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Nortriptyline

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Nortriptyline chemical structure
Nortriptyline

3-(10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ylidene)- N-methyl-1-propanamine
IUPAC name
CAS number
72-69-5
ATC code

N06AA10

PubChem
4543
DrugBank
APRD00602
Chemical formula {{{chemical_formula}}}
Molecular weight 263.377 g/mol
Bioavailability well absorbed
Metabolism Hepatic
Elimination half-life 16 and 90 hours
Excretion Renal
Pregnancy category C
Legal status Rx-only
Routes of administration oral

Nortriptyline is a second generation tricyclic antidepressant marketed as the hydrochloride under the tradenames Aventyl®, Pamelor® and Nortrilen®. It is used in the treatment of depression and childhood nocturnal enuresis (bedwetting). In addition it is sometimes used for chronic pain modification and labile affect in some neurological conditions.

Clinical pharmacologyEdit

Nortriptyline inhibits the reuptake of serotonin, and, to a lesser extent, norepinephrine (noradrenalin) (Basic & Clinical Pharmacology, 10th Edition, Bertram G. Katzung, MD, PhD). Operant conditioning techniques in rats and pigeons suggest that nortriptyline has a combination of stimulant and depressant properties.

IndicationsEdit

FDA-approved for treatment of depressive disorders. In the United Kingdom also may be used for treating nocturnal enuresis with courses of treatment lasting no more than three months. Also used off-label for the treatment of panic disorder, irritable bowel disease, prevention of migraine headaches and chronic pain or neuralgia modification (particularly Temporomandibular joint disorder).[1] 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.[2]

MetabolismEdit

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.[How to reference and link to summary or text] Blood levels of nortriptyline should be obtained during long term treatment to avoid toxicity and optimise response.

DosageEdit

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.[3]

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 electrocardiogram (ECG or EKG) required before further courses.[3]

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 effectsEdit

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/EKG 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 (e.g. imipramine (Tofranil®), amitriptyline (Elavil®)).

WarningsEdit

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

ContraindicationsEdit

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 crises and/or severe convulsions; fatalities have occurred.

OverdoseEdit

Main article: Tricyclic antidepressant

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

ReferencesEdit

  1. (2002) Sweetman SC Martindale. The complete drug reference, 33, Pharmaceutical Press. ISBN 0-85369-499-0.
  2. Prochazka A, Weaver M, Keller R, Fryer G, Licari P, Lofaso D (1998). A randomized trial of nortriptyline for smoking cessation.. Arch Intern Med 158 (18): 2035-9. PMID 9778204.
  3. 3.0 3.1 British National Formulary 45 March 2003

