Nortriptyline

263.38

263.38

200-788-8

BL03SY4LXB

757234

DTXSID9023384

C62060

N - Nervous system

2921499090

12

4.7

Solid

1.084 g/cm3

58 °C

150-160 °C @ Press: 0.03 Torr

194.9ºC

1.633

8.74e-04 g/L

Keep container tightly closed in a dry and well-ventilated place. Light sensitive. Keep in a dry place. /Nortriptyline hydrochloride/

2.21X10-6 mm Hg at 25 deg C (est)

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

9.7None

Henry's Law constant = 3.1X10-8 atm-cu m/mol at 25 °C (est)

9.7|pKa = 10.47 (amide) (est)

164.5 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|163.1 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

White to off-white powder; slight, characteristic odor /Nortriptyline hydrochloride/|Crystals from ether and ethanol, MP 213-215 °C. Soluble in ethanol, water, chlorofrom; sparingly soluble in methanol; practiacllyinsoluble in ether, acetone, benzne and in most other organic solvents. UV max (methanol): 240 nm (epsilon 13900) /Nortryiptyline hydrocloride/|Hydroxyl radical reaction rate constant = 1.74X10-10 cu cm/molec-sec at 25 °C (est)

Stable under recommended storage conditions. /Nortriptyline hydrochloride/

P264, P270, P301+P312, P330, P501

H302

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product. /Nortriptyline hydrochloride/

Incompatible materials: Oxidizing agents /Nortriptyline hydrochloride/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including nortriptyline hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Nortriptyline hydrochloride/

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 38 companies from 1 notifications to the ECHA C&L Inventory.|H302: Harmful if swallowed [Warning Acute toxicity, oral]

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Nortriptyline hydrochloride/|Skin protection: Handle with gloves. /Nortriptyline hydrochloride/|Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Nortriptyline hydrochloride/|Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Nortriptyline hydrochloride/

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Nortriptyline hydrochloride/|Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Nortriptyline hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust; Environmental precautions: Do not let product enter drains; Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Nortriptyline hydrochloride/

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Nortriptyline hydrochloride/|Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Nortriptyline hydrochloride/|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Nortriptyline hydrochloride/|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Nortriptyline was detected at a range of 5.1-114 ng/L and 7.6-33 ng/L in unspecified wastewater treatment plant influent and effluent samples, respectively; secondary removal ranged from 50-80%(1).

The oral LD50 of nortriptyline in the rat is 405 mg/kg.Symptoms of overdose with nortriptyline include cardiac arrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, convulsions, coma, and CNS depression. Changes in the electrocardiogram, particularly in QRS segment, may be indicative of tricyclic antidepressant toxicity.|IDENTIFICATION AND USE: Nortriptyline is a tricyclic antidepressant. HUMAN EXPOSURE AND TOXICITY: Symptoms of overdose/poisoning include the following: arrhythmias, bundle branch block, cardiac arrest, hypotension, circulatory collapse, mydriasis, blurred vision, tachycardia, vasodilation, urinary retention, decreased gastrointestinal motility, decreased bronchial secretions, dry mucous membranes and skin, hypothermia, respiratory depression, seizures, abnormal tendon reflexes, disorientation, agitation, myoclonic jerks, coma and pyramidal signs. A woman with chronic obstructive pulmonary disease receiving nortriptyline experienced depression of CO2 sensitivity and ventilatory load compensation with a concomitant increase in exercise tolerance with decreased dyspnea. In other words, nortriptyline demonstrated a depressant effect on ventilatory control. Nortriptyline increases the risk for sudden cardiac arrest in the general population, particularly in the presence of genetic and/or non-genetic factors that decrease cardiac excitability by blocking the cardiac sodium channel. Antidepressant have been shown to increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. ANIMAL STUDIES: Dogs receiving nortriptyline hydrochloride orally for twelve months tolerated as much as 20 mg/kg/day. However, a large oral dose (40 mg per kg daily) caused signs of depression and ataxia and, with continued treatment, death at the end of the first month. In chronic toxicity studies, rats tolerated a concentration of nortriptyline hydrochloride in the diet equivalent to 150 mg/kg/day for one year. Rats showed some growth retardation but no visceral damage. Nortriptyline was tested for genotoxicity using the somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster. The drug was not genotoxic at concentrations up to 100 mM.

