Atomoxetine

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Atomoxetine
Atomoxetine structure.svg
Atomoxetine ball-and-stick model.png
Clinical data
Trade names Strattera, others
Other names(R)-N-Methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine
AHFS/Drugs.com Monograph
MedlinePlus a603013
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Norepinephrine reuptake inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 63–94% [7] [8] [9]
Protein binding 98% [7] [8] [9]
Metabolism Liver, via CYP2D6 [7] [8] [9]
Elimination half-life 4.5–25 hours [7] [8] [9] [10] [11]
Excretion Kidney (80%) and faecal (17%) [7] [8] [9]
Identifiers
  • (3R)-N-Methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.120.306 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H21NO
Molar mass 255.361 g·mol−1
3D model (JSmol)
  • CC1=C(C=CC=C1)O[C@H](CCNC)C2=CC=CC=C2
  • InChI=1S/C17H21NO/c1-14-8-6-7-11-16(14)19-17(12-13-18-2)15-9-4-3-5-10-15/h3-11,17-18H,12-13H2,1-2H3/t17-/m1/s1 Yes check.svgY
  • Key:VHGCDTVCOLNTBX-QGZVFWFLSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Atomoxetine, formerly sold under the brand name Strattera, [12] is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) [13] and, to a lesser extent, cognitive disengagement syndrome (CDS). [14] [15] [16] It may be used alone or along with stimulant medication. [17] [18] It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time, [19] and emotional self-regulation. [20] [21] Use of atomoxetine is only recommended for those who are at least six years old. [13] It is taken orally. [13] The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate. [22] [23] [24] [25]

Contents

Common side effects of atomoxetine include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness. [13] Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression. [13] [26] There is a lack of data regarding its safety during pregnancy; as of 2019, its safety during pregnancy and for use during breastfeeding is not certain. [27] [28]

It was approved for medical use in the United States in 2002. [13] In 2022, it was the 213th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [29] [30]

Medical uses

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD). [5]

Attention deficit hyperactivity disorder

Atomoxetine is approved for use in children, adolescents, and adults. [5] However, its efficacy has not been studied in children under six years old. [8] One of the primary differences with the standard stimulant treatments for ADHD is that it has little known abuse potential. [8] Meta-analyses and systematic reviews have found that atomoxetine has comparable efficacy and equal tolerability to methylphenidate in children and adolescents. In adults, efficacy and tolerability are equivalent. [22] [23] [24] [25]

While its efficacy may be less than that of lisdexamphetamine, [31] there is some evidence that it may be used in combination with stimulants. [17] Doctors may prescribe non-stimulants including atomoxetine when a person has bothersome side effects from stimulants; when a stimulant was not effective; in combination with a stimulant to increase effectiveness; [32] [33] when the cost of stimulants is prohibitive; or when there is concern about the abuse potential of stimulants in a patient with a history of substance use disorder.

Atomoxetine alleviates ADHD symptoms through norepinephrine reuptake inhibition and by indirectly increasing dopamine in the prefrontal cortex, [34] sharing 70-80% of the brain regions with stimulants in their produced effects. [35]

Unlike α2-adrenergic receptor agonists such as guanfacine and clonidine, atomoxetine's use can be abruptly stopped without significant withdrawal symptoms being observed. [8]

The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent. [7] [36] [37] A further 2 to 4 weeks may be required for the full therapeutic effects to be seen. [38] [36] Incrementally increasing response may occur up to 1 year or longer. [37] [39] The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg. [5]

Other uses

Cognitive disengagement syndrome

Atomoxetine may be used to treat cognitive disengagement syndrome (CDS), [15] as multiple randomised controlled clinical trials (RCTs) have found that it is an effective treatment. [15] [14] [16] In contrast, multiple RCTs have shown that it responds poorly to the stimulant medication methylphenidate. [40] [41] [42] [43]

Traumatic brain injury

Atomoxetine is sometimes used in the treatment of cognitive impairment and frontal lobe symptoms due to conditions like traumatic brain injury (TBI). [44] [45] It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition, [46] lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome. [44] A 2015 Cochrane review identified only one study of atomoxetine for TBI and found no positive effects. [47] Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid hemorrhage in a case report. [45] [48]

Contraindications

Contraindications include: [8]

Adverse effects

Common side effects include abdominal pain, decreased appetite, nausea, feeling tired, dizziness [13] and urinary retention. [49] Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression. [13] [26] A 2020 meta-analysis found that atomoxetine was associated with anorexia, weight loss, and hypertension, rating it as a "potentially least preferred agent based on safety" for treating ADHD. [50] [51] As of 2019, safety in pregnancy and breastfeeding is not clear; [27] a 2018 review stated that, "because of lack of data, the treating physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy." [28]

The U.S. Food and Drug Administration (FDA) has issued a black box warning for suicidal behavior/ideation. [9] Similar warnings have been issued in Australia. [8] [52] Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation. [8] [53]

Overdose

Atomoxetine is relatively non-toxic in overdose. Single-drug overdoses involving over 1500 mg of atomoxetine have not resulted in death. [8]

