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Nortriptyline – Mechanism of action, uses, dosage, side effects

Last reviewed by Editorial Team on October 14th, 2018.

What is nortriptyline?

Nortriptyline hydrochloride is an active metabolite of amitriptyline, is a tricyclic antidepressant and is a dibenzocycloheptene-derivative. It has a structure similar to phenothiazine.

They contain a tricyclic ring system with an alkyl amine substituent on the central ring. Nortriptyline causes sedation and does not affect mood or arousal in a patient who is nondepressed.

Nortriptyline causes a positive effect on the depressed patient. Serotonin reuptake and norepinephrine reuptake is inhibited by the tricyclic antidepressants.

Tertiary amine tricyclic antidepressant is weaker and has less potency as compared to secondary amine tricyclic antidepressants in inhibiting the norepinephrine reuptake.

With chronic usage, tricyclic antidepressants down regulates the cerebra cortical beta-adrenergic receptors and they also sensitize the post-synaptic serotonergic receptors.

The sedative properties, hypotensive activity, anticholinergic effects are caused due to blockage of histamine H1 receptors, alpha-1 adrenergic receptors, and muscarinic receptors respectively, caused by tricyclic antidepressant such as nortriptyline.

Nortriptyline causes fewer drug interactions and is less toxic as compared to other tricyclic antidepressants.

As compared to amitriptyline (a tertiary amine tricyclic antidepressant), nortriptyline exerts less anticholinergic and sedative side effects.

Nortriptyline IUPAC name, mlecular formula, weight, structure and drug class

IUPAC name of nortriptyline: methyl(3-{tricyclo[³,⁸]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene}propyl)amine

Molecular formula: C19H21N

Molecular weight: 263.384 g/mol

Molecular structure:

Drug class: Dibenzocycloheptenes is a class of organic compounds that contains nortriptyline. A dibenzocycloheptene moiety that consists of 2 benzene rings which is connected by cycloheptene ring in these compounds.

What are the indications of nortriptyline?

Nortriptyline is indicated for the treatment of symptoms relief, which are associated with depression.

As compared to other depressive states, endogenous depressions are more likely to get reduced.

What is the mechanism of action of nortriptyline?

Nortriptyline acts by inhibiting the reuptake of neurotransmitter known as serotonin at the neuronal membrane or acts at beta-adrenergic receptors.

The relief and improvement of biological symptoms of nortriptyline therapy are achieved by the selective noradrenaline reuptake inhibition.

Many tricyclic antidepressants do not affect various mechanisms such as dopamine reuptake and monoamine oxidase inhibition.

Nortriptyline displays an affinity for other receptors such as mACh receptors, histamine receptors, and other 5-HT receptors, just like other tricyclic antidepressants.

Pharmacokinetics of nortriptyline

Nortriptyline absorbed well from the gastrointestinal tract. Its peak plasma concentration occurs within 4 to 9 hours after oral administration, with the mean time of 6 hours.

The mean oral bioavailability is 51%. The mean oral bioavailability of nortriptyline is 51%. It may also cross the placental plasma barrier. It binds to the plasma protein to 93% approximately.

Just like other tricyclic antidepressants, nortriptyline also undergoes hepatic metabolism via a similar pathway. In which the metabolism takes place via demethylation and hydroxylation after conjugation with glucuronic acid.

The major active metabolite of this compound is  10-  hydroxynortriptyline which found in cis as well as trans form. Out of the both, the trans form is more potent and dominant.

To some extent,  N-demethylnortriptyline is also formed. These metabolites possess the same but weaker pharmacological effects like nortriptyline. The main excretion of nortriptyline and its metabolites takes place in the urine.

A very small amount of the parent drug (nearly 2%) is excreted in the urine as parent compound. Around one-third of a single orally administered dose is excreted in urine within 24 hours.

Biliary elimination also takes place as small amount also excreted in feces. The elimination half-life of this drug is 26 hours approximately after oral administration of nortriptyline.

How long does nortriptyline stay in your system?

The elimination half-life of nortriptyline is 26 hours approximately and the elimination of the drug is equaled to 5 times to that of the elimination half-life of a drug. Therefore it will be eliminated in 5 to 6 days from your system completely.

What are the brand names of nortriptyline?

The multiple brand names of nortriptyline include Allergen, Aventyl, Nortrilen, and Pamelor.

Can nortriptyline be taken by pregnant women?

Nortriptyline comes under the pregnancy category C which means that this drug does not have significant studies in human and in animal studies it shows the significant risk to the fetus therefore one should use this medication in pregnancy only if the benefit outweighs the risk.

The drug-related risk of this medication showed inconclusive data in pregnant women, therefore, precaution is needed while using this medication in pregnancy.

Can nortriptyline be given to nursing mother?

Nortriptyline can be given to nursing mother only when benefit outweighs the risk. As per few experts, the use of this medication by the nursing mothers is contraindicated because it can excrete into the human milk.

