Atomoxetine

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Atomoxetine chemical structure
Atomoxetine
Systematic (IUPAC) name
(3S)-N-methyl-3-(2-methylphenoxy)-3-phenyl-propan-1-amine
Identifiers
CAS number 82248-59-7
ATC code N06BA09
PubChem 54841
DrugBank APRD00614
Chemical data
Formula C17H21NO·HCl
Mol. weight 255.355 g/mol
291.820 g/mol (hydrochloride)
Pharmacokinetic data
Bioavailability 63 to 94%
Protein binding 98%
Metabolism Hepatic, via CYP2D6
Half life 5 hours
Excretion Renal (>80%) and fecal (<17%)
Therapeutic considerations
Pregnancy cat.

B3(AU) C(US)

Legal status

POM(UK) Unscheduled (US)

Routes Oral (Capsules: 5, 10, 18, 25, 40 and 60 mg)

Atomoxetine is the first non-stimulant drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is sold in the form of the hydrochloride salt of atomoxetine. It is manufactured and marketed under the brand name Strattera® by Eli Lilly and Company. There is currently no generic available within the United States due to patent restrictions; however, a generic is available outside the United States, which is manufactured by Torrent Pharmaceuticals.

Atomoxetine is classified as a norepinephrine reuptake inhibitor, and is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under 6 years old. Its advantage over stimulants for the treatment of ADHD is that it has less abuse potential than stimulants, is not scheduled as a controlled substance and has proven in clinical trials to offer 24 hour coverage of symptoms associated with ADHD in adults and children.

Strattera was originally intended to be a new antidepressant drug; however, in clinical trials, no such benefits could be proven. Since norepinephrine is believed to play a role in ADHD, Strattera was tested and subsequently approved as an ADHD treatment.

Contents

[edit] Nomenclature

Atomoxetine was originally known as "tomoxetine". However, the U.S. Food and Drug Administration (FDA) requested the name be changed because, in their opinion, the similarity of "tomoxetine" to "tamoxifen" (a breast cancer drug) could lead to dispensing errors at pharmacies.

[edit] Chemistry and Composition

Atomoxetine is designated chemically as (-)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride, and has a molecular mass of 291.82. It has a solubility of 27.8 mg/mL in water. Atomoxetine is a white solid that exists as a granular powder inside the capsule, along with pregelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide, red iron oxide, edible black ink, and trace amounts of other inactive ingredients.

[edit] Side effects

The most common side effect in adults is drowsiness. This can be counteracted in some patients by measures as simple as a cup of coffee, or breathing exercises, while others become exhausted after a short while after taking the pills, and can sleep for up to 10+ hours. Some patients tend to feel lightheaded, dizzy, or "buzzed" as a minor side effect along with the drowsiness. To diminish these side effects, which can interfere with daytime work, study, etc., dosing time is sometimes changed to just before bed; as Strattera is long-acting, it does not "wear off" overnight. Mild hallucinations can be experienced under high doses (300mg).

Also very common is digestive discomfort, such as heartburn. The most common side effects in children and adolescents (and, after drowsiness, in adults) are upset stomach, nausea, and vomiting. The medication's tendency to decrease appetite may contribute to this problem, as taking Strattera on an empty stomach is usually discouraged; it can also be a problem in itself, in the form of hunger pangs. Consumption of dairy products can cause further upset.

Some studies suggest that Strattera has a tendency to exacerbate existing anxiety disorders, particularly social anxiety and panic attacks. This may be linked to the theory that the production and reuptake of norepinephrine in excess is the cause of such disorders. As a side effect, mood swings are less common, but in some cases these can be chronic and extreme.

A significant minority of adult male patients taking Strattera suffer minor to severe sexual side effects, including erectile dysfunction, retrograde ejaculation, painful orgasm, and the decoupling of orgasm from ejaculation, wherein ejaculation takes place up to ten seconds before or after orgasm.

