Nortriptyline, sold under the brand name Pamelor, among others, is a medication used to treat depression. This medicine is used for:

neuropathic pain Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous ...

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...

(ADHD),

smoking cessation Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is addictive and can cause dependence. As a result, nicotine withdrawal often m ...

and

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

. As with many antidepressants, its use for young people with depression and other psychiatric disorders may be limited due to increased suicidality in the 18-24 population initiating treatment. Nortriptyline is a less preferred treatment for ADHD and stopping smoking. It is taken by mouth. Common side effects include dry mouth, constipation, blurry vision, sleepiness, low blood pressure with standing, and weakness. Serious side effects may include

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

s, an increased risk of suicide in those less than 25 years of age,

urinary retention Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include loss of bladd ...

glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...

, mania, and a number of heart issues. Nortriptyline may cause problems if taken during pregnancy. Use during

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...

appears to be relatively safe. It is a

tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...

(TCA) and is believed to work by altering levels of serotonin and

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...

. Nortriptyline was approved for medical use in the United States in 1964. It is available as a generic medication. In 2020, it was the 155th most commonly prescribed medication in the United States, with more than 3million prescriptions.

Medical uses

Nortriptyline is used to treat depression. This medication is in capsule or liquid and is taken by the mouth one to four times a day, with or without food. Usually people are started on a low dose and it is gradually increased. A level between 50 and 150 ng/mL of nortriptyline in the blood generally corresponds with an antidepressant effect. In the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the European mainland, continental mainland. It comprises England, Scotlan ...

, it may also be used for treating nocturnal enuresis, with courses of treatment lasting no more than three months. It is also used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although ...

for the treatment of

panic disorder Panic disorder is a mental and behavioral disorder, specifically an anxiety disorder characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, short ...

irritable bowel syndrome Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...

, migraine prophylaxis and chronic pain or

neuralgia Neuralgia (Greek ''neuron'', "nerve" + ''algos'', "pain") is pain in the distribution of one or more nerves, as in intercostal neuralgia, trigeminal neuralgia, and glossopharyngeal neuralgia. Classification Under the general heading of neural ...

modification, particularly temporomandibular joint disorder.

Neuropathic pain

Although not approved by the FDA for

, many randomized controlled trials have demonstrated the effectiveness of TCAs for the treatment of this condition in both depressed and non-depressed individuals. In 2010, an evidence-based guideline sponsored by the International Association for the Study of Pain recommended nortriptyline as a first-line medication for neuropathic pain. However, in a 2015 Cochrane systematic review the authors did not recommend nortriptyline as a first-line agent for neuropathic pain.

Irritable Bowel Syndrome

Nortriptyline has also been used as an off-label treatment for

Irritable Bowel Syndrome Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...

, or IBS.

Contraindications

Nortriptyline should not be used in the acute recovery phase after

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...

(viz, heart attack). Use of tricyclic antidepressants along with a monoamine oxidase (MAO) inhibitor,

linezolid Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, v ...

, and IV methylene blue are contraindicated as it can cause an increased risk of developing serotonin syndrome. Closer monitoring is required for those with a history of cardiovascular disease, stroke,

, or

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

, as well as in persons with

hyperthyroidism Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidis ...

or receiving thyroid hormones.

Side effects

The most common side effects include dry mouth, sedation, constipation, increased appetite, blurred vision and tinnitus. An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects.

Overdose

The symptoms and the treatment of an overdose are generally the same as for the other TCAs, including

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous sys ...

effects,

serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include high ...

and adverse cardiac effects. TCAs, particularly nortriptyline, have a relatively narrow

therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...

, which increase the chance of an overdose (both accidental and intentional). Symptoms of overdose include: irregular heartbeat,

, coma,

confusion In medicine, confusion is the quality or state of being bewildered or unclear. The term "acute mental confusion"

hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinati ...

, widened pupils,

drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

, agitation,

fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...

, low

body temperature Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...

, stiff muscles and

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

Interactions

Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or suicidal ideation. It may interact with the following drugs: * heart rhythm medications such as

flecainide Flecainide is a medication used to prevent and treat abnormally fast heart rates. This includes ventricular and supraventricular tachycardias. Its use is only recommended in those with dangerous arrhythmias or when significant symptoms cannot ...

(Tambocor),

propafenone Propafenone, sold under the brand name Rythmol among others, is a class 1c anti-arrhythmic medication, which is used to treat illnesses associated with rapid heart beat such as atrial and ventricular arrhythmias. Mechanism of action Propafen ...

(Rhythmol), or

quinidine Quinidine is a class I antiarrhythmic agent, class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is the enantiomer of Antimalarial medication, antimalarial agent quinine, originally derived from the bark of the cinchona tre ...

(Cardioquin, Quinidex, Quinaglute) * cimetidine * guanethidine * reserpine

Pharmacology

Nortriptyline is a strong

norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epin ...

and a moderate

serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the action of the serotonin transporter (SERT). This in turn leads to incre ...

. Its pharmacologic profile is as the table shows with (inhibition or antagonism of all sites).Brunton L, Chabner B, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.

