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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 46. This is the beginning of the thread.
Posted by mike99 on February 24, 2006, at 17:33:54
Does anyone know provigil's mechanism of action? I've found two contradictory statments on the web:
1. Pharmacologic Action: alpha-1-adrenoceptor antagonist, dopamine reuptake inhibitor (neurotransmitter.net--future list of drugs...)
2. Modafanil does not appear to be a direct or indirect alpha-adrenergic agonist (modafanil.com)
Also: "(modafanil) has minimal effects on cardiovascular and hemodynamic parameters". Is this true? If so why caution in patients with cardiovascular conditions?
Thanks for any feedback.
Posted by mike99 on February 24, 2006, at 17:41:37
In reply to provigil mechanism of action?, posted by mike99 on February 24, 2006, at 17:33:54
I meant alpha-1-adrenoceptor AGonist in the first statement, NOT ANTagnoist.
Posted by Racer on February 25, 2006, at 3:22:53
In reply to provigil mechanism of action?, posted by mike99 on February 24, 2006, at 17:33:54
When I looked it up, back when the earth's crust was still cooling, I got the impression that it affected GABA, rather than any of the Big Three MAOs. Never heard it affected dopamine at all.
Here's rxlist.com
"At pharmacologically relevant concentrations, modafinil does not bind to most potentially relevant receptors for sleep/wake regulation, including those for norepinephrine, serotonin, dopamine, GABA, adenosine, histamine-3, melatonin, or benzodiazepines. Modafinil also does not inhibit the activities of MAO-B or phosphodiesterases II-V.
Modafinil is not a direct- or indirect-acting dopamine receptor agonist and is inactive in several in vivo preclinical models capable of detecting enhanced dopaminergic activity. In vitro, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. In a preclinical model, the wakefulness induced by amphetamine, but not modafinil, is antagonized by the dopamine receptor antagonist haloperidol."
"Modafinil does not appear to be a direct or indirect alpha-adrenergic agonist. Although modafinil-induced wakefulness can be attenuated by the a1-adrenergic receptor antagonist, prazosin, in assay systems known to be responsive to a1-adrenergic agonists, modafinil has no activity."
Best I can make out, doesn't seem to do anything... ;-) I know I've read, though, that it decreases GABA, and that's what makes it work. Guess that's wrong, according to this.
Hope that helps.
Posted by SLS on February 25, 2006, at 6:50:48
In reply to provigil mechanism of action?, posted by mike99 on February 24, 2006, at 17:33:54
Hi.
Provigil (modafinil) seems to possess at least two properties that can increase wakefulness and vigilence:
1. Glutamate release
2. Orexin (hypocretin) releaseI don't think modafinil is a direct-acting receptor ligand for these two separate neurotransmitter systems.
- Scott
Posted by mike99 on February 25, 2006, at 8:55:35
In reply to Re: provigil mechanism of action?, posted by Racer on February 25, 2006, at 3:22:53
Very funnny..."doesn't seem to do anything" =)
Good point.I'm always skeptical when the pharm companies say "we have no idea how it works"---like with the stimulants for example.
Thanks for the info. Novartis and Saegis were/are working on a GABA-B receptor antagonist for ADHD and Alzheimers called SGS-742, but I think they dropped the ADHD trials.
The RxList seems to only claim it doesn't bind to GABA receptors, so I guess that doesn't rule out some sort of GABA reuptake enhancer, if there is such a thing.
There does seem to be a consensus on weak dopamine reuptake inhibition, though that doesn't appear to be the primary mechanism.
Posted by mike99 on February 25, 2006, at 9:01:19
In reply to Re: provigil mechanism of action?, posted by SLS on February 25, 2006, at 6:50:48
Thanks Scott. I don't think I would have found that iout anywhere else.I wonder if there is a potential for neurotoxicity with the increase of glutamate release as this seems to be a hot topic in cognitive decline/dysfunction.
I've never heard of Orexin before. Interesting--I'll have to check it out. Thanks again.
-Mike
Posted by tessellated on February 25, 2006, at 12:31:34
In reply to correction, posted by mike99 on February 24, 2006, at 17:41:37
My Pdoc who was a hardcore biochemical guy.
i.e. based his info on research papers, and did often water things down, but was clear.He said provigil blocked presynaptic norephinephrine (NE) autoreceptors.
Autorecptors are molecules located in the presynaptic neuron's axon terminal. It is thought to play a role in providing feedback to the presynaptic neuron and play a role in modulating synaptic activity.
