SEROXAT 20MG TABLETS

Indications

• Major depressive disorder
• Generalized anxiety disorder
• Panic disorder
• Obsessive-compulsive disorder
• Post-traumatic stress disorder
• Menopausal symptoms (off-label)

Dosage

Adults: Initially 20 mg daily, increased in steps of 10 mg as necessary, maximum 40 mg per day for depressive illness. For panic disorder, initially 50–100 mg daily, increased gradually, maximum 300 mg per day.

Mechanism of action

Paroxetine enhances serotonergic activity by inhibiting the presynaptic reuptake of serotonin via the serotonin transporter (SERT). This inhibition increases serotonin levels in the synaptic cleft, alleviating symptoms associated with mood and anxiety disorders. It has a higher selectivity for serotonin reuptake inhibition compared to other SSRIs like citalopram and fluoxetine. While the mechanism for its effects on menopausal symptoms is not fully understood, it may relate to its influence on thermoregulation.

Pharmacodynamics

Paroxetine effectively treats symptoms of depression, anxiety disorders, obsessive-compulsive disorder, and post-traumatic stress disorder through serotonin reuptake inhibition. Its therapeutic effects typically begin to manifest around 6 weeks after initiation of treatment. Due to its serotonergic properties, there is a risk of serotonin syndrome, particularly when combined with monoamine oxidase inhibitors (MAOIs). A two-week interval is recommended before initiating paroxetine following MAOI treatment.

Pharmacokinetics

Paroxetine is well-absorbed after oral administration, with a peak plasma concentration occurring in approximately 4 to 8 hours. It is extensively metabolized in the liver via the cytochrome P450 2D6 pathway to various metabolites. The elimination half-life is approximately 21 hours, and it is excreted primarily in urine. Dose adjustments may be required in patients with hepatic or renal impairment.

Contra-indications

• Hypersensitivity to paroxetine or any of its ingredients
• Use with monoamine oxidase inhibitors (MAOIs) within 2 weeks
• Pregnancy, especially in the first trimester due to increased risk of congenital malformations

Adverse effects

• Common: Nausea, dry mouth, dizziness, insomnia, somnolence, sweating, sexual dysfunction
• Uncommon: Diabetic control impaired, blurred vision
• Rare: Acute glaucoma, hepatic disorders, peripheral edema
• Very rare: Neuroleptic malignant-like syndrome, bone fracture

Interactions

• Moderate: Increased exposure when used with procyclidine
• Increased exposure when used with second-generation antipsychotics, asenapine, and terbinafine
• Risk of serotonin syndrome when co-administered with other serotonergic agents, particularly MAOIs

Precautions

• Use with caution in patients with hepatic or renal impairment
• Monitor for serotonin syndrome, especially when used with other serotonergic drugs
• Gradual reduction of dose is recommended upon cessation to avoid withdrawal symptoms

Pregnancy

Increased risk of congenital malformations, especially if used in the first trimester. Caution is advised.

Breast-feeding

Present in breast milk but the amount is too small to be harmful. Nevertheless, caution is advised.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets: 10 mg, 20 mg, 30 mg, 40 mg
• Oral suspension: dosage forms available from special-order manufacturers

Mechanism of action

Paroxetine enhances serotonergic activity via the inhibition presynaptic reuptake of serotonin by the serotonin (SERT) receptor. This inhibition raises the level of serotonin in the synaptic cleft, relieving various symptoms. This drug has been demonstrated to be a stronger inhibitor of serotonin reuptake than other members of the same drug class, including [Citalopram], [Fluoxetine], and [Fluvoxamine]. The mechanism of action of paroxetine in relieving the vasomotor symptoms of menopause is unknown, according to the Brisdelle prescribing information, but may occur due to its effects on thermoregulation. Paroxetine shows a clinically insignificant affinity for adrenergic alpha-1 and alpha-2 receptors and β-adrenergic receptors, dopamine D1 and D2 receptors, histamine H1 receptors and serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors. This drug shows some affinity for muscarinic cholinergic receptors and 5-H2B receptors. The delayed onset of paroxetine therapeutic effects may be explained by the initial paroxetine actions on the 5-HT neurons. In rats, paroxetine activates 5-HT1A receptors when it is first administered, inhibiting the stimulation of the 5-HT neurons and subsequent release of serotonin at the synaptic cleft. Functional and structural approaches were used to examine the inhibitory mechanisms and binding site location for fluoxetine and paroxetine, two serotonin selective reuptake inhibitors, on nicotinic acetylcholine receptors (AChRs) in different conformational states. The results establish that: (a) fluoxetine and paroxetine inhibit h alpha1beta1 gammadelta AChR-induced Ca(2+) influx with higher potencies than dizocilpine. The potency of fluoxetine is increased approximately 10-fold after longer pre-incubation periods, which is in agreement with the enhancement of (3)H-cytisine binding to resting but activatable Torpedo AChRs elicited by these antidepressants, (b) fluoxetine and paroxetine inhibit the binding of the phencyclidine analog piperidyl-3,4-(3)H(N)]-(N-(1-(2 thienyl)cyclohexyl)-3,4-piperidine to the desensitized Torpedo AChR with higher affinities compared to the resting AChR, and (c) fluoxetine inhibits (3)H-dizocilpine binding to the desensitized AChR, suggesting a mutually exclusive interaction. This is supported by our molecular docking results where neutral dizocilpine and fluoxetine and the conformer of protonated fluoxetine with the highest LUDI score interact with the domain between the valine (position 13') and leucine (position 9') rings. Molecular mechanics calculations also evidence electrostatic interactions of protonated fluoxetine at positions 20', 21', and 24'. Protonated dizocilpine bridges these two binding domains by interacting with the valine and outer (position 20') rings. The high proportion of protonated fluoxetine and dizocilpine calculated at physiological pH suggests that the protonated drugs can be attracted to the channel mouth before binding deeper within the AChR ion channel between the leucine and valine rings, a domain shared with phencyclidine, finally blocking ion flux and inducing AChR desensitization. Paroxetine was shown to be a potent (Ki = 1.1 nM) and specific inhibitor of [3H]-5-hydroxytryptamine (5-HT) uptake into rat cortical and hypothalamic synaptosomes in vitro. Lineweaver-Burk kinetic analysis determined that this inhibition was competitive in nature, implying a direct interaction with the 5-HT uptake transporter complex. Oral administration of paroxetine produced a dose-related inhibition of [3H]-5-HT uptake (ED50 = 1.9 mg/kg) into rat hypothalamic synaptosomes ex vivo with little effect on [3H]-l-noradrenaline (NA) uptake (ED50 greater than 30 mg/kg). This selectivity for 5-HT uptake was maintained after oral dosing for 14 days. Paroxetine (ED50 1-3 mg/kg PO) prevented the 5-HT depleting effect of p-chloroamphetamine (PCA) in rat brain, demonstrating 5-HT uptake blockade in vivo. Radioligand binding techniques in rat brain in vitro showed that paroxetine

Pharmacodynamics

Paroxetine treats the symptoms of depression, various anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, and the vasomotor symptoms of menopause via the inhibition of serotonin reuptake. The onset of action of paroxetine is reported to be approximately 6 weeks. Due its serotonergic activity, paroxetine, like other SSRI drugs, may potentiate serotonin syndrome. This risk is especially high when monoamine oxidase (MAO) inhibitors are given within 2 weeks of paroxetine administration. Upon cessation of MAO inhibitors, a 2-week interval before paroxetine administration is recommended. Do not coadminister these agents.