Nortriptyline

Nortriptyline is well absorbed from the gastrointestinal tract with peak plasma concentrations occurring between 2 and 8 hours after administration. Bioavailability is about 30 to 70%, with extensive first-pass hepatic metabolism. Nortriptyline is approximately 90% protein bound, and is a substrate of CYP1A2 and CYP2D6. Its inactive metabolites are excreted in the urine.

The average elimination half-life of nortriptyline in adults is 30 hours with a range of 18 to 56 hours. The mean half-life in children is 18 hours. The therapeutic serum concentration is considered to be in the range of 190 to 570 nmol/L. Routine serum drug concentration monitoring is not warranted but may be useful in assessing adherence, suspected toxicity or lack of effect. Recommended therapeutic trough levels range from 170 to 495 nmol/L. Ideally, the trough level should be taken 12 hours following administration of the last dose.

Elderly patients may be more susceptible to the anticholinergic, cardiovascular and CNS effects of TCAs. Nortriptyline has a lower propensity to cause anticholinergic side effects (e.g., dry mouth, decreased perspiration, visual disturbances, urinary retention), orthostatic hypotension and sedation than many other TCAs. When nortriptyline is prescribed to an older patient, lower initial dosages with more gradual increases are recommended.

Anticholinergics: Concurrent use of TCAs and other drugs with anticholinergic activity may necessitate dosage adjustments to minimize the additive effects. Hyperpyrexia has been reported when TCAs are administered with other anticholinergic agents, particularly during hot weather. Elderly patients may be particularly susceptible to anticholinergic effects, especially delirium, constipation and urinary retention.

Antihypertensives: TCAs may antagonize the antihypertensive effects of clonidine or guanethidine.

Hepatic Enzyme Inducers: Plasma concentrations of nortriptyline may be decreased when it is used concurrently with inducers of CYP1A2 and/or CYP2D6 such as barbiturates, carbamazepine, phenytoin or rifampin.

Hepatic Enzyme Inhibitors: Plasma concentrations of nortriptyline may be increased when it is used concurrently with inhibitors of CYP1A2 or CYP2D6 such as amiodarone, celecoxib, chloroquine, cimetidine, ciprofloxacin, clarithromycin, erythromycin, ethinyl estradiol, isoniazid, ketoconazole, methadone, mexiletine, propranolol and quinidine. See also SSRIs.

CNS Depressants: The concomitant use of TCAs and other CNS depressants may result in additive depressant effects.

Lithium: There is some evidence that concurrent use of lithium and TCAs may increase the risk of neurotoxicity, particularly in the elderly. It has been suggested that reducing the dose of lithium in elderly patients may reduce the risk of neurotoxicity without compromising its clinical effect. Elderly patients should be monitored carefully for signs of neurotoxicity (e.g., tremor, ataxia, seizures) when on combined therapy.

MAO Inhibitors: Because of the additive serotonergic effects, combination therapy with TCAs and MAO inbibitors is not recommended, except under certain conditions (see Contraindications).

Sympathomimetics: TCAs can significantly enhance the pressor response to norepinephrine and may potentiate the cardiovascular effects (e.g., arrhythmia) of sympathomimetics in general.

Selective Serotonin Reuptake Inhibitors (SSRIs): Nortriptyline toxicity may occur if used concurrently with fluoxetine, because of inhibition of CYP2D6. Reduction of nortriptyline dose by as much as 75% may be necessary. The potential for this interaction occurring with other SSRIs must be considered. Because of the extremely long elimination half-life of fluoxetine, the potential for interacting with other drugs remains for several weeks after its discontinuation.

Serotonin syndrome has also been reported rarely following combination of TCAs and SSRIs. The reader is referred to the SSRI general monograph for more information on the serotonin syndrome.

Thyroid Hormones: Concomitant use of nortriptyline and levothyroxine may potentiate the cardiovascular effects (e.g., arrhythmias) of both drugs.

Drug-Herb Interactions: It has been recommended that, although the clinical significance of any interaction is not known, concurrent administration of the following herbs with nortriptyline be avoided: essiac, kava, marshmallow, St. John's wort, Indian snake root, rhubarb root and valerian.

Nortriptyline is excreted into breast milk in small quantities. It should be used with caution in breast-feeding mothers.

Allergic reactions have included rash, edema, drug fever and photosensitivity. The possibility of cross-sensitivity among the tricyclic agents must be considered.

Rarely, blood dyscrasias have occurred in patients taking TCAs. A leukocyte and differential count should be performed in patients who develop symptoms such as sore throat and fever while taking these drugs.

Nortriptyline has not been associated with an increased risk of fetal malformations or other long-term effects on exposed fetuses. Antidepressant therapy is often continued during pregnancy because of the known risks of untreated depression. The decision to use nortriptyline during pregnancy must be based on an assessment of the potential risks/benefits for each patient.