Therefore making the neuron produce more NE, by inhibiting its ability to sense these raised levels of NE.
or
The presynaptic source of norephi (NE) release would be increased due to the autoreceptor not inhibiting the production of more norephinephrine.
Pretty cool no?kinda like tweaking your cars thermostat so it might run hotter.
or altering your computers micro fuse so it would run faster (fun to do on both mac/pc but you can destroy your chip).I think therefore the cardio issues are of concern due to increased levels of NE and the diverse range of effects it has on vasoconstriction and cardio output, respiration, and all sorts of stuff.
I've not personally noticed any BloodPressure and/or cardio effects that are much different than caffeine. Though its got moderate poop out.
But again, the conclusions are not there yet.
Though enough is know to raise concern-untill this concern is proved wrong-which takes research monies.
It's still-relatively a new chemical.Isn't it generic yet? Geesh. Its suppose to be, but is held up in litigation by Cephalon who's gonna market the r-isomer as nuvigil-what b.s.
Modafinil had $289 million, of sales in 2004!Still I would say it is probably the best stim/cognitive enhancing agent to come out for a Loooong time!
Posted by tessellated on February 25, 2006, at 12:33:28
In reply to correction, posted by mike99 on February 24, 2006, at 17:41:37
My Pdoc who was a hardcore biochemical guy.
i.e. based his info on research papers, and did often water things down, but was clear.He said provigil blocked presynaptic norephinephrine (NE) autoreceptors.
Autorecptors are molecules located in the presynaptic neuron's axon terminal. It is thought to play a role in providing feedback to the presynaptic neuron and play a role in modulating synaptic activity.
Therefore making the neuron produce more NE, by inhibiting its ability to sense these raised levels of NE.
or
The presynaptic source of norephi (NE) release would be increased due to the autoreceptor not inhibiting the production of more norephinephrine.
Pretty cool no?kinda like tweaking your cars thermostat so it might run hotter.
or altering your computers micro fuse so it would run faster (fun to do on both mac/pc but you can destroy your chip).I think therefore the cardio issues are of concern due to increased levels of NE and the diverse range of effects it has on vasoconstriction and cardio output, respiration, and all sorts of stuff.
I've not personally noticed any BloodPressure and/or cardio effects that are much different than caffeine. Though its got moderate poop out.
But again, the conclusions are not there yet.
Though enough is know to raise concern-untill this concern is proved wrong-which takes research monies.
It's still-relatively a new chemical.Isn't it generic yet? Geesh. Its suppose to be, but is held up in litigation by Cephalon who's gonna market the r-isomer as nuvigil-what b.s.
Modafinil had $289 million, of sales in 2004!Still I would say it is probably the best stim/cognitive enhancing agent to come out for a Loooong time!
Posted by mike99 on February 25, 2006, at 13:13:45
In reply to provigil discussion, posted by tessellated on February 25, 2006, at 12:31:34
That's interesting. Thanks for the info Tessellated.Remeron, Tenex and Clonidine work on presynaptic autoreceptors (by central alpha-2 antagonism and agonism).
I wonder how significant the increase in peripheral NE is, as I think this would/should be clearly stated in the drug monograph.
I can't take stims due to extremely excessive cardiovascular activation and so I wonder if I'd have the same problem w/ Provigil if it in effect increases NE.
Any thoughts on this would be appreciated.
Thanks again for the feedback.
And yeah, I agree the patenting of the active isomer strategy has gotten a little out of control, though I imagine it's sometimes beneficial.
Posted by mike99 on February 25, 2006, at 13:21:12
In reply to Re: provigil discussion, posted by mike99 on February 25, 2006, at 13:13:45
If provigil does antagonize presynaptic noradrenergic autoreceptors resulting in increased NE, wouldn't this classify it as a sympathomimetic?Or perhaps not since I don't think Strattera is considered a sympathomimetic. I wonder then what is the technical definition of a sympathomimetic.
Posted by SLS on February 25, 2006, at 13:38:51
In reply to provigil discussion, posted by tessellated on February 25, 2006, at 12:33:28
> He said provigil blocked presynaptic norephinephrine (NE) autoreceptors.
I respectfully submit that your doctor's information is at least 5 years out of date. The other possibility, of course, is that mine is no longer current.
http://www.rxlist.com/cgi/generic2/modafinil_cp.htm
Modafinil does not appear to be a ligand for any NE receptor. The original work suggesting NE receptor binding by modafinil was spurious.
- Scott
Posted by mike99 on February 25, 2006, at 13:51:04
In reply to Re: provigil discussion » tessellated, posted by SLS on February 25, 2006, at 13:38:51
Scott,It does seem the most recent theory is that provigil is not a ligand for any NE receptor as you state.
