Venlafaxine

Mechanism

Chemical and Commercial Profile

Common trade names: Vandral, Dobupal, Conervin.
Group: Dual antidepressant (SNRI, derived from phenylethylamine).

Mechanism of Action

It shows a free concentration-dependent sequential inhibition profile:

• At low doses (<75 mg/day): Acts predominantly as an SSRI, blocking SERT.
• At medium/high doses (75-150 mg/day): It additionally blocks the norepinephrine transporter (NET).
• At very high doses (>225 mg/day): It exerts a weak inhibition on the dopamine transporter (DAT).

It lacks significant affinity for H₁ histaminergic, M₁ muscarinic or α₁ adrenergic receptors, reducing the profile of autonomic adverse effects.

Pharmacokinetics

Pharmacokinetics

• Routes of administration: Oral (delayed release capsules, conventional tablets).
• Bioavailability: ~45% due to important hepatic first pass effect.
• Metabolism: Metabolized in the liver by the CYP2D6 system to its main active metabolite, O-desmethylvenlafaxine (ODV). CYP3A4 acts as a secondary pathway.
• Excretion: Renal (87% as unchanged drug and conjugates).
• Half-life (t_1/2): Venlafaxine parent: 5 hours. ODV: 11 hours. In XR formulations, the absorption profile extends the dosing interval to once daily.

Indicators and dose

Indications

• Generalized Anxiety Disorder (GAD).
• Panic Disorder with or without agoraphobia.
• Social Phobia.
• Off-label: Neuropathic pain (diabetic neuropathy), migraine prevention, climacteric hot flashes.

Dosage and Settings

• Initial Dose: 37.5 mg to 75 mg once daily (XR).
• Therapeutic range: 75-225 mg/day. Maximum dose in hospitalized patients: 375 mg/day.
• Kidney Failure:
  • Cl_Cr [10-30 ml/min]: Reduce dose by 25-50%.
  • Cl_Cr < 10 ml/min: Reduce dose by at least 50% and monitor closely.
• Liver Failure: Moderate: Reduce dose by 50%. Serious: Not recommended.

Security

Contraindications

Absolute

• Concomitant administration with MAOI (wait 14 days after stopping the MAOI).
• Unstable heart disease, uncontrolled ventricular arrhythmias.

Relative

• Uncontrolled diastolic arterial hypertension.
• Narrow-angle glaucoma.
• Active bleeding disorders.

Adverse Effects (ADR)

Alert · Dose-dependent hypertension

Due to increased systemic noradrenergic activity, venlafaxine may induce elevations in systolic and diastolic blood pressure. This effect is linearly dependent on the dose (incidence of HTN of ~3% at doses <150 mg/day, rising to >13% with doses greater than 300 mg/day). Strict monitoring of blood pressure levels is required before and during treatment.

• Gastrointestinal: Severe initial nausea (mitigated by XR formulations), xerostomia, constipation due to digestive motor slowdown.
• Cardiovascular: Sinus tachycardia, palpitations, prolongation of the QTc interval (in overdose).
• CNS: Generalized profuse sweating (noradrenergic effect), insomnia, headache, symmetrical mydriasis.
• Discontinuation Syndrome: Especially intense and early due to its short half-life. It presents with rotatory dizziness, paresthesias ("electric shocks"), easy crying and extreme irritability.

Clinical Interactions

• Pharmacodynamics: Toxic synergy with agents that prolong the QTc interval (antipsychotics, erythromycin). Increased risk of mucocutaneous bleeding with NSAIDs or anticoagulants due to blocking the reuptake of 5-HT in platelets.
• Pharmacokinetics: Strong CYP2D6 inhibitors (such as fluoxetine) increase the concentration of venlafaxine but reduce that of its metabolite ODV, with little overall clinical impact due to the similar biological activity of both compounds.

Pregnancy and Breastfeeding

FDA Category: C. Risk of neonatal toxicity characterized by irritability, feeding difficulties and tremors if administered in the third trimester. Breastfeeding: Compatible with caution. The infant receives approximately 6-8% of the weight-adjusted maternal dose. Monitor irritability or excessive sedation in the newborn.