Liver test abnormalities have been reported to occur in up to 16% of patients being treated with tricyclic antidepressants, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported due to nortriptyline. The onset of jaundice is usually within 2 to 3 months of starting nortriptyline and the predominant enzyme pattern has been hepatocellular. Several acute instances of nortriptyline hepatotoxicity with marked elevations in serum aminotransferase levels and acute liver failure have been described. Signs and symptoms of hypersensitivity and autoimmunity are usually not present.

This case illustrates a pharmacokinetic interaction between the tricyclic antidepressant, nortriptyline, and the antituberculosis drug, rifampin. Higher than expected doses of nortriptyline were required to obtain a therapeutic drug level while the patient was receiving rifampin. Following the discontinuation of rifampin, the patient became drowsy and the serum nortriptyline levels rose precipitously into the toxic range.|A case of significant hypoglycemia has been reported in a type II diabetic patient maintained on chlorpropamide (250 mg/day), after the addition of nortriptyline (125 mg/day).|Using data from a therapeutic drug monitoring database, kinetic interactions between the neuroleptics zuclopenthixol and perphenazine and tricyclic antidepressives were studied. Out of 290 patients monitored for amitriptyline and 611 patients monitored for nortriptyline, 77 patients were comedicated with perphenazine and 50 patients with zuclopenthixol. Comedication with perphenazine incr the median steady-state serum concn to daily dose ratio (C/D) of nortriptyline by 30-45%, whereas the median C/D of amitriptyline was unaffected. On the contrary, median C/D values of nortriptyline and amitriptyline were not significantly influenced by comedication with zuclopenthixol.|Two cases are described in which a 33-yr-old woman and a 36-yr-old man developed adverse effects resulting from an interaction between valproic acid (valproate) and nortriptyline. The first patient was taking 25 mg/day nortriptyline and within 1 wk of the addition of valproic acid in doses up to 1000 mg/day, she developed marked tremulousness of her hands and fingers. The plasma level of nortriptyline was 393 ng/mL and that of valproic acid was 105 mg/L. Both drugs were stopped and tremulousness subsided over the next 2 days. The second patient was receiving 75 mg/day nortriptyline and up to 1250 mg/day valproic acid. A plasma level of nortriptyline was 345 ng/mL. The nortriptyline dosage was titrated down to 25 mg/day and a subsequent drug level was 82 ng/mL. Thioridazine and loxapine were given concomitantly.|For more Interactions (Complete) data for NORTRIPTYLINE (31 total), please visit the HSDB record page.

LD50 Mouse iv 17 mg/kg|LD50 Mouse ip 70 mg/kg|LD50 Mouse oral 387 mg/kg|LD50 Rat iv 22 mg/kg

The use of nortriptyline hydrochloride in schizophrenic patients may result in an exacerbation of the psychosis or may activate latent schizophrenic symptoms. If the drug is given to overactive or agitated patients, increased anxiety and agitation may occur. In manic-depressive patients, nortriptyline hydrochloride may cause symptoms of the manic phase to emerge.|Patients with preexisting cardiovascular disease may be especially sensitive to the cardiotoxicity of tricyclic antidepressants. In addition, those with disturbed eating behaviors (e.g., purging) that result in adequate hydration and/or compromised cardiac status also may be at greater risk of severe adverse cardiovascular effects (e.g., hypotension, increased cardiac conduction time, arrhythmia). /Tricyclic antidepressants/|Nortriptyline hydrochloride is not approved for use in pediatric patients.|Levothyroxine and liothyronine have been reported to accelerate the onset of therapeutic effects of tricyclic antidepressants; however, concomitant use may also produce cardiovascular toxicity, including arrhythmias. Tricyclic antidepressants should be administered with extreme caution to patients who have thyroid disease or who are receiving thyroid agents. /Tricyclic antidepressants/|For more Populations at Special Risk (Complete) data for NORTRIPTYLINE (7 total), please visit the HSDB record page.

The plasma protein binding of nortriptyline is approximately 93%.

