any better ideas on how provigil (modafinil) works?

[Colin]

the general description say its unclear how it works, although its suposed to work on dopamine, and something to do with 2 proteins involved.

im wondering if it is a reuptake inhibitor or increases release, or increases production or response to it etc..

I have problems with tiredness, but ritalin seems to be no more and posibly less effective at 60mg as 40mg, if ritalin is a reuptake inhibitor then presumably this means the reuptake is totaly blocked and further increases would be no benefit.

I do feel i have a lot more time to think about what i can do when on 30-40mg of ritalin, just too tired to realy do much, whereas usualy im totaly thinking about it long after ive started doing or not at all.

im on a trial upto 120mg (single daily dose) but im wondering if theres going to be no effect all the way, and if so what would be next, something to ensure enough dopamine is available, or make sure its released more, or make sure the response to it is bigger etc...

im also not sure whether dopamine or nerephinprine is afected more by ritalin/dex/others, or wich of those is involved in tiredeness esp mine.

[Batman55]

From the sparse reading I did on Provigil, what I found is that it increases histamine levels which increases wakefulness, basically.

Ever taken Benadryl or your run-of-the-mill sleeping pill? Both contain diphenhydramine which is an anti-histamine. Both cause drowsiness for most people.

Provigil does the opposite.

[Tylerlee17]

CLINICAL PHARMACOLOGY
Mechanism of Action and Pharmacology

The precise mechanism(s) through which modafinil promotes wakefulness is unknown.
Modafinil has wake-promoting actions similar to sympathomimetic agents like amphetamine and
methylphenidate, although the pharmacologic profile is not identical to that of sympathomimetic
amines.
Modafinil has weak to negligible interactions with receptors for norepinephrine, serotonin,
dopamine, GABA, adenosine, histamine-3, melatonin, and benzodiazepines. Modafinil also does
not inhibit the activities of MAO-B or phosphodiesterases II-V.
1

NDA 20-717 PROVIGIL

® (modafinil) Tablets
FDA Approved Labeling dated August 17, 2007

Modafinil-induced wakefulness can be attenuated by the

α1-adrenergic receptor antagonist
prazosin; however, modafinil is inactive in other in vitro assay systems known to be responsive
to α-adrenergic agonists, such as the rat vas deferens preparation.
Modafinil is not a direct- or indirect-acting dopamine receptor agonist. However, in vitro,
modafinil binds to the dopamine transporter and inhibits dopamine reuptake. This activity has
been associated in vivo with increased extracellular dopamine levels in some brain regions of
animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil
lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the
wake-promoting effects of modafinil, unlike those of amphetamine, were not antagonized by the
dopamine receptor antagonist haloperidol in rats. In addition, alpha-methyl-p-tyrosine, a
dopamine synthesis inhibitor, blocks the action of amphetamine, but does not block locomotor
activity induced by modafinil.
In the cat, equal wakefulness-promoting doses of methylphenidate and amphetamine increased
neuronal activation throughout the brain. Modafinil at an equivalent wakefulness-promoting
dose selectively and prominently increased neuronal activation in more discrete regions of the
brain. The relationship of this finding in cats to the effects of modafinil in humans is unknown.
In addition to its wake-promoting effects and ability to increase locomotor activity in animals,
modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking,
and feelings typical of other CNS stimulants in humans. Modafinil has reinforcing properties, as
evidenced by its self-administration in monkeys previously trained to self-administer cocaine.
Modafinil was also partially discriminated as stimulant-like.
The optical enantiomers of modafinil have similar pharmacological actions in animals. Two
major metabolites of modafinil, modafinil acid and modafinil sulfone, do not appear to
contribute to the CNS-activating properties of modafinil.

Pharmacokinetics

Modafinil is a racemic compound, whose enantiomers have different pharmacokinetics (e.g., the
half-life of the

l-isomer is approximately three times that of the d-isomer in adult humans). The
2

NDA 20-717 PROVIGIL

® (modafinil) Tablets
FDA Approved Labeling dated August 17, 2007

enantiomers do not interconvert. At steady state, total exposure to the

l-isomer is approximately
three times that for the d-isomer. The trough concentration (Cminss) of circulating modafinil after
once daily dosing consists of 90% of the l-isomer and 10% of the d-isomer. The effective
elimination half-life of modafinil after multiple doses is about 15 hours. The enantiomers of
modafinil exhibit linear kinetics upon multiple dosing of 200-600 mg/day once daily in healthy
volunteers. Apparent steady states of total modafinil and l-(-)-modafinil are reached after 2-4
days of dosing.

Absorption

Absorption of PROVIGIL tablets is rapid, with peak plasma concentrations occurring at 2-4
hours. The bioavailability of PROVIGIL tablets is approximately equal to that of an aqueous
suspension. The absolute oral bioavailability was not determined due to the aqueous insolubility
(<1 mg/mL) of modafinil, which precluded intravenous administration. Food has no effect on
overall PROVIGIL bioavailability; however, its absorption (t

max) may be delayed by
approximately one hour if taken with food.

Distribution

Modafinil is well distributed in body tissue with an apparent volume of distribution (~0.9 L/kg)
larger than the volume of total body water (0.6 L/kg). In human plasma, in vitro, modafinil is
moderately bound to plasma protein (~60%, mainly to albumin). At serum concentrations
obtained at steady state after doses of 200 mg/day, modafinil exhibits no displacement of protein
binding of warfarin, diazepam or propranolol. Even at much larger concentrations (1000μM; >
25 times the C

max of 40μM at steady state at 400 mg/day), modafinil has no effect on warfarin
binding. Modafinil acid at concentrations >500μM decreases the extent of warfarin binding, but
these concentrations are >35 times those achieved therapeutically.

