Nortriptyline

Oral
Depression

Oral
Nocturnal enuresis

Pharmacogenomics:

Nortriptyline is metabolised by CYP2D6 via hydroxylation to 10-hydroxy nortriptyline metabolite (less-active). Available studies show that approx 7-10% of Caucasians cannot metabolise CYP2D6 substrates and are classified as poor CYP2D6 metabolisers.

Monitor for nortriptyline serum concentration and genetic testing for CYP2D6 is recommended prior to initiation of treatment.

CYP2D6 ultrarapid metabolisers (carriers of more than 2 copies of functional alleles e.g. *1/*1xN, *1/*2xN)
Increased metabolism reduces the plasma concentration of nortriptyline resulting in ineffectiveness of therapy; may also result to increased risk of cardiotoxic effects due to an increase in the plasma concentration of the cardiotoxic metabolite, Z-10-hydroxynortriptyline. Avoid use and consider an alternative drug not metabolised by CYP2D6 (e.g. citalopram, sertraline). Titration to a higher dose should be considered if TCA is necessary for the patient. Use therapeutic dose monitoring to guide succeeding dose adjustments. Observe clinical response with symptom improvement and minimal side effects.

CYP2D6 normal metabolisers (approx. 72-88% of patients with activity score of 1.0-2.0; carriers of 2 normal function alleles or 2 decreased function alleles or 1 normal and no function allele or 1 normal and decreased function allele or combinations of duplicated alleles e.g. *1/*1, *1/*2, *2/*2, *1/*9, *1/*41, *41/*41, *1/*4, *1/*5)
Initiate therapy with recommended starting dose. No dose adjustment.

CYP2D6 intermediate metabolisers (carriers of 1 decreased and 1 no function allele e.g. *4/*41, *5/*9, *4/*10)
Reduced metabolism of nortriptyline resulting to increased plasma concentration and increased risk of adverse effects. Consider 25% dose reduction of recommended starting dose. Titrate dose according to observed clinical response with improvement of symptom and minimal side effects. Use therapeutic dose monitoring to guide succeeding dose adjustments.

CYP2D6 poor metabolisers (carriers of only no function alleles e.g. *4/*4, *4/*4xN, *3/*4, *5/*5, *5/*6)
Increased plasma concentration and risk of adverse effects because of greatly reduced metabolism of nortriptyline. Avoid use and consider an alternative drug not metabolised by CYP2D6. If TCA is necessary for the patient, consider 50% dose reduction of initial dose. Titrate dose according to observed clinical response with improvement of symptom and minimal side effects. Use therapeutic dose monitoring to guide succeeding dose adjustments.

Depression: Severe: Contraindicated.

May be taken with or without food.

Recent MI, arrythmias, heart block or other cardiac arrhythmias, manic phase of bipolar disorder, known or suspected Brugada syndrome. Concomitant or within 14 days of MAOI therapy (e.g. linezolid, IV methylene blue). Severe hepatic impairment. Children <6 years. Lactation.

Patients with major depressive disorder, history of suicide, bipolar disorder. Patients with CV disease (e.g. stroke, tachycardia, conduction abnormalities), diabetes, history of seizures and narrow-angle glaucoma. Patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, benign prostatic hyperplasia, xerostomia and visual problems. Concurrent electroconvulsive therapy and elective surgery. CYP2D6 ultrarapid, intermediate and poor metabolisers. Avoid abrupt withdrawal. Elderly and children. Renal and mild to moderate hepatic impairment. Pregnancy.

