Paroxetine

BRAND NAMES

• Paxil – original immediate-release formulation. 

• Paxil CR or Pexeva – controlled/extended-release tablets.

MECHANISM OF ACTION

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that works by blocking the serotonin transporter (SERT) on presynaptic neurons, preventing the reuptake of serotonin (5-HT) from the synaptic cleft. This leads to increased serotonin levels in the synapse, enhancing serotonergic neurotransmission and improving communication between neurons in brain regions involved in mood, anxiety, and cognition.

PHARMACOKINETICS:

Absorption: 

Paroxetine is well absorbed orally, with peak plasma concentrations typically reached within 5–6 hours for the immediate-release (IR) formulation and slightly longer for the controlled- or extended-release (CR/ER) formulations. 

Distribution

paroxetine is widely distributed throughout the body, including the central nervous system, where it exerts its therapeutic effects.

Metabolism

Paroxetinein the is liver extensively metabolized, primarily by the cytochrome P450 enzyme CYP2D6, with minor contributions from CYP3A4. 

Elimination

Paroxetine and its metabolites are primarily excreted via the kidneys and to a lesser extent in feces, following extensive hepatic metabolism.

PHARMACODYNAMICS

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) whose therapeutic effects result from enhancing serotonergic neurotransmission in the central nervous system. 

ADMINISTRATION

Paroxetine is administered orally in the form of immediate-release (IR) tablets, controlled- or extended-release (CR/ER) tablets, and oral suspension. It is typically taken once daily, with IR tablets usually given in the morning or evening depending on tolerability, while CR/ER tablets are generally taken in the morning. Paroxetine can be taken with or without food, though taking it with food may help reduce gastrointestinal side effects. Tablets should be swallowed whole and not chewed or crushed, especially for extended-release formulations.

DOSAGE AND STRENGTH

Paroxetine is available in immediate-release (IR) tablets of 10 mg, 20 mg, 30 mg, and 40 mg,extended-release (CR/ER) tablets of 12.5 mg, 25 mg, and 37.5 mg, and an oral suspensionof 10 mg/5 mL. For major depressive disorder and generalized anxiety disorder, the typical starting dose is 20 mg once daily for IR tablets, with gradual titration up to 50 mg/day depending on response and tolerability. For panic disorder, social anxiety disorder, and obsessive-compulsive disorder, treatment usually starts at 10–20 mg/day and may be increased gradually to 40 mg/day. The extended-release formulation is generally started at 25 mg once daily and titrated to 62.5–75 mg/day.

DRUG INTERACTIONS

Paroxetine is a potent inhibitor of the CYP2D6 enzyme, which makes it prone to interactions with drugs metabolized by this pathway. Co-administration with other serotonergic agents—such as SSRIs, SNRIs, MAO inhibitors, or triptans—can increase the risk of serotonin syndrome, a potentially life-threatening condition. Drugs that are metabolized by CYP2D6, including certain beta-blockers, antipsychotics, and antiarrhythmics, may have increased plasma levels, raising the risk of adverse effects.

FOOD INTERACTIONS

Paroxetine can be taken with or without food, as food does not significantly affect its absorption or bioavailability. Taking the medication with meals may help reduce gastrointestinal side effects such as nausea or upset stomach, which are common during the initial phase of treatment. There are no specific foods known to cause clinically significant interactions with paroxetine. However, patients should avoid excessive alcohol consumption, as alcohol can enhance sedation and central nervous system depressionwhen combined with paroxetine.

CONTRAINDICATIONS

Paroxetine is contraindicatedin individuals with a known hypersensitivity to paroxetine or any of its components, as this can trigger severe allergic reactions. It should never be used concomitantly with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI therapy, due to the risk of serotonin syndrome, which can be life-threatening. Paroxetine is also contraindicated in pregnant women during the third trimester for certain indications because of potential neonatal complications and in patients with severe liver impairment, as metabolism may be significantly reduced, increasing the risk of toxicity.

SIDE EFFECTS

Paroxetine is generally well tolerated, but it can cause a range of common and serious side effects. The most frequent include nausea, diarrhea, constipation, headache, dizziness, drowsiness, and insomnia, often occurring during the first few weeks of treatment. Sexual dysfunction, including decreased libido, delayed ejaculation, or anorgasmia, is also common. Less frequent but important effects include weight gain, dry mouth, sweating, and tremor.

TOXICITY

Paroxetine overdose can lead to central nervous system and cardiovascular toxicity, although fatalities are relatively uncommon when taken alone. Common manifestations of toxicity include nausea, vomiting, dizziness, somnolence, tremor, and agitation. Severe cases may present with seizures, confusion, hypotension, tachycardia, and serotonin syndrome, particularly if combined with other serotonergic drugs. Management of paroxetine toxicity is primarily supportive, focusing on airway protection, cardiovascular monitoring, and symptomatic treatment.