indication

For the treatment of depression, chronic pain, irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation and insomnia, and migraine prophylaxis.

pharmacology

Similar to protriptyline, nortriptyline is a tricyclic antidepressant of the dibenzocycloheptene type and is the active metabolite of amitriptyline.

mechanism of action

It is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at beta-adrenergic receptors. Tricyclic antidepressants do not inhibit monoamine oxidase nor do they affect dopamine reuptake.

toxicity

Symptoms of overdose include cardiac dysrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia.

biotransformation

Undergoes hepatic metabolism via the same pathway as other TCAs.

absorption

Well absorbed from the GI tract. Peak plasma concentrations occur 7-8.5 hours following oral administration.

half life

16 to 90+ hours

route of elimination

Approximately one-third of a single orally administered dose is excreted in urine within 24 hours. Small amounts are excreted in feces via biliary elimination.

drug interactions

Altretamine: Risk of hypotension

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Atazanavir: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if atazanavir if initiated, discontinued or dose changed.

Butabarbital: Barbiturates like butabarbital may increase the metabolism of tricyclic antidepressants like nortriptyline. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.

Butalbital: Barbiturates such as butalbital may increase the metabolism of tricyclic antidepressants such as nortriptyline. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.

Carbamazepine: Carbamazepine may decrease the serum concentration of the tricyclic antidepressant, nortriptyline, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if carbamazepine is initiated, discontinued or dose changed.

Cimetidine: Cimetidine may increase the effect of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if cimetidine is initiated, discontinued or dose changed.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clonidine: The tricyclic antidepressant, nortriptyline, decreases the effect of clonidine.

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dihydroquinidine barbiturate: Dihydroquinidine barbiturate increases the effect of the tricyclic antidepressant, nortriptyline.

Dobutamine: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of dobutamine.

Donepezil: Possible antagonism of action

Dopamine: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of dopamine.

Duloxetine: Possible increase in the levels of this agent when used with duloxetine

Ephedra: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of ephedra.

Ephedrine: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of ephedrine.

Epinephrine: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of epinephrine.

Fenoterol: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of fenoterol.

Fluconazole: Fluconazole may increase the effect and toxicity of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Additive QTc-prolonging effects may also occur. Monitor for changes in the therapeutic and adverse effects of nortriptyline if fluconazole is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy.

Fluoxetine: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of nortriptyline if fluoxetine is initiated, discontinued or dose changed.

Fluvoxamine: The SSRI, fluvoxamine, may increase the serum concentration of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of nortriptyline if fluvoxamine is initiated, discontinued or dose changed.

Galantamine: Possible antagonism of action

Grepafloxacin: Increased risk of cardiotoxicity and arrhythmias

Guanethidine: The tricyclic antidepressant, nortriptyline, decreases the effect of guanethidine.

Isocarboxazid: Possibility of severe adverse effects

Isoproterenol: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of isoproterenol.

Ketoconazole: Ketoconazole, a moderate CYP2D6 inhibitor, may increase the serum concentration of nortriptyline by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if ketoconazole is initiated, discontinued or dose changed.

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mephentermine: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of mephentermine.

Metaraminol: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of metaraminol.

Methoxamine: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of methoxamine.

Moclobemide: Possible severe adverse reaction with this combination

Norepinephrine: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of norepinephrine.

Orciprenaline: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of orciprenaline.

Phenelzine: Possibility of severe adverse effects

Phenylephrine: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of phenylephrine.

Phenylpropanolamine: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of phenylpropanolamine.

Pirbuterol: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of pirbuterol.

Procaterol: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of procaterol.

Pseudoephedrine: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of pseudoephedrine.

Quinidine: Additive QTc-prolonging effects may occur. Quinidine may also increase the serum concentration of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if quinidine is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy.

Quinidine barbiturate: Quinidine barbiturate increases the effect of the tricyclic antidepressant, nortriptyline.

Rasagiline: Possibility of severe adverse effects

Rifabutin: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, nortriptyline, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if rifabutin is initiated, discontinued or dose changed.

Rifampin: The rifamycin, rifampin, may decrease the effect of the tricyclic antidepressant, nortriptyline, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if rifampin is initiated, discontinued or dose changed.

Ritonavir: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if ritonavir if initiated, discontinued or dose changed.

Rivastigmine: Possible antagonism of action

Salbutamol: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of salbutamol.

Sibutramine: Increased risk of CNS adverse effects

Sparfloxacin: Increased risk of cardiotoxicity and arrhythmias

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Nortriptyline, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Terbinafine: Terbinafine may increase the effect and toxicity of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if terbinafine is initiated, discontinued or dose changed.

Terbutaline: The tricyclic antidepressant, nortriptyline, increases the sympathomimetic effect of terbutaline.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Tramadol: Tramadol increases the risk of serotonin syndrome and seizures.

Tranylcypromine: Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trimethobenzamide: Trimethobenzamide and Nortriptyline, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. Additive QTc-prolongation may also occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Triprolidine: Triprolidine and Nortriptyline, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.

Trospium: Trospium and Nortriptyline, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Vilazodone: Monitor for toxic effects of tricyclic antidepressants if a selective serotonin reuptake inhibitor (SSRI) is initiated or the dose is increased. The influence of the SSRI may take several days or weeks to be fully realized or resolved.

Voriconazole: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and nortriptyline, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).