Pharmacology fluoxetine

In terms of comparative adverse effects, imipramine produces more dry mouth than reboxetine probably because imipramine blocks muscarinic cholinergic receptors as well as inhibiting NE uptake (47,5). Imipramine also produces more tremulousness and hypotension than reboxetine. Consistent with their pharmacology, fluoxetine produces more serotonin-mediated adverse effects than does reboxetine (i.e., nausea, loose stools, and somnolence), whereas reboxetine causes more sympathomimetic adverse effects (476). To date, reboxetine has not been reported to cause an increased incidence of laboratory abnormalities. 

Naranjo CA, Sellers EM, Chater K, et al Non-pharmacological interventions in acute alcohol withdrawal. Clin Pharmacol Ther 34 214—219, 1983 Naranjo CA, Sellers EM, Roach CA, et al Zimelidine-induced variations in alcohol intake hy nondeptessed heavy drinkers. Clin Pharmacol Ther 35 374-381, 1984 Naranjo CA, Sellers EM, Sullivan ]T, et al The serotonin uptake inhibitor citalopram attenuates ethanol intake. Clin Pharmacol Ther 41 266-274, 1987 Naranjo CA, Sullivan ]T, Kadlec KE, et al Differential effects of viqualine on alcohol intake and other consummatory behaviors. Clin Pharmacol Ther 46 301 -309,1989 Naranjo CA, Kadlec KE, Sanhueza P, et al Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers. Clin Pharmacol Ther 47 490 98, 1990... 

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

C. R., Klemens, C.A., Gillman, B.M., Anderson, C.L., Holzem, KM., Delisle, B.P., Anson, B.D., Makielski, J.C. and January, C.T. (2006) Drug-induced long QT syndrome hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine. British Journal of Pharmacology, 149, 481 189. 

Hancox, J.C. and Mitcheson, J.S. (2006) Combined hERG channel inhibition and disruption of trafficking in drug-induced long QT syndrome by fluoxetine a case-study in cardiac safety pharmacology. British Journal of Pharmacology, 149, 457 159. 

Basic pharmacology. Fluvoxamine is an effective serotonin reuptake inhibitor with an ICjg value of 0.3 pmol/L comparable ICjg values for desipramine and fluoxetine are 0.8 jmol/L and 1.3 omol/L, respectively [Bradford 1984]. The ICjo values for NA and dopamine were 100 times higher than those for serotonin [Bradford 1984]. In vitro data indicate that fluvoxamine has little or no affinity for Oj, a, Pi, P2, Dj, S-HTj, muscarinic, or histaminergic receptors [Benfield and Ward 1986]. Fluvoxamine has a total of 11 metabolites, and the 2 principal ones have little or no pharmacological activity [Claassen 1983]. 

Treatment of GAD can be undertaken using a number of pharmacological agents. Benzodiazepines have been found to be superior to placebo in several studies and all benzodiazepines appear to be equally effective. However, side effects include sedation, psvchomotor impairment, amnesia and tolerance (Chapter 1). Recent clinical data indicate that SSRIs and SNRIs are effective in the treatment of acute GAD symptoms. Venlafaxine, paroxetine and imipramine have been shown to be effective antianxiety medications in placebo-controlled studies. Case studies also indicate the usefulness of clomipramine, nefazodone, mirtazapine, fluoxetine and fluvoxamine in GAD. Buspirone, a 5-HTla receptor partial agonist, has been shown to be effective in several placebo-controlled, double-blind trials (Roy-Byme and Cowley, 2002). Buspirone has a later onset of action than both benzodiazepines and SSRIs but with the advantage of being non-addictive and non-sedating. 

