Review of the histamine system and the clinical effects of H₁ antagonists: Basis for a new model for understanding the effects of insomnia medications

Summary

The pharmacologic management of insomnia has long been dominated by agents that facilitate gamma amino butyric acid inhibition. These agents have served as the clinical model for understanding the pharmacodynamic effects of insomnia agents according to which sleep effects parallel plasma drug levels (pharmacokinetic effects). Agents with other mechanisms also exist for treating insomnia; however, their effects are less well understood. Many of these diminish the activity in one or more of the key wake-promoting systems. This review focuses on one such mechanism, blockade of the wake promoting effects of histamine via H₁ receptor antagonism. Although drugs with H₁ antagonist effects have long been available, this review was prompted by new studies of a selective H₁ antagonist, which provide the first indication of the effects that are specifically associated with H₁ antagonism. The findings do not conform to our long-standing model of insomnia agents in that factors other than drug blood level are needed to explain the clinical effects. We suggest a model for understanding these unique effects based on a review of the basic neurobiology of the histamine system. In addition to drug blood level, clinical effects reflect circadian variation in activity in the histamine system and other parallel wake promoting systems as well as factors such as pain and stress. We hypothesize that significant sleep enhancing effects are likely when the histamine system is relatively active and the activity in other parallel wake promoting systems is relatively minimal. Although the focus of this review is on the novel properties of H₁ antagonism, the principles that emerge from this analysis are most likely relevant to all agents that selectively block wake promoting systems, and as such, this review provides a new paradigm for understanding the effects of insomnia medications.

Introduction

Gamma amino butyric acid (GABA), the predominant inhibitory neurotransmitter in the central nervous system, promotes sleep by inhibiting all of the key arousal systems.¹ For decades, agents that facilitate GABA-mediated inhibition have dominated the pharmacologic management of insomnia. As a result, these agents, including barbiturates, benzodiazepines, and “non-benzodiazepines,” have served as the clinical model for understanding the pharmacodynamic effects of insomnia agents.1, 2 According to the model based on these medications the pharmacodynamics of a medication's effect on sleep parallels plasma drug levels (pharmacokinetic effects).3, 4 Although circadian and other factors can impact the clinical effects of these agents, the available evidence suggests that pharmacokinetics is the predominant determinant of clinical effect.5, 6, 7

Medications with mechanisms other than enhancing GABA-mediated inhibition also exist for treating insomnia; however, their effects are less well characterized and less well understood than those of the GABA-ergic enhancing agents. Many of these agents diminish the activity in one or more of the key brain wake-promoting systems, which include norepinephrine, histamine, serotonin, acetylcholine, dopamine, and hypocretin/orexin.⁸ This review focuses on one such mechanism, the blockade of the wake promoting effects of histamine via antagonism of H₁ receptors. Although H₁ antagonists have long been available, this review was prompted by new research findings suggesting that this mechanism has novel effects that differ fundamentally from GABA-enhancing medications. These results do not conform to our predominant model of the effects of insomnia medications, which is based on the properties of the GABA-enhancing agents.

The sedating properties of histamine H₁ receptor antagonists were first noted in the 1930s and agents that enhance sleep by blocking H₁ receptors have existed for more than 50 y.⁹ Most of these agents, such as diphenhydramine, chlorpheniramine, doxylamine, and brompheniramine, have been available over-the-counter (OTC).¹⁰ These antihistamines are constituents in many medications used to treat allergies, cold symptoms, itching, nausea, and insomnia. Antidepressants such as doxepin, amitriptyline, and trimipramine, and antipsychotics such as chlorpromazine, olanzapine, and risperidone also exert significant antihistaminergic activity in addition to their other neurotransmitter effects and are sometimes used to treat insomnia.10, 11

Given our many years of experience with these agents, one would expect that the clinical effects of H₁ antagonists would have been well characterized and understood. However, this experience using H₁ antagonists to treat insomnia has provided only limited insight into the properties associated specifically to H₁ receptor antagonism. This is because: 1) there has been a lack of systematic research on the H₁ antagonist-specific effects of these agents; and 2) the available H₁ antagonists all have effects on non-histaminergic receptors, which may be responsible for adverse effects and which can affect the sleep–wake effects of these agents, thereby clouding the picture as to the effects specifically associated with H₁ antagonism.

