What are the common and serious adverse effects of nortriptyline?

Nortriptyline Side Effects

Nortriptyline commonly causes anticholinergic side effects (dry mouth, constipation, blurred vision, urinary retention) and cardiovascular effects (orthostatic hypotension, QTc prolongation, arrhythmias), with serious cardiac risks increasing significantly at doses above 100 mg/day, particularly in elderly patients and those with preexisting heart disease. 1, 2

Common Anticholinergic Side Effects

The most frequently reported adverse effects are related to anticholinergic activity:

• Dry mouth occurs commonly and may rarely progress to sublingual adenitis or gingivitis 1
• Constipation results from anticholinergic effects on gastrointestinal motility, and can progress to paralytic ileus in severe cases 1, 3
• Blurred vision and accommodation disturbances with mydriasis are typical 1, 2
• Urinary retention and delayed micturition with dilation of the urinary tract 1, 3
• Drowsiness and somnolence are prominent, making bedtime dosing advantageous for patients with insomnia 2, 1

Nortriptyline produces fewer anticholinergic effects than amitriptyline, making it the preferred tricyclic antidepressant for elderly patients 3, 4

Cardiovascular Side Effects (Most Serious)

Cardiac effects represent the most concerning adverse reactions:

• Orthostatic hypotension occurs significantly more often than with placebo (relative risk 2.8; 95% CI 1.4-5.3) 5, 3
• QTc interval prolongation requires baseline ECG monitoring before initiating therapy 2, 6
• Arrhythmias, heart block, tachycardia, and palpitations can occur at therapeutic doses 1, 7
• Myocardial infarction and stroke have been reported, particularly in patients with preexisting cardiac disease 1, 8
• Sudden cardiac death risk increases at doses exceeding 100 mg/day, especially in patients with cardiovascular disease or elderly patients 6, 2

A study of elderly patients receiving tricyclic antidepressants found that 5 of 7 patients who developed cardiac side effects had prior organic heart disease, emphasizing the need for careful cardiac monitoring 8

Neurological and Psychiatric Effects

• Confusion, disorientation, and hallucinations occur especially in elderly patients 1
• Tremors, incoordination, and ataxia are common 1
• Numbness, tingling, and paresthesias of extremities may develop 1
• Seizures and alterations in EEG patterns can occur 1
• Anxiety, restlessness, agitation, and insomnia are reported 1
• Exacerbation of psychosis in susceptible patients 1

Metabolic and Endocrine Effects

• Weight gain is common and may worsen obstructive sleep apnea in susceptible patients 2, 1
• Elevation or depression of blood sugar levels 1
• Gynecomastia in males and breast enlargement with galactorrhea in females 1
• Altered libido and impotence 1

Hematologic Effects (Rare but Serious)

• Bone marrow depression including agranulocytosis 1
• Aplastic anemia 1
• Thrombocytopenia and purpura 1

Gastrointestinal Effects

• Nausea and vomiting are among the most common reasons for discontinuation 3, 1
• Dysgeusia (altered taste perception) is significantly associated with nortriptyline use 5, 1
• Diarrhea, epigastric distress, and abdominal cramps 1

Hepatic Effects

• Jaundice simulating obstructive disease 1
• Altered liver function, hepatitis, and liver necrosis 1

Dermatologic and Allergic Reactions

• Photosensitization requiring avoidance of excessive sunlight exposure 1
• Skin rash, urticaria, and itching 1
• Edema of face and tongue 1
• Drug fever and cross-sensitivity with other tricyclic drugs 1

Critical Monitoring Requirements

Baseline ECG is essential before starting treatment; if PR or QTc interval is prolonged, nortriptyline should not be used 2, 6

Therapeutic drug monitoring with target plasma levels of 50-150 ng/mL helps optimize efficacy while minimizing toxicity 2, 9

Elderly patients require substantially lower starting doses (10 mg at bedtime) due to increased sensitivity to side effects and higher plasma concentrations of active metabolites 2, 6

Withdrawal Effects

Abrupt cessation after prolonged therapy produces nausea, headache, and malaise, though these symptoms are not indicative of addiction 1

Safety Profile Summary

A systematic review of 2,885 individuals exposed to nortriptyline at 75-100 mg doses for 4-12 weeks found no life-threatening events in patients without underlying cardiovascular disease 5. However, the incidence of cardiac side effects in elderly patients receiving usual therapeutic doses for prolonged periods is substantial enough to warrant frequent careful cardiac monitoring 8