Nortriptyline

Article Author:
Gagindip Merwar
Article Editor:
Abdolreza Saadabadi
Updated:
6/23/2019 10:53:45 PM
PubMed Link:
Nortriptyline

Indications

Nortriptyline is indicated for use in the treatment of depression (FDA-approved). It can also be used off-label for conditions such as chronic pain, diabetic neuropathy, myofascial pain, orofacial pain, postherpetic neuralgia. Nortriptyline has also shown to be useful in patient’s trying to quit smoking. Nortriptyline is not FDA approved for use in children.[1][2][3][4]

Mechanism of Action

Nortriptyline is an antidepressant that falls under the pharmacological category of tricyclics (secondary amine), more commonly known as TCAs.

It is the consensus that nortriptyline inhibits the reuptake of serotonin and norepinephrine by the presynaptic neuronal membrane, thereby increasing the concentration of those neurotransmitters in the synapse. Additionally, nortriptyline inhibits the activity of histamine, 5-hydroxytryptamine, and acetylcholine. Nortriptyline increases the pressor effect of norepinephrine but hinders the pressor response of phenethylamine. However, additional receptor effects have been found including desensitization of adenylyl cyclase, down-regulation of beta-adrenergic receptors, and downregulation of serotonin receptors.

Administration

Nortriptyline is usually taken orally in capsule form or an oral solution.  Capsule form comes in the following dosages 10 mg, 25 mg, 50 mg, 75 mg.  Oral solution form is usually of the following composition 10 mg/5 mL (473 mL).

Adverse Effects

Nortriptyline has a black box warning for increased risk of suicide in adolescents, children, and young adults with major depressive disorder and multiple other psychiatric disorders.[5][6][7][8]

The most common adverse effects of nortriptyline include downiness, xerostomia, dizziness, constipation, blurred visions, palpitations, tachycardia, impaired coordination, increased appetite, nausea/vomiting, diaphoresis, weakness, disorientation, confusion, restlessness, insomnia, anxiety/agitation, urinary retention, urinary frequency, rash, urticaria, pruritus, weight gain, libido changes, impotence, gynecomastia, galactorrhea, tremor, hypo/hyperglycemia, paraesthesia, and photosensitivity.

The most serious adverse effects include orthostatic hypotension, HTN, syncope, ventricular arrhythmias, AV block, MI, stroke, seizures, EPS symptoms, ataxia, tardive dyskinesia paralytic ileus, glaucoma, increased IOP, agranulocytosis, leukopenia, thrombocytopenia, hallucinations, psychosis exacerbation, hypomania/mania, depression exacerbation, suicidality, serotonin syndrome, SIADH, hepatitis, angioedema, anticholinergic psychosis, hyperthermia, and heat stroke.

A patient can also have withdrawal symptoms such as dizziness, gastrointestinal (GI) problems such as nausea and vomiting, anxiety, headaches, and restlessness if nortriptyline is discontinued abruptly. These withdrawal symptoms can be avoided by gradually decreasing the dose of nortriptyline over a period.

Drug Interactions

Concurrent usage of cimetidine and tricyclic antidepressants such as nortriptyline results in increased concentration of TCAs. Using nortriptyline along with alcohol can increase the effects of alcohol in patients. Cytochrome P450 2D6 metabolizes nortriptyline. All pharmacological drugs that inhibit 2D6 can produce an adverse reaction. Examples of major drug interactions that can result in inhibition of cytochrome P450 2D6 include quinidine and cimetidine.  Cimetidine increases bioavailability and decreases the clearance of this drug due to its inhibition of metabolic pathways of both demethylation and hydroxylation, as well as its ability to reduce hepatic extraction of nortriptyline. Other drugs are substrates for P450 2D6 such as other antidepressants, phenothiazines and type-1C antiarrhythmics such as propafenone and flecainide.

Concurrent usage of nortriptyline with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either nortriptyline or the other drug.

Many patients who are prescribed nortriptyline may already be taking SSRIs such as fluoxetine. If the benefit of switching from fluoxetine to nortriptyline is higher than the risk, it should be considered that fluoxetine has an active metabolite, norfluoxetine, with a long half-life.  The risk of adverse effect and interaction may be high for several weeks after discontinuation of fluoxetine. Therefore, usage of nortriptyline with SSRIs like fluoxetine can result in an increased risk for serotonin syndrome.

Contraindications

Use of tricyclic antidepressants along with a monoamine oxidase (MAO) inhibitor, linezolid, and IV methylene blue are contraindicated as it can cause an increased risk of developing serotonin syndrome. Serotonin syndrome can be life-threatening as it can cause a change in mental status, autonomic instability, neuromuscular changes, seizures and gastrointestinal symptoms. More importantly, concurrent use of both medications can cause convulsions, hyper-pyretic crises, and death. MOA inhibitors must be discontinued for at least 14 days before starting nortriptyline.

