Nortriptyline Hydrochloride 72-69-5 894-71-3

Clinical pharmacology

Nortriptyline is the active metabolite of amitriptyline that is demethylated in the liver. It inhibits the reuptake of norepinephrine (noradrenaline) and, to a lesser extent, serotonin with negligible effects on dopamine reuptake. Nortriptyline also has antagonistic effects at a variety of receptors:

• Strong: H₁
• Moderate: 5-HT₂, α₁-adrenergic, mACh
• Weak: 5-HT₁

These effects account for some therapeutic actions as well as for most side effects (sedation, hypotension, anticholinergic effects, etc). Nortriptyline may also have a sleep-improving effect due to it's affinity for 5HT_2A and histaminergic receptors. In the short run however, nortriptyline may disturb sleep due to its activating effect. Like other tricyclic antidepressants, nortriptyline also blocks sodium channels, possibly accounting in part for its analgesic action.

Indications

Nortriptyline is FDA-approved for the treatment of major depression. In the United Kingdom, 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 for the treatment of panic disorder, irritable bowel syndrome, migraine prophylaxis and chronic pain or neuralgia modification (particularly TMJ disorder). It can also aid in quitting smoking, with one study showing a six-month abstinence rate of 14% for subjects receiving nortriptyline compared to 3% for subjects not undergoing pharmacological treatment. Research has been done suggesting it can reduce symptoms of ADHD.

Metabolism

Nortriptyline is metabolised in the liver by hepatic enzyme CYP2D6. Approximately 7 to 10 percent of caucasians are poor metabolisers and might experience more adverse effects, so a lower dosage is often necessary in these individuals. Blood levels of nortriptyline should be obtained during long term treatment to avoid toxicity and optimise response.

Dosage

For depression: Low starting doses are used, increasing as necessary to 75–100 mg (0–50 mg for adolescents and the elderly). Maximum daily dosage is 150 mg. For the management of nocturnal enuresis: lower dosages are used with the maximum period of treatment, including gradual withdrawal, being three months and a full examination including electrocardiogram (ECG or EKG) required before further courses.

Warnings

Closer monitoring is required for those with a history of cardiovascular disease, stroke, glaucoma, and/or seizures, as well as those that have hyperthyroidism or are receiving thyroid medication. 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.

Contraindications

In the acute recovery phase after myocardial infarction (e. g. , heart attack). As for all tricyclic antidepressants, concurrent use, or failure to allow a two week gap, with monoamine oxidase inhibitors (MAO inhibitors, e. g. , phenelzine, tranylcypromine, etc. ) may precipitate hyperpyretic crisis and/or severe convulsions; fatalities have occurred.

Overdose

The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.