IMIPRAMINE HYDROCHLORIDE
Clinical safety rating: caution
Animal studies have proved adverse effects but may be safe for humans
Tricyclic antidepressant that inhibits the reuptake of norepinephrine and serotonin at presynaptic neuronal membranes, increasing their synaptic concentrations. Also has anticholinergic, antihistaminergic, and alpha-1 adrenergic blocking effects.
| Metabolism | Primarily hepatic via CYP1A2, CYP2D6, CYP3A4; active metabolite desipramine; also glucuronidation. |
| Excretion | Renal (70% as metabolites, <5% unchanged), biliary/fecal (30%) |
| Half-life | Terminal half-life 11-25 hours (mean ~20 h); clinical context: steady-state achieved in ~1 week, dosing adjustment needed in hepatic impairment |
| Protein binding | 90-95% bound to alpha1-acid glycoprotein, albumin, and lipoproteins |
| Volume of Distribution | 10-20 L/kg (mean 15 L/kg); clinical meaning: extensive tissue distribution, large Vd indicates slow elimination |
| Bioavailability | Oral: 20-70% due to extensive first-pass metabolism (mean ~40%); IM: not available; IV: not available |
| Onset of Action | Oral: 2-4 weeks for antidepressant effect; IV: not applicable |
| Duration of Action | Variable; anticholinergic effects persist for hours after single dose; antidepressant effect requires steady-state levels |
| Molecular Weight | 316.87 |
Initial 75 mg/day orally in divided doses, increase to 150-200 mg/day; maximum 300 mg/day. For maintenance, 50-150 mg/day orally.
| Dosage form | TABLET |
| Renal impairment | GFR 30-59 mL/min: reduce dose by 50%. GFR <30 mL/min: use with caution, reduce dose by 75% or consider alternative. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: contraindicated or reduce dose by 75% with close monitoring. |
| Pediatric use | For enuresis: age 6-12 years, 25 mg/day orally; >12 years, 50 mg/day. For depression: not recommended under 12 years; age 12-18, start 25-50 mg/day, max 100 mg/day. |
| Geriatric use | Initial 30-40 mg/day orally, increase slowly; maximum 100 mg/day. Monitor for orthostatic hypotension, sedation, and anticholinergic effects. |
| 1st trimester | Teratogenic risk: Limited human data; animal studies show fetal harm. Use only if benefit outweighs risk. Associated with cardiovascular malformations. |
| 2nd trimester | May cause neonatal withdrawal syndrome (irritability, seizures) if used near term. Use with caution. |
| 3rd trimester | Neonatal withdrawal syndrome reported; avoid during third trimester if possible. Monitor neonate for symptoms. |
Clinical note
MAOIs can cause serotonin syndrome and hyperpyrexia Strong anticholinergic effects may occur with other drugs Increased risk of suicide in children and young adults.
| Placental transfer | Crosses placenta; detectable in fetal circulation. Lipid-soluble, readily crosses. |
| Breastfeeding | Enters breast milk in small amounts; may cause drowsiness or irritability in infant. Use with caution, especially in neonates. Consider risk of accumulation. |
■ FDA Black Box Warning
Suicidality and Antidepressant Drugs: Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies. Monitor closely for worsening or emergence of suicidal thoughts and behaviors.
| Common Effects | enuresis |
| Serious Effects |
Recent myocardial infarctionConcurrent use of MAOIs within 14 daysHypersensitivity to tricyclic antidepressantsAcute phase of recovery from myocardial infarction
| Precautions | Clinical worsening and suicide risk, Activation of mania/hypomania, Increased intraocular pressure in narrow-angle glaucoma, Urinary retention, Cardiovascular effects (QT prolongation, arrhythmias, orthostatic hypotension), Seizure threshold lowering, Serotonin syndrome with concurrent serotonergic drugs, Bone marrow suppression, Discontinuation syndrome with abrupt cessation |
| Food/Dietary |
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| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Limited human data; animal studies show embryotoxicity. Second and third trimesters: Associated with neonatal withdrawal (irritability, tachypnea, poor feeding) and anticholinergic effects (ileus, urinary retention). Avoid in third trimester unless benefits outweigh risks. |
| Fetal Monitoring | Maternal: ECG (QTc prolongation risk), serum drug levels, blood pressure, mood assessment. Fetal/neonatal: Observational monitoring for withdrawal and anticholinergic effects. |
| Fertility Effects | May impair fertility in both sexes via hyperprolactinemia and sexual dysfunction; reversible upon discontinuation. |
| Avoid grapefruit juice (may increase plasma levels). Avoid tyramine-rich foods (aged cheese, cured meats, sauerkraut, soy sauce, fava beans) if also taking MAOI. Limit caffeine intake (may potentiate cardiac effects). St. John's Wort reduces imipramine efficacy; avoid concurrent use. |
| Clinical Pearls | Imipramine is a tricyclic antidepressant (TCA) with active metabolite desipramine. Monitor ECG for QTc prolongation, especially at doses >300 mg/day. Therapeutic drug monitoring of imipramine+desipramine levels (target 150-300 ng/mL) is recommended. Avoid in recent MI, narrow-angle glaucoma, or urinary retention. Discontinue MAOIs at least 14 days before starting. Use with caution in epilepsy and hyperthyroidism. Abrupt discontinuation may cause withdrawal symptoms (cholinergic rebound). For enuresis, dose at bedtime; rule out organic causes first. |
| Patient Advice | Take exactly as prescribed; do not stop suddenly without consulting your doctor. · May cause drowsiness; avoid driving or operating machinery until you know how it affects you. · Avoid alcohol and over-the-counter medications (especially cold remedies) without MD approval. · Report any vision changes, difficulty urinating, rapid heartbeat, or yellowing of skin/eyes. · May take 2-4 weeks for full therapeutic effect; do not increase dose without MD guidance. · Rise slowly from lying or sitting position to prevent dizziness. · Store at room temperature away from moisture and light. · If you miss a dose, skip it if near next dose; do not double. · Weight gain possible; maintain dietary and exercise routine. |