Nortriptyline's production and administration as a human antidepressant and for treatment of canine behavior disorders(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), a measured Koc value of 3236(2) indicates that nortriptyline is expected to have slight mobility in soil(SRC). The estimated pKa of nortriptyline is 10.47(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Nortriptyline is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.2X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). A half-life of 40.5 days using a loam soil incubated for 78 days(6) suggests that biodegradation may be an important environmental fate process in soil(SRC).|AQUATIC FATE: Based on a classification scheme(1), a measured Koc value of 3236(2) indicates that nortriptyline is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 10.47(3) indicates nortriptyline will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water and moist soil surfaces are not expected to be an important fate processes(SRC). According to a classification scheme(4), an estimated BCF of 440(SRC), from its log Kow of 4.51(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is high(SRC). A half-life of 40.5 days using a loam soil incubated for 78 days(7) suggests that biodegradation may be an important environmental fate process in water(SRC).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), nortriptyline, which has an estimated vapor pressure of 2.2X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase nortriptyline is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 0.74 hours(SRC), calculated from its rate constant of 1.7X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase nortriptyline may be removed from the air by wet and dry deposition(SRC). The hydrochloride salt of nortriptyline absorbs light at wavelengths 240 nm(4); therefore, nortriptyline is not expected to be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm(SRC).

The rate constant for the vapor-phase reaction of nortriptyline with photochemically-produced hydroxyl radicals has been estimated as 1.7X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 0.74 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of nortriptyline with ozone has been estimated as 1.6X10-15 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(1). This corresponds to an atmospheric half-life of about 11 minutes at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). Nortriptyline is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). The hydrochloride salt of nortriptyline absorbs light at wavelengths 240 nm(4); therefore, nortriptyline is not expected to be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm(SRC).

An estimated BCF of 440 was calculated in fish for nortriptyline(SRC), using a log Kow of 4.51(1) and a regression-derived equation(2). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC).

A log Koc of 3.51 (Kd = 117 L/kg), corresponding to a Koc of 3236, was measured using an agricultural soil (pH 6.3) from Corrstown, Co Dublin, Ireland(1). According to a classification scheme(2), this Koc value suggests that nortriptyline is expected to have slight mobility in soil. The estimated pKa of nortriptyline is 10.47(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). A Kd values of 600 L/kg hahes been reported using a digester sludge from wastewater treatment plant, Dublin Ireland (pH 6.3)(1).

An estimated pKa of 10.47(1) indicates nortriptyline will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water or moist soil surfaces are not expected to be an important fate processes. Nortriptyline is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.2X10-6 mm Hg(SRC), determined from a fragment constant method(3).

SURFACE WATER: Nortriptyline was detected at a range of 0.8-6.8 ng/L with a maximum of 19 ng/L in unspecified surface water samples(1).

Nortriptyline is distributed into milk. Nortriptyline concentrations in milk appear to be similar to or slightly greater than those present in maternal serum.

NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,440 workers (1,459 of these are female) were potentially exposed to nortriptyline in the US(1). Occupational exposure to nortriptyline may occur through inhalation and dermal contact with this compound at workplaces where nortriptyline is produced or used. The general public is not likely to be exposed to nortriptyline unless by direct medical treatment. (SRC)

Nortriptyline is indicated for the relief of the symptoms of major depressive disorder (MDD). Some off-label uses for this drug include treatment of chronic pain, myofascial pain, neuralgia, and irritable bowel syndrome.|FDA Label

Nortriptyline is a tricyclic antidepressant that is also used in smoking cessation. Nortriptyline can cause mild and transient serum enzyme elevations and is rare cause of clinically apparent acute and chronic cholestatic liver injury.

Antidepressant Agents

Nortriptyline is a known transformation product of Amitriptyline.

Adrenergic Uptake Inhibitors; Antidepressive Agents, Tricyclic|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Nortriptyline is included in the database.|Nortriptyline hydrochloride is indicated for the relief of symptoms of depression. Endogenous depressions are more likely to be alleviated than are other depressive states. /Included in US product label/|Tricyclic antidepressants have been used for the treatment of attention deficit hyperactivity disorder (ADHD). /Tricyclic antidepressant; NOT included in US product label/|For more Therapeutic Uses (Complete) data for NORTRIPTYLINE (13 total), please visit the HSDB record page.