Do you have any thoughts then on how provigil stimulates the cardiovascular system, (though this is supposed to be minimal)? And if a beta blocker would safely and effectively counter these effects (my guess is it would)?
Mike
Posted by tessellated on February 25, 2006, at 14:42:49
In reply to Re: provigil discussion » SLS, posted by mike99 on February 25, 2006, at 13:51:04
Guys,
RE: health issues and cardio, i can only say there is the potential for problems. augmenting it w/propanol or a beta blocker etc to compensate sounds logical, but heck man talk to specialist before you start something like that. I'm big on self help, but heart/cardio issues aren't things to take lightly like "moods". 8)Hard to say, who's out of date, and we're getting rather deep symantically here.
The RX list's info is the same as it was years back, and it isn't even the PDR, and probably about a nurses level of science. As far as the specifics, "direct or indirect alpha-adrenergic agonist" does not necessarily include "auto-adrenergic receptor (modulation)", as these structures are presynaptic and located in the axon not at the synaptic cleft where most neurotransmission occurs.Notice they don't even mention beta adrenergic activity.
An additional point is that there are probably more than just the alpha/beta receptor adrenergic subtypes that have yet to be isolated and/or understood. Look at serotonin (5HT). Its got 5HT1A, 5HT1B, 5HT2A, I think 8 and still counting....
Regardless: modafinil is probably an atypical sympathomimetic as it has effects upon NE-but not dopamine(DA). These are both subtypes of a larger chemical family the catecholamines which create excitation similar to (mimetic/mimicry) and directly upon the sympathetic nervous system. here's a cool diagram
http://en.wikipedia.org/wiki/Sympathetic_nervous_systemI do know that if I take 400mg I definitely notice increased heart rate, respiration, and the impulse to ramble and do things. At that quantity it feels very close to other stims-and a tad unpleasant.
Phwew!
8ed> Scott,
>
> It does seem the most recent theory is that provigil is not a ligand for any NE receptor as you state.
>
> Do you have any thoughts then on how provigil stimulates the cardiovascular system, (though this is supposed to be minimal)? And if a beta blocker would safely and effectively counter these effects (my guess is it would)?
>
> Mike>
> Scott,
>
> It does seem the most recent theory is that provigil is not a ligand for any NE receptor as you state.
>
> Do you have any thoughts then on how provigil stimulates the cardiovascular system, (though this is supposed to be minimal)? And if a beta blocker would safely and effectively counter these effects (my guess is it would)?
>
> Mike
Posted by mike99 on February 25, 2006, at 15:30:19
In reply to Re: provigil discussion, posted by tessellated on February 25, 2006, at 14:42:49
Hmmm...confusing, confusing.
I'll definitely talk w/ my Dr. about cardio issues related to provigil, but in all likelihood he probably knows less about it than everyone who's posted to this thread (and he's a sharp guy--board-certified in sleep medicine and pulmonology, so he should be quite knowledgeable about provigil).
I'm generally healthy but extremely senstive to/intolerant of stimulants.
I wonder about the sympathomimetic activity of provigil because this might have negative consequences when combined with a beta blocker (as beta blockers "increase pressor affects of sympathomimetics" due to beta receptors being blocked but alpha adrenergic receptors not).
Posted by tessellated on February 25, 2006, at 17:12:33
In reply to Re: provigil discussion, posted by mike99 on February 25, 2006, at 15:30:19
Yeah,
I just cant wait untill its ALL figured out.
Everything would be sooo much easier.
Posted by mike99 on February 25, 2006, at 17:29:01
In reply to Re: provigil discussion, posted by tessellated on February 25, 2006, at 14:42:49
>> As far as the specifics, "direct or indirect alpha-adrenergic agonist" does not necessarily include "auto-adrenergic receptor (modulation)", as these structures are presynaptic and located in the axon not at the synaptic cleft where most neurotransmission occurs.
Good point--the monograph states "At pharmacologic concentrations, modafanil does not bind to MOST POTENTIALLY RELEVANT receptors for norepinephrine, serotonein, dopamine..."
Whatever "most potentially relevant" means. Not very informative IMHO.
> Notice they don't even mention beta adrenergic activity.
They sure don't.
Ditto's on wishing there was more to go on.
Posted by zeugma on February 25, 2006, at 17:42:12
In reply to Re: provigil discussion, posted by mike99 on February 25, 2006, at 15:30:19
I have to agree with SLS, Provigil is not an alpha-2 antagonist (antagonist of pre-synaptic NE autoreceptors). If that were the case then depleting an animal of norepinephrine would result in a loss of its effect (similar to the way depleting an individual whose depression has remitted on desipramine results in a relapse), but this seems not to be the case.
