From the Guidelines
Doxepin's Affinity for Histamine Receptors
Doxepin has a higher affinity for histamine receptors at low doses, making it effective for treating pruritus.
- Specifically, doxepin exhibits a high affinity for H1 and H2 histamine receptors 1, with a dose of 10-30 mg taken orally at bedtime, demonstrating significant antipruritic effects.
- At these low doses, doxepin's antihistaminic properties are more pronounced, allowing for effective management of itch with minimal sedative side effects.
- A study of 24 patients on haemodialysis used doxepin 10 mg twice daily and reported complete resolution of symptoms in 58% of the treatment group vs. 8% on placebo, and relative improvement in 29% vs. 17%, respectively 1.
- However, it is essential to note that sedative antihistamines, including doxepin, may predispose to dementia and should be avoided, except in palliative situations 1.
- The British Association of Dermatologists' guidelines recommend considering nonsedative antihistamines, such as fexofenadine or loratadine, before sedative antihistamines like doxepin 1.
From the Research
Doxepin Affinity for Histamine Receptors
- Doxepin has been shown to have a high affinity for histamine H1 receptors, which is relevant for its use in treating pruritus 2, 3, 4.
- The high-affinity binding site for doxepin has a dissociation constant (KD) of 3.1 +/- 0.3 X 10(-10) M, indicating a strong interaction with histamine H1 receptors 3.
- Studies have also identified a subclass of histamine H1 receptors that may be specifically targeted by doxepin, with a high-affinity site having a KD of 0.020 nM 4.
Low-Dose Doxepin and Histamine Receptors
- Low-dose doxepin has been shown to be effective in treating pruritus, with a significant improvement in symptoms compared to placebo 2.
- At low doses, doxepin selectively antagonizes H1 receptors, which is believed to promote the initiation and maintenance of sleep, and may also contribute to its effectiveness in treating pruritus 5.
- The Z-isomer of doxepin has been shown to have a higher affinity for histamine H1 receptors than the E-isomer, with a 5.2-fold higher affinity for the wild-type H1R 6.
Binding Characteristics of Doxepin
- The binding characteristics of doxepin to histamine H1 receptors have been studied using receptor-bound ligand analysis and molecular dynamics simulations 6.
- These studies have shown that the hydroxyl group of Thr1123.37 in the H1R binding pocket contributes to the formation of a chemical environment that is slightly more favorable for the Z-isomer of doxepin 6.
- The distribution of histamine H1 receptors in the human central nervous system has been shown to correlate with the binding of doxepin, with the highest binding found in cerebral neocortex and the limbic system 3.