Paroxetine half-life

Elderly Clearance of fluvoxamine is decreased by about 50% in elderly patients. A lower starting dose of paroxetine is recommended. Sertraline plasma clearance may be lower. In 2 pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in elderly subjects as compared with younger subjects, and its half-life was increased by 30% and 50%, respectively. In 2 pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared with young subjects and C ax was unchanged. 

Venlafaxine, although its re-uptake inhibitory activity is not restricted to serotonin, is often classified as an SSRI because of its similar spectrum of adverse reactions. It has a short elimination half-life in contrast to the other serotonin re-uptake inhibitors. Fluoxetine, norfluoxetine and paroxetine are inhibitors of their own metabolism by CYP2D6 resulting in non-linear pharmacokinetic behavior. 

The presence of an active metabolite and the duration of parent compound and metabolite half-life all impact the clinical interpretation of dosing, side effects, and potential for withdrawal. Fluoxetine and its active metabolite, both of which have a relatively long half-life, remain in the system for a long time after discontinuation. Industry prescribing instructions for fluvoxamine recommend a bid dosing regimen, in part because of the absence of an active metabolite. Paroxetine, without an active metabolite and with a relatively short half-life, has been anecdotally associated with late-day withdrawal effects. 

Several reports have described a series of symptoms after discontinuation or dose reduction of serotonergic antidepressant medications. The most common symptoms include dizziness, headache, paresthesia, nausea, diarrhea, insomnia, and irritability. Of note, these symptoms may also be seen when a patient misses doses. A prospective, double-blind, placebo-substitution study confirmed that discontinuation symptoms are most common with short half-life antidepressants, such as paroxetine (Rosenbaum et al. 1998). 

Discontinuation symptoms appear to occur most commonly after discontinuation of short-half-life serotonergic drugs (Coupland et al. 1996), such as fluvoxamine, paroxetine, and venlafaxine. 

Atomoxetine has not been shown to exert clinically significant inhibition of CYP 1A2, CYP 2C9, CYP 2D6, and CYP 3A isoenzymes (Sauer et al. 2004). However, paroxetine, a potent CYP 2D6 inhibitor, has been shown to increase plasma concentrations of atomoxetine and significantly increase the half-life of atomoxetine approximately 2.5-fold in extensive 2D6 metabolizers (Belle et al. 2002). Caution should be used when administering atomoxetine to patients taking albuterol or pressor agents because atomoxetine may potentiate the cardiovascular effects of albuterol or pressor agents. 

Autoinhibition The inhibition or saturation of the highest affinity enzymes responsible for the biotransformation of a drug by the drug itself, such that lower affinity enzymes become important in elimination and the half-life increases with chronic exposure to the drug (e.g., fluoxetine, paroxetine). 

Paroxetine at low concentration is dependent on CYP 2D6 for its clearance. However, this enzyme is almost completely saturated by paroxetine at low concentrations, which accounts for the nonlinear pharmacokinetics of paroxetine and why its half-life goes from 10 to 20 hours when the dose is advanced from 10 to 20 mg per day. At higher concentrations, paroxetine is most likely dependent on CYP 3A3/4 for its clearance. This dose-dependent change in the clearance of paroxetine probably accounts for the higher incidence of withdrawal reactions with this SSRI than might otherwise be expected for a drug with a half-life of 20 hours at steady-state on 20 mg per day (296, 297). 

As mentioned previously, beyond the unusually long half-life of fluoxetine and norfluoxetine, the other clinically meaningful distinction between the SSRIs is whether they produce substantial inhibition of specific CYP enzyme (Table 7-29). Fluvoxamine, fluoxetine, and paroxetine do, whereas citalopram and sertraline do not. As mentioned earlier, it is doubtful that the first three would be developed or approved for today s market because of their effects on CYP enzymes, which can cause serious and even fatal drug-drug interactions. 

Hilleret H, Voirol P, Bovier P, et al. Very long half-life of paroxetine following intoxication in an extensive cytochrome P4502D6 metabolizer. Ther Drug Monit 2002 24 567-569. 

Paroxetine metabolism at low concentrations is dependent on CYP2D6, which is almost saturated at these concentrations, Thus, there are non-linear pharmacokinetics and an increase in the half-life of paroxetine from 10 to 20 hours when the dose is increased from lOmg to 20mg, At higher concentrations, the metabolism is mainly by CYP3A4 isoenzymes, Paroxetine inhibits the activity of CYP2D6 in the lowest usually effective antidepressant dose,... 