/BOXED WARNING/ Suicidality and Antidepressant Drugs. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of nortriptyline hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Nortriptyline hydrochloride is not approved for use in pediatric patients.|The pupillary dilation that occurs following use of many antidepressant drugs including nortriptyline hydrochloride may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.|... They should be used with caution in patients with urinary retention, glaucoma, diabetes, impaired liver function, asthma, and a history of convulsive seizures. / Tricyclic antidepressants/|... Many patients who take tricyclics and/or antipsychotic medications have a high risk for suicide. The margin of safety for antipsychotics is relatively high. For tricyclics, the margin is much less favorable. A rule of thumb is that the quantity of tricyclic antidepressants dispensed should be limited to a one week supply. /Tricyclic Antidepressants/|For more Drug Warnings (Complete) data for NORTRIPTYLINE (32 total), please visit the HSDB record page.

Nortriptyline exerts antidepressant effects likely by inhibiting the reuptake of serotonin and norepinephrine at neuronal cell membranes. It also exerts antimuscarinic effects through its actions on the acetylcholine receptor.

Substances that contain a fused three-ring moiety and are used in the treatment of depression. These drugs block the uptake of norepinephrine and serotonin into axon terminals and may block some subtypes of serotonin, adrenergic, and histamine receptors. However the mechanism of their antidepressant effects is not clear because the therapeutic effects usually take weeks to develop and may reflect compensatory changes in the central nervous system. (See all compounds classified as Antidepressive Agents, Tricyclic.)|Drugs that block the transport of adrenergic transmitters into axon terminals or into storage vesicles within terminals. The tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC) and amphetamines are among the therapeutically important drugs that may act via inhibition of adrenergic transport. Many of these drugs also block transport of serotonin. (See all compounds classified as Adrenergic Uptake Inhibitors.)

Nortriptyline is readily absorbed in the gastrointestinal tract with extensive variation in plasma levels, depending on the patient. This drug undergoes first-pass metabolism and its plasma concentrations are attained within 7 to 8.5 hours after oral administration. The bioavailability of nortriptyline varies considerably and ranges from 45 to 85%.|Nortriptyline and its metabolites are mainly excreted in the urine, where only small amounts (2%) of the total drug is recovered as unchanged parent compound. Approximately one-third of a single orally administered dose is excreted in urine within 24 hours. Small amounts are excreted in feces via biliary elimination.|The apparent volume of distribution (Vd)β, estimated after intravenous administration is 1633 ± 268 L within the range of 1460 to 2030 (21 ± 4 L/kg). Nortriptyline crosses the placenta and is found in the breast milk. It distributes to the heart, lungs, brain, and the liver.|The average plasma clearance of nortriptyline in a study of healthy volunteers was 54 L/h. The average systemic clearance of nortriptyline is 30.6 ± 6.9 L / h, within the range of 18.6 to 39.6 L/hour.|/MILK/ Nortriptyline is distributed into milk. Nortriptyline concentrations in milk appear to be similar to or slightly greater than those present in maternal serum.|Peak plasma concentrations occur within 7-8.5 hours after oral administration. Optimal response to the drug appears to be associated with plasma concentrations of 50-150 ng/mL.|The clinical pharmacokinetics of amitriptyline were studied in four volunteers after the oral administration of 75 mg. Peak amitriptyline plasma concentrations ranged from 10.8 to 43.7 ng/mL. The disappearance was biphasic and followed first-order kinetics. The mean elimination half-life was 36.1 hours. The mean estimated first-pass metabolism of amitriptyline was 60 per cent. Significant quantities of the metabolite, nortriptyline, were produced although peak concentrations ranged from only 5.9 to 12.3 ng/mL.|Although tricyclic antidepressants (TCAs) have gained wide acceptance for use in the treatment of depression in pregnant women, their pharmacokinetics during pregnancy have been poorly characterized. The aim of the present study was to investigate the transplacental transfer of amitriptyline (AMI) and its main active metabolite nortriptyline (NOR) in isolated perfused human placenta. Nine term human placentae were obtained immediately after delivery with maternal consent and a 2-h non-recirculating perfusion of a single placental cotyledon was performed. AMI (200 ng/ml) and NOR (150 ng/ml), with antipyrine as a reference compound, were added to the maternal reservoir and their appearance to the fetal circulation was followed for 2 h. AMI and NOR concentrations were measured by high performance liquid chromatography (HPLC) and antipyrine concentrations spectrophotometrically. The mean (SD) transplacental transfers (TPT(SS)%) for AMI and NOR were 8.2 (2.3)% and 6.5 (1.8)%, respectively, calculated as the ratio between the steady-state concentrations in fetal venous and maternal arterial sides. The TPTs of AMI and NOR were 81% and 62% of the freely diffusable antipyrine. The absolute fraction of the dose that crossed the placenta (TPT(A)) was moderately, but significantly higher for AMI (7.7%) than for NOR (5.7%) (P=0.037). In all perfusions, steady state at the fetal side was reached by 30 min for AMI and by 50 min for NOR in the fetal side. The viability of the placentae was retained during the 2-h perfusion, as evidenced by unchanged pH of the perfusate and by stable perfusion pressures in fetal artery and stable antipyrine transfer. Both AMI and NOR cross the human placenta. However, the fetal exposure with NOR may be somewhat smaller compared with AMI, probably due to the higher lipophilicity of AMI.

