Modafinil (modafinil)

Modafinil, a 50:50 racemic mixture of the R- and S-enantiomers, is a wakefulness-promoting agent.

Modafinil, a benzhydryl sulfinylacetamide derivative, is a CNS stimulant that is structurally and pharmacologically distinct from most other currently available CNS stimulants (e.g., amphetamines, caffeine, cocaine, methylphenidate). The drug is a 50:50 racemic mixture of the R- and S-enantiomers; the R-enantiomer of modafinil is also commercially available as armodafinil. Modafinil promotes vigilance and wakefulness and decreases the number of daytime sleep episodes associated with narcolepsy and obstructive sleep apnea/hypopnea syndrome and reduces the excessive sleepiness associated with shift work sleep disorder.

Although the wakefulness-promoting effects of modafinil are comparable to those exhibited by amphetamines or methylphenidate, modafinil alters metabolic activity and increases neuronal activity in specific areas of the brain that control sleep/wakefulness and the biologic clock while amphetamines increase neuronal activity more widely throughout the brain, suggesting distinct mechanisms for modafinil and relatively high selectivity.

The exact mechanism(s) of action of modafinil is unknown, but animal studies have shown that the drug inhibits the release of gamma-aminobutyric acid (GABA) and increases the release of glutamate from the cerebral cortex, hippocampus, nucleus acumbens, medial preoptic area, and posterior hypothalamus. GABA is an inhibitory neurotransmitter that acts as a CNS depressant while glutamate is an excitatory neurotransmitter. Modafinil does not appear to be an indirect- or direct-acting dopamine-receptor agonist nor to act as a sympathomimetic agent.

Haloperidol, a dopamine-receptor antagonist, inhibits the wake-promoting activity of amphetamine but not the wake-promoting activity of modafinil.

The manufacturer states that modafinil does not appear to be a direct or indirect alpha1-adrenergic agonist, as evidenced by lack of activity in assay systems known to be responsive to such agonists. However, the drug's stimulant effects (e.g., on wakefulness, locomotion, and the EEG) are antagonized by alpha1-antagonists (e.g., prazosin, phenoxybenzamine), thus indicating that an intact central alpha1-adrenergic system is necessary for modafinil's CNS activity. In addition, it has been suggested that the drug itself may stimulate central alpha1-adrenergic activity (e.g., at the postsynaptic level).

Modafinil does not appear to exhibit clinically important peripheral adrenergic activity, even at high doses. In animals, modafinil increased locomotor activity but did not increase dopamine activity; however, in vitro studies showed that modafinil binds to dopamine reuptake sites and increases extracellular dopamine concentrations. Modafinil was also found to block dopamine transporters and increase dopamine concentrations in the human brain (including the nucleus accumbens) in one pilot study; drugs with such activity generally are associated with abuse potential.

At usual pharmacologic concentrations, modafinil does not bind to certain norepinephrine, serotonin, dopamine, GABA, adenosine, histamine H3, melatonin, or benzodiazepine receptors that regulate sleep and wakefulness. The drug also does not inhibit type B monoamine oxidase (MAO-B) or phosphodiesterase and does not alter plasma melatonin or cortisol hormone profiles, which may limit short-term adverse effects.

Modafinil is readily absorbed following oral administration, with peak plasma concentrations occurring at 2-4 hours in the fasted state. Food has no effect on the overall bioavailability of modafinil, but time to achieve peak concentrations may be delayed by approximately 1 hour in the fed state. The enantiomers of modafinil exhibit linear pharmacokinetics following administration of multiple oral doses of the drug over the dosage range of 200-600 mg daily.

Steady-state plasma concentrations of total modafinil and its R-enantiomer are achieved within 2-4 days of daily administration, and the elimination half-life of the drug is approximately 15 hours. Modafinil is 60% bound to plasma proteins, predominantly albumin. Interactions with highly-protein bound drugs are expected to be minimal.

Modafinil undergoes hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Modafinil is mainly eliminated via metabolism, predominantly in the liver, with 80% of the drug excreted in urine and 1% in feces, mainly as metabolites. Pharmacokinetic analyses indicate gender has no impact on modafinil pharmacokinetics.

It is not known whether race affects the pharmacokinetics of modafinil.

USES: Modafinil reduces extreme sleepiness due to narcolepsy and other sleep disorders, such as periods of stopped breathing during sleep (obstructive sleep apnea). It is also used to help you stay awake during work hours if you have a work schedule that keeps you from having a normal sleep routine (shift work sleep disorder). This medication does not cure these sleep disorders and may not get rid of all your sleepiness.

Modafinil does not take the place of getting enough sleep. It should not be used to treat tiredness or hold off sleep in people who do not have a sleep disorder. It is not known how modafinil works to keep you awake.

It is thought to work by affecting certain substances in the brain that control the sleep/wake cycle.

Generic name: modafinil
Pronunciation: (moe-DAF-i-nil)

The following indications are listed for Modafinil:

• Narcolepsy Syndrome
• Sleepiness Due To Obstructive Sleep Apnea
• Sleepiness Due To Shift Work Sleep Disorder

Also known as: Excessive Sleepiness Associated With Osahs, Friedmann's Disease, Gelineau's Syndrome, Hypnolepsy, Narcolepsy, Paroxysmal Sleep, Sleepiness Associated With Hypopnea Syndrome, Sleepiness Associated With Obstructive Sleep Apnea, Sleepiness Associated With Shifting Sleep-Work Schedule, Somnolence From Obstructive Sleep Apnea.

No ICD codes are available for this drug.