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imipramine (Tofranil, Janimine)

Tradenames: Tofranil, Janimine. Indications: - treatment of depression - enuresis in children - analgesic for neuropathic pain - panic & anxiety disorders - attention-deficit hyperactivity disorder (ADHD) [6] Contraindications: 1) MAO inhibitor within 2 weeks 2) fluoxetine within 2 weeks 3) narrow angle glaucoma 4) ineffective, & even harmful, for treating major depression in adolescents [7] Dosage: 1) start 75 mg PO QHS or 25 mg TID 2) increase to max of 400 mg/day 3) childhood enuresis (> 6 yo): - start 25 mg PO 1 hour before bedtime, max 50 mg/day Tabs: 10, 25, 50 mg. Injection: 12.5 mg/mL (2 mL). Pharmacokinetics: 1) well absorbed following oral administration 2) peak effect may take more than 2 weeks 3) metabolized in the liver to desipramine (active) -> metabolized by cyt P450 1A2, 2C19, 2D6, 3A4 4) elimination 1/2life 6-18 hours 5) metabolites eliminated in the urine 6) therapeutic range: 150-300 ng/mL. Adverse effects: 1) common (> 10%) - dizziness, drowsiness, dry mouth, constipation, headache, increased appetite, nausea, weakness, unpleasant taste, weight gain 2) less common (1-10%) - blurred vision, confusion, delirium, hallucinations, difficult urination, eye pain, arrhythmias, fine muscle tremors, hypotension, nervousness, restlessness, parkinsonism, sexual dysfunction, diarrhea, excessive sweating, heartburn, insomnia 3) uncommon (< 1%) - agranulocytosis, leukopenia, eosinophilia, alopecia, anxiety, breast enlargement, galactorrhea, cholestatic jaundice, seizures, SIADH, tinnitus,testicular swelling, gingivitis, decreased lower esophageal sphincter tone, GERD, increased liver function tests, increased intraocular pressure, allergic reactions, photosensitivity, falls 4) other - moderate sedation - moderate anti-cholinergic effects - high incidence of orthostatic hypotension Drug interactions: 1) coadministration enhances metabolism of imipramine a) barbiturates b) carbamazepine c) smoking 2) coadministration decreases protein binding a) phenytoin b) phenylbutazone c) aspirin d) scopolamine e) phenothiazines 3) coadministration inhibits metabolism of imipramine a) fluoxetine b) methylphenidate c) oral contraceptives d) haloperidol e) cimetidine f) chloramphenicol g) phenothiazines 4) reduced hypotensive effects of clonidine & guanethidine 5) increased anticoagulant effect of warfarin 6) increased CNS effects of CNS depressants & sympathomimetic agents 7) additive effects in combination with anticholinergic agents 8) agents which prolong the QT interval a) astemizole b) terfenadine c) cisapride 9) any drug which inhibits cyt P450 1A2, 2C19, 2D6, 3A4 can increase imipramine levels 10) any drug which induces cyt P450 1A2, 2C19, 2D6, 3A4 can diminish imipramine levels Laboratory: 1) imipramine in serum/plasma a) serum, plasma (EDTA) b) collect at steady state trough; > 12 hours after dose c) separate from cells d) stable for 4 months at -20 degrees C 2) methods: HPLC, GLC, GC-MS, RIA, EIA 3) interferences: a) iminodibenzyl & desipramine may contaminate dosage forms & contribute to metabolite concentrations b) mesoridazine interferes with HPLC assay c) specificity must be assