NORTRIPTYLINE Chemical Properties

Melting point:

58 °C

Boiling point:

396.62°C (rough estimate)

Density 

0.9790 (rough estimate)

refractive index 

1.4900 (estimate)

storage temp. 

4°C, protect from light

pka

pKa 9.7 (Uncertain)

BCS Class

1

EPA Substance Registry System

Nortriptyline (72-69-5)

Safety Information

Hazardous Substances Data

72-69-5(Hazardous Substances Data)

Toxicity

LD50 orl-rat: 502 mg/kg HEPHD2 55,527,80

NORTRIPTYLINE Usage And Synthesis

Originator

Aventyl,Lilly,UK,1963

Uses

Nortriptyline is a drug with a relatively short latent period of action. It is practically devoid of sedative effects. It is used in manic-depressive psychoses, in all forms of endogenous depression, and also in major depressive conditions.

Uses

Antidepressant.

Definition

ChEBI: An organic tricyclic compound that is 10,11-dihydro-5H-dibenzo[a,d][7]annulene substituted by a 3-(methylamino)propylidene group at position 5. It is an active metabolite of amitriptyline.

Manufacturing Process

A mixture of 114.5 g of 5-(3-chloropropylidene)dibenzo[a,d]cyclohepta[1,4] diene, 75 ml of benzene, and about 400 ml of methylamine is heated in an autoclave at 120°C for six hours. The excess methylamine is distilled from the reaction mixture under vacuum and the residue is stirred with 300 ml of water. Acidification of the mixture with hydrochloric acid causes the separation of the hydrochloride of 5-(3-methylaminopropylidene)dibenzo[a,d] cyclohepta[1,4]diene. The product is collected by filtration and is purified by recrystallization from a mixture of absolute ethanol and ethyl acetate. MP 210°C to 212°C.

brand name

Aventyl Hydrochloride (Lilly); Aventyl Hydrochloride (Ranbaxy); Pamelor (Tyco).

Therapeutic Function

Antidepressant

Clinical Use

Tricyclic antidepressant

Safety Profile

Poison by ingestion,intraperitoneal, and intravenous routes. When heated todecomposition it emits toxic fumes of NOx.

Synthesis

Nortriptyline is 5-(3-methylaminopropyliden)-10,11-dihydrodibenzcycloheptene (7.1.17). Nortriptyline differs from desipramine in the same manner in which amitriptyline differs from imipramine. In nortriptyline, the nitrogen atom in the central part of the tricyclic system of desipramine is replaced by a carbon atom, which is bound to a side chain by a double bond.
Two suggested methods of nortriptyline synthesis are based on the N-demethylation of amitriptyline. The third way utilizes the reaction of methylamine with 5-(3-bromopropyliden)-10,11-dihydro-5H-dibenz[a,d]cycloheptene (7.1.18).
According to the first scheme, demethylation takes place by the reaction of amitriptyline (7.1.4) with methyliodide, which leads to the formation of a quaternary ammonium salt (7.1.16), the reaction of which with methylamine at a relatively high temperature gives the desired nortriptyline (7.1.17) [25].

According to the third scheme, nortriptyline is synthesized by reacting methylamine with 5-(3-bromopropyliden)-10,11-dihydro-5H-dibenz[a,d]cycloheptene (7.1.6) [8].

Drug interactions

Potentially hazardous interactions with other drugs
Alcohol: increased sedative effect.
Analgesics: increased risk of CNS toxicity with tramadol; possibly increased risk of side effects with nefopam; possibly increased sedative effects with opioids.
Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone - avoid; increased risk of ventricular arrhythmias with disopyramide, flecainide or propafenone; avoid with dronedarone.
Antibacterials: increased risk of ventricular arrhythmias with delamanid, moxifloxacin and possibly telithromycin - avoid with moxifloxacin.
Anticoagulants: may alter anticoagulant effect of coumarins.
Antidepressants: enhanced CNS excitation and hypertension with MAOIs and moclobemide - avoid; concentration possibly increased with SSRIs; risk of ventricular arrhythmias with citalopram and escitalopram - avoid; increased risk of convulsions with vortioxetine.
Antiepileptics: convulsive threshold lowered; concentration reduced by carbamazepine, fosphenytoin, phenobarbital and possibly phenytoin.
Antimalarials: avoid with artemether/lumefantrine and piperaquine with artenimol.
Antipsychotics: increased risk of ventricular arrhythmias especially with droperidol, haloperidol, pimozide, risperidone and sulpiride - avoid; increased antimuscarinic effects with clozapine and phenothiazines; concentration increased by antipsychotics.
Antivirals: increased risk of ventricular arrhythmias with saquinavir - avoid; concentration possibly increased with ritonavir.
Atomoxetine: increased risk of ventricular arrhythmias and possibly convulsions.
Beta-blockers: increased risk of ventricular arrhythmias with sotalol.
Clonidine: tricyclics antagonise hypotensive effect; increased risk of hypertension on clonidine withdrawal.
Dapoxetine: possible increased risk of serotonergic effects - avoid.
Dopaminergics: avoid use with entacapone; CNS toxicity reported with selegiline and rasagiline.
Pentamidine: increased risk of ventricular arrhythmias.
Sympathomimetics: increased risk of hypertension and arrhythmias with adrenaline and noradrenaline; metabolism possibly inhibited by methylphenidate.

Metabolism

Nortriptyline is a secondary amine dibenzocycloheptene TCA as well as the major metabolite of amitriptyline. Similar to desipramine, nortriptyline appears in mother's milk and is metabolized by CYP2D6 to the primary amine and by ring hydroxylation to its E-10-hydroxy metabolite. Approximately one-third of a dose of nortriptyline is excreted in urine as metabolites within 24 hours, and small amounts are excreted in feces via biliary elimination.

NORTRIPTYLINE(72-69-5)Related Product Information

• Cotriptyline
• Amitriptyline hydrochloride
• NORTRIPTYLINE
• PIROHEPTINE
• nortriptyline hydrochloride methanol*solution,NORTRIPTYLINE HCL USP,Nortriptyline solution hydrochloride,NORTRIPTYLINE HYDROCHLORIDE,NORTRIPTYLINE HCL
• Amitriptyline
• AMITRIPTYLINE HCL (D6)
• AMITRIPTYLINE-D3 HCL (N-METHYL-D3)
• cyproheptadine 10,11-epoxide
• NORTRIPTYLINE METABOLITE (+/-)-(Z),NORTRIPTYLINE METABOLITE (+/-)-Z-10-HYDR OXYLAT
• AMITRIPTYLINE METABOLITE (+/-)-
• amitriptyline N-oxide
• Piroheptine
• NORTRIPTYLINE-D3 HYDROCHLORIDE
• NORTRIPTYLINE HCL (METHYL-D3),NORTRIPTYLINE-D3 HYDROCHLORIDE,NORTRIPTYLINE HCL (D3),NORTRIPTYLINE-D3 HCL (N-METHYL-D3)
• Nortriptyline-d3 HCl
• cis-10,11-Dihydroxy Nortriptyline
• 10,11-DIHYDRO-5 H-DIBENZO[A,D]CYCLOHEPTENE