic actions) and crossed the blood-brain barrier led to the development of the second-generation drugs, which are more selective for H1-receptors, have less access to the central nervous system, and, therefore, a more favorable benefit-to-risk ratio (therapeutic index). The potential for combined H1-H3-antagonists remains to be fully explored, but offers another exciting opportunity for this ever-expanding family of beneficial drugs.