Venlafaxine INDEX

Those who fail to respond to an SSRI may respond to a TCA, and vice versa. Thus, these two broad-spectrum classes can be used in a sequential strategy to adequately treat the majority of cases. However, many physicians try another newer antidepressant (e.g, venlafaxine, bupropion, nefazodone) in such patients because of the safety and tolerability problems associated with TCAs. Of note, the tolerability profile of secondary amine TCAs such as desipramine is as favorable as any of the newer antidepressants and probably better than nefazodone. Nevertheless, the secondary amine TCAs have a therapeutic index as narrow as tertiary amine TCAs (e.g., amitriptyline, imipramine) in terms of lethality in overdoses resulting from cardiotoxicity. 

Venlafaxine is converted by CYP 2D6 to ODV, which is subsequently cleared by CYP 3A3/4 ( 501). ODV has virtually the same in vitro pharmacology as venlafaxine. Thus, the total of venlafaxine plus ODV is believed to be the relevant concentration determining clinical effect ( 137). Theoretically, venlafaxine should be relatively impervious to even substantial CYP 2D6 inhibition because ODV levels would decrease proportionate to the increase in venlafaxine levels such that the total level would remain the same. In contrast, the inhibition of CYP 3A3/4 would be potentially more clinically relevant because it should decrease ODV clearance and thus increase total levels. Nevertheless, such an interaction would not be expected to do more than increase the usual dose-dependent adverse effects of venlafaxine because of its wide therapeutic index. 

CANNABIS SERTRALINE, VENLAFAXINE Unpredictable changes in plasma concentration. Risk of toxicity or therapeutic failure, particularly of drugs with a narrow therapeutic index Induction or inhibition of CYP3A4-mediated metabolism by cannabis. It is not yet known whether the effects are dependent on the degree of cannabis consumption Be aware. Watch for signs of toxicity, especially when cannabis use abruptly changes... 

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Antidepressant drugs A major class of psychotropic drugs with diverse chemical configurations including the monoamine oxidase inhibitors (MAOIs), the heterocyclic drugs (composed of mono-, di-, tri-, and hetero-cyclics), the serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, trazodone, and venlafaxine), and bupropion are more recent innovations. Antidepressants usually must be taken for several weeks to have the desired effect and they often have a low therapeutic index, so they must be closely monitored. 

Although venlafaxine is a weak inhibitor of CYP2D6, variability has been observed in the pharmacokinetic parameters of venlafaxine in patients with hepatic or renal function impairment. As a precaution, elderly patients taking venlafaxine concurrently with a drug that has a narrow therapeutic index and also is metabolized by CYP2D6 should be carefully monitored. Concurrent use of CYP3A4 inhibitors with venlafaxine has been shown to interfere with its metabolism and clearance. Similar to the other antidepressants that block 5-HT reuptake, venlafaxine may interact pharmacodynamically to cause toxic levels of 5-HT to accumulate, leading to the 5-HT syndrome. 

The magor metabolite having a similar potency for 5-HT uptake inhibition as venlafaxine tends to be the more selective 5-HT uptake inhibitor, because the selectivity index (IC50 NE/ICjo 5-HT) increases from 3 for venlafaxine to 6 for the mayor metabolite. Both minor metabolites are considerably less potent tham the mayor metabolite in the uptake inhibition of 5-HT, NE amd DA. 

Exchanging the 4-MeO group of venlafaxine for a CF3 group results in an increase in selectivity index with a concomitant twofold decrease in affinity for the... 

The same phenomenon holds true for other electron withdrawing groups like Cl and Br (data not shown). Ring contraction of the cydohexyl moiety to a cyclo pentyl group results for venlafaxine and its CF3 analogue in a considerable increase in selectivity index with a concomitant moderate reduction in ICgg for 5-HT uptake inhibition. 

Except by ring contraction the rather moderate 5-HT selectivity index of 3 of venlafaxine can also be increased by the introduction of a second MeO group in the... 

This compound (3-MeO, 4-MeO) with a selectivity index of 10.6 also shows a slight increase in potency as a 5-HT uptake inhibitor (IC50 0.13 pM vs 0.21 pM for venlafaxine). However, selectivity is completely lost if the 3-MeO, 4-MeO phenyl group is replaced by a 3-Cl, 4-Cl phenyl group. 

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