Interactions

Atomoxetine is a substrate for CYP2D6. Concurrent treatment with a CYP2D6 inhibitor such as bupropion, fluoxetine, or paroxetine has been shown to increase plasma atomoxetine by 100% or more, as well as increase N-desmethylatomoxetine levels and decrease plasma 4-hydroxyatomoxetine levels by a similar degree. [54] [55] [56]

Atomoxetine has been found to directly inhibit hERG potassium currents with an IC50 of 6.3 μM, which has the potential to cause arrhythmia. [55] [57] QT prolongation has been reported with atomoxetine at therapeutic doses and in overdose; it is suggested that atomoxetine not be used with other medications that may prolong the QT interval, concomitantly with CYP2D6 inhibitors, and caution to be used in poor metabolizers. [55]

Other notable drug interactions include:

Atomoxetine prevents norepinephrine release induced by amphetamines and has been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans. [59] [60] [61]

Pharmacology

Pharmacodynamics

Atomoxetine (and metabolites) [62] [63]
SiteATX4-OH-ATXN-DM-ATX
SERT Tooltip Serotonin transporter7743ND
NET Tooltip Norepinephrine transporter5392
DAT 1,451NDND
MOR Tooltip μ-Opioid receptor>1,000 [64] 422 (antagonist?)ND
DOR Tooltip δ-Opioid receptorND300 (antagonist?)ND
KOR Tooltip κ-Opioid receptor>1,000? [64] 95 (partial agonist)ND
σ1 >1,000NDND
GABAA 200>30,000>10,000
NMDA 0.66 - 3,470aNDND
5-HT1A >1,000NDND
5-HT1B >1,000NDND
5-HT1D >1,000NDND
5-HT2 2,0001,0001,700
5-HT6 >1,000NDND
5-HT7 >1,000NDND
α1 11,40020,00019,600
α2A 29,800>30,000>10,000
β1 18,00056,10032,100
M1 >100,000>100,000>100,000
M2 >100,000>100,000>100,000
D1 >10,000>10,000>10,000
D2 >10,000>10,000>10,000
H1 12,100>100,000>100,000
Kir3.1/3.2 10,900bNDND
Kir3.2 12,400bNDND
Kir3.1/3.4 6,500bNDND
hERG 6,30020,0005,710
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All values are for human receptors unless otherwise specified. arat cortex. bXenopus oocytes. Additional sources: [65] [64] [10] [58]

Atomoxetine inhibits the presynaptic norepinephrine transporter (NET), preventing the reuptake of norepinephrine throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex, where dopamine transporter (DAT) expression is minimal. [10] In rats, atomoxetine increased prefrontal cortex catecholamine concentrations without altering dopamine levels in the striatum or nucleus accumbens; in contrast, methylphenidate, a dopamine reuptake inhibitor, was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree. [66] [65] In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice. [67]

Atomoxetine's status as a serotonin transporter (SERT) inhibitor at clinical doses in humans is uncertain. A PET imaging study on rhesus monkeys found that atomoxetine occupied >90% and >85% of neural NET and SERT, respectively. [68] However, both mouse and rat microdialysis studies have failed to find an increase in extracellular serotonin in the prefrontal cortex following acute or chronic atomoxetine treatment. [65] [67] Supporting atomoxetine's selectivity, a human study found no effects on platelet serotonin uptake (a marker of SERT inhibition) and inhibition of the pressor effects of tyramine (a marker of NET inhibition). [69]

Atomoxetine has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations. [70] [71] It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site. [70] [71] Atomoxetine's ability to increase prefrontal cortex firing rate in anesthetized rats could not be blocked by D1 or α1-adrenergic receptor antagonists, but could be potentiated by NMDA or an α2-adrenergic receptor antagonist, suggesting a glutaminergic mechanism. [72] In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels. [73] Aberrant glutamate and NMDA receptor function have been implicated in the etiology of ADHD. [74] [75]

Atomoxetine also reversibly inhibits GIRK currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner. [76] Kir3.1/3.2 ion channels are opened downstream of M2, α2, D2, and A1 stimulation, as well as other Gi-coupled receptors. [76] Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers. [76] It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.

4-Hydroxyatomoxetine, the major active metabolite of atomoxetine in CYP2D6 extensive metabolizers, has been found to have sub-micromolar affinity for opioid receptors, acting as an antagonist at μ-opioid receptors and a partial agonist at κ-opioid receptors. [64] It is not known whether this action at the kappa-opioid receptor leads to CNS-related adverse effects.

