Source: Medicines Authority (MT) Revision Year: 2022 Publisher: H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
Pharmacotherapeutic group: Antidepressants – Non-selective monoamine reuptake inhibitor (tricyclic antidepressant)
ATC-code: N06AA10
Nortriptyline is a tricyclic antidepressant. Nortriptyline, a secondary amine, is also the main active metabolite of amitriptyline. Nortriptyline is a more potent inhibitor of noradrenaline than of serotonin uptake, while amitriptyline inhibits the uptake of noradrenaline and serotonin equally well. Nortriptyline is less anticholinergic than amitriptyline but has quite potent antihistaminergic effect and it potentiates the effects of catecholamines.
Suppression of rapid eye movement (REM) sleep is considered a predictor of antidepressant activity. Tricyclic antidepressants, as well as SSRI’s and MAO inhibitors, suppresses REM-sleep and increases deep slow-wave sleep.
Nortriptyline elevates the pathological lowered mood level. Due to its central stimulating properties nortriptyline is of special value in depressions when inhibition, apathy and lack of initiative are features of the illness. The antidepressant effectusually sets in after 2-4 weeks, whereas release of inhibition may set in considerably sooner. Among tricyclics, nortriptyline may have a particularly low risk of inducing orthostatic changes.
Oral administration results in maximum plasma levels in about 5 hours (Tmax = 5.5±1.9 hours; range 4.0-8.8 hours). The mean absolute oral bioavailability is 51% (Fabs = 0.51±0.05; range 0.46-0.59).
The apparent volume of distribution (Vd)β estimated after intravenous administration is 1633±268 l; range 1460-2030 l (21±4 l/kg). The plasma protein binding is about 93%. Nortriptyline passes across the placental barrier.
The metabolism of nortriptyline proceeds by demethylation and hydroxylation followed by conjugation with glucuronic acid. The metabolism is subject to genetic polymorphism (CYP2D6).
The main active metabolite is 10-hydroxynortriptyline, which exists in a cis and trans form with the trans form dominating in the organism. N-demethylnortriptyline is also formed to some degree. The metabolites have the same profile as nortriptyline but are somewhat weaker. Trans 10-hydroxynortriptyline is more potent than the cis form. In plasma the amount of total 10-hydroxynortriptyline dominates but most of the metabolites are conjugated.
The elimination half-life (T½β) of nortriptyline after peroral administration is about 26 hours (25.5±7.9 hours; range 16-38 hours). The mean systemic clearance (Cls) is 30.6±6.9 l/h; range 18.6-39.6 l/h.
The excretion proceeds mainly with urine. The renal elimination of unchanged nortriptyline is insignificant (about 2%).
In nursing mothers nortriptyline is excreted in small amounts with the breast milk. The ratio milk conc./plasma conc. in women is 1:2. The estimated daily infant exposure averages 2% of the corresponding maternal weight related doses of nortriptyline (in mg/kg).
Steady state plasma levels of nortriptyline are reached within a week for most patients.
Longer half-lives and decreased oral (Clo) clearance values due to a reduced rate of metabolism have been demonstrated in elderly patients.
Hepatic affection of a certain degree of severity may reduce hepatic extraction resulting in higher plasma levels.
Renal failure has no influence on the kinetics.
The metabolism is subject to genetic polymorphism (CYP2D6).
The therapeutic plasma concentration in endogenous depression is 50-140 ng/ml (~190-530 nmol/l). Levels above 170-200 ng/ml are associated with increased risk of disturbance in cardiac conduction in terms of prolonged QRS-complex or AV block.
The acute toxicity of tricyclic antidepressants including nortriptyline is high.
LD50 of nortriptyline hydrochloride in rats was 502 mg/kg p.o.
Nortriptyline has been used clinically since 1963.
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