Further readingEdit

  • Alexanderson, B., Evans, D. A., & Sjoqvist, F. (1969). Steady-state plasma levels of nortriptyline in twins: Influence of genetic factors and drug therapy: BMJ: British Medical Journal Vol 4(5686) Dec 1969, 764-768.
  • Alexanderson, B., Price Evans, D. A., & Sjoqvist, F. (1969). Steady-state plasma levels of nortriptyline in twins: Influence of genetic factors and drug therapy: BMJ: British Medical Journal Vol 4(5686) Dec 1969, 764-768.
  • Ambrosini, P. J., Bianchi, M. D., Metz, C., & Rabinovich, H. (1994). Evaluating clinical response of open nortriptyline pharmacotherapy in adolescent major depression: Journal of Child and Adolescent Psychopharmacology Vol 4(4) Win 1994, 233-244.
  • Angelico, P., Ibba, M., Abbiati, G. A., & Testa, R. (1986). Different effects of nortriptyline on electroconvulsive shock and footshock-induced analgesia in rats: IRCS Medical Science: Psychology & Psychiatry Vol 14(1-2) Jan-Feb 1986, 126-127.
  • Appioti, A., & et al. (1974). The combination of nortriptyline and fluphenazine in the treatment of the depression-anxiety syndrome: Rivista di Psichiatria Vol 9(4) Jul-Aug 1974, 346-363.
  • Apter, J. T., Kushner, S. F., & Woolfolk, R. L. (1994). Bupropion/nortriptyline combination for refractory depression: Annals of Clinical Psychiatry Vol 6(4) Dec 1994, 255-258.
  • Atkinson, J. H., Slater, M. A., Williams, R. A., Zisook, S., Patterson, T. L., Grant, I., et al. (1998). A placebo-controlled randomized clinical trial of nortriptyline for chronic low back pain: Pain Vol 76(3) Jun 1998, 287-296.
  • Austin, L. S., Arana, G. W., & Ballenger, J. C. (1990). Rapid response of patients simultaneously treated with lithium and nortriptyline: Journal of Clinical Psychiatry Vol 51(3) Mar 1990, 124-125.
  • Baumann, P., Jonzier-Perey, M., Koeb, L., Le, P. K., & et al. (1986). Amitriptyline pharmacokinetics and clinical response: I. Free and total plasma amitriptyline and nortriptyline: International Clinical Psychopharmacology Vol 1(2) Apr 1986, 89-101.
  • Beaglehole, B., Luty, S. E., Mulder, R. T., Kennedy, M. A., & Joyce, P. R. (2007). Low red cell folate levels are associated with poor response to nortriptyline in major depression: Acta Neuropsychiatrica Vol 19(3) Jun 2007, 204-207.
  • Bebchuk, J. M., & Stewart, D. E. (1991). Drug interaction between rifampin and nortriptyline: A case report: International Journal of Psychiatry in Medicine Vol 21(2) 1991, 183-187.
  • Behnke, K., Mejer-Nielsen, B., Korner, A., Arup, P., & et al. (1992). Rolipram versus nortriptyline in gerontopsychiatric inpatients with major depression: Nordic Journal of Psychiatry Vol 46(6) 1992, 407-411.
  • Benazzi, F. (1997). Venlafaxine-fluoxetine-nortriptyline interaction: Journal of Psychiatry & Neuroscience Vol 22(4) Jul 1997, 278-279.
  • Berger, A., Dukes, E., Edelsberg, J., Stacey, B., & Oster, G. (2007). Use of Tricyclic Antidepressants in Older Patients With Diabetic Peripheral Neuropathy: Clinical Journal of Pain Vol 23(3) Mar-Apr 2007, 251-258.
  • Bertschy, G., Vandel, S., Jounet, J. M., & Allers, G. (1990). Valpromide-amitriptyline interaction: Increase of amitriptyline and nortriptyline biodisposition by valpromide: L'Encephale Vol 16(1) Jan-Feb 1990, 43-45.
  • Biegon, A. (1984). The complex binding of tricyclic antidepressants to rat brain: The case of nortriptyline: Brain Research Vol 321(2) Nov 1984, 347-351.
  • Bondareff, W., Alpert, M., Friedhoff, A. J., Richter, E. M., Clary, C. M., & Batzar, E. (2000). Comparison of sertraline and nortriptyline in the treatment of major depressive disorder in late life: American Journal of Psychiatry Vol 157(5) May 2000, 729-736.
  • Borson, S., McDonald, G. J., Gayle, T., Deffebach, M., & et al. (1992). Improvement in mood, physical symptoms, and function with nortriptyline for depression in patients with chronic obstructive pulmonary disease: Psychosomatics: Journal of Consultation Liaison Psychiatry Vol 33(2) Spr 1992, 190-201.
  • Bump, G. M., Mulsant, B. H., Pollock, B. G., Mazumdar, S., Begley, A. E., Dew, M. A., et al. (2001). Paroxetine versus nortriptyline in the continuation and maintenance treatment of depression in the elderly: Depression and Anxiety Vol 13(1) 2001, 38-44.
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  • Burch, J. E., Roberts, S. G., & Raddats, M. A. (1981). Binding of amitriptyline and nortriptyline in plasma determined from their equilibrium distributions between red cells and plasma, and between red cells and buffer solution: Psychopharmacology Vol 75(3) Nov 1981, 262-272.
