Progesterone Reverses The Side Effects Of Anti-serotonin Drugs Like Ondansetron

Discussion in 'Scientific Studies' started by haidut, Apr 11, 2016.

  1. haidut

    haidut Member

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    Ray has written about the benefits of 5-HT3 antagonists like ondansetron. Tehse drugs have remerkable properties are known to have central as well as peripheral effects. Ondansteron is one of the most potent drugs available for reversing learned helplessness and it does so in doses below 4mg, which is the starting therapeutic dose. Unfortunately, drugs like ondansetron have a number of potentially serious side effects, the most prominent of which is the prolongation of the QT-interval. That side effect can lead to dangerous arrhythmia and even cardiac arrest.

    This showed that the combined administration of 400mg oral progesterone for 7 days and a drug (ibutilide) that prolongs the QT-interval essentially reversed that side effect of the drug. The plasma concentrations achievable with 400mg oral progesterone can be achieved with about 600mg pregnenolone, so that approach should work as well for people using ondansetron.
    The positive heart effects of progesterone are not surprising given that it is BOTH a positive ionotropic and chronotropic agent as Ray wrote in one of his articles. Estrogen is the exact opposite in this respect, so it is not far fetched to supposed that it would have opposite effects on the heart and thus also prolong the QT-interval. Yet another reason to keep estrogen under control.

    http://medicalxpress.com/news/2016-04-progesterone-attenuates-drug-induced-qt-interval.html
    "...James E. Tisdale, Pharm.D., from Purdue University in Indianapolis, and colleagues conducted a double-blind crossover study involving 19 healthy females. Participants were randomized to receive progesterone 400 mg or matching placebo once daily for seven days timed to the menses phase of the menstrual cycle, with a 49-day between-phase washout period. Ibutilide was infused over 10 minutes on day seven, after which, QT intervals were recorded; blood samples were collected for 12 hours. To calculate individualized heart rate-corrected QT intervals (QTcI), subjects underwent electrocardiographic monitoring for 12 hours prior to the treatment phases."

    "...Oral progesterone administration attenuates drug-induced QTcI lengthening," the authors write."
     
  2. Such_Saturation

    Such_Saturation Member

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    Is QT an issue with tianeptine?
     
  3. OP
    haidut

    haidut Member

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    Not that I know of. It seems to be specific to the *setron drugs acting on 5-HT3.
    Broken heart: depression in cardiovascular disease
    "...Also, cardiac events were more frequent among patients on nortriptyline (18%) compared with paroxetine (2%). Moreover, other antidepressants, such as tianeptine, are also known to be free of deleterious cardiovascular effects and interactions in polymedicated patients due to lack of action on cytochrome P-450; tianeptine can thus be freely administered in depressed patients with concomitant cardiovascular disease."


    There is a study specifically absolving cyproheptadine of the *setron sins though.
    The conventional antihistamine drug cyproheptadine lacks QT-interval-prolonging action in halothane-anesthetized guinea pigs: comparison with hydro... - PubMed - NCBI
     
  4. Regina

    Regina Member

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    Hello Haidut,

    Would this be a concern with Ritanserin? Thanks!
     
  5. OP
    haidut

    haidut Member

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    Probably not, as ritanserin has no known activity on 5-HT3 receptor.
     
  6. DaveFoster

    DaveFoster Member

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    Apparently mirtazapine is not exempt from cardiovascular side effects:

    Antidepressants and the risk of sudden cardiac death and ventricular arrhythmia. - PubMed - NCBI

    PURPOSE:
    To examine the association between exposure to antidepressants and emergency department or inpatient admission for sudden cardiac death and ventricular arrhythmia (SD/VA), and to examine the impact of dose and cytochrome P-450 inhibition.

    METHODS:
    A cohort study was conducted using 1999-2003 Medicaid claims data from beneficiaries of five large states, supplemented with Medicare claims for dually eligible individuals. Exposures were prescription claims for antidepressants of interest or a reference antidepressant. Outcomes were incident first-listed emergency department or principal inpatient diagnoses indicative of SD/VA originating in the outpatient setting, an outcome previously found to have a positive predictive value of 85%.

    RESULTS:
    In 1.3 million person-years of antidepressant exposure, we identified 4222 SD/VA outcomes for a rate of 3.3/1000 person-years (95%CI, 3.2-3.4). Compared with paroxetine (a referent with a putatively favorable cardiovascular risk profile), adjusted hazard ratios (HRs) were 0.80 (0.67-0.95) for bupropion, 1.24 (0.93-1.65) for doxepin, 0.79 (0.55-1.15) for lithium, and 1.26 (1.11-1.42) for mirtazapine. HRs for amitriptyline, citalopram, fluoxetine, nefazodone, nortriptyline, sertraline, trazodone, and venlafaxine were near unity. For antidepressants having nonnull risks (bupropion and mirtazapine), we observed no relationship with antidepressant dose and some relationships with concomitant cytochrome P-450 inhibition.

    CONCLUSIONS:
    Of antidepressants studied, only mirtazapine had a statistically significantly greater SD/VA risk versus paroxetine. However, baseline differences between these users suggest that this finding may be attributable to residual confounding. Eleven other antidepressants had SD/VA risks no greater than that of paroxetine, thereby providing reassurance regarding the comparative cardiovascular safety of antidepressants.

    @haidut

    Do you think co-administered cyproheptadine can help prevent these effects in the same way that it prevents fibrosis from ergot derivatives? I might recall that you mentioned it protects against ondansetron as well, but I may be incorrect.
     
  7. ddjd

    ddjd Member

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    haidut would this QT heart issue be of concern with regards to 5aDHP, as you mentioned it antagonises the 5ht3 receptor
     
  8. OP
    haidut

    haidut Member

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    Not that I know of. AFAIK, the QT issue is specific to the *setron drugs and other specific 5-HT3 antagonists like tropanserin do not have this issue.
     
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