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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 15 of 15. This is the beginning of the thread.
Posted by Sad Panda on July 8, 2004, at 4:33:37
Hi All,
I am switching to Effexor + Nortriptyline & am wondering what my plasma levels of each drug will do since they both use the same enzyme. Should I reduce my Effexor doseage by 50%?
Any & All help appreciated. :)
Panda.
Posted by zeugma on July 8, 2004, at 7:09:36
In reply to P450-CYP2D6, posted by Sad Panda on July 8, 2004, at 4:33:37
> Hi All,
>
> I am switching to Effexor + Nortriptyline & am wondering what my plasma levels of each drug will do since they both use the same enzyme. Should I reduce my Effexor doseage by 50%?
>
> Any & All help appreciated. :)Hi Panda,
Effexor is not a strong inhibitor of 2D6 but you will definitely want to titrate slowly on the nortriptyline. Unlike Effexor, it blocks NE reuptake at low dosages, so you may find benefit in lowering the Effexor dosage. Effexor and nortriptyline are pharmacologically more similar than Effexor and Rem. I think nortriptyline will raise Effexor levels more than the reverse, which should not be a problem since Effexor poses few toxicity problems. Good luck,
z
> Panda.
>
Posted by King Vultan on July 8, 2004, at 8:16:52
In reply to P450-CYP2D6, posted by Sad Panda on July 8, 2004, at 4:33:37
> Hi All,
>
> I am switching to Effexor + Nortriptyline & am wondering what my plasma levels of each drug will do since they both use the same enzyme. Should I reduce my Effexor doseage by 50%?
>
> Any & All help appreciated. :)
> Panda.
>
Table 6.10 in this reference gives an indication of the degree to which Effexor will inhibit nortriptyline:http://www.preskorn.com/books/omd_s6.html#p91
I believe nortriptyline, as a secondary amine TCA, has approximately the same degree of 2D6 inhibition itself. I don't believe you will see any gigantic increases in blood plasma level of either drug beyond what might normally be expected. Of course, the blood plasma level of the nortriptyline can be monitored, as it is a tricyclic that has well established therapeutic levels. I believe they are generally considered to be 50-150 ng/ml for this drug.
Todd
Posted by SLS on July 8, 2004, at 8:23:29
In reply to P450-CYP2D6, posted by Sad Panda on July 8, 2004, at 4:33:37
> Hi All,
>
> I am switching to Effexor + Nortriptyline & am wondering what my plasma levels of each drug will do since they both use the same enzyme. Should I reduce my Effexor doseage by 50%?
Hi Panda.Is this for moderate - severe major depression?
I wouldn't worry about the interaction. You would be doing yourself a disservice by reducing the dosage of either drug by 50%. Just treat the drugs as you would normally. I was on this combination for over 6 months. I responed only minimally, unfortunately.
I would decide upon a target dosage of Effexor and then use 75mg as your initial target for nortriptyline. Get a blood level after two weeks and go from there.
Effexor 300mg + nortriptyline 75-100mg
That should make for a good maximum. That's what I took. Opt for blood levels of nortriptyline closer to 150 mcg/mL
- Scott
Posted by chemist on July 8, 2004, at 9:40:31
In reply to P450-CYP2D6, posted by Sad Panda on July 8, 2004, at 4:33:37
> Hi All,
>
> I am switching to Effexor + Nortriptyline & am wondering what my plasma levels of each drug will do since they both use the same enzyme. Should I reduce my Effexor doseage by 50%?
>
> Any & All help appreciated. :)
> Panda.
>
hey panda, just chiming in with my two-cents to say i agree with the other posters in re: inhibition of cyp4502d6 not being much of an issue...both drugs are strong substrates and relatively weak inhibitors of this isoenzyme....i would argue that venlafaxine is *slightly* more likely to have a smaller K_{i} for 2D6 than nortriptyline, as the tertiary amine is actually a quaternary amine in the salt and thus higher affinity for 2D6 than the (in salt) tertiary amine in nortriptylline....all the best as usual, chemist
Posted by Sad Panda on July 8, 2004, at 10:20:10
In reply to Re: P450-CYP2D6, posted by SLS on July 8, 2004, at 8:23:29
Thanks all for the replies, I'm going to drop my Effexor from 225 down to 150mg just to err on the safe side. I know that 300mg is too much Effexor for me & if Nort pushes my Effexor level up I will not know if Nort is causing me grief or my Effexor plasma level has gone to high.
I was taking 225mg Effexor + 30mg Remeron. Tonight I took 150mg Effexor, 15mg Remeron & 25mg of Nortriptyline. I will do this for a few days & then drop Remeron & increase Nort to 50mg. So far Nort is 'alerting', I hope it lets me sleep.
>
> Is this for moderate - severe major depression?
