+Binding affinities (Ki in nM) MolecularTarget<unk>  Norfluoxetine SERT 1 19 NET 660 2700 DAT 4180 420 5-HT2A 200 300 5-HT2B 5000 5100 5-HT2C 72.6 91.2 α1 3000 3900 M1 870 1200 M2 2700 4600 M3 1000 760 M4 2900 2600 M5 2700 2200 H1 3250 10000 Pharmacodynamics<unk>  is a selective serotonin reuptake inhibitor (SSRI) and does not appreciably inhibit norepinephrine and dopamine reuptake at therapeutic doses. It does, however, delay the reuptake of serotonin, resulting in serotonin persisting longer when it is released. Large doses in rats have been shown to induce a significant increase in synaptic norepinephrine and dopamine. Thus, dopamine and norepinephrine may contribute to the antidepressant action of<unk>  in humans at supratherapeutic doses (60–80 mg). This effect may be mediated by 5HT2C receptors, which are inhibited by higher concentrations of<unk> .<unk>  increases the concentration of circulating allopregnanolone, a potent GABAA receptor positive allosteric modulator, in the brain. Norfluoxetine, a primary active metabolite of<unk> , produces a similar effect on allopregnanolone levels in the brains of mice. Additionally, both<unk>  and norfluoxetine are such modulators themselves, actions which may be clinically-relevant. In addition,<unk>  has been found to act as an agonist of the σ1-receptor, with a potency greater than that of citalopram but less than that of<unk> uvoxamine. However, the significance of this property is not fully clear.<unk>  also functions as a channel blocker of anoctamin 1, a calcium-activated chloride channel. A number of other ion channels, including nicotinic acetylcholine receptors and 5-HT3 receptors, are also known to be at similar concentrations.<unk>  has been shown to inhibit acid sphingomyelinase, a key regulator of ceramide levels which derives ceramide from sphingomyelin. Mechanism of action<unk>  elicits antidepressant effect by inhibiting serotonin reuptake in the synapse by binding to the reuptake pump on the neuronal membrane to increase serotonin availability and enhance neurotransmission. Norfluoxetine and desmethylfluoxetine are metabolites of<unk>  and also act as serotonin reuptake inhibitors, increasing the duration of action of the drug. Pharmacokinetics The S enantiomer of norfluoxetine,<unk> 's chief active metabolite. The bioavailability of<unk>  is relatively high (72%), and peak plasma concentrations are reached in 6–8 hours. It is highly bound to plasma proteins, mostly albumin and α1-glycoprotein.<unk>  is metabolized in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6. The role of CYP2D6 in the metabolism of<unk>  may be clinically important, as there is great genetic variability in the function of this enzyme among people. CYP2D6 is responsible for converting<unk>  to its only active metabolite, norfluoxetine. Both drugs are also potent inhibitors of CYP2D6. The extremely slow elimination of<unk>  and its active metabolite norfluoxetine from the body distinguishes it from other antidepressants. With time,<unk>  and norfluoxetine inhibit their own metabolism, so<unk>  elimination half-life increases from 1 to 3 days, after a single dose, to 4 to 6 days, after long-term use. Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use. Therefore, the concentration of the drug and its active metabolite in the blood continues to grow through the first few weeks of treatment, and their steady concentration in the blood is achieved only after four weeks. Moreover, the brain concentration of<unk>  and its metabolites keeps increasing through at least the first five weeks of treatment. The full benefit of the current dose a patient receives is not realized for at least a month following ingestion. For example, in one 6-week study, the median time to achieving consistent response was 29 days. Likewise, complete excretion of the drug may take several weeks. During the first week after treatment discontinuation, the brain concentration of<unk>  decreases by only 50%, The blood level of norfluoxetine four weeks after treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and, seven weeks after discontinuation, norfluoxetine is still detectable in the blood. Measurement in body<unk> uids<unk>  and norfluoxetine may be quantitated in blood, plasma or serum to monitor therapy, confirm a diagnosis of poisoning in hospitalized person or assist in a medicolegal death investigation. Blood or plasma<unk>  concentrations are usually in a range of 50–500 μg/L in persons taking the drug for its antidepressant effects, 900–3000 μg/L in survivors of acute overdosage and 1000–7000 μg/L in victims of fatal overdosage. Norfluoxetine concentrations are approximately equal to those of the parent drug during chronic therapy, but may be substantially less following acute overdosage, since it requires at least 1–2 weeks for the metabolite to achieve equilibrium.
Fluoxetine
Atomoxetine
Duloxetine
Dapoxetine
Edivoxetine
Vortioxetine
Bupropion
Citalopram