Nortriptyline is metabolized via demethylation and hydroxylation in the liver followed by glucuronic acid conjugation. CYP2D6 plays a large role in nortriptyline metabolism, with contributions from CYP1A2, CYP2C19 and CY3A4. The main active metabolite is 10-hydroxynortriptyline exists in both cis and a trans form, with the trans form is higher in potency. 10-hydroxynortriptyline is the most frequently found in the plasma. Most of the other metabolites are conjugated, and are less potent.|Biotransformation of amitriptyline to its demethylated product nortriptyline was studied in vitro with human liver microsomes from four different donors, preselected to reflect a range of metabolic rates. Reaction velocity versus substrate concn was consistent with a sigmoid Vmax model. Vmax varied from 0.42 to 3.42 nmol/mg/min, Km from 33 to 89 uM amitriptyline. Ketoconazole was a highly potent inhibitor of N-demethylation, with a mean Ki value of 0.11 + or - 0.013 uM ... whereas quinidine (up to 50 uM), a CYP2D6 inhibitor, and alpha-naphthoflavone (up to 5 uM), a CYP1A2 inhibitor only at low concn, showed no effect. All selective serotonin reuptake inhibitors tested had an inhibitory effect on the formation of nortriptyline, with mean Ki values of 4.37 (+ or - 3.38) uM for sertraline, 5.46 (+ or - 1.95) uM for desmethylsertraline, 9.22 (+ or - 3.69) uM for fluvoxamine, 12.26 (+ or - 5.67) uM for norfluoxetine, 15.76 (+ or - 5.50) uM for paroxetine, and 43.55 (+ or - 18.28) uM for fluoxetine. A polyclonal rabbit antibody against rat liver CYP3A1, in antibody/microsomal protein ratios varying from 1:1 to 10:1, inhibited N-demethylation of amitriptyline to an asymptotic max of 60%.|The metabolic disposition of the antidepressants and antipsychotics has been reported to be significantly influenced by the cytochrome P450 (CYP) 2D6 isozyme. The two most studied antidepressants are amitriptyline and imipramine. Amitriptyline conversion to nortriptyline and nortriptyline metabolism to its 10-hydroxymetabolite were shown to be influenced by the 2D6 isozyme.|The stability of amitriptyline, nortriptyline, desipramine and imipramine in formalin-fixed human liver tissue and formalin soln was investigated. The levels of the tricyclic and its primary demethylated metabolite in the frozen liver were determined and compared with levels obtained in the formalin-fixed liver and formalin soln in which the liver was stored. It was obvious that some methylation of the secondary amine, nortriptyline, to the corresponding tertiary amine, amitriptyline, and of desipramine to imipramine took place in the formalin environment. Nortriptyline was not detected in most cases, suggesting that it may degrade more rapidly than desipramine. There was no consistent ratio between the concn of the drug in the frozen liver tissue versus formalin-preserved tissue or versus formalin soln. The methylation rates of the secondary amines could not be quantitated. Storage of the liver tissue in formalin at room temp resulted in leaching of the drugs into the formalin soln. The drugs tested may be detected for up to 22 mo in the formalin-fixed liver and in the formalin medium.|Nortriptyline has known human metabolites that include E-10-hydroxynortriptyline and demethylnortriptyline.