However, its effects in the nursing infants are unknown, but still, it may be of concern. Some authorities also consider this drug as a preferred antidepressant for use during breastfeeding.

Can nortriptyline be taken with alcohol?

The administration of alcohol along with nortriptyline or any other tricyclic antidepressant is contraindicated. Because the concurrent administration of both can result in changed plasma levels of nortriptyline and also it can cause a change in efficacy, disturbance in motor skills (mainly driving skills).

Nortriptyline metabolism can be affected by the administration of the alcohol while a hepatic metabolism can be induced by high administration of the alcohol.

Therefore one should avoid taking alcohol while on nortriptyline. The patient who has undergone detoxification can also see the reduced efficacy of nortriptyline. The patient may require dosage adjustment.

What are the side effects of nortriptyline?

Nortriptyline can cause multiple side effects which should be considered as soon as they appear. You should consult your doctor if any of these symptoms do not go away.

Some common side effects are:

  • Drowsiness
  • Weakness or fatigue
  • Nausea
  • Nightmares
  • Anxiety or excitement
  • Anorexia
  • Changes in weight
  • Dry mouth
  • Constipation
  • Difficulty in urination
  • Frequent urination
  • Night sweats or excessive sweating
  • Blurred vision
  • Change on sex ability

Some serious side effects are:

Call your doctor immediately, or seek emergency care, if you see any of these serious side effects:

  • Slow speech or difficult speech
  • Shuffling walk
  • Uncontrollable shaking of any part of body
  • Difficulty in breathing or swallowing
  • Rashes
  • Irregular heart beat
  • Fever and chills
  • Jaundice
  • Muscles spasms (mainly of jaw, neck or muscle)

What are the precautions and warnings of the nortriptyline?

Warning for heart problems: If you already have some heart-related problems, you should avoid taking this medication without prior consultation with the doctor  because nortriptyline can put you at a risk of many heart problems.

Nortriptyline is known to cause fasten heart rate, heart attack, myocardial infarction, stroke and other cardiovascular diseases. You should also avoid taking this medication if you recently had a heart attack.

Increased eye pressure warning: You may also feel increased pressure in your eyes after taking nortriptyline. Patients who are at the risk of glaucoma, should avoid this medication as it can cause glaucoma in them.

Serotonin syndrome warning: A severe disease known as serotonin syndrome can be caused by administration of nortriptyline.

Serotonin syndrome is a disease in which a patient suffers from the symptoms like hallucinations and delusions, agitation, coma, fast heart rate, changes in blood pressure, dizziness, loss of consciousness, seizures, shakiness, muscle tremors or stiff muscles, sweating, nausea, and vomiting.

When you take other medications such as fentanyl, lithium, St. John’s wort, tramadol and other along with nortriptyline, the risk of getting serotonin syndrome increases to many folds.

Can nortriptyline get you high?

Administering very high doses of nortriptyline can cause hallucinations in some people and also it can get you high when taken in more than recommended doses.

It is dangerous to take this medication in high doses and it can lead to severe adverse events. It can lead to life-threatening overdose.

You should keep this medication away from the children and teenagers and should take it in the recommended doses or as per directions. One should also not take this medication if it is not prescribed to you.

Can nortriptyline be taken with amitriptyline?

The concurrent administration of nortriptyline and amitriptyline can cause severe side effects such as drowsiness, blurred vision, dry mouth, heat intolerance, flushing, decreased sweating, difficulty urinating, irregular heartbeat, constipation, cramps in abdomen, psychiatric problems, memory loss, or confusion. Elderly patients or debilitating patients are more prone to get such side effects.

While being treated with these medications, you should limit the use of alcohol. Until you know how these medications affect your body, you should avoid activities that require mental alertness, for example, driving, or you should also not operate hazardously.

You should also let your doctor know about all the medications that you are already taking. Without talking to your doctor, you should not stop this medication as it may cause withdrawal symptoms.

Can nortriptyline be taken with phenylephrine?

One should avoid the concurrent administration of nortriptyline and phenylephrine because tricyclic antidepressant such as nortriptyline can increase the pressor response to sympathomimetic agents that act directly when given parenteral, and vasoconstrictor-containing local anesthetics response. In patients, who are treated with nortriptyline, the effects of norepinephrine increase to sevenfold.

Management: Parenteral administration of direct-acting sympathomimetic agents should preferably be avoided during therapy with tricyclic antidepressants except in cases of emergency (e.g., treatment of anaphylaxis).

If concomitant use is necessary, initial dose and rate of administration of the sympathomimetic should be reduced, and cardiovascular status including blood pressure should be monitored closely.

Although clinical data are lacking, it may be prudent to follow the same precaution with mixed-acting sympathomimetic agents.

Is nortriptyline beneficial in treatment-resistant depression?

Nortriptyline is considered as an effective treatment for the depression.  People who are taking serotonin reuptake inhibitors as initial treatment failed to respond antidepressants.

A study was conducted in order to check the efficacy of nortriptyline in patients with treatment-resistant major depression.

