Clinical Pharmacology

Nortriptyline inhibits the reuptake of norepinephrine (noradrenalin) and, to a lesser extent, serotonin. Operant conditioning techniques in rats and pigeons suggest that nortriptyline has a combination of stimulant and depressant properties.

Indications

FDA-approved for treatment of depressive disorders. In UK also may be used for treating nocturnal enuresis with courses of treatment lasting no more than 3 months. Also off-label used for the treatment of panic disorder, prevention of migraine headaches and chronic pain or neuralgia modification (particularly Temporomandibular joint disorder). It can also aid in quitting smoking with one study showing a 6-month abstinence rate of 14% for subjects receiving nortriptyline compared to 3% for subjects not undergoing pharmacological treatment.

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, thus, 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 - 100mg (0 - 50mg for adolescents and the elderly). Maximum daily dosage is 150mg.

For the management of noctiral enuresis: lower dosages are used with the maximum period of treatment, including gradual withdrawal, being three months and a full examination including ECG required before further courses.

For its off-label use for migraine and headache prophylaxis and treating chronic pain: treatment is started at very low 10mg once at night to minimise side-effects. The dose is then increased every two weeks if required to a maximum of 50mg.

Side effects

Dry mouth, drowsiness, orthostatic hypotension, urinary retention, constipation, and rapid or irregular heartbeat. Some sexual side effects may be a problem as well. Less commonly, seizures and ECG/ECG changes have been reported, especially in overdose.

Alcohol may exacerbate some of its side effects and should be avoided.

However, the incidence of side effects with nortriptyline is somewhat lower than with the first generation tricyclics (eg. imipramine (Tofranil®), amitriptyline (Elavil®)).

Warnings

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

Contraindications

In the acute recovery phase after myocardial infarction (eg. heart attack). As for all tricyclic antidepressants concocurrent use, or failure to allow a two week gap, with MAO Inhibitors (eg. phenelzine, tranylcypromine, etc) may precipitate hyperpyretic crises, severe convulsions, and fatalities have occurred.

Overdose

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