The average plasma half-life of nortriptyline in healthy volunteers is about 26 hours, but is said to range from 16 to 38 hours. One study mentions a mean half-life of about 39 hours.|The plasma half-life of nortriptyline ranges from 16 to more than 90 hours.|The clinical pharmacokinetics of amitriptyline were studied in four volunteers after the oral administration of 75 mg. ... The mean elimination half-life was 36.1 hours. ...

Though prescribing information does not identify a specific mechanism of action for nortriptyline, is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at the level of the beta-adrenergic receptors. It displays a more selective reuptake inhibition for noradrenaline, which may explain increased symptom improvement after nortriptyline therapy. Tricyclic antidepressants do not inhibit monoamine oxidase nor do they affect dopamine reuptake. As with other tricyclics, nortriptyline displays affinity for other receptors including mACh receptors, histamine receptors, 5-HT receptors, in addition to other receptors.|The mechanism of adverse imipramine-induced reactions ... was investigated by precipitating such reactions in rats with three injections (ip) of imipramine (5-40 mg/kg) at 24, 5, and 1 hr before testing, and comparing their occurrence with comparable treatments using specific noradrenergic and serotonergic reuptake inhibitors (nortriptyline (10 or 30 mg/kg, ip), citalopram (0.5-5.0 mg/kg, ip)). This initial study indicated that these reactions were mediated by imipramine's noradrenergic effects.|The effect of equal-dose regimens of amitriptyline and nortriptyline on the concn of serotonin, dopamine and major acidic metabolites was compared in 5 distinct brain regions as a function of inbred mouse strain. Amitriptyline incr to a greater extent the regional brain serotonin levels in the albino BALB/c mouse than did nortriptyline. Both drugs incr serotonin levels but decr cerebral 5-hydroxyindoleacetic acid levels in some distinct brain regions of the black C57BL/6 mouse strain. The results suggest a strain-dependent differential incr in brain serotonin turnover in specific mouse strain brain regions which may account for the greater incidence of amitriptyline-induced sedation and seizures. The BALB/c mouse was also found to be more sensitive than the C57BL/6 strain to the action of both drugs on dopamine and major acidic metabolites with amitriptyline showing more regional brain potency than nortriptyline. The data suggest an incr in dopamine turnover particularly in brain areas assoc with motor function and posture which may account for tricyclic antidepressant-induced extrapyramidal disorders. The results also indicate that the C57BL/6 mouse strain may be of experimental value for studying the mechanism underlying tricyclic-induced adverse reactions relevant to sedation and movement disorders as a function of genetic predisposition.|Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through beta2-adrenoceptors (beta2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressant's effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor a (TNFa) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on beta2-ARs expressed by non-neuronal satellite cells. This stimulation of beta2-ARs decreases the neuropathy-induced production of membrane-bound TNFa, resulting in relief of neuropathic allodynia. This indirect anti-TNFa action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the beta2-AR agonist terbutaline. Our data revealed an original therapeutic mechanism that may open novel research avenues for the management of painful peripheral neuropathies.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. Caution: Respiratory arrest can occur abruptly and without warning. 2. Treat coma, seizures, hyperthermia, hypotension, and arrhythmias if they occur. Note: Do not use procainamide or other type Ia or Ic antiarrhythmic agents for ventricular tachycardia because these drugs may aggravate cardiotoxicity. 3. Consider cardiac pacing for bradyarrhythmias and high-degree AV block, and overdrive pacing for torsade de pointes. 4. Mechanical support of the circulation (eg, cardiopulmonary bypass) may be useful (based on anecdotal reports) in stabilizing patients with refractory shock, allowing time for the body to eliminate some of the drug. 5. If seizures are not immediately controlled with usual anticonvulsants, paralyze the patient with a neuromuscular blocker to prevent hyperthermia, which may induce further seizures, and lactic acidosis, which cardiotoxicity. Note: Paralysis abolishes the muscular manifestations of seizures but has no effect on brain seizure activity. After paralysis, electroencephalographic (EEG) monitoring is necessary to determine the efficiency of anticonvulsant therapy. 6. Continuously monitor the temperature, other vital signs, and ECG in asymptomatic patients for a minimum of 6 hours, and admit patients to an intensive care setting for at least 24 hours if there are any signs of toxicity. /Antidepressants, tricyclic/|For more Antidote and Emergency Treatment (Complete) data for NORTRIPTYLINE (8 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Characteristics of acute tricyclic antidepressant poisoning: Cardiovascular effects: ventricular rate >120 beats/min, QRS duration >100 msec, arrhythmias, bundle branch block, cardiac arrest, hypotension, and circulatory collapse. /Tricyclic Antidepressants; From table/|/SIGNS AND SYMPTOMS/ Characteristics of acute tricyclic antidepressant poisoning: Anticholinergic effects: mydriasis, blurred vision, tachycardia, vasodilation, urinary retention, decreased gastrointestinal motility, decreased bronchial secretions, and dry mucous membranes and skin. /Tricyclic Antidepressants; From table/|/SIGNS AND SYMPTOMS/ ... In overdose, delayed conduction may lead to a complete heart block or ventricular reentry arrhythmias. Either of these complications, or a combo of both, may lead to death. ... /Tricyclic antidepressants/|/SIGNS AND SYMPTOMS/ The most crucial period for cardiac arrhythmias is the first 12 hr after ingestion. Even after the coma phase is terminated and neurologic signs appear normal, the chance for delayed life threatening cardiovascular toxicity, often unexpected, remains. Cardiovascular complications have been reported to onset as long as 6 days after ingestion, even after significant clinical improvement was noted. /Tricyclic Antidepressants/|For more Human Toxicity Excerpts (Complete) data for NORTRIPTYLINE (13 total), please visit the HSDB record page.