On the other hand, animals that lacked dopamine transporters experienced no stimulating effect from either methamphetamine or Provigil, indicating that DA reuptake inhibition is involved. These animals were hypersensitive to caffeine, so it's safe to say that caffeine and Provigil do not share the same mechanisms.
An experiment was also conducted in which Provigil's effect on the ventrolateral proptic nucleus (a major site of sleep regulation) and apparently Provigil blocked the NE transporters in that region:
If Provigil does act as an NE transport blocker it must be extremely localized, because every other NE transport blocker inhibits cataplexy, and Provigil does not do so at all.
The author who comments on the study I cited above theorizes that the combination of weak DA reuptake inhibition, and localized NE reuptake inhibition, may combine to produce its wakefulness effect. Provigil does release orexin, but it has no direct effect on that system (i.e. it is not a ligand for a known orexin receptor). Its effect on GABA inhibition is also well documented:
These effects on GABA and norepinephrine are extremely localized and peculiar, at they seem so to me.
-z
Posted by tessellated on February 25, 2006, at 20:15:32
In reply to Re: provigil discussion, posted by zeugma on February 25, 2006, at 17:42:12
Zuegma,
cool refs, like this serious kinda info.
now are alpha-2 sites presynaptic autoreceptors?
i did not believe this to be the case.
but....
lemme spend time on the refs many thanks,
8edps: antagonizing a presynaptic autoreceptor can result in an increase of NE release. as they modulate NE production; and can infact inhibit NE release/production if agonists/excess NE are present. An antagonist can have post synaptic agonistic affect. Get it? Stimulation can cause inhibition and vice versa.. It's freaking complex....
> I have to agree with SLS, Provigil is not an alpha-2 antagonist (antagonist of pre-synaptic NE autoreceptors). If that were the case then depleting an animal of norepinephrine would result in a loss of its effect (similar to the way depleting an individual whose depression has remitted on desipramine results in a relapse), but this seems not to be the case.
>
> On the other hand, animals that lacked dopamine transporters experienced no stimulating effect from either methamphetamine or Provigil, indicating that DA reuptake inhibition is involved. These animals were hypersensitive to caffeine, so it's safe to say that caffeine and Provigil do not share the same mechanisms.
>
> An experiment was also conducted in which Provigil's effect on the ventrolateral proptic nucleus (a major site of sleep regulation) and apparently Provigil blocked the NE transporters in that region:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14998233&query_hl=3&itool=pubmed_docsum
>
> If Provigil does act as an NE transport blocker it must be extremely localized, because every other NE transport blocker inhibits cataplexy, and Provigil does not do so at all.
>
> The author who comments on the study I cited above theorizes that the combination of weak DA reuptake inhibition, and localized NE reuptake inhibition, may combine to produce its wakefulness effect. Provigil does release orexin, but it has no direct effect on that system (i.e. it is not a ligand for a known orexin receptor). Its effect on GABA inhibition is also well documented:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8813612&query_hl=6&itool=pubmed_docsum
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9774168&query_hl=10&itool=pubmed_docsum
>
> These effects on GABA and norepinephrine are extremely localized and peculiar, at they seem so to me.
>
> -z
>
>
Posted by mike99 on February 25, 2006, at 20:55:34
In reply to Re: provigil discussion, posted by tessellated on February 25, 2006, at 20:15:32
..rs
This may likely be to what your doc was referring.
In the CNS alpha-2 receptors are presynaptic autoreceptors.
Stimulating this receptor by NE or drugs such as clonidine or tenex inhibits NE release (presynaptically), which theoretically should result in decreased activation of the corresponding post-synaptic noradrenergic receptors.
Antagonizing the same receptor by a drug like remeron/mirtazapine conversely results in increased NE release.
To the best I could gather, the 2006 PDR still states provigil is not an agonist or antagonist at any "potentially relevant receptors for NE, etc...". I think this would, or at least should include the alpha-2 autoreceptor.
Posted by mike99 on February 25, 2006, at 21:13:55
In reply to Re: provigil mechanism of action?, posted by Racer on February 25, 2006, at 3:22:53
By what mechanism would provigil stimulate the heart/sympathetic nervous system? And how does this compare to the sympathomimetics?
I realize the peripheral stimulation of provigil is supposed to be minimal (one of its advantages), but it does seem to activate the sympathetic system.
Could provigil possibly cause release of epinephrine and epinephrine from the adrenals?
Thanks Zeugma for the excellent references.