>Hi Scott, I had major depression, I am relatively happy these days, but I'm not ready to give up Effexor just yet to find out that I am still depressed.
Cheers,
Panda.
Posted by SLS on July 8, 2004, at 15:09:38
In reply to Re: P450-CYP2D6, posted by Sad Panda on July 8, 2004, at 10:20:10
> > Is this for moderate - severe major depression?
> Hi Scott, I had major depression,"had" is such a cool word.
:-)
Stay well.
- Scott
Posted by zeugma on July 8, 2004, at 15:58:21
In reply to Re: P450-CYP2D6, posted by Sad Panda on July 8, 2004, at 10:20:10
I was taking 225mg Effexor + 30mg Remeron. Tonight I took 150mg Effexor, 15mg Remeron & 25mg of Nortriptyline. I will do this for a few days & then drop Remeron & increase Nort to 50mg. So far Nort is 'alerting', I hope it lets me sleep.
>
YMMV, but i found 25 mg nortriptyline to have no sedative effect. At 50 mg there was one, but due to nortriptyline's slow absorption (peak plasma levels reached 7-8.5 hours after administration) i took it 8 hours before I wanted to go to sleep. At 75 mg i would take it about 6 hours before sleep, and the drowsiness would come on slowly. at 100 mg there is less of a 'drowsy' effect; i just fall asleep about 3-4 hours after i take it.
Posted by Sad Panda on July 9, 2004, at 9:50:41
In reply to nortriptyline as sedative » Sad Panda, posted by zeugma on July 8, 2004, at 15:58:21
> I was taking 225mg Effexor + 30mg Remeron. Tonight I took 150mg Effexor, 15mg Remeron & 25mg of Nortriptyline. I will do this for a few days & then drop Remeron & increase Nort to 50mg. So far Nort is 'alerting', I hope it lets me sleep.
>
> >
>
> YMMV, but i found 25 mg nortriptyline to have no sedative effect. At 50 mg there was one, but due to nortriptyline's slow absorption (peak plasma levels reached 7-8.5 hours after administration) i took it 8 hours before I wanted to go to sleep. At 75 mg i would take it about 6 hours before sleep, and the drowsiness would come on slowly. at 100 mg there is less of a 'drowsy' effect; i just fall asleep about 3-4 hours after i take it.
>
>Thanks for the info, I guess I will have to wait a week or so to see if I sleep OK on it. I am mostly immune to Remeron's H1 blockade now, some nights I don't even notice it. Still sleep like a log however & did so last night after my first dosage of Nort.
Cheers,
Panda.
Posted by Sad Panda on July 9, 2004, at 9:55:03
In reply to Re: P450-CYP2D6 » Sad Panda, posted by SLS on July 8, 2004, at 15:09:38
> > > Is this for moderate - severe major depression?
>
> > Hi Scott, I had major depression,
>
> "had" is such a cool word.
>
> :-)
>
> Stay well.
>
>
> - Scott
>I'm glad the suicidal thoughts are long gone, but it will still be a while before a test the water.
Cheers,
Panda.
Posted by Sad Panda on August 23, 2004, at 5:53:54
In reply to Re: P450-CYP2D6, posted by SLS on July 8, 2004, at 8:23:29
Hi All,
Found this interesting at Pubmed
"Effect of venlafaxine versus fluoxetine on metabolism of dextromethorphan, a CYP2D6 probe.
Amchin J, Ereshefsky L, Zarycranski W, Taylor K, Albano D, Klockowski PM.
Wyeth-Ayerst Laboratories, 240 North Radnor-Chester Road, St. Davids, PA 19087, USA.
Two antidepressants, venlafaxine and fluoxetine, were evaluated in vivo for their effect on cytochrome P450 2D6 (CYP2D6) activity, measured by the ratio of dextromethorphan, a sensitive CYP2D6 marker, to its metabolite dextrorphan (i.e., DM:DT) excreted in urine after DM coadministration. Twenty-eight healthy extensive metabolizers of CYP2D6 received either venlafaxine (37.5 mg bid for 7 days, then 75 mg bid until Day 28) or fluoxetine (20 mg daily for 28 days); 26 completed the study. Plasma concentrations of both drugs and their active metabolites were determined. DM:DTs were evaluated at baseline (Day 0), on Days 7 and 28 of dosing, and 2 weeks after drug discontinuation (Day 42). Steady-state drug and metabolite levels were achieved in both groups by Day 28. Mean DM:DTs for venlafaxine and fluoxetine differed statistically significantly (p < 0.001) on Days 7, 28, and 42. Comparisons of DM:DT as a percentage of baseline values showed that DM:DT increased 1.2-fold for venlafaxine and 9.1-fold for fluoxetine on Day 7 (p < 0.001) and increased 2.1-fold for venlafaxine and 17.1-fold for fluoxetine on Day 28 (p < 0.001). Inhibition of CYP2D6 metabolism persisted for 2 weeks after discontinuation of fluoxetine, unlike the case with venlafaxine. These in vivo results confirm in vitro data demonstrating significantly weaker inhibition of CYP2D6 with venlafaxine than with fluoxetine. This suggests that clinically significant interactions involving CYP2D6 inhibition could occur between fluoxetine and drugs metabolized by CYP2D6 but may be less likely to occur with venlafaxine."
