ノルトリプチリン

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.

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.

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).

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.

Like many other TCAs, the toxicity of nortriptyline can be very harmful to the body. During an overdose, there is a blockade of the following receptors: sodium channels (fast) in the heart, muscarinic Ach receptors (central and peripheral), alpha-1 receptors in the periphery, and H1 and GABA-A in the central nervous system. Therefore, the most crucial initial step when assessing a patient with toxicity is ensuring the patient can adequately breathe. Intubation is usually mandatory for airway protection and proper ventilation. In addition, the clinician can administer IV fluids for hypotension.

It is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at beta-adrenergic receptors. Tricyclic antidepressants do not inhibit monoamine oxidase nor do they affect dopamine reuptake.

Symptoms of overdose include cardiac dysrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity.

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).

/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.

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/

MEDICATION

Adrenergic Uptake Inhibitors; Antidepressive Agents, Tricyclic

Use (kg; approx.) in Germany (2009): >100

For the treatment of depression, chronic pain, irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation and insomnia, and migraine prophylaxis.

Table: Nortriptyline Hydrochloride Preparations [Table#4557]

Acetexa; Allegron; Aventyl; Noritren; Nortrilen; Pamelor; Sensaval; Vividyl. /Nortriptyline hydrochloride/

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