Pharmacodynamics

Nortriptyline is an active metabolite of

amitriptyline Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...

by demethylation in the liver. Chemically, it is a

secondary amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...

dibenzocycloheptene Preferably called dibenzosuberane (other less common names are Dibenzocycloheptene and dibenzocycloheptadiene) is a tricyclic chemical compound featuring two benzene rings bound to a cycloheptene group. It is an occasional motif in synthetic o ...

and pharmacologically it is classed as a first-generation antidepressant. Nortriptyline may also have a sleep-improving effect due to antagonism of the H₁ and 5-HT_2A receptors. In the short term, however, nortriptyline may disturb sleep due to its activating effect. In one study, nortriptyline had the highest affinity for the

dopamine transporter The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dop ...

among the TCAs (K_D = 1,140 nM) besides

amineptine Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family. It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a lesser ...

(a norepinephrine–dopamine reuptake inhibitor), although its affinity for this transporter was still 261- and 63-fold lower than for the

and

serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein tha ...

s (K_D = 4.37 and 18 nM, respectively).

Pharmacokinetics

Pharmacogenetics

Nortriptyline is metabolized in the liver by the hepatic enzyme

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D ...

, and genetic variations within the gene coding for this enzyme can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of nortriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy. Individuals can be categorized into different types of

metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most individuals (about 77–92%) are extensive metabolizers, and have "normal" metabolism of nortriptyline. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use nortriptyline much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure. The Clinical Pharmacogenetics Implementation Consortium recommends avoiding nortriptyline in persons who are

ultrarapid or poor metabolizers, due to the risk of a lack of efficacy and side effects, respectively. A reduction in starting dose is recommended for patients who are

intermediate metabolizers. If use of nortriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments. The Dutch Pharmacogenetics Working Group recommends reducing the dose of nortriptyline in

poor or intermediate metabolizers, and selecting an alternative drug or increasing the dose in ultrarapid metabolizers.

Chemistry

Nortriptyline is a

tricyclic compound Tricyclics are chemical compounds that contain three interconnected rings of atoms. Many compounds have a tricyclic structure, but in pharmacology, the term has traditionally been reserved to describe heterocyclic drugs. Among these are antid ...

, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a

side chain In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called the "main chain" or backbone. The side chain is a hydrocarbon branching element of a molecule that is attached to a ...

attached in its

chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of ...

. Other dibenzocycloheptadiene TCAs include

(''N''-methylnortriptyline), protriptyline, and butriptyline. Nortriptyline is a

TCA, with its ''N''-

methylated In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...

parent A parent is a caregiver of the offspring in their own species. In humans, a parent is the caretaker of a child (where "child" refers to offspring, not necessarily age). A ''biological parent'' is a person whose gamete resulted in a child, a male t ...

amitriptyline being a

tertiary amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...

. Other secondary amine TCAs include

desipramine Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activiti ...

and protriptyline. The chemical name of nortriptyline is 3-(10,11-dihydro-5''H''-dibenzo 'a'',''d''yclohepten-5-ylidene)-''N''-methyl-1-propanamine and its

free base Free base (freebase, free-base) is the conjugate base ( deprotonated) form of an amine, as opposed to its conjugate acid ( protonated) form. The amine is often an alkaloid, such as nicotine, cocaine, morphine, and ephedrine, or derivatives ther ...

form has a

chemical formula In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbol ...

of C₁₉H₂₁N₁ with a

molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

of 263.384 g/mol. The drug is used commercially mostly as the

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative n ...

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quant ...

; the free base form is used rarely. The

CAS Registry Number A CAS Registry Number (also referred to as CAS RN or informally CAS Number) is a unique identification number assigned by the Chemical Abstracts Service (CAS), US to every chemical substance described in the open scientific literature. It inclu ...

of the free base is 72-69-5 and of the hydrochloride is 894-71-3.

History

Nortriptyline was developed by

Geigy Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loca ...

. It first appeared in the literature in 1962 and was patented the same year. The drug was first introduced for the treatment of depression in 1963.

Society and culture

Nortriptyline HCL capsules - 50mg and 25mg

Generic names

''Nortriptyline'' is the

English English usually refers to: * English language * English people English may also refer to: Peoples, culture, and language * ''English'', an adjective for something of, from, or related to England ** English national ide ...

and French generic name of the drug and its , , and , while ''nortriptyline hydrochloride'' is its , , , and . Its generic name in

Spanish Spanish might refer to: * Items from or related to Spain: **Spaniards are a nation and ethnic group indigenous to Spain **Spanish language, spoken in Spain and many Latin American countries **Spanish cuisine Other places * Spanish, Ontario, Can ...

and

Italian Italian(s) may refer to: * Anything of, from, or related to the people of Italy over the centuries ** Italians, an ethnic group or simply a citizen of the Italian Republic or Italian Kingdom ** Italian language, a Romance language *** Regional Ita ...

and its are ''nortriptilina'', in German is ''nortriptylin'', and in

Latin Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through the power of the ...

is ''nortriptylinum''.

Brand names

Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensoval, among many others.

References

External links

* {{Portal bar , Medicine Alpha-1 blockers Antihistamines Dibenzocycloheptenes Human drug metabolites Muscarinic antagonists Secondary amines Serotonin receptor antagonists Serotonin–norepinephrine reuptake inhibitors Sodium channel blockers Tricyclic antidepressants Wikipedia medicine articles ready to translate