A 9x increase of dextromethorphan caused by fluoxetine is rather awesome & scary. I think I read somewhere that Paxil & Luvox are just as bad.
For my original dilemma of adding nortriptyline to venlafaxine I have found that I had to lower my intake of venlafaxine which was painfull for awhile because we don't have 37.5mg capsules here.
Cheers,
Panda.
Posted by chemist on August 23, 2004, at 6:44:08
In reply to Re: P450-CYP2D6, posted by Sad Panda on August 23, 2004, at 5:53:54
> Hi All,
>
> Found this interesting at Pubmed
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11304901
>
> "Effect of venlafaxine versus fluoxetine on metabolism of dextromethorphan, a CYP2D6 probe.
>
> Amchin J, Ereshefsky L, Zarycranski W, Taylor K, Albano D, Klockowski PM.
>
> Wyeth-Ayerst Laboratories, 240 North Radnor-Chester Road, St. Davids, PA 19087, USA.
>
> Two antidepressants, venlafaxine and fluoxetine, were evaluated in vivo for their effect on cytochrome P450 2D6 (CYP2D6) activity, measured by the ratio of dextromethorphan, a sensitive CYP2D6 marker, to its metabolite dextrorphan (i.e., DM:DT) excreted in urine after DM coadministration. Twenty-eight healthy extensive metabolizers of CYP2D6 received either venlafaxine (37.5 mg bid for 7 days, then 75 mg bid until Day 28) or fluoxetine (20 mg daily for 28 days); 26 completed the study. Plasma concentrations of both drugs and their active metabolites were determined. DM:DTs were evaluated at baseline (Day 0), on Days 7 and 28 of dosing, and 2 weeks after drug discontinuation (Day 42). Steady-state drug and metabolite levels were achieved in both groups by Day 28. Mean DM:DTs for venlafaxine and fluoxetine differed statistically significantly (p < 0.001) on Days 7, 28, and 42. Comparisons of DM:DT as a percentage of baseline values showed that DM:DT increased 1.2-fold for venlafaxine and 9.1-fold for fluoxetine on Day 7 (p < 0.001) and increased 2.1-fold for venlafaxine and 17.1-fold for fluoxetine on Day 28 (p < 0.001). Inhibition of CYP2D6 metabolism persisted for 2 weeks after discontinuation of fluoxetine, unlike the case with venlafaxine. These in vivo results confirm in vitro data demonstrating significantly weaker inhibition of CYP2D6 with venlafaxine than with fluoxetine. This suggests that clinically significant interactions involving CYP2D6 inhibition could occur between fluoxetine and drugs metabolized by CYP2D6 but may be less likely to occur with venlafaxine."
>
> A 9x increase of dextromethorphan caused by fluoxetine is rather awesome & scary. I think I read somewhere that Paxil & Luvox are just as bad.
>
> For my original dilemma of adding nortriptyline to venlafaxine I have found that I had to lower my intake of venlafaxine which was painfull for awhile because we don't have 37.5mg capsules here.
>
> Cheers,
> Panda.
>
>
hi panda.....as for luvox, increased serum levels of DXM are reported in the prescribing information, but fluvoxamine is a weak inhibitor of 2D6: it is a potent substrate, however, of 2D6 and 1A2, and a potent inhibitor of 1A2. i would suspect that serum levels of DXM and metabolites via the 2D6 route would not be significantly enhanced by fluvoxamine as they are by fluoxetine, although i have no personal experience with DXM and luvox (xanax, dexedrine, caffeine/theophylline/theobromine, ambien, and several 1,4-benzos are fine with luvox, in my experience, past and present).....cheers to you, chemist
Posted by Sad Panda on August 23, 2004, at 6:53:53
In reply to Re: P450-CYP2D6 » Sad Panda, posted by chemist on August 23, 2004, at 6:44:08
> > Hi All,
> >
> > Found this interesting at Pubmed
> >
> > http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11304901
> >
> > "Effect of venlafaxine versus fluoxetine on metabolism of dextromethorphan, a CYP2D6 probe.
> >
> > Amchin J, Ereshefsky L, Zarycranski W, Taylor K, Albano D, Klockowski PM.
