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Mechanism of action

drivinthattrain

drivinthattrain

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Two drugs , both classified as DNRI's , both can be perscribed for same condition. Bupropion/Methylphenidate. Since they are both dopamine norepinephrine reuptake inhbitors, How do they metabolize differently that cause one to be a mild stim with little CNS activity and the other have major CNS activity. I asked my P-doc and he gave me the "George Bush" answer...talked for ten minutes about the drugs and never directly answered the question. I am a Paramedic and have just a basic foundation on Pharmacology compaired to alot of you on this site. But I am very fascinated on how our bodies change up drugs, and how pharm companies spend millions of dollars to invent a drug to fit a certain class, then during clinical trials when it doesnt, they just re assign it....example, Atomoxetine.
 
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They both have near identical mechanisms of action but bupropion has a much longer half life (>10 as long). In practice this means that Ritalin will be taken in a dose to precipitate CNS changes instantly Bupropion is taken at a sub active doses and slowly tapered up to an active dose to allow for neuroadaptation. So lets say 20mg of Ritalin causes dopamine levels to rise by x amount, 5g (a wild guess) might be needed of bupropion to produce the same effect. However the Bupropion would then keep you awake for several day (or longer) so this is impractical.

I hope this answers your question.
 
A significant portion of bupropion's therapeutic effects are mediated through active metabolites. Bupropion has a fairly long half life I believe, and some of its active metabolites have half-lives that are similar if not longer than that of bupropion. I wouldn't consider bupropion to have little CNS activity though. I've never tried the stuff but it is certainly very psychoactive. Even though it is a DNRI like methylphenidate; its rate of metabolism and the role of active metabolites are quite different.

I wonder if bupropion's ideal therapeutic effects are brought about by a certain ratio of bupropion and certain metabolites. If this is the case, it would sort of explain why bupropion requires so time to become optimally effective.

I wouldn't really consider bupropion a weak stimulant. It might not seem as strong as methylphenidate, but I am sure it would be very stimulating (and dangerous) at higher dosages.
 
Thank you for clearing that up for me guys. I agree Sekio. I take Wellbutrin, and have taken it orally as well as Insufflated.
orally its primary action is on dopamine because it is metabolized into hydroxybupropion,
Insufflated it works primarly on norepinephrine. I am perscribed 300mgs a day, and have taken up to 800mgs. Its effects wear off and tolerance builds far too fast for it to be recreational, and for me, it is a weak stimulant, but for others it is not, I guess that determines your own levels of dopamine and norepinephrine.
Ritalin to me, taken via daytrana patches, chewed...was like comparing coffee to cocaine. But every one is different and Its impact on dopamine taken properly is its primary principle. It is such a strange drug, with so many uses. Unfortunatly, for me, it was not effective at safe doses.
 
After research cannibalsnail is spot on, it does release, just very mild, unlike amphetamines which are major releasers.
 
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That's probably not true.

This study finds that during clinical use, bupropion blocks approximately 22% of DAT (PSYCHOPHARMACOLOGY Volume 163, Number 1 (2002), 102-105, DOI: 10.1007/s00213-002-1166-3). This study finds a 26% occupancy (Biol Psychiatry. 2003 Oct 15;54(8):800-5.) This study finds a 20% occupancy (Neuropsychopharmacol Hung. 2004 Jun;6(2):79-81.). This study finds a 20.84% occupancy (J Affect Disord. 2005 Dec;89(1-3):115-23. Epub 2005 Oct 5.)

I would assume that >20% would be clinically significant.

This study finds enhanced DA levels, not simply receptor occupancy (J Clin Psychiatry. 1995 Sep;56(9):395-401.)
 
Hammilton said:
That's probably not true.

This study finds that during clinical use, bupropion blocks approximately 22% of DAT (PSYCHOPHARMACOLOGY Volume 163, Number 1 (2002), 102-105, DOI: 10.1007/s00213-002-1166-3). This study finds a 26% occupancy (Biol Psychiatry. 2003 Oct 15;54(8):800-5.) This study finds a 20% occupancy (Neuropsychopharmacol Hung. 2004 Jun;6(2):79-81.). This study finds a 20.84% occupancy (J Affect Disord. 2005 Dec;89(1-3):115-23. Epub 2005 Oct 5.)

I would assume that >20% would be clinically significant.

This study finds enhanced DA levels, not simply receptor occupancy (J Clin Psychiatry. 1995 Sep;56(9):395-401.)
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I find that doubtfull, i have to dig up references but i beleive more inhibition needs to take place for therapeutic effects.
"The occupancy of dopamine transporter (DAT) by bupropion and its metabolites in the human brain as measured by positron emission tomography was 6–22% in an independent study[129] and 12–35% according to GlaxoSmithKline researchers.[130] Based on analogy with serotonin reuptake inhibitors, higher than 50% inhibition of DAT would be needed for the dopamine reuptake mechanism to be a major mechanism of the drug's action. By contrast, approximately 65% occupancy or greater of DAT is required to achieve euphoria and reach abuse potential.[131] "
Refs are on wiki but will dig them up when requested, also the ref that

J Clin Psychopharmacol. 2003 Jun;23(3):233-9.
Neurochemical and psychotropic effects of bupropion in healthy male subjects.