Sedation is the most common CNS effect of TCAs. Other reactions have occurred such as agitation, confusion (i.e., delirium, hallucinations), nightmares, restlessness, hostility, exacerbation of psychosis and extrapyramidal symptoms. Elderly patients may be more susceptible to these effects.

TCAs can lower the seizure threshold and should be used with caution in patients with a history of seizures or those who may be predisposed to seizures.

TCAs should be used with caution in patients who are hyperthyroid or receiving thyroid medication, because of the possibility of cardiac arrhythmias.

The use of antidepressants during the depressed phase of bipolar disorder may precipitate a hypomanic or manic state.

Temporary discontinuation of nortriptyline may be considered prior to elective surgery. Patients receiving nortriptyline in the perioperative period may be predisposed to intraoperative arrhythmias. Risks of temporary discontinuation must be weighed against those of continued therapy throughout the perioperative period. If therapy is to be interrupted, nortriptyline should be stopped approximately 10 days prior to surgery. If the patient is at risk of experiencing withdrawal symptoms, consideration should be given to tapering the dose (see Adverse Effects).

Nortriptyline therapy should be gradually rather than abruptly discontinued, especially after prolonged use of higher doses, to avoid withdrawal symptoms such as sleep disturbances, gastrointestinal discomfort, flu-like symptoms, anxiety, depression, hypomania, mania, panic and depersonalization, delirium, dizziness, tremor, muscle twitching and, rarely, dyskinesia. These usually occur within 1 to 3 days of discontinuation, are mild and self-limiting and resolve within 2 weeks. Very rarely, cardiac disturbances may also occur.

TCAs can have significant effects on the cardiovascular system (see Adverse Effects). Patients with a history of cardiovascular disease who require treatment with nortriptyline should be started on a low dose which may be cautiously increased over time. These patients also require close monitoring, including periodic ECG tracings. In addition, all patients receiving higher than usual dosage should have periodic ECG tracings, whether or not cardiac abnormalities were present prior to treatment. Lying and standing blood pressure should be checked.

The potential for attempted suicide must always be considered in depressed patients. It is considered prudent to provide a limited supply of nortriptyline to patients considered to be at high risk for attempted suicide.

Patients should be warned about the possible sedation and mental or motor impairment associated with nortriptyline therapy and advised of the potential danger of operating machinery or driving a motor vehicle if this occurs.

Orthostatic hypotension, arrhythmias and conduction abnormalities have occurred during therapy with TCAs. An increased incidence of sudden death has been reported in cardiac patients receiving therapeutic doses of tricyclic antidepressants. Caution is advised if TCAs are used in patients with pre-existing cardiovascular disease.

Urinary retention.

Occasionally: nausea, vomiting, anorexia. Rarely: elevated transaminases. In isolated cases: diarrhea, bitter taste, stomatitis, epigastric distress, abdominal cramps, black tongue, dysphagia, increased salivation, hepatitis with or without jaundice.

Frequently: weight gain. Occasionally: increased or decreased libido, impotence. In isolated cases: gynecomastia in the male, breast enlargement and galactorrhea in the female, testicular swelling, elevation or depression of blood sugar levels, weight loss, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Frequently: drowsiness, fatigue, tremors (although nortriptyline causes less sedation than many other TCAs). Occasionally: insomnia, dizziness, headache, paresthesia (numbness, tingling sensation, symptoms suggestive of peripheral neuropathy). Rarely: seizures. In isolated cases: tinnitus, incoordination, ataxia, alterations in EEG patterns, extrapyramidal symptoms, myoclonus, speech disorders.

In isolated cases: agranulocytosis, eosinophilia, leukopenia, purpura and thrombocytopenia may occur as an idiosyncratic response.

Occasionally: skin rash, urticaria. In isolated cases: petechiae, itching, photosensitization (avoid excessive exposure to sunlight), edema (general or of face and tongue), drug fever, obstructive jaundice, nasal congestion, alopecia, allergic alveolitis (pneumonia) with or without eosinophilia.

Frequently: hypotension, particularly orthostatic hypotension (although nortriptyline causes less orthostasis than many other TCAs) with associated dizziness/lightheadedness, tachycardia, ECG changes including flattening or inversion of T waves. Occasionally: arrhythmia, disturbances in cardiac conduction, palpitation, syncope. In isolated cases: hypertension, congestive heart failure, myocardial infarction, heart block, asystole, stroke, peripheral vasospastic reactions.

Nortriptyline and other TCAs are extremely toxic in overdose. Consultation with a Poison Control Centre is recommended. See the CPS Directory section for contact numbers.

Cardiac arrhythmias and CNS involvement pose the greatest threat and may occur suddenly even when initial symptoms appear to be mild. The toxic dose is variable but, in general, acute ingestion of 10 to 20 mg/kg may result in serious toxicity and may be lethal. TCA overdose has one of the highest mortality rates of any type of ingestion. Toxicity most commonly begins within two hours of ingestion. The onset of symptoms is frequently precipitous, with patients progressing from a wakeful, interactive state to having severe CNS and cardiac involvement within a matter of minutes.

