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Atomoxetine



Atomoxetine
Systematic (IUPAC) name
(3R)-N-methyl-3-(2-methylphenoxy)-3-phenyl-propan-1-amine
Identifiers
CAS number 83015-26-3
ATC code N06BA09
PubChem 54841
DrugBank APRD00614
Chemical data
Formula C17H21NO 
Mol. mass 255.355 g/mol
291.820 g/mol (hydrochloride)
Pharmacokinetic data
Bioavailability 63 to 94%
Protein binding 40%
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 (U.S.)

Routes Oral (Capsules: 10, 18, 25, 40, 60, 80 and 100 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. This chemical is manufactured and marketed under the brand name Strattera® by Eli Lilly and Company and as a generic Tomoxetin by Torrent Pharmaceuticals. There is currently no generic available within the United States due to patent restrictions.

Atomoxetine is classified as a norepinephrine reuptake inhibitor (Noradrenaline reuptake inhibitor), and is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six 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.

Although the drug can be "felt" right away, it does not start "working properly" for 3-4 weeks time. Users should expect to feel tired and groggy for a few weeks. Eventually, the system adapts to the drug and the benefits can be felt. The key message to people starting out on the drug: If the first week or two is difficult, give it a chance to work before choosing to stop taking it.

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.

Even though being approved for ADHD - both for children and adults - many doctors are prescribing it as a substitute to the available anti-psychotic drugs in cases of certain disorders of thought and less serious mental problems - like dyslexia, clumsiness and schizoaffective disorder - for its positive effects in calming down and in helping having more steady thought processes - improving the symptoms of people with thought disorders likely to be associated with the less serious types and degrees of schizophrenia. For that matter this drug has great potential helping in the treatment of schizophrenia and attention-deficit disorder without manifest symptoms and manneirisms of hyperactivity (formerly known just as ADD and now designated as ADHD-PI). In many cases of the above mentioned disorders of thought it is said to work seamlessly better and with less negative side-effects than any other of the available anti-psychotics.

Additional recommended knowledge

Contents

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.

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 pre-gelatinized 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.

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 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, sporadic nausea, and sudden 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.

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.

Occasionally after prolonged use some teenagers have experienced slow onset mild depression while using Strattera[citation needed]

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.

Discontinuation adverse effects

Further information: Chemical synapse

The central nervous system (CNS) adapts to the presence of psychoactive drugs. Such adaptation commonly involves the readjustment of neuroreceptors to compensate for the acute pharmacological action of the medication. This adaptation theory also explains why withdrawal symptoms and signs can occur on the discontinuation of such medications as clearance of drug can occur at a rate faster than the brain can readjust to the absence of medication. Hence, pharmacodynamic and pharmacokinetic factors contribute to the risk of a withdrawal syndrome.

Psychiatric reactions

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 was 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.

In less than three years on the market 10,988 adverse "psychiatric reactions" have been reported to Eli Lilly for the ADHD drug Strattera, according to the British Medicines and Healthcare products Regulatory Agency (MHRA), January 2006.

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. It may be abused if taken in larger amounts than the daily dosage, the effects may be compared to those experienced on amphedemines that are also used for ADHD medication.

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, but did not show a benefit to risk ratio in trials. Failed clinical trials are not submitted to drug regulatory agencies and are considered trade secrets. Subsequently, Lilly then chose to pursue an ADHD treatment route for atomoxetine. Many patients have seen a pronounced anti-depressive effect in conjunction with other antidepressants. More study is needed to understand the full pharmacodynamics.[1][2][3][4]

Experimental uses

A small (40 people), 10-week, double-blind clinical trial was reported in the Journal of Clinical Psychiatry on the effectiveness of atomoxetine for treating binge eating disorder. The results of the trial was that atomoxetine was "associated with a significantly greater rate of reduction in binge-eating episode frequency, weight, [and] body mass index." The average daily dose given was 106 mg/day. The authors concluded that atomoxetine is effective for short term treatment of binge eating disorder.[5]

A preliminary 12-week, randomized, double-blind, placebo-controlled trial was conducted at Duke University Medical Center which studied the effectiveness of atomoxetine on adult obese women. The study included 30 obese women with an average body mass index of 36.1. Fifteen women were given atomoxetine therapy starting at 25 mg/day with a gradual increase to 100 mg/day over 1 week. Fifteen women were given a placebo with identical dosing. By the end of the trial, the atomoxetine group lost an average of 3.6 kg (3.7% of their body mass) vs a 0.1 kg gain in the placebo group (0.2% gain). Three participants in the atomoxetine group and none in the placebo group lost greater than 5% of their mass.[6]

References

  1. ^ Biederman J, Spencer TJ (March, 2006). "Atomoxetine and adult attention-deficit/hyperactivity disorder: the effects of comorbidity.".
  2. ^ Adli M, Pilhatsch MK (March, 2006). "Augmentation with atomoxetine in treatment-resistant depression with psychotic features. A case report.".
  3. ^ Price LH, Carpenter LL (Oct, 2005). "Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants.".
  4. ^ Biederman, J, Kratochvil CJ (Sept, 2005). "Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms.".
  5. ^ McElroy, Susan (2007), " ", Journal of Clinical Psychiatry 68 (3): 390–398, PMID 17388708,
  6. ^ Gadde, K.M. (July 2006), " ", International Journal of Obesity 30 (7): 1138–1142, PMID 16418753
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Atomoxetine". A list of authors is available in Wikipedia.
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