Mechanism of Action and Uses of Doxylamine
Doxylamine is a first-generation H1-antihistamine (histamine H1-receptor antagonist) with anticholinergic and sedative properties, primarily used as a sleep aid for occasional insomnia and as first-line pharmacologic therapy for nausea and vomiting of pregnancy when combined with pyridoxine (vitamin B6). 1, 2
Mechanism of Action
- Doxylamine functions as an H1-receptor inverse agonist, blocking histamine receptors in the central nervous system to produce sedative effects 3
- The drug exhibits anticholinergic properties that contribute to its sedative and antiemetic effects 4, 5
- At therapeutic doses, doxylamine causes impairment of cognitive and psychomotor performance due to its central nervous system depressant effects 5
Clinical Uses
Nausea and Vomiting of Pregnancy (Primary Indication)
- The doxylamine-pyridoxine combination (Diclegis/Diclectin) is FDA-approved and recommended by ACOG as first-line pharmacologic therapy for persistent nausea and vomiting of pregnancy that fails non-pharmacologic interventions 1, 2
- Available as 10 mg doxylamine/10 mg pyridoxine delayed-release tablets, with standard dosing of 4 tablets daily 1, 2
- Early intervention with doxylamine-pyridoxine may prevent progression to hyperemesis gravidarum, a more severe and potentially dangerous condition 1, 2
- Dosing should be adjusted based on symptom severity using the PUQE score: mild (≤6), moderate (7-12), or severe (≥13) 1, 2
Insomnia Management
- Doxylamine is used for short-term management of occasional insomnia due to its sedative effects 3, 6
- Available in 12.5 mg and 25 mg strengths for sleep induction 6
- The drug demonstrates dose-proportional pharmacokinetics between 12.5-25 mg doses, with predictable linear increases in systemic exposure 6
- Food intake does not significantly affect doxylamine absorption or bioavailability, allowing flexible administration timing 7
Pharmacokinetic Profile
- Mean Cmax for 25 mg dose is approximately 120 ng/mL, with AUC of approximately 1700 ng·h/mL 6, 7
- The drug exhibits similar bioavailability in fed and fasting states, with fed:fasting ratios within 80-125% for both Cmax and AUC 7
- Plasma samples can be detected for up to 60 hours post-dose, indicating prolonged elimination 6, 7
Safety Considerations and Adverse Effects
Common Side Effects at Therapeutic Doses
- Somnolence is the most common adverse effect 6
- Anticholinergic effects including dry mouth, constipation, and urinary retention 5
- Postural hypotension and agitation may occur 5
Serious Toxicity Concerns
- At toxic doses, doxylamine can cause seizures, rhabdomyolysis, and death through severe anticholinergic effects 8
- Syndrome of inappropriate antidiuresis (SIAD) with severe hyponatremia has been reported in overdose cases 5
- Delayed rhabdomyolysis may occur even after initial stabilization 8
- False-positive urine drug screens for methadone and phencyclidine can occur at toxic levels when using immunoassay-based testing 8
Important Clinical Pitfalls
- Doxylamine is prone to abuse due to its sedative properties and over-the-counter availability 8
- Confirmatory secondary testing may be required when positive urine drug screens occur in patients with suspected doxylamine toxicity 8
- For pregnancy-related nausea, if symptoms persist despite optimal doxylamine-pyridoxine dosing, escalate to second-line agents (metoclopramide, ondansetron, or promethazine) rather than continuing ineffective therapy 1, 2
- In severe hyperemesis gravidarum cases, thiamine supplementation (100 mg daily for 7 days, then 50 mg maintenance) should be considered to prevent Wernicke encephalopathy 1