Peripheral anticholinergic symptoms may include urinary retention, dry mucous membranes, mydriasis, constipation, and occasionally adynamic ileus. Patients may also be hyperpyrexic. CNS signs and symptoms can be highly variable and may range from somnolence to agitation, irritability, confusion, delirium, and hallucinations. In severe cases, patients may display extreme drowsiness, areflexia, respiratory depression, and coma. Patients may occasionally become hypothermic. Seizures are common and may precipitate cardiac toxicity.

Cardiac irregularities are frequent. Sinus tachycardia is common. Its presence is not a reliable predictor of serious toxicity, and its absence does not ensure a benign clinical course. An effect on cardiac conduction similar to that of quinidine may be seen with slowing of conduction, widening of the QRS complex, rightward shift in the axis of the terminal 40 milliseconds of the QRS complex, prolongation of the PR and QT intervals, right bundle branch and AV block, ventricular tachyarrhythmias (including torsades de pointes and fibrillation), and death. Prolongation of the QRS duration to more than 0.1 seconds is generally associated with more severe toxicity. Bradycardia may be seen in severely poisoned patients. Hypotension is common and may be severe, resulting from vasodilation, central and peripheral alpha-adrenergic blockade, and myocardial depression. Metabolic and/or respiratory acidosis may occur secondary to seizures, poor tissue perfusion, respiratory depression or poor gas exchange. In an otherwise healthy young person, prolonged resuscitation may be required.

All cases of accidental pediatric exposure or adult overdose should be monitored at a health care facility. Asymptomatic cases without ECG abnormalities should be monitored for a minimum of 6 hours. Plasma concentrations of nortriptyline are of little use and should not guide management of the patient. In managing overdose, consider the possibility of multiple drug overdose, interactions among drugs and altered pharmacokinetics, including delayed absorption. Protect the patient's airway and support ventilation and perfusion. Closely monitor and maintain the patient's vital signs, ECG, blood gases, serum electrolytes, and acid-base balance. Minimize external stimulation to reduce the risk of seizures.

Consultation with a regional poison centre is advisable in all patients with TCA overdose. Activated charcoal (1 gram per kilogram) may reduce absorption of drug from the gastrointestinal tract, and should be considered in patients who present within 2 hours of ingestion. This can be given through a nasogastric tube if necessary. Although it should not be routinely performed, gastric lavage may be considered in the unusual case where a patient presents within 30 to 60 minutes of a massive TCA overdose, but only on the advice of a Poison Control Centre. If performed, gastric lavage should be followed by administration of activated charcoal. If the patient has a decreased level of consciousness, consideration should be given to placement of an endotracheal tube with cuff inflated before beginning the lavage procedure, to lessen the likelihood of aspiration of gastric contents.

Hypotension should be promptly corrected. If hypotension does not respond to a rapid isotonic fluid bolus and the patient has a widened QRS interval ( > 0.1 seconds), sodium bicarbonate boluses should be administered at a dose of 1 to 2 mmol/kg (an average adult would typically receive 1 to 3 ampoules of 50 mmol/50 mL). If hypotension still hasn't responded, vasopressors should be employed, with a direct-acting agonist such as norepinephrine being the drug of choice.

Widened QRS intervals (> 0.14 seconds) and ventricular arrhythmias should be treated with iv sodium bicarbonate. An iv bolus of 1 to 2 mmol/kg (one or two 50 mmol ampoules) should be administered and repeated if necessary to achieve a serum pH of 7.45 to 7.55. Maintain the pH between 7.45 and 7.55. Do not exceed pH 7.6. Monitor for hypokalemia and fluid overload. Hyperventilation may also be used to maintain alkalemia.

Ventricular arrhythmias refractory to sodium bicarbonate may respond to lidocaine. Quinidine, procainamide and other type IA or IC antiarrhythmics should not be used because they may exacerbate arrhythmias and conduction slowing due to the overdosage. Overdrive pacing should be considered in patients whose arrhythmias are not responsive to drug therapy.

In patients with severe/refractory toxicity, consideration should be given to the use of intravenous lipid emulsion. Consult a toxicologist.

Seizures should be aggressively treated with iv benzodiazepines such as lorazepam or diazepam. If this is unsuccessful, barbiturates and other measures should be employed as for status epilepticus. However, phenytoin is no longer recommended for the treatment of TCA-induced seizures.

Diuresis, hemoperfusion and dialysis are not helpful in TCA overdose.

Flumazenil is contraindicated in any patient with an altered level of consciousness who has or may have taken a TCA or any drug that can cause seizures or arrhythmias, as it may precipitate seizures or even cardiac arrest. This is true even in cases of mixed overdose where the patient is known to have coingested benzodiazepines.