For some patients A/ith severe problems discontinuing paroxetine, it may be useful to add an SSRI A/ith a long half-life, especially fluoxetine, prior to taper of paroxetine A/hile maintaining fluoxetine dosing, first slo A/ly taper paroxetine and then taper fluoxetine... 

Paroxetine is a phenylpiperidine derivative. Its half-life is about 17-22 hours and about 95 % of it is bound to plasma proteins. Its metabolites have no more than 1/50 of the potency of the parent compound in inhibiting serotonin re-uptake. The metabolism of paroxetine is accomplished in part by CYP2D6, saturation of which at therapeutic doses appears to account for the non-linearity of paroxetine kinetics at higher doses and increasing durations of treatment. The adverse effects of paroxetine are those of the SSRIs in general. Commonly observed adverse events... 

Another difference between the SSRI antidepressants is their half-lives. Paroxetine has a half-life of approximately one day, sertraline one to two days, and fluoxetine seven to ten days. A long half-life is an advantage in maintaining a stable blood level but a disadvantage when starting or stopping the mediciaton. It takes six weeks to reach a steady state with fluoxetine. 

Paroxetine. Paroxetine is a selective serotonin reuptake inhibitor with demonstrated clinical utility as an antidepressant. Paroxetine is completely absorbed after oral ingestion and reaches peak steady-state levels of 30 to 70 ng/mL in approximately 5 hours. It xmdergoes hepatic metabolism by Cyp 2D6, has a half-life of 21 hours, and metabolites are inactive. Steady-state concentrations of paroxetine on a typical dose of 20mg/day are achieved in 10 days. Clinical response appears to be related to serum concentration and a chromatographic method is available. ... 

The diversity of the SSRIs is evident not only in their chemical structures, but also in their pharmacokinetic profiles. Fluoxetine has an elimination half-fife of 2 to 3 days (4 to 5 days with multiple dosing). The single-dose hah-hfe of norfluoxetine, the active metabolite, is 7 to 9 days. Paroxetine and sertrahne have half-lives of approximately 24 hours. Unlike paroxetine, sertraline has an active metabolite, but the metabohte contributes minimally to the pharmacologic effects. Escitalopram has a half-life of approximately 30 hours. Peak plasma concentrations of citalopram are observed within 2 to 4 hours after dosing, and the elimination half-life is about 30 hours. The SSRIs, with the exception of fluvoxamine, escitalopram, and citalopram, are extensively bound to plasma proteins (94% to 99%). The SSRIs are extensively distributed to the tissues, and aU, with the possible exception of citalopram, may have a nonlinear pattern of drug accumulation with long-term administration. ... 

In cirrhotics, the half-lives of fluoxetine and norfluoxetine increased to 7.6 and 12 days, respectively. Patients with hepatic impairment had a twofold increase in plasma concentrations of paroxetine. Similarly, in patients with mild stable cirrhosis, the half-life of sertraline was 2.5 times greater than in patients without liver disease. Patients with renal impairment had a two- to fourfold increase in paroxetine plasma concentrations compared with normal volunteers. Plasma concentrations of SSRIs in the elderly are reported to be greater than in younger patients. ... 

Withdrawal effects possible with short half-life drugs (paroxetine greatest, fluoxetine least). 

I Discontinuation syndrome related to half-life (especially paroxetine, rare with fluoxetine) (see below). 

Sixty percent of serum paroxetine is eliminated through renal filtration. Mild to moderate renal impairment may cause a two-fold increase in peak serum concentrations. Severe renal impairment (creatinine clearance < 30 rnl/min) may increase the half-life of the drug by over 150 percent. 

Paroxetine levels might be increased (tricyclic antidepressants (TCAs) inhibit its metabolism) this is evident mainly with amitriptyline, desipramine, imipramine, and nortriptyline. Note that TCA levels could also increase, since paroxetine concomitantly inhibits their metabolism. Studies so far have confirmed this with desipramine and imipramine (whose half-life can increase by 5-fold). 

ECT, fluoxetine (third-iine oniy due to its very iong half-life ), paroxetine (third-line only due to its relative high anticholinergic capacity among the SSRIs)... 

Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine is the prototype of a group of drugs that selectively inhibit the reuptake of serotonin. AH of them require hepatic metabolism and have half-lives of 18—24 hours. However, fluoxetine forms an active metabolite with a half-life of several days. Other members of this group (eg, sertraline, citalopram, paroxetine), do not form long-acting metabolites. 

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