Doxepin

BRAND NAMES

Doxepin is marketed under several brand names:

• Sinequan® – capsules or oral solution for depression and anxiety.

• Silenor® – tablets used at low doses for insomnia.

• Other generic versions are also available depending on the region.
  Brand selection depends on the indication and formulation required.

MECHANISM OF ACTION

Doxepin is a tricyclic antidepressant (TCA) that works by inhibiting the reuptake of nor13

epinephrine and serotonin, increasing their levels in the brain to improve mood and reduce anxiety. Additionally, it has antihistamine and anticholinergic effects, which contribute to sedation and help treat insomnia at low doses. Its effects on multiple neurotransmitter systems make it effective for both depression and anxiety disorders.

PHARMACOKINETICS:

Absorption

Doxepin is well absorbed orally, with peak plasma concentrations occurring within 2–6 hours. Food does not significantly affect its absorption.

Distribution

The drug is highly protein-bound (~95%) and is widely distributed in body tissues, including the brain, with a volume of distribution of approximately 10–20 L/kg.

Metabolism

Doxepin is extensively metabolized in the liver by cytochrome P450 enzymes, mainly CYP2D6, producing active and inactive metabolites that contribute to its therapeutic and side effects.

Excretion

Metabolites are primarily excreted via urine. The elimination half-life ranges from 8–24 hours, varying with dose, age, and liver function.

PHARMACODYNAMICS

Doxepin increases synaptic norepinephrine and serotonin, improving mood and reducing anxiety symptoms. Its sedative effects are largely due to strong H1 histamine receptor antagonism, particularly at low doses used for insomnia. Anticholinergic activity can cause side effects such as dry mouth, constipation, and urinary retention. Therapeutic benefits for depression or anxiety generally appear within 2–4 weeks, while sedation is noticeable within hours at insomnia doses.

ADMINISTRATION

Doxepin is administered orally as capsules, tablets, or liquid solution. For depression and anxiety, doses are typically taken once or twice daily, while for insomnia, very low doses are taken 30 minutes before bedtime. It is recommended to take the medication at the same time each day to maintain stable blood levels. Dose adjustments may be required for elderly patients or those with liver impairment.

DOSAGE AND STRENGTH

For depression and anxiety, the usual dose ranges from 75–150 mg/day, divided into one or two doses, with some patients requiring up to 300 mg/day. For insomnia, low doses of 3–6 mg are taken once daily at bedtime (Silenor). Dosage should be individualized based on age, liver function, tolerance, and indication. Starting with lower doses and gradually increasing reduces the risk of side effects.

DRUG INTERACTIONS

Doxepin can interact with other central nervous system depressants, including alcohol, benzodiazepines, and opioids, enhancing sedation. Concurrent use with MAO inhibitors can result in hypertensive crises. CYP2D6 inhibitors may increase plasma concentrations, raising the risk of toxicity. Combining with other serotonergic drugs increases the risk of serotonin syndrome. Drugs affecting heart rhythm require careful monitoring due to potential cardiac effects.

FOOD INTERACTIONS

Food does not significantly alter doxepin absorption, but alcohol should be avoided due to additive sedative effects. Caffeine may reduce sedative efficacy at low insomnia doses. Maintaining consistent meal patterns helps ensure stable drug levels. Patients should be counseled about possible interactions with other substances that depress the central nervous system.

CONTRAINDICATIONS

Doxepin is contraindicated in patients with hypersensitivity to TCAs, concurrent or recent use of MAO inhibitors, acute recovery after myocardial infarction, severe liver impairment, and in those with angle-closure glaucoma or urinary retention due to its anticholinergic effects.

SIDE EFFECTS

• Sleepiness and light-headedness

• Dry mouth

• Constipation

• Blurred or impaired vision

• Nausea and vomiting

• Trouble urinating (urinary retention)

• Rapid heartbeat (tachycardia)

• Weight gain

• Changes in sexual desire

• Heightened sensitivity to sunlight

• Excessive sweating

• Confusion or disorientation

OVER DOSE

Overdose symptoms can include severe drowsiness, confusion, agitation, seizures, hypotension, and cardiac arrhythmias. Doxepin overdose can be life-threatening due to its cardiotoxic and CNS effects. Management involves supportive care, gastric lavage, activated charcoal, and cardiac monitoring. Severe cases may require ICU care, and early intervention significantly improves outcomes.

TOXICITY

Toxicity risk increases with higher doses or accidental overdose. Cardiac toxicity may manifest as arrhythmias or conduction delays, while CNS toxicity includes seizures, severe sedation, or coma. Anticholinergic toxicity can cause urinary retention, hyperthermia, or delirium. Adhering to prescribed doses and careful monitoring minimize the risk of toxicity.