If nortriptyline must be used alongside serotonergic drugs such as triptans, other TCAs, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort, the benefits must outweigh the risks.

Postmarketing reports have shown a possible association between nortriptyline and the unmasking of Brugada syndrome. For this reason, the patient’s with Brugada syndrome or suspected for it should generally avoid nortriptyline as it can result in ECG abnormalities, syncope and even sudden cardiac death.

Nortriptyline can cause pupillary dilation which can result in an angle closure attack in an individual with anatomically narrow angles.

Use of nortriptyline is also contraindicated in patients with hypersensitivity to nortriptyline or its components. Cross-sensitivity between nortriptyline hydrochloride and other dibenzazepines is a possibility.

Finally, nortriptyline is contraindicated during the acute recovery period after myocardial infarction.

Monitoring

As an antidepressant, the therapeutic range for nortriptyline is between 50 to 150 ng/mL (190 to 570 nmol/L).

As per APA guidelines, patients using nortriptyline should be monitored for suicidal ideation especially at the start of therapy as well as when dosage changes are made. Cardiac parameters such as heart rate, ECG and blood pressure should frequently be monitored in adults who already have existing cardiac disease and in elderly patients.

Toxicity

During overdose the following receptors are blocked: sodium channels (fast) in the heart, muscarinic Ach receptors (central and peripheral), alpha-1 receptors in the periphery, H1 and GABA-A in the central nervous system (CNS). Like many other TCAs, the toxicity of nortriptyline can be very harmful to the body. The most important initial step taken when assessing a patient with toxicity is making sure the patient has adequate breathing.  Intubation is usually mandated for airway protection and proper ventilation. IV fluids can be administered for hypotension. Additionally, for patients with prolonged QRS (greater than 100 milliseconds) or ventricular arrhythmia, sodium bicarbonate is the recommended treatment. The dosage of sodium bicarbonate is dependent on the weight of the patient, usually 1 to 2 mEq/kg. TCAs can also cause seizures. These can be treated with benzodiazepines such as lorazepam 2 mg or diazepam 5 mg, administered through the intravenous (IV) route. Treatment with activated charcoal for gastrointestinal decontamination is only indicated in patients who present within 2 hours of overdose (1 g/kg). Although there is strong blockage of muscarinic acetylcholine receptors, physostigmine is absolutely contraindicated in the event of TCA toxicity as it can cause adverse cardiac effects such as cardiac arrest.

Enhancing Healthcare Team Outcomes

Healthcare workers including the primary care provider and nurse practitioner should be aware that nortriptyline is no longer used. There are many better and safer antidepressants on the market. The drug has many side effects which are often not well tolerated.[9]


References

[1] de Souza IBMB,Costa LRF,Tiago PRF,Cagni FC,Lima RH,Silva Junior ED,Gavioli EC, Venlafaxine and nortriptyline reverse acute dexamethasone-induced depressive-like behaviors in male and female mice. Experimental and clinical psychopharmacology. 2019 Feb 4;     [PubMed PMID: 30714753]
[2] Pollok J,van Agteren JE,Carson-Chahhoud KV, Pharmacological interventions for the treatment of depression in chronic obstructive pulmonary disease. The Cochrane database of systematic reviews. 2018 Dec 19;     [PubMed PMID: 30566235]
[3] Hou S,Huh B,Kim HK,Kim KH,Abdi S, Treatment of Chemotherapy-Induced Peripheral Neuropathy: Systematic Review and Recommendations. Pain physician. 2018 Nov;     [PubMed PMID: 30508986]
[4] Nortriptyline 2006;     [PubMed PMID: 30000235]
[5] Gawecka E,Viken O, Postherpetic neuralgia: New hopes in prevention with adult vaccination and in treatment with a concentrated capsaicin patch. Scandinavian journal of pain. 2012 Oct 1;     [PubMed PMID: 29913873]
[6] Qin B,Chen H,Gao W,Zhao LB,Zhao MJ,Qin HX,Chen W,Chen L,Yang MX, Efficacy, acceptability, and tolerability of antidepressant treatments for patients with post-stroke depression: a network meta-analysis. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2018;     [PubMed PMID: 29742266]
[7] Molyneaux E,Telesia LA,Henshaw C,Boath E,Bradley E,Howard LM, Antidepressants for preventing postnatal depression. The Cochrane database of systematic reviews. 2018 Apr 18;     [PubMed PMID: 29669175]
[8] Euwema MS,Swanson TJ, Deadly Single Dose Agents 2018 Jan;     [PubMed PMID: 28722879]
[9] Riediger C,Schuster T,Barlinn K,Maier S,Weitz J,Siepmann T, Adverse Effects of Antidepressants for Chronic Pain: A Systematic Review and Meta-analysis. Frontiers in neurology. 2017;     [PubMed PMID: 28769859]