Allegron

Table: Nortriptyline Hydrochloride Preparations [Table#4559]|Acetexa; Allegron; Aventyl; Noritren; Nortrilen; Pamelor; Sensaval; Vividyl. /Nortriptyline hydrochloride/

The product is available as the free base or hydrochloride.

Analyte: nortriptyline hydrochloride; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: nortriptyline hydrochloride; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards|Analyte: nortriptyline hydrochloride; matrix: chemical identification; procedure: visual reaction (white, curdy precipitate) with silver nitrate and nitric acid (Chloride test)|Analyte: nortriptyline hydrochloride; matrix: chemical purity; procedure: reaction with acetic acid and mercuric acetate; potentiometric titration with perchloric acid|For more Analytic Laboratory Methods (Complete) data for NORTRIPTYLINE (10 total), please visit the HSDB record page.

Gas chromatography method using either a conventional, packed column or a capillary column for measurement of therapeutic plasma concentrationn of tricyclic antidepressant drugs and their demethylated metabolites.|High pressure liquid chromatographic procedure /is/ reported for determination of amitriptyline and nortriptyline. Separations and quantitations were carried out at ambient temp using a silica column with a variable wavelength UV detector. Analysis performed on 0.25 mL serum.|A sensitive, selective and rapid reverse-phase HPLC method was developed for the simultaneous analysis of imipramine, desipramine, amitriptyline and nortriptyline in human plasma. the procedure consisted of extracting the drugs and the internal standard (clomipramine) from 1 ml plasma with hexane:isoamyl alcohol (99:1, v:v) in alkaline medium. A newly marketed column, LiChrospher 60 RP-select B (dp 5 um) of Merck was employed. The mobile phase, consisting of acetonitrile:0.25 N sodium acetate buffer at pH 5.5 (50:50, v:v), was delivered at a flow rate of 1.0 ml/min, and detection at 254 nm.|A sensitive capillary GC method with ECD is described for the determination of plasma concn of nortriptyline hydrochloride and its metabolite, 10-hydroxynortriptyline, in humans.|For more Clinical Laboratory Methods (Complete) data for NORTRIPTYLINE (6 total), please visit the HSDB record page.

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