Gobbi G, Slater S, Boucher N, Debonnel G, Blier P.

Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montréal, Quebec, Canada.
Abstract

Bupropion is a weak inhibitor of noradrenaline (NE) and dopamine (DA) reuptake and has no direct action on serotonin (5-HT) neuronal elements. In the rat brain, bupropion suppresses NE neuron firing activity via the activation of alpha(2)-adrenoceptors and increases that of 5-HT neurons through an indirect action on NE neurons. Twenty-five healthy young male volunteers, with no previous history of psychiatric disorders, were randomized to one of four 7-day regimens: placebo, bupropion (150 mg) once daily, bupropion (150 mg) twice a day, and methylphenidate SR (20 mg daily). To assess the activity of the NE reuptake process, the blood pressure response to intravenous tyramine was determined. A decrease in the systolic pressure response to tyramine was considered evidence of NE reuptake inhibition. Effects on 5-HT reuptake were assessed by measuring whole blood 5-HT concentration, with a decrease serving as an index of 5-HT reuptake blockade. The Profile of Mood States (POMS) scale was used to assess behavioral and psychological changes. Neither bupropion nor methylphenidate altered the tyramine pressor response, in contrast to previous data that demonstrated decreases were obtained with NE reuptake inhibitors. Neither drug modified 5-HT concentrations. However, POMS scores revealed that bupropion at a dosage of 150 mg/day increased composedness, agreeability, and energy, whereas 300 mg/day improved only attention. In contrast, methylphenidate improved only energy. These data provide no evidence that bupropion acts as an inhibitor of NE or 5-HT reuptake in healthy humans. Presumably it enhances synaptic availability of NE by increasing release. Yet, because its behavioral profile is different from that of methylphenidate, it may not share all the biochemical properties of psychostimulants.
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Psychopharmacology (Berl). 2001 Apr;155(1):52-7.
Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment.

Dong J, Blier P.

Department of Psychiatry and Neuroscience, McKnight Brain Institute, University of Florida, P.O. Box 100256, Gainesville, FL 32610, USA.
Abstract

RATIONALE: Bupropion is widely used in the treatment of depression and as an anti-craving medication for the cessation of tobacco smoking. Because it is a very weak inhibitor of norepinephrine (NE) and dopamine (DA) reuptake, its mechanisms of action remain to be elucidated.

METHODS: Bupropion was administered subcutaneously via osmotic minipumps over 2 days to determine its effects on the spontaneous firing activity of NE, serotonin (5-HT), and DA neurons in the brain of anaesthetised male Sprague-Dawley rats. This treatment was used in order to obtain levels of the parent compound and its putatively active metabolites that would more adequately reflect the clinical condition than utilizing acute injections.

RESULTS: When given by minipump for 2 days, bupropion produced a dose-dependent attenuation of the mean spontaneous firing NE neurons (7.5 mg/kg per day: 15%; 15 mg/kg per day: 61%; 30 mg/kg per day: 80%) which was reversed by the alpha 2-adrenoceptor antagonist idazoxan. At the highest regimen, the mean firing rate of 5-HT neurons was 100% higher than in control rats, but unaffected in NE-lesioned rats. In contrast, DA neurons in the ventral tegmental area displayed a normal firing rate during the latter bupropion treatment.

CONCLUSIONS: Sustained bupropion administration decreased the firing rate of NE neurons due to an increased activation of their inhibitory somatodendritic alpha 2-adrenoceptors. This effect of the bupropion treatment would be attributable mainly to an enhancement of NE release and not to reuptake inhibition. This contention is based essentially on the observation that NE reuptake blockers leave unaltered the firing rate of 5-HT neurons, whereas bupropion enhanced it via a NE-dependent mechanism. The present study did not put into evidence any DA activity of bupropion at the level of the cell body of mesolimbic/cortical DA neurons at a regimen exerting profound alterations of the firing activity of NE and 5-HT neurons.

PMID: 11374336
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The metabolite does increase da enough but to get that you must be a rodent or have a rodent liver.
 
MeDieval thanks for the studies

I've been on both for several weeks and they did feel remarkably different to have the same (or almost) proposed mechanism of action

Bupropion can hardly be summarized as just an NDRI. We know it antagonizes a specific subset of the nicotonic receptors but there is probably something beyond that, if just based on the fact that its classified as an atni-depressant rather than psycho-stimulant.
 
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