Pharmacology of H1 antihistamines

H1 receptors are a type of G-protein-coupled-receptors (GPCRs), and exist in two different conformational states. A conformation is a shape, and the way a receptor is shaped affects its activity. One of the H1 receptor conformations makes it active, so it is effectively the “on” position. The other makes it inactive, so it is effectively the “off” position.

When histamine binds to the H1 receptor, it keeps the receptor in the “on” position. This causes many things to occur. If too many H1 receptors are bound in the “on” position for too long, it can cause airway constriction, difficulty breathing, dilation of blood vessels, hiving, pain and itching, among other symptoms.

In pharmacology, two terms are used to describe the effect a substance has when it binds to a receptor. An agonist fully activates the receptor it binds to. Histamine is an agonist of the H1 receptor because when it binds the receptor, it activates it and thus turns it on. An antagonist binds the receptor but doesn’t turn it on (which is not the same as turning it off). By the antagonist binding the receptor, it prevents histamine from binding there are turning it on.

The medications we use to mediate H1 receptor actions, like diphenhydramine or cetirizine, are often called H1 antagonists, but this is a misnomer. All known medications that act on H1 receptors are more correctly classed as H1 reverse agonists, which is a trickier concept. Basically this means that when these medications bind the H1 receptor, they turn it off. In turn, this prevents a series of actions that are executed by the action of histamine.

First generation H1 antihistamines have a wide ranging group of effects. I have described receptors in the past as being like locks, and the substances that bind them (called ligands) are like keys. In this analogy, first generation H1 antihistamines like diphenhydramine would be like a master key. They are capable of binding to many receptors, including muscarinic, serotonin and a-adrenergic receptors. They also cross the blood-brain barrier. Histamine is an important neurotransmitter with a lot of activity of the brain. By crossing into the brain, these first generation H1 antihistamines can interfere with the sleep-wake cycle, learning, memory, fluid balance, regulation of body temperature, regulation of the cardiovascular system, and stress release of ACTH and b-endorphin from the pituitary.

During the day, first generation H1 antihistamines often cause sleepiness, sedation, drowsiness, fatigue and impaired concentration and memory, even at recommended doses. At night, they delay the onset and reduce the duration of REM sleep. This in turn causes a lower quality sleep, with decreases in attention, vigilance and working memory still observable in the morning.

Second generation H1 antihistamines have largely dealt with the issues present in first generation formulations. Unlike first generation medications, they bind with excellent specificity to the H1 receptor, rather than binding promiscuously. They demonstrate very limited penetration of the blood brain barrier so there is little associated sedation. Desloratadine in the most potent antihistamine, followed by levocetirizine and then fexofenadine.

H1 antihistamines are universally well absorbed with the exception of fexofenadine, which relies on a unique transport mechanism that can be more variable. Studies have shown that in adults, the maximum inhibition of allergic response occurs about four hours after taking levocetirizine, fexofenadine or desloratadine. Loratadine requires metabolism to release the active portion of the molecule, and thus can take hours longer to become efficacious. Fexofenadine has a shorter duration of action at about 8.5 hours, compared to 19 hours for cetirizine at a typical dose.

References:

Church, Diana S., Church, Martin K. Pharmacology of antihistamines. World Allergy Organization Journal 2011, 4 (Suppl 3): S22-S27.

Leurs, R., et al. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clinical and Experimental Allergy 32 (2002): 489-498.

2 Responses

  1. Karen Neill April 13, 2015 / 7:40 pm

    Thank You! This makes perfect sense! What about Ceterizine? I believe it is a second generation H1 antagonist. Is it more or less potent than desloratidine? TIA.

    • Lisa Klimas April 13, 2015 / 8:09 pm

      Cetirizine is less potent than desloratadine but still very potent. It also has anti-inflammatory effects I will get to tomorrow.

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