Pharmacology Fluoxetine

1 pharmacology

1.1 pharmacodynamics
1.2 pharmacokinetics
1.3 measurement in body fluids

pharmacology

pharmacodynamics

fluoxetine selective serotonin reuptake inhibitor (ssri) , not appreciably inhibit norepinephrine , dopamine reuptake @ therapeutic doses. does, however, delay reuptake of serotonin, resulting in serotonin persisting longer when released. large doses in rats have been shown induce significant increase in synaptic norepinephrine , dopamine. thus, dopamine , norepinephrine may contribute antidepressant action of fluoxetine in humans @ supratherapeutic doses (60–80 mg) . effect may mediated 5ht2c receptors, inhibited higher concentrations of fluoxetine.

fluoxetine increases concentration of circulating allopregnanolone, potent gabaa receptor positive allosteric modulator, in brain. norfluoxetine, primary active metabolite of fluoxetine, produces similar effect on allopregnanolone levels in brains of mice. additionally, both fluoxetine , norfluoxetine such modulators themselves, actions may clinically-relevant.

in addition, fluoxetine has been found act agonist of σ1-receptor, potency greater of citalopram less of fluvoxamine. however, significance of property not clear. fluoxetine functions channel blocker of anoctamin 1, calcium-activated chloride channel. number of other ion channels, including nicotinic acetylcholine receptors , 5-ht3 receptors, known inhibited @ similar concentrations.

fluoxetine has been shown inhibit acid sphingomyelinase, key regulator of ceramide levels derives ceramide sphingomyelin.

pharmacokinetics

seproxetine ((s)-norfluoxetine) — fluoxetine s chief active metabolite.

the bioavailability of fluoxetine relatively high (72%), , peak plasma concentrations reached in 6–8 hours. highly bound plasma proteins, albumin , α1-glycoprotein. fluoxetine metabolized in liver isoenzymes of cytochrome p450 system, including cyp2d6. role of cyp2d6 in metabolism of fluoxetine may clinically important, there great genetic variability in function of enzyme among people. cyp2d6 responsible converting fluoxetine active metabolite, norfluoxetine. both drugs potent inhibitors of cyp2d6.

the extremely slow elimination of fluoxetine , active metabolite norfluoxetine body distinguishes other antidepressants. time, fluoxetine , norfluoxetine inhibit own metabolism, fluoxetine elimination half-life changes 1 3 days, after single dose, 4 6 days, after long-term use. similarly, half-life of norfluoxetine longer (16 days) after long-term use. therefore, concentration of drug , active metabolite in blood continues grow through first few weeks of treatment, , steady concentration in blood achieved after 4 weeks. moreover, brain concentration of fluoxetine , metabolites keeps increasing through @ least first 5 weeks of treatment. means full benefits of current dose patient receives not realized @ least month since initiation. example, in 1 6-week study, median time achieving consistent response 29 days. likewise, complete excretion of drug may take several weeks. during first week after treatment discontinuation, brain concentration of fluoxetine decreases 50%, blood level of norfluoxetine 4 weeks after treatment discontinuation 80% of level registered end of first treatment week, , 7 weeks after discontinuation norfluoxetine still detectable in blood.

measurement in body fluids

fluoxetine , norfluoxetine may quantitated in blood, plasma or serum monitor therapy, confirm diagnosis of poisoning in hospitalized patients or assist in medicolegal death investigation. blood or plasma fluoxetine concentrations in range of 50–500 μg/l in persons taking drug antidepressant effects, 900–3000 μg/l in survivors of acute overdosage , 1000–7000 μg/l in victims of fatal overdosage. norfluoxetine concentrations approximately equal of parent drug during chronic therapy, may substantially less following acute overdosage, since requires @ least 1–2 weeks metabolite achieve equilibrium.