In this regard, many antihistamines, antidepressants, and antipsychotics with H₁ antagonist activity exert significant sleep-promoting and/or wake-promoting effects via non-histaminergic-related mechanisms. For example, serotonin reuptake inhibition, α₂ adrenergic receptor blockade, and 5-HT_2C receptor antagonism can promote wakefulness and thus detract from the sleep-promoting effects of H₁ receptor antagonism, while enhancement of the effects of H₁ antagonism would be expected with α₁ adrenergic receptor antagonists, which are sleep promoting, as well as antagonists or inverse agonists at 5-HT_2A receptors, which increase slow-wave sleep (SWS).11, 12, 13, 14 Table 1 includes several agents that have such non-histaminergic effects that may cause them to have wake-promoting and/or sleep-promoting properties. This affinity of classic antihistamines, antidepressants, and antipsychotics for multiple non-histaminergic receptors may explain some of the sleep–wake effects that have been noted clinically with the use of these drugs.

There also exists the possibility that activity at non-histaminergic receptor sites may affect the histaminergic system and undermine or potentially enhance the sleep-inducing effects of H₁ receptor antagonism. For example, antipsychotic agents that block dopamine receptors may also influence the release of histamine. In freely moving rats, superfusion with a selective dopamine D₁ receptor antagonist in the anterior hypothalamus enhances the release of histamine, while blocking D₂ receptor activity decreases histamine release.¹⁵ Additionally, cholinergic activity in the anterior hypothalamus inhibits histamine release. Thus, superfusion of muscarinic receptor agonists lowers histamine release, while atropine, a non-selective muscarinic receptor antagonist, greatly enhances histamine release.¹⁶ Many drugs, including diphenhydramine, doxylamine, hydroxyzine, promethazine, chlorpromazine, amitriptyline, doxepin, and olanzapine, cause significant dose-dependent inhibition of muscarinic receptors, thereby increasing histamine release, which may compete with and undermine the potential therapeutic effects of their H₁ receptor antagonism.¹¹

Non-histaminergic pharmacologic effects may also be responsible for side-effects of antihistamines, antidepressants, and antipsychotics with H₁ antagonist effects. These side-effects may infact be attributable to antagonism of 5-HT_2C, muscarinic cholinergic, and α₁ adrenergic receptors.11, 17, 18, 19, 20, 21, 22 Agents with H₁ antagonist effects and possible nonhistamine-related side effects are listed in Table 2. The well-known anticholinergic side effects of dry mouth, constipation, urinary retention, and blurred vision associated with many existing antihistamines can be attributed to their affinity for muscarinic M₁ receptors. Agents that block α₁ adrenergic receptors can cause orthostatic hypotension. Further, weight gain may occur with blockade of 5-HT_2C receptors. Studies in mice support a key role of the 5-HT_2C receptor in the serotonergic control of appetite and body weight.23, 24

Thus, despite many years of experience with agents with H₁ antihistaminergic effects, our understanding of the clinical effects specifically associated with H₁ antagonism is clouded by the broad pharmacological effects of these agents. This article discusses recent work with agents that block H₁ receptors and that are relatively lacking in other receptor effects (selective H₁ antihistamines). These agents for the first time provide evidence of the effects that are specifically associated with H₁ antagonism. These recent studies indicate that the effects of selective H₁ antihistamines are fundamentally different from those of agents that enhance GABA-ergic inhibition. Based on a review of the basic science work on the properties of the histamine system, we suggest a model for understanding the basis for these unique effects. Although the focus of this review is on the novel properties of H₁ antagonism the principles that emerge from analysis of the effects of H₁ antagonists are most likely relevant to all agents that selectively block wake promoting systems, and as such, this review provides a new paradigm for understanding the effects of insomnia medications.