Metabolism and Elimination

The major route of elimination is metabolism (~90%), primarily by the liver, with subsequent
renal elimination of the metabolites. Urine alkalinization has no effect on the elimination of
modafinil.
3

NDA 20-717 PROVIGIL

® (modafinil) Tablets
FDA Approved Labeling dated August 17, 2007

Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation,
and glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent
compound. In a clinical study using radiolabeled modafinil, a total of 81% of the administered
radioactivity was recovered in 11 days post-dose, predominantly in the urine (80% vs. 1.0% in
the feces). The largest fraction of the drug in urine was modafinil acid but at least six other
metabolites were present in lower concentrations. Only two metabolites reach appreciable
concentrations in plasma, i.e., modafinil acid and modafinil sulfone. In preclinical models,
modafinil acid, modafinil sulfone, 2-[(diphenylmethyl)sulfonyl]acetic acid and 4-hydroxy
modafinil, were inactive or did not appear to mediate the arousal effects of modafinil.
In adults, decreases in trough levels of modafinil have sometimes been observed after multiple
weeks of dosing, suggesting auto-induction, but the magnitude of the decreases and the
inconsistency of their occurrence suggest that their clinical significance is minimal. Significant
accumulation of modafinil sulfone has been observed after multiple doses due to its long
elimination half-life of 40 hours. Induction of metabolizing enzymes, most importantly
cytochrome P-450 (CYP) 3A4, has also been observed in vitro after incubation of primary
cultures of human hepatocytes with modafinil and in vivo after extended administration of
modafinil at 400 mg/day. (For further discussion of the effects of modafinil on CYP enzyme
activities, see

PRECAUTIONS, Drug Interactions.)
Drug-Drug Interactions: Based on in vitro data, modafinil is metabolized partially by the 3A
isoform subfamily of hepatic cytochrome P450 (CYP3A4). In addition, modafinil has the
potential to inhibit CYP2C19, suppress CYP2C9, and induce CYP3A4, CYP2B6, and CYP1A2.
Because modafinil and modafinil sulfone are reversible inhibitors of the drug-metabolizing
enzyme CYP2C19, co-administration of modafinil with drugs such as diazepam, phenytoin and
propranolol, which are largely eliminated via that pathway, may increase the circulating levels of
those compounds. In addition, in individuals deficient in the enzyme CYP2D6 (i.e., 7-10% of
the Caucasian population; similar or lower in other populations), the levels of CYP2D6
substrates such as tricyclic antidepressants and selective serotonin reuptake inhibitors, which
have ancillary routes of elimination through CYP2C19, may be increased by co-administration
of modafinil. Dose adjustments may be necessary for patients being treated with these and
similar medications (See PRECAUTIONS, Drug Interactions). An in vitro study

For additional info on how provigil works go to: http://www.fda.gov/medwatch/safety/2...rovigil_PI.pdf

[Colin]

thanks lots of reading, digested a bit of it so far
too sleepy to take in much more for now lol !

[Batman55]

From the wikipedia entry on modafinil:

"Modafinil, like other stimulants, increases the release of monoamines but also elevates hypothalamic histamine levels,^[2] leading some researchers to consider Modafinil a "wakefulness promoting agent" rather than a classic amphetamine-like stimulant (as evidenced by the difference in c-fos distribution caused by modafinil as compared to amphetamine)."

and..

"A newly proposed mechanism of action involves brain peptides called orexins, also known as hypocretins. Orexin neurons are found in the hypothalamus but project to many different parts of the brain, including several areas that regulate wakefulness. Activation of these neurons increases dopamine and norepinephrine in these areas, and excite histaminergic tuberomammillary neurons increasing histamine levels there. There are two receptors for hypocretins, namely hcrt1 and hcrt2. Animal studies have shown that animals with defective orexin systems show signs and symptoms similar to narcolepsy. Modafinil seems to activate these orexin neurons thus promoting wakefulness. However, a study of genetically modified dogs lacking orexin receptors showed that modafinil still promoted wakefulness in these animals, suggesting that orexin activation is not required for the effects of modafinil.
It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine and norepinephrine reuptake, as well as orexin activation.
It has been shown in rats that modafinil increases histamine release in the brain, and this may be a possible mechanism of action in humans.^[60]"



Just to show you that my last post couldn't be THAT far off. I don't want to look like an idiot.

[Colin]

thanks ever so much.

its more information than i can understand at the moment, but it seems like it has some sort of reuptake inhibitor action, wich im inclined to think that with 60mg ritalin my reuptake is completly inhibited so any further inhibitor wil have little effect.

however as for the other mechanisms Im not realy clear what they mean or if they are realy certain about them. however i did read somewhere that its action on the (cat) brain was in a more slective region than most other drugs.

im just trying to work out if theres any way to predict how useful it might be given my comorbid tiredness and response to various drugs so far, or if it would be advantagous to take in combination with them.

[Captain Sanity]

wellbutrin is good for tiredness, too.

[Contrapunctus]

While it does inhibit the reuptake of dopamine, Modafinil's affinity for the DAT (dopamine transporter) is quite low (something like ~10uM), so this could not truly explain its efficacy as a wakefullness promoting agent. Also keep in mind that wakefullness is also NE-mediated, so inhibition of the reuptake of norepinephrine could also play a role.

But from what I understood, the stimulating effects from modafinil was a result of the inhibition of GABA neurons which in turn, may cause a central release of histamine (thus causing CNS-stimulation). Perhaps this release of histamine may have an inhibitory effect on NE, but this is only a guess...