In the study, nortriptyline was found to be effective for patients with treatment-resistant depression. Therefore when patients fail to respond to other antidepressants, nortriptyline considered as a potential treatment.

What are the contraindications of nortriptyline?

The use of nortriptyline is contraindicated when you are:

  1. Hypersensitive to tricyclic antidepressants, nortriptyline or any other ingredient of nortriptyline formulation.
  2. When you take MAOIs (Mono aminase oxidase inhibitors) for treating psychiatric disorders within 14 days of stopping treatment with nortriptyline is highly contraindicated as it can result in increased risk of serotonin syndrome.
  3. Also one should not use nortriptyline within 14 days of stopping an MAO inhibitor for treating psychiatric disorders.
  4. In patients who are being treated with the agents such as linezolid or intravenous methylene blue (another MAOIs), the use of nortriptyline is contraindicated due to chances of increase in the risk of serotonin syndrome.
  5. if you are in the recovery period after a myocardial infarction, the use of nortriptyline is contraindicated.

Can nortriptyline relive nerve pain or neurotic pain?

Neuropathic pain is the pain that comes from the damaged nerves in the body. One should not misunderstand this pain with the pain from the healthy nerves that comes from the damaged tissue or organ such as cut, osteoarthritis, or fall etc.

There is different medication given for the neurotic pain. Pain killers such as paracetamol or Ibuprofen are known to be no use in treating such conditions, however, the medications which are used for treating depression or epilepsy can provide some relief in such situations.

Nortriptyline is considered to be effective in treating many types of persistent pain. It is considered highly effective in treating nerve pain, such as burning, shooting pain or stabbing pain and for the pain that may trouble you in the night and keep you awake overnight.

Mainly the nortriptyline class drugs are indicated for the treatment of depression.

Therefore the dose needed for pain relief is smaller than that used for depression. However, there is no indication for pain relief was given by the manufacturer, still, it was used for pain relief for years.

Moreover, there was very little information was given about use of nortriptyline as pain medication, therefore, you should consult your doctor for its adverse events before taking this medication for pain relief.

Can nortriptylline be taken for headaches?

Nortriptyline can downregulate for the migraine headaches (please check use of nortriptyline in a migraine)cerebral it is effective in treating headaches too.

Can nortriptyline be taken for fibromyalgia?

Nortriptyline is an active metabolite of amitriptyline, which can cause adverse events lesser than amitriptyline itself. When tried for the treatment of fibromyalgia, they both (amitriptyline and nortriptyline) showed no significant improvement in fibromyalgia.

Therefore when taken for the treatment of fibromyalgia, nortriptyline may not show any significant effect in treating the condition.

Can nortriptyline be taken for sleep?

Previously, tricyclic antidepressants such as amitriptyline and nortriptyline were used as sleep agents but their usage was decreased due to the availability of newer agents and due to side effects such as anticholinergic effects of these agents.

However, these agents possess sedation as a side effect, it stared using for treating insomnia. Therefore one can take this medication as a sleep aid, however, prior consultation with your doctor is necessary in order to prevent any kind of interaction with the medications that you may already taking.

Can nortriptyline be given to the patients with liver disease?

Tricyclic antidepressant such as nortriptyline and amitriptyline undergo hepatic metabolism. Some tricyclic antidepressant produce metabolites such as imipramine, clomipramine and desipramine which can be active pharmacologically.

There is no sufficient data is given about the use of such agents in patients with renal or liver disease. Therefore one should use nortriptyline with extreme caution in patients with impaired hepatic function.

Can nortriptyline be given for a migraine?

Nortriptyline or any other tricyclic antidepressants can be considered as first-line treatment for migraine prophylaxis. When compared with beta blockers, these agents proved effective in preventing the migraines and the effect is usually more rapid i.e. within 4 weeks.

However, when tried for the combination of beta blockers and tricyclic antidepressants, they were proved to reduce a tension-type headache, however, the combination was not proved beneficial in treating migraines.

Among the complete class of tricyclic antidepressants, amitriptyline is more effective than nortriptyline in a migraine.

Can nortriptyline cause night sweats?

When you discontinue he nortriptyline or any other tricyclic antidepressants, your body will detoxify itself from the drug.

Discontinuation of any tricyclic antidepressant can result in excessive sweating which may occur in day or in nights, however, the sweating can be more during the daytime as compared to the night.

You may even wake up in the middle of the night covered in sweat.

Can nortriptyline be given to the patients with thyroid disorders?

One should not give the tricyclic antidepressant such as nortriptyline and amitriptyline to the patients with hyperthyroid. Or if necessary, it should be used with extreme precaution.

The combination of this medication should be avoided because they can develop arrhythmias or fastens the heart beat of such patients.

Can nortriptyline be given to the patients with urinary retention?

In patients with a history of urinary retention, the tricyclic antidepressant should be used with caution due to their anticholinergic properties. Especially, doxepin hydrochloride is contraindicated to be administered with nortriptyline in such patients.

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