> >
> > Wyeth-Ayerst Laboratories, 240 North Radnor-Chester Road, St. Davids, PA 19087, USA.
> >
> > Two antidepressants, venlafaxine and fluoxetine, were evaluated in vivo for their effect on cytochrome P450 2D6 (CYP2D6) activity, measured by the ratio of dextromethorphan, a sensitive CYP2D6 marker, to its metabolite dextrorphan (i.e., DM:DT) excreted in urine after DM coadministration. Twenty-eight healthy extensive metabolizers of CYP2D6 received either venlafaxine (37.5 mg bid for 7 days, then 75 mg bid until Day 28) or fluoxetine (20 mg daily for 28 days); 26 completed the study. Plasma concentrations of both drugs and their active metabolites were determined. DM:DTs were evaluated at baseline (Day 0), on Days 7 and 28 of dosing, and 2 weeks after drug discontinuation (Day 42). Steady-state drug and metabolite levels were achieved in both groups by Day 28. Mean DM:DTs for venlafaxine and fluoxetine differed statistically significantly (p < 0.001) on Days 7, 28, and 42. Comparisons of DM:DT as a percentage of baseline values showed that DM:DT increased 1.2-fold for venlafaxine and 9.1-fold for fluoxetine on Day 7 (p < 0.001) and increased 2.1-fold for venlafaxine and 17.1-fold for fluoxetine on Day 28 (p < 0.001). Inhibition of CYP2D6 metabolism persisted for 2 weeks after discontinuation of fluoxetine, unlike the case with venlafaxine. These in vivo results confirm in vitro data demonstrating significantly weaker inhibition of CYP2D6 with venlafaxine than with fluoxetine. This suggests that clinically significant interactions involving CYP2D6 inhibition could occur between fluoxetine and drugs metabolized by CYP2D6 but may be less likely to occur with venlafaxine."
> >
> > A 9x increase of dextromethorphan caused by fluoxetine is rather awesome & scary. I think I read somewhere that Paxil & Luvox are just as bad.
> >
> > For my original dilemma of adding nortriptyline to venlafaxine I have found that I had to lower my intake of venlafaxine which was painfull for awhile because we don't have 37.5mg capsules here.
> >
> > Cheers,
> > Panda.
> >
> >
> hi panda.....as for luvox, increased serum levels of DXM are reported in the prescribing information, but fluvoxamine is a weak inhibitor of 2D6: it is a potent substrate, however, of 2D6 and 1A2, and a potent inhibitor of 1A2. i would suspect that serum levels of DXM and metabolites via the 2D6 route would not be significantly enhanced by fluvoxamine as they are by fluoxetine, although i have no personal experience with DXM and luvox (xanax, dexedrine, caffeine/theophylline/theobromine, ambien, and several 1,4-benzos are fine with luvox, in my experience, past and present).....cheers to you, chemist
>
>Hi there chemist,
When you say fluvoxamine is only a weak inhibitor of 2D6, where would it fall between velafaxine at 1.2x & fluoxetine at 9.1x?
Cheers,
Panda.
Posted by chemist on August 23, 2004, at 7:01:38
In reply to Re: P450-CYP2D6 » chemist, posted by Sad Panda on August 23, 2004, at 6:53:53
hello panda, the quick answer is: very much closer to that of venlafaxine in terms of comparable inhibition of 2D6. let me dig for a number, as i do have at my fingertips only the qualitative stats (fluoxetine is indeed noted at a strong inhibitor, venlafaxine and fluvoxamine come up the same for 2D6 inhibition, qualitatively). more soon, chemist
> > hi panda.....as for luvox, increased serum levels of DXM are reported in the prescribing information, but fluvoxamine is a weak inhibitor of 2D6: it is a potent substrate, however, of 2D6 and 1A2, and a potent inhibitor of 1A2. i would suspect that serum levels of DXM and metabolites via the 2D6 route would not be significantly enhanced by fluvoxamine as they are by fluoxetine, although i have no personal experience with DXM and luvox (xanax, dexedrine, caffeine/theophylline/theobromine, ambien, and several 1,4-benzos are fine with luvox, in my experience, past and present).....cheers to you, chemist
> >
> >
>
> Hi there chemist,
>
> When you say fluvoxamine is only a weak inhibitor of 2D6, where would it fall between velafaxine at 1.2x & fluoxetine at 9.1x?
>
> Cheers,
> Panda.
>
>
>
Posted by J. Backer on August 23, 2004, at 12:17:42
In reply to Re: P450-CYP2D6 » Sad Panda, posted by chemist on August 23, 2004, at 7:01:38
tried the Effexor DXM experiment myself, heh heh
i didnt notice any significant change in the nature of my tripp except for slightly smoother sailing.
This is the end of the thread.
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