Significant: CNS depression, behavioural changes, bone marrow suppression (e.g. aplastic anaemia, agranulocytosis), pupillary dilation, orthostatic hypotension (at risk patient), syndrome of inappropriate antidiuretic hormone secretion (SIADH) and hyponatremia, bone fractures, anticholinergic effects (e.g. blurred vision, xerostomia, constipation, urinary retention).
Cardiac disorders: Hypotension, hypertension, tachycardia, palpitation, MI, arrythmias, heart block, stroke.
Ear and labyrinth disorders: Tinnitus.
Eye disorders: Disturbance of accommodation, mydriasis.
Gastrointestinal disorders: Paralytic ileus, nausea, vomiting, anorexia, epigastric distress, diarrhoea, peculiar taste, stomatitis, abdominal cramps, parotid gland swelling.
General disorders and administration site conditions: Drug fever, weakness, fatigue.
Hepatobiliary disorders: Jaundice, altered liver function.
Immune system disorders: Cross-sensitivity with other TCAs.
Investigations: Blood sugar levels elevation or depression, weight gain or loss.
Nervous system disorders: Numbness, tingling, paraesthesia of extremities, incoordination, ataxia, tremors, peripheral neuropathy, extrapyramidal symptoms, seizures, alteration in EEG patterns, drowsiness, dizziness, headache.
Psychiatric disorders: Confusional states (especially in elderly), hallucinations, disorientation, delusions, anxiety, restlessness, agitation, insomnia, panic, nightmares, hypomania, exacerbation of psychosis.
Renal and urinary disorders: Delayed micturition, dilation of urinary tract, urinary frequency, nocturia.
Reproductive system and breast disorders: Gynecomastia; breast enlargement and galactorrhea (female); increased or decreased libido, impotence, testicular swelling.
Skin and subcutaneous tissue disorders: Skin rash, petechiae, urticaria, itching, photosensitisation.
Vascular disorders: Flushing, alopecia.
Potentially Fatal: Suicidal ideation and behaviour.

This drug may impair mental or physical abilities, if affected, do not drive or operate machinery.

Monitor plasma concentration. Monitor for signs of serotonin syndrome (e.g. agitation, hallucinations, delirium, coma). Monitor blood pressure, pulse rate and ECG in patient at risk. Monitor blood glucose, weight and BMI. Monitor TCA plasma levels on concomitant use with CYP2D6 inhibitor. Monitor CBC. Assess mental status, suicidal ideation, anxiety, social functioning, mania, panic attacks or other unusual changes in behaviour.

Symptoms: Blurred vision, confusion, restlessness, dizziness, agitation, vomiting, dry mouth, hypo- or hyperthermia, Severe hypotension, cardiac dysrhythmias, shock, CHF, pulmonary oedema, convulsions, and CNS depression, including coma; changes in ECG. Management: Symptomatic and supportive treatment. Secure airway and establish an IV line. Gastric lavage followed by activated charcoal may be given to reduce absorption. Emesis is contraindicated. Initiate cardiac monitoring and observe for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures. Na bicarbonate may be given to treat ventricular arrhythmias while refractory arrhythmias may respond to bretylium, propranolol or lignocaine. In case of seizures, diazepam or phenytoin may be administered.

Increased plasma concentration with cimetidine. Increased risk of hypoglycaemia with chlorpropamide in type II diabetic patient. May decrease the antihypertensive effect of guanethidine, debrisoquine, bethanidine and clonidine. Barbiturates may increase the rate of metabolism of nortriptyline. Risk of arrythmias and hypotension may be increased when given with anaesthetics. CYP2D6 inhibitors (e.g. quinidine) may increase nortriptyline toxicity.
Potentially Fatal: Increased risk of serotonin syndrome with MAOIs (e.g. linezolid, IV methylene blue).

Increased risk of serotonin syndrome with St John's wort. May potentiate the CNS depressant effect of alcohol.

Description:
Mechanism of Action: Nortriptyline, a dibenzocycloheptadiene tricyclic antidepressant, is the primary active metabolite of amitriptyline. It increases synaptic concentration of serotonin and/or norepinephrine in the CNS by blocking the neuronal reuptake of norepinephrine and serotonin. It inhibits the activity of such diverse agents as histamine, 5-hydroxytryptamine, and acetylcholine. Additionally, it increases the pressor effect of norepinephrine but interferes with the transport, release, and storage of catecholamines.
Pharmacokinetics:
Absorption: Rapidly absorbed. Bioavailability: 46-70%. Time to peak plasma concentration: 4-9 hours.
Distribution: Crosses the placenta and detected in cord blood. Enters breast milk. Volume of distribution: 21.1-31.1 L/kg. Plasma protein binding: Extensive.
Metabolism: Metabolised in the liver via extensive first-pass effect to active metabolite, 10-hydroxynortriptyline.
Excretion: Via urine (as metabolites and small amounts as unchanged drug). Half-life elimination: Mean: 26 hours (range: 14-51 hours).

Source: National Center for Biotechnology Information. PubChem Database. Nortriptyline, CID=4543, https://pubchem.ncbi.nlm.nih.gov/compound/Nortriptyline (accessed on Jan. 22, 2020)

Store between 20-25°C. Protect from light.

Antidepressants

N06AA10 - nortriptyline ; Belongs to the class of non-selective monoamine reuptake inhibitors. Used in the management of depression.

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