Paxil | Pharmacology Mentor

Generic Name

Paxil

Brand Names

for the selective serotonin reuptake inhibitor (SSRI) paroxetine.

Mechanism

Selective inhibition of the serotonin transporter (SERT) in the presynaptic neuron, increasing synaptic 5‑hydroxytryptamine (5‑HT) levels.
Acts largely at the central nervous system (CNS) serotonin receptors, thereby enhancing serotonergic neurotransmission in mood, anxiety, and obsessive‑compulsive circuits.
The blockade of SERT is highly selective and has low affinity for other monoamine transporters, minimizing off‑target dopaminergic or noradrenergic effects.

Pharmacokinetics

Route & onset: Oral; peak plasma concentration in 2–3 h.
Absorption: ~70 % bioavailability; food reduces early exposure slightly.
Metabolism: Predominantly hepatic by CYP2D6 (≈65 %) and CYP3A4; inhibitors of CYP2D6 markedly ↑ plasma levels.
Elimination: Excreted 50‑60 % as metabolites, 20‑30 % unchanged in urine.
Half‑life: ~21 h in adults; markedly reduced (~12 h) in the elderly or those with hepatic impairment.
Drug interactions: Strong CYP2D6 inhibitor (e.g., fluoxetine, cimetidine). Potent CYP3A4 inhibitor (e.g., ketoconazole) or inducer (e.g., carbamazepine) can alter exposure.

Indications

Major Depressive Disorder (MDD)
Obsessive‑Compulsive Disorder (OCD)
Generalized Anxiety Disorder (GAD)
Panic Disorder
Social Anxiety Disorder (Social Phobia)
Premenstrual Dysphoric Disorder (PMDD)

Contraindications

Contraindicated with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI therapy (serotonin‑syndrome risk).
Known hypersensitivity to paroxetine or any excipients.
Severe hepatic or renal impairment (dose adjustment or alternative therapy).
Pregnancy category C; caution in lactation (minimal transfer; potential infant effects).
Warnings:
*Serotonin syndrome* (elevated sympathetic activity, neuromuscular aberrancy).
*QT prolongation* (particularly when combined with other QT‑longing agents).
*Suicidal ideation* in adolescents and young adults (monitor clinically).
*Hyponatremia* (especially in elderly, accompanied by SIADH).

Dosing

Population	Initial Dose	Titration	Max Dose	Notes
Adults	20 mg daily (30 mg if severe depression, 4–6 h after dinner)	Increase by 10 mg every 1‑2 weeks	50 mg/day (max)	Titrate slowly to avoid discontinuation syndrome.
Elderly	20 mg daily	10‑mg increments	30 mg/day	Reduced half‑life warrants lower maintenance.
Pediatric (7–17 y)	5 mg daily (age < 12 yr) or 10 mg (12–17 yr)	5‑mg increments	30 mg/day	Limited long‑term safety data.
Pregnancy	10 mg (up to 20 mg)	10‑mg increments	20 mg/day	Avoid 3rd trimester if possible.

• Give evening doses to reduce insomnia and weight changes.
• Continuous daily therapy; abrupt cessation precipitates withdrawal (discontinuation syndrome).

Monitoring

Baseline & periodic complete blood count (CBC), fasting glucose, liver function tests (ALT/AST).
Weight & BMI at each visit; counsel on diet/exercise.
Serotonin‑syndrome precautions: educate patient/family about early signs.
Electrocardiogram (ECG) for patients with existing QT abnormalities or on interacting drugs.
Stop‑watch: if pregnancy suspected, ask on p.o. any counseling regarding teratogenic risk.
Suicidal ideation log: baseline and every 2–3 weeks for first 12 weeks.
Renal/hepatic function: adjust dose if CrCl  B.

Clinical Pearls

1. CYP2D6 inhibition powerhouse: paroxetine is one of the strongest CYP2D6 inhibitors; co‑administration with CYP2D6 substrates (e.g., codeine → morphine, metoprolol) can lead to toxicity or inadequate analgesic effect.

2. Short, “buried” half‑life: its relatively short half‑life (≈21 h) makes discontinuation syndrome more likely; a gradual taper over 6–8 weeks is essential to avoid withdrawal.

3. Sexual side‑effects outlier: paroxetine ranks top among SSRIs for sexual dysfunction (≈50‑60 %) – educate patients early and consider switching if troublesome.

4. Pregnancy concerns: first‑trimester exposure linked to a subtle cardiac defect *persistent pulmonary hypertension of the newborn (PPHN)*; third‑trimester exposure associated with neonatal withdrawal (5‑10 %).

5. Perceived “better tolerance” myths: Despite its strong anticholinergic action, many patients report diurnal dosing leads to insomnia that may mask underlying CNS activity – switching to a morning dose can alleviate.

--
• Paxil pharmacology at a glance:
• Action: SERT inhibition → ↑5‑HT
• PK: CYP2D6/CYP3A4 metabolized, ~21‑h t½
• Indications: MDD, OCD, GAD, panic, social anxiety, PMDD
• Worries: sexual dysfunction, discontinuation syndrome, serotonin syndrome, QT prolongation, pregnancy‑associated risks
• Take home: Use low dose, monitor closely for drug interactions and suicidal ideation; taper slowly, and watch for sexual adverse events.