Posted by mike99 on February 25, 2006, at 21:16:34
In reply to so how does provigil stimulate the heart?, posted by mike99 on February 25, 2006, at 21:13:55
if provigil could result in the release of epinephrine and norepinephrine from the adrenals.
Posted by zeugma on February 26, 2006, at 8:48:11
In reply to Typo...I meant to ask.., posted by mike99 on February 25, 2006, at 21:16:34
>
> if provigil could result in the release of epinephrine and norepinephrine from the adrenals. >>yes, modafinil does.
I experienced a syncopal episode when I switched from 30 mg Ritalin to Provigil 200 mg. I experienced this in the evening (I took Provigil early in the am). I experienced much more profound effects on heart rate on Ritalin (I experience none on Provigil). Neither drug affected my BP.
-z
Posted by SLS on February 26, 2006, at 9:11:37
In reply to Re: provigil discussion » SLS, posted by mike99 on February 25, 2006, at 13:51:04
> Do you have any thoughts then on how provigil stimulates the cardiovascular system,
Not really. Again, I would refer you to structures in the hypothalamus and reticular formation that contain orexinergic (hypocretin) and glutamatergic neurons. The hypothalamus most certainly serves to regulate vital bodily functions.
Regarding modafinil and dopamine, at least one mechanism by which limbic areas rich in DA neurons are stimulated is via the glutamate-releasing properties of modafinil in the thalamus. The GABA-glutamate balance is shifted towards glutamate, thus stimulating (disinhibiting) the nucleus accumbens, a reward center located in the limbic system. I don't believe modafinil affects directly any DA receptor or transporter.
My first guess is that beta blockers would help to mitigate any tachycardia or perhaps even anxiety. The beta blocker probably would not act to antagonize the pharmacology of modafinil, but, rather, to simply compensate for it downstream. Losartan might be an ideal drug as it would also help mitigate the increase in blood pressure seen with modafinil. It would help reduce the effects of the excess plasma NE that modafinil is capable of producing. It should accomplish this by preventing the stimulation of peripheral NE alpha-1 receptors by endogenous NE.
The problem with some of the older studies of modafinil is that they focused almost exclusively on the effects it had on aminergic neurotransmission, particularly NE and DA. Unfortunately, some of the investigators jumped to conclusions prematurely regarding the mechanisms of involvement of these neurotransmitters. Just because a particular pathway must be intact for a drug to produce changes downstream doesn't mean that this pathway is directly affected by the test drug. However, this was the basis by which the original research inferred a direct effect for modafinil on NE receptors.
Modafinil was originally pronounced to be a central alpha-1 adrenergic agonist. No more.
The package label and PDR entries for modafil were written after the NE receptor theories were debunked. The mechanisms by which modafinil produces wakefulness are not well understood, but probably do involve hypocretin. By contrast, the mechanisms by which modafinil improves depression (usually implemented as an augmenting agent) might involve the shifting of thalamic glutamate/GABA balance towards glutamate and the subsequent activation of DA neurons in the nucleus accumbens.Sorry for the redundancies.
- Scott
Posted by zeugma on February 26, 2006, at 12:50:20
In reply to Re: provigil discussion, posted by SLS on February 26, 2006, at 9:11:37
the mechanisms by which modafinil improves depression (usually implemented as an augmenting agent) might involve the shifting of thalamic glutamate/GABA balance towards glutamate and the subsequent activation of DA neurons in the nucleus accumbens.>>
Modafinil also elevates serotonin levels in cortex and dorsal raphe, which is surely relevant to depression.
-z
Posted by SLS on February 26, 2006, at 14:38:46
In reply to Re: provigil discussion » SLS, posted by zeugma on February 26, 2006, at 12:50:20
> the mechanisms by which modafinil improves depression (usually implemented as an augmenting agent) might involve the shifting of thalamic glutamate/GABA balance towards glutamate and the subsequent activation of DA neurons in the nucleus accumbens.>>
>
> Modafinil also elevates serotonin levels in cortex and dorsal raphe, which is surely relevant to depression.
>
> -z
I did not know this. Do you think this is an effect secondary to another mechanism of action of modafinil, or does the molecule affect 5-HT neurons directly? In other words, are the outflows of 5-HT in these areas secondary to increases in the releases of hypocretin or glutamate produced elsewhere by modafinil?Again, we see hypocretin:
I found this interesting:
Here, modafinil seems to act as an amplifier. By itself, though, it does not elicit 5-HT increase. I noticed some other work by these same authors suggesting otherwise, but at concentrations too high to be relevant to those in clinical use.
- Scott
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