If you follow geriatrics or are board-certified, you probably know that nortriptyline is generally preferred over amitriptyline in this patient population. It’s kind of weird to think there is such a difference because nortriptyline is an active metabolite of amitriptyline. When comparing amitriptyline versus nortriptyline, it is important to remember that the parent drug (amitriptyline) can have activity as well.
Amitriptyline is a tertiary amine TCA, while nortriptyline is a secondary amine TCA. In the tricyclic antidepressants (TCAs), “tertiary amine” versus “secondary amine” refers to the chemical structure of the nitrogen-containing side chain — and that structural difference strongly affects pharmacology, receptor binding, and adverse effects. That structural difference changes receptor binding affinity significantly. Amitriptyline tends to have higher antihistamine and anticholinergic activity than nortriptyline. Nortriptyline tends to be more selective for the norepinephrine reuptake inhibitor.
Let’s look at the activity and the negative aspects of amitriptyline. The antihistamine action of amitriptyline is typically going to cause more sedation and weight gain than nortriptyline. This is usually problematic. In addition, the stronger anticholinergic activity can lead to an increase in dry eyes, dry mouth, confusion, urinary retention, and constipation. Again, more problems here – especially as patients age. Small structural changes can dramatically alter pharmacologic behavior.
With amitriptyline being a “dirtier” drug, why would you even choose amitriptyline versus nortriptyline? In some cases, sedation can be a valuable effect. If you want more sedation, you may consider amitriptyline over nortriptyline. An example of this would be a patient with neuropathy symptoms that keep them up at night.
Hopefully, this post helps explain the difference between these two agents and where one might select one over the other.
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