What is the mechanism of action (MOA) of Doxepin?

Mechanism of Action of Doxepin

Doxepin primarily works through potent histamine H1 receptor antagonism at low doses, while at higher antidepressant doses it functions as a tricyclic antidepressant by inhibiting reuptake of norepinephrine and serotonin at neuronal synapses.

Primary Mechanisms

Doxepin has a complex pharmacological profile with multiple mechanisms that vary based on dosage:

At Low Doses (1-6mg)

• Potent histamine H1 receptor antagonism: Doxepin has subnanomolar affinity for the H1 receptor, making it one of the most potent antihistamines available 1
• This mechanism is primarily responsible for its sedative effects and use in insomnia at low doses

At Higher Antidepressant Doses (75-300mg)

• Norepinephrine reuptake inhibition: Prevents deactivation of norepinephrine by blocking reuptake into nerve terminals 2
• Serotonin reuptake inhibition: Similar to other tricyclic antidepressants, though less potent than its noradrenergic effects 3
• Anticholinergic effects: Antagonism of muscarinic receptors, contributing to side effects like dry mouth and constipation 2

Secondary Pharmacological Properties

• Antiserotonergic effects: Demonstrated in animal studies on smooth muscle 2
• Antihistaminergic effects: Beyond H1 antagonism, affects smooth muscle function 2
• Potentiation of norepinephrine response: Observed at higher than usual clinical doses in animal studies 2

Pharmacokinetic Considerations

• Metabolized primarily through the cytochrome P450 2D6 (CYP2D6) pathway 4
• Forms active metabolites including desmethyldoxepin (nordoxepin) 4
• Plasma concentrations at therapeutic doses typically range from 130±113 ng/mL (parent compound) to 132±94 ng/mL (metabolite) at 250mg daily dosing 4

Clinical Implications of MOA

• The strong H1 antagonism explains why doxepin is particularly effective for depression with anxiety and sleep disturbances 3
• At antidepressant doses, doxepin has a similar profile to amitriptyline but with potentially fewer side effects than imipramine 3
• The sedative properties make it more suitable for depressed patients with insomnia compared to more activating antidepressants 3
• Unlike benzodiazepines, doxepin's combined antidepressant and anxiolytic effects make it more effective when anxiety is accompanied by significant depression 3

Important Contraindications Based on MOA

• Contraindicated with drugs that have potential arrhythmic properties due to its intrinsic cardiotoxicity similar to other tricyclics 4, 5
• Should not be taken concurrently with drugs that inhibit hepatic metabolism via cytochrome P450, including macrolide antibiotics and imidazole antifungals 4
• Contraindicated in patients with glaucoma due to anticholinergic effects 2
• Should not be combined with MAOIs due to risk of serotonin syndrome 2

Doxepin's unique combination of strong antihistaminic properties with noradrenergic and serotonergic reuptake inhibition explains its versatility in treating conditions ranging from insomnia (at low doses) to major depression with anxiety (at higher doses).