Classification Details
Nortriptyline belongs to the tricyclic antidepressant class, specifically categorized as a secondary-amine TCA, which distinguishes it from tertiary-amine TCAs like amitriptyline and imipramine. 1 This structural distinction is clinically significant because secondary-amine TCAs have lower affinity for muscarinic receptor antagonism, resulting in fewer anticholinergic side effects compared to tertiary-amine TCAs. 1
Mechanism of Action
- Primary mechanism: Nortriptyline inhibits the reuptake of norepinephrine and serotonin in the central nervous system, though it functions predominantly as a noradrenaline reuptake inhibitor (NRI). 3
- The drug is actually the active metabolite of amitriptyline, demonstrating the metabolic relationship between tertiary and secondary-amine TCAs. 1, 4
Clinical Significance of Drug Class
The secondary-amine classification makes nortriptyline pharmacologically superior to tertiary-amine TCAs in terms of tolerability:
- Reduced anticholinergic effects: Lower rates of dry mouth, constipation, urinary retention, blurred vision, and confusion compared to amitriptyline and imipramine. 1, 5
- Better cardiovascular tolerability: Relatively fewer cardiac side effects and less orthostatic hypotension, even in patients with preexisting cardiac disease. 5, 6
- Preferred for elderly patients: The American Geriatric Society's Beers Criteria identifies tertiary-amine TCAs as potentially inappropriate medications in older adults, while secondary-amine TCAs like nortriptyline are considered safer alternatives. 1
Metabolism and Drug Interactions
- Nortriptyline is metabolized primarily by cytochrome P450 2D6 (CYP2D6), with some involvement of CYP3A4 and CYP1A2. 1, 2
- Approximately 5-8% of Caucasians are poor metabolizers of CYP2D6, which can lead to higher plasma concentrations and increased risk of adverse effects. 1, 2
- The drug can inhibit CYP2D6 activity, potentially causing interactions with other medications metabolized by this enzyme. 2
Common Pitfalls
- Do not confuse with tertiary-amine TCAs: While all TCAs share the same general class, the secondary-amine designation is critical for understanding nortriptyline's superior side effect profile. 1
- Avoid assuming all TCAs are equivalent: Nortriptyline has distinct pharmacological properties that make it preferable to tertiary-amine TCAs, particularly in elderly patients and those with cardiac disease. 1, 5