A larger set of placebo-controlled studies show conclusively that imipramine is also effective for the treatment of panic disorders. Other agents shown to be effective in panic disorders include the SSRIs paroxetine, sertraline, fluvoxamine, fluoxetine and citalopram. Generally, initial treatment of moderate to severe panic disorders may require the initiation of a short course of benzodiazepines e.g. clonazepam (0.5 1 mg twice daily), and an SSRI. The patient will obtain immediate relief from panic attacks with the benzodiazepine whereas the SSRI may take 1 6 weeks to become effective. Once a patient is relieved of initial panic attacks, clonazepam should be tapered and discontinued over several weeks and SSRI therapy continued thereafter. There are no pharmacological treatments available for specific phobias, however controlled trials have shown efficacy for several agents, e.g. phenelzine, moclobemide. clonazepam, alprazolam, fluvoxamine. sertraline and paroxetine in the treatment of social phobia (Roy-Byrne and Cowlev, 2002). 

Pharmacological treatments were used by nearly half of the 149 services which offered any treatment, with a wide range of medications directed at various features of cocaine usage. Fluoxetine and desipramine were the most frequently prescribed antidepressants, with benzodiazepines used to aid sleep and reduce distress in withdrawal states. Sedative antipsychotics were used, apparently in states of severe agitation as well as more directly for psychotic complications. 

Oxidative biotransformation results in the formation of metabolites whose pharmacological effects may be similar or dissimilar to the parent compound. Either way, active metabolites contribute to the final overall clinical effects. For example, norfluoxetine has essentially the same activity as fluoxetine in terms of both serotonin uptake blockade and inhibition of several CYP enzymes, but is cleared more slowly (11, 36, 37). As a result, norfluoxetine accumulates extensively in the body following chronic administration of fluoxetine, making it, rather than the parent compound, the principal determinant of the clinical effect. 

Venlafaxine is dependent on CYP 2D6 and 3A3/4 enzymes for its biotransformation and eventual clearance ( 138, 139 and 140). CYP 2D6 converts venlafaxine into 0-desmethylvenlafaxine (ODV), which is believed to have pharmacological activity comparable with the parent drug based on in vitro studies (141). Thus, this metabolite is to venlafaxine as norfluoxetine is to fluoxetine in that the half-life of ODV is longer than that of the parent drug, although it is only 12 hours versus 14 days for norfluoxetine. 

Baron B, Ogden A, Siegel B, et al. Rapid down regulation of adrenoceptors by co-administration of desipramine and fluoxetine. Pharmacology 1988 154 125-134. 

Stark P, Fuller R, Wong D. The pharmacologic profile of fluoxetine. J din Psychiatry 1985 46 7-13. 

Although behavioral treatments for social phobia have been well studied, there are very limited data on its pharmacological management, b- Blockers (propranolol, atenolol) have been recommended, but available evidence indicates their effect may be no different than that of placebo ( 78). In a controlled study, the monoamine oxidase inhibitor (MAOl) phenelzine has been shown to be more effective than placebo (78, 79). Anecdotal reports have also described efficacy with alprazolam, clonidine, and fluoxetine, but systematic data are lacking (80, 81, 82 and 83). 

Goodman has opined that the backbone of pharmacologic treatment for OCD is a 10- to 12-week trial with an SRI in adequate doses. In most cases, treatment should be initiated with an SSRI because of the superior safety, tolerability, and equivalent efficacy of this class of drugs compared with clomipramine ( 195). Fluoxetine, sertraline, fluvoxamine, and paroxetine have, in separate multicenter trials, demonstrated efficacy and tolerability in the treatment of OCD ( 196). Citalopram, a recently marketed SSRI, also should be effective in the treatment of OCD (197). 

It has been known since the mid-1980s that clomipramine, a potent but nonse-lective serotonin reuptake inhibitor, is effective in reducing OCD symptoms. Since then, numerous studies have confirmed the superiority of clomipramine over placebo in OCD patients, whereas other antidepressant medications with less potent inhibitory effects on serotonin reuptake (e.g., nortripytline, desipramine) seem to be ineffective in OCD. Demonstration of the anti-OCD actions of all five SSRIs, namely, fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram, also supports the hypothesis that the antiobsessional effects of these various pharmacologic agents is due to their potent serotonergic reuptake blocking activity. 

Berlanga C, Mendieta D, Alva G, Del Carmen Lara M. Failure of tibolone to potentiate the pharmacological effect of fluoxetine in postmenopausal major depression. J Women s Health 2003 12 33-9. 

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