  • Burrows, G., & et al. (1974). A sequential trial comparing two plasma levels of nortriptyline: Australian and New Zealand Journal of Psychiatry Vol 8(1) Mar 1974, 21-23.
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  • Buysse, D. J., Reynolds, C. F., Houck, P. R., Perel, J. M., Frank, E., Begley, A. E., et al. (1997). Does Lorazepam impair the antidepressant response to nortriptyline and psychotherapy? : Journal of Clinical Psychiatry Vol 58(10) Oct 1997, 426-432.
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  • Dahl, M.-L., Bertilsson, L., & Nordin, C. (1996). Steady-state plasma levels of nortriptyline and its 10-hydroxy metabolite: Relationship to the CYP2D6 genotype: Psychopharmacology Vol 123(4) Feb 1996, 315-319.
  • Davies, B., Burrows, G., & Scoggins, B. (1975). Plasma nortriptyline and clinical response: Australian and New Zealand Journal of Psychiatry Vol 9(4) Dec 1975, 249-253.
  • Dawling, S., Crome, P., Heyer, E. J., & Lewis, R. R. (1981). Nortriptyline therapy in elderly patients: Dosage prediction from plasma concentration at 24 hours after a single 50 mg dose: British Journal of Psychiatry Vol 139 Nov 1981, 413-416.
  • de Oliveira, I. R., Brito, P. R., Peres, M. F., Dardennes, R., & et al. (1992). Fluoxetine seems to widen the nortriptyline antidepressant-like dose range in mice submitted to the tail suspension test (TST): European Psychiatry Vol 7(1) 1992, 33-37.
  • Desai, A., & Chibnall, J. T. (1999). "Comparative efficacy and safety of sertraline versus nortriptyline in major depression in patients 70 and older": Comment: International Psychogeriatrics Vol 11(3) Sep 1999, 339-340.
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  • Dietch, J. T., & Fine, M. (1990). The effect of nortriptyline in elderly patients with cardiac conduction disease: Journal of Clinical Psychiatry Vol 51(2) Feb 1990, 65-67.
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  • Dubovsky, S. L. (1987). Severe nortriptyline intoxication due to change from a generic to a trade preparation: Journal of Nervous and Mental Disease Vol 175(2) Feb 1987, 115-117.
  • Ejsing, T. B., & Linnet, K. (2005). Influence of P-glycoprotein inhibition on the distribution of the tricyclic antidepressant nortriptyline over the blood-brain barrier: Human Psychopharmacology: Clinical and Experimental Vol 20(2) Mar 2005, 149-153.
  • Ejsing, T. B., Pedersen, A. D., & Linnet, K. (2005). P-glycoprotein interaction with risperidone and 9-OH-risperidone studied in vitro, in knock-out mice and in drag-drag interaction experiments: Human Psychopharmacology: Clinical and Experimental Vol 20(7) Oct 2005, 493-500.
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  • Fava, M., Rush, A. J., Wisniewski, S. R., Nierenberg, A. A., Alpert, J. E., McGrath, P. J., et al. (2006). A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A STAR*D Report: American Journal of Psychiatry Vol 163(7) Jul 2006, 1161-1172.
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  • Finkel, S. I., Richter, E. M., & Clary, C. M. (1999). "Comparative efficacy and safety of sertraline versus nortriptyline in major depression in patients 70 and older": Reply: International Psychogeriatrics Vol 11(3) Sep 1999, 340-342.
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Antidepressants (ATC N06A) edit
Monoamine oxidase inhibitors (MAOI) Harmaline, Iproclozide, Iproniazid, Isocarboxazid, Nialamide, Phenelzine, Selegiline, Toloxatone, Tranylcypromine
Reversible inhibitor of monoamine oxidase A (RIMA) Brofaromine, Moclobemide
Dopamine reuptake inhibitor (DARI) Amineptine, Phenmetrazine, Vanoxerine, Modafinil
Norepinephrine-dopamine reuptake inhibitors Bupropion
Norepinephrine reuptake inhibitor (NRI) or (NARI) Atomoxetine, Maprotiline, Reboxetine, Viloxazine
Serotonin-norepinephrine reuptake inhibitor (SNRI) Duloxetine, Milnacipran, Venlafaxine
Selective serotonin reuptake inhibitor (SSRI) Alaproclate, Etoperidone, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Zimelidine
Selective serotonin reuptake enhancer (SSRE) Tianeptine
Tricyclic antidepressants (TCA) Amitriptyline, Amoxapine, Butriptyline, Clomipramine, Desipramine, Dibenzepin, Dothiepin, Doxepin, Imipramine, Iprindole, Lofepramine, Melitracen, Nortriptyline, Opipramol, Protriptyline, Trimipramine
Tetracyclic antidepressants Maprotiline, Mianserin, Nefazodone, Trazodone
Noradrenergic and specific serotonergic antidepressant (NaSSA) Mirtazapine
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