In September 2005, Strattera was determined to increase risk of suicidal thoughts among children and adolescents; one attempted suicide and five cases of suicidal thoughts were reported out of 1,357 young patients taking Strattera, while none were reported out of a control group of 851 taking placebos. [1], [2]. The FDA has required that black box warnings be placed on all antidepressant medications warning they may result in increased risk of suicidal tendencies in children and adolescents, therefore Strattera bears such a warning.

Two confirmed cases of liver injury have been reported by Eli Lilly and Company out of approximately two million prescriptions written. In both cases upon discontinuation of atomoxetine, patients' liver functions returned to normal.

[edit] Potential for abuse

To date, the potential for abuse of Strattera has not been exhaustively researched. The two studies that have been performed suggest that atomoxetine has a low to moderate risk for abuse, since it has a long titration time (meaning that it may have no effect on the user unless they've been taking it regularly for days) and does not produce strong stimulating effects like most other ADHD medications (which are usually dopamine reuptake inhibitors). Monkeys will not self-administer atomoxetine at the doses tested (Gasior et al, Neuropharm 30:758, 2005; Wee & Woolverton, Drug Alcohol Depend 75:271, 2004). However, rats, pigeons and monkeys trained to distinguish cocaine or methamphetamine from saline indicate that atomoxetine produces effects indistinguishable from low doses of cocaine or methamphetamine, but not at all like high doses of cocaine (Spealman, JPET 271:53, 1995; Sasaki et al., Psychopharm 120:303, 1995). No place preference studies have been conducted with atomoxetine.

[edit] Off-label Uses

While depression is most commonly associated with the neurotransmitter serotonin, an imbalance of other neurotransmitters may also result in clinical depression. To that end, atomoxetine, which inhibits the reuptake of norepinephrine, was originally explored by Eli Lilly as a treatment for depression. While the phase-II trials showed a clinically significant improvement in many patients with depression, Lilly chose to pursue an ADHD treatment route for atomoxetine. However, many patients have seen a pronnounced anti-depressive effect; atomoxetine has been used by some physicians as a first-line medication for patients with comorbid ADHD and depression.[1][2][3][4][5]

[edit] References

  1. ^ "ADHD and Depression".
  2. ^ Biederman J, Spencer TJ (March, 2006). "Atomoxetine and adult attention-deficit/hyperactivity disorder: the effects of comorbidity.".
  3. ^ Adli M, Pilhatsch MK (March, 2006). "Augmentation with atomoxetine in treatment-resistant depression with psychotic features. A case report.".
  4. ^ Price LH, Carpenter LL (Oct, 2005). "Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants.".
  5. ^ Biederman, J, Kratochvil CJ (Sept, 2005). "Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms.".

[edit] External links


Antidepressants (ATC N06A) edit
Monoamine oxidase inhibitors (MAOI) Harmaline, Iproclozide, Iproniazid, Isocarboxazid, Nialamide, Phenelzine, Selegiline, Toloxatone, Tranylcypromine
Reversible inhibitor of monoamine oxidase A (RIMA) Brofaromine, Moclobemide
Dopamine reuptake inhibitor (DARI) Amineptine, Phenmetrazine, Vanoxerine
Norepinephrine-dopamine reuptake inhibitors Bupropion, Modafinil
Norepinephrine reuptake inhibitor (NRI) or (NARI) Atomoxetine, Maprotiline, Reboxetine, Viloxazine
Serotonin-norepinephrine reuptake inhibitor (SNRI) Duloxetine, Milnacipran, Venlafaxine
Selective serotonin reuptake inhibitor (SSRI) Alaproclate, Etoperidone, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Zimelidine
Selective serotonin reuptake enhancer (SSRE) Tianeptine
Tricyclic antidepressants (TCA) Amitriptyline, Amoxapine, Butriptyline, Clomipramine, Desipramine, Dibenzepin, Dothiepin, Doxepin, Imipramine, Iprindole, Lofepramine, Melitracen, Nortriptyline, Opipramol, Protriptyline, Trimipramine
Tetracyclic antidepressants Maprotiline, Mianserin, Nefazodone, Trazodone
Noradrenergic and specific serotonergic antidepressant (NaSSA) Mirtazapine
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