Posted by Sunnely on November 8, 2001, at 23:12:27
In reply to Paxil interaction?, posted by Elizabeth on November 8, 2001, at 20:48:15
> Hey, I just saw the Paxil for GAD commercial on TV. Does anyone happen to know why they specifically recommend avoiding Mellaril (but not phenothiazines in general)?
>
> Just curious.
>
> -elizabeth**************************************
Must be the concern for a serious and potentially deadly drug-drug interaction.
Thioridazine (Mellaril) is metabolized by cytochrome P450 2D6 (among other P450 enzymes) or CYP2D6 for short. Paroxetine (Paxil), as well as fluoxetine (Prozac) are potent inhibitors of CYP2D6. Inhibition of Mellaril metabolism by Paxil or Prozac via CYP2D6 leads to increased blood level of Mellaril, which in turn could lead to prolonged QTc which could lead to a serious heart beat irregularity called "torsades des pointes" and sudden death.
Last year, the US FDA and the manufacturer of Mellaril (Novartis) issued a warning that CYP2D6 inhibitors and thioridazine should not be coadministered. For the same reason, mesoridazine (Serentil), the active metabolite of Mellaril should not be combined with CYP2D6 inhibitors. The low-potency phenothiazines (e.g., Mellaril, Serentil, and Thorazine) are more prone to cardiac side effects and therefore, should not be combined with drugs that inhibit their metabolism or have the potential to cause prolonged QTc. High-potency phenothiazines (e.g., Stelazine, Prolixin, Trilafon) appear to cause less cardiovascular side effects than the low-potency phenothiazines.
For the same reason, but involving a different cytochrome enzyme (CYP3A4), pimozide (Orap) should not combined with CYP3A4 inhibitors, including grapefruit juice. Seldane, Hismanal and Propulsid are no longer available in the US market. Several deaths (heart) have been reported with the use of these drugs which tend to occur when combined with other drugs that inhibit their metabolism (via CYP3A4).
On a related note, ziprasidone (Geodon) can also cause prolonged QTc. Geodon's metabolism depends heavily on an enzyme called aldehyde oxidase and only partly on CYP3A4. Aldehyde oxidase has no known inhibitors and inducers. Therefore, combining Geodon with a CYP3A4 inhibitor (e.g., ketoconazole, grapefuit juice), will probably not lead to clinically significant elevation of Geodon's blood level and risk of prolonged QTc. However, Geodon should not be taken with drugs that themselves prolonged QTc including Mellaril, Serentil, Pimozide, the tricyclic antidepressants, certain antibiotics, certain heart medications, to name a few. Also, Geodon should not be given to those with recent heart attack, congested heart failure, heart block, and congenital long QT syndrome (born with this condition). The following people should have their potassium and magnesium levels, and electrocardiogram checked first, and should be normal before taking Geodon: eating disorders, alcoholics, dehydration, vomiting, diarrhea.
poster:Sunnely
thread:83603
URL: http://www.dr-bob.org/babble/20011104/msgs/83629.html