Selective NRI Safety and Tolerability

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The side-effect profiles of reboxetine, atomoxetine, and viloxazine can be attributed to the unwanted effects of norepinephrine, as activity at other receptors is limited. The concept of selectivity can thus be a bit deceiving. While an agent such as reboxetine is selective for the neurotransmitter ► norepinephrine, its activity is nonse-lective in terms of distribution, contributing to effects not only in the brain but in the body as well (Table 3). In the limbic system, the stimulation of noradrenergic receptors has been correlated with agitation. Acute stimulation of norepinephrine receptors in the brainstem and spinal cord can contribute to elevations in blood pressure, although the extent of these elevations does not appear to reach clinical relevance in most cases. Such elevations have been reported with atomoxetine use. In most cases, the side effects that are present with selective NRIs lessen over time. The most frequent side effects of reboxetine include dry mouth, constipation, urinary retention, blurred vision, headache, drowsiness, dizziness, excessive sweating, and insomnia. When looking at these side effects, one might associate dry mouth, constipation, urinary retention, and blurred vision with anticholinergic activity, but as was already mentioned, reboxetine does not directly block muscarinic cholinergic receptors. Instead, anticholin-ergic-like effects are the result of norepinephrine receptor stimulation in the sympathetic nervous system, which in turn causes a reduction of parasympathetic cholinergic tone, frequently referred to as sympathomimetic effects. This is observed clinically in the fact that reboxetine, ato-moxetine, and viloxazine are generally better tolerated than tertiary amine TCAs, which elicit full effects at these receptor sites. In addition to anticholinergic effects, TCAs are linked to lethal cardiac arrhythmias, seizures, and neuro-toxicity associated with elevated serum TCA levels. Toxic levels are generally accepted as >500 ng/ml for desipramine and nortriptyline.

Selective NRIs should be used cautiously in several patient populations. The potential of antidepressants to lower the seizure threshold is a class effect, and as such, all drugs in this class should be used with caution in patients with seizure disorders. Bupropion is contraindicated in patients who have epilepsy or concomitant medical conditions that may lower the seizure threshold, including the active discontinuation of ► alcohol or ► benzodiazepines

NARI Antidepressants. Table 3. Noradrenergic pathways. (Adapted from Stahl 2004)

Beginning of the pathway

Projecting to

Control of

Locus Coeruleus

Frontal cortex Alpha-2 receptor

Attention Concentration Cognition Libido increase

Locus Coeruleus

Frontal cortex Beta-1 receptor


Locus Coeruleus

Limbic cortex

Energy Fatigue Emotions

Psychomotor agitation and retardation

Locus Coeruleus



Locus Coeruleus


Blood pressure

Locus Coeruleus

Spine Alpha-2

Pain modulation

Spinal sympathetic neurons


Beta-1 receptor

Heart rate

Spinal sympathetic neurons

Urinary Bladder Alpha-1

Bladder emptying

and eating disorders. Daily doses greater than 450 mg of bupropion are associated with increased incidence of seizure.

As a class, selective NRIs depend on hepatic function for proper metabolism. Caution should be used, and dosage adjustments may be warranted, in hepatic insufficiency. In 2004, the FDA mandated that a warning be added to the atomoxetine drug label following two reports in which patients with no documented liver insufficiencies presented with elevated bilirubin levels and hepatic enzymes.

Selective NRIs are contraindicated with ► monoamine oxidase inhibitors (MAOIs). Concurrent use can result in increased catecholamine concentrations, which present, clinically, as hypertensive crisis, confusion, and seizures. Reboxetine has the ability to block the neuronal uptake of tyramine and, as a result, would theoretically be protective against hypertensive crisis secondary to the dietary ingestion of tyramine. As the threshold and duration of these effects are unknown, the combination of reboxetine and MAOIs should be avoided.

The effects of selective NRIs have not been extensively studied in pregnancy or breast-feeding, and should be used only when it is determined that the benefits outweigh the potential risks. Currently, maprotiline is the only selective NRI that is classified as pregnancy category B. Bupropion was previously classified as ► pregnancy category B but this labeling was changed by the FDA to category C. All other selective NRIs are category C, with the exception of nortriptyline, which is classified as category D due to its increased risk of teratogenicity, and therefore should be avoided in pregnancy.

The FDA mandated the addition of a ► black box warning disclosing the risk of suicide in children and adolescents in October 2004 and later extended the warning to include young adults. Close monitoring for suicidal ideation or changes in behaviors is warranted in patients who are started on therapy, particularly during the first few months of therapy or following dosage changes. Along with the warning, manufacturers in the USA must provide Patient Medication Guides that are to be given to the patient with all prescriptions for antidepressants.

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  • Jasmine
    Is nortriptyline an nri?
    2 years ago

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