Pharmacokinetics

Orally administered atomoxetine is rapidly and completely absorbed. [10] First-pass metabolism by the liver is dependent on CYP2D6 activity, resulting in an absolute bioavailability of 63% for extensive metabolizers and 94% for poor metabolizers. [10] Maximum plasma concentration is reached in 1–2 hours. [10] If taken with food, the maximum plasma concentration decreases by 10–40% and delays the tmax by 3 hours. [10] Drugs affecting gastric pH have no effect on oral bioavailability. [5]

Following intravenous delivery, atomoxetine has a volume of distribution of 0.85 L/kg (indicating distribution primarily in total body water), with limited partitioning into red blood cells. [10] [77] It is highly bound to plasma proteins (98.7%), mainly albumin, along with α1-acid glycoprotein (77%) and IgG (15%). [10] [58] Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound. [10]

The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours. [10] [11] As atomoxetine is metabolized by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolizers. [11] Among CYP2D6 extensive metabolizers, the half-life of atomoxetine averaged 5.34 hours and the half-life of the active metabolite N-desmethylatomoxetine was 8.9 hours. [10] [78] By contrast, among CYP2D6 poor metabolizers the half-life of atomoxetine averaged 20.0 hours and the half-life of N-desmethylatomoxetine averaged 33.3 hours. [10] [78] Steady-state levels of atomoxetine are typically achieved at or around day 10 of regular dosing, with trough plasma concentrations (Ctrough) residing around 30–40°ng/mL; however, both the time to steady-state levels and Ctrough are expected to vary based on a patient's CYP2D6 profile. [79] [80]

Atomoxetine, N-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhibition of CYP1A2 and CYP2C9, but inhibit CYP2D6 in human liver microsomes at concentrations between 3.6 and 17 μmol/L.[ citation needed ] Plasma concentrations of 4-hydroxyatomoxetine and N-desmethylatomoxetine at steady state are 1% and 5% that of atomoxetine in CYP2D6 extensive metabolizers, and 0.1% and 45% that of atomoxetine in CYP2D6 poor metabolizers, respectively. [5]

Atomoxetine is excreted unchanged in urine at <3% in both extensive and poor CYP2D6 metabolizers, with >96% and 80% of a total dose being excreted in urine, respectively. [10] The fractions excreted in urine as 4-hydroxyatomoxetine and its glucuronide account for 86% of a given dose in extensive metabolizers, but only 40% in poor metabolizers. [10] CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates. [10]

Major metabolites of atomoxetine in humans. Atomoxetine metabolism.png
Major metabolites of atomoxetine in humans.

Pharmacogenomics

Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit two-fold higher area-under-the-curve (AUCs) and 1.5-fold higher maximum plasma concentrations compared to extensive metabolizers. [10]

Japanese men homozygous for CYP2D6*10 have similarly been found to experience two-fold higher AUCs compared to extensive metabolizers. [10]

Chemistry

Atomoxetine, or (−)-methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropylamine, is a white, granular powder that is highly soluble in water.

Synthesis

Original synthesis of atomoxetine, as patented by Eli Lilly and Company Atomoxetine-synthesis.png
Original synthesis of atomoxetine, as patented by Eli Lilly and Company

Detection in biological fluids

Atomoxetine may be quantitated in plasma, serum, or whole blood to distinguish extensive versus poor metabolizers in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdosage. [83]

History

Atomoxetine is manufactured, marketed, and sold in the United States as the hydrochloride salt (atomoxetine HCl) under the brand name Strattera by Eli Lilly and Company, the original patent-filing company and current U.S. patent owner. Atomoxetine was initially intended to be developed as an antidepressant, but it was found to be insufficiently efficacious for treating depression. It was, however, found to be effective for ADHD and was approved by the FDA in 2002, for the treatment of ADHD. Its patent expired in May 2017. [84] On 12 August 2010, Lilly lost a lawsuit that challenged its patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market. [85] On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States. [86] In a 29 July 2011 conference call, however, Sun Pharmaceutical's Chairman stated "Lilly won that litigation on appeal so I think [generic Strattera]'s deferred." [87]

In 2017 the FDA approved the generic production of atomoxetine by four pharmaceutical companies. [88]

Society and culture

The drug was originally known as tomoxetine. It was renamed to avoid medication errors, as the name may be confused with tamoxifen. [89]

Brand names

In India, atomoxetine is sold under brand names including Axetra, Axepta, Attera, Tomoxetin, and Attentin. In Australia, Canada, Italy, Portugal, Romania, Spain, Switzerland, and the US, atomoxetine is sold under the brand name Strattera. In France, hospitals dispense atomoxetine under the brand name Strattera (it is not marketed in France). In the Czech Republic, it is sold under brand names including Mylan. In Poland, it is sold under the brand name Auroxetyn. In Iran, atomoxetine is sold under brand names including Stramox. In Brazil, it is sold under the brand name Atentah. In Turkey, it is sold under the brand names Attex, Setinox, and Atominex. In 2017, a generic version was approved in the United States. [88]

Research

There has been some suggestion that atomoxetine might be a helpful adjunct in people with major depression, particularly in cases with concomitant ADHD. [90]

Atomoxetine may be used in those with ADHD and bipolar disorder although such use has not been well established. [91] Some benefit has also been seen in people with ADHD and autism. [92] As with other norepinephrine reuptake inhibitors it appears to reduce anxiety and depression symptoms, although research has focused mainly on specific patient groups such as those with concurrent ADHD [93] or methamphetamine dependence. [94]

References

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  2. ↑ Anvisa (15 September 2023). "RDC Nº 816 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 816 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 18 September 2023). Archived from the original on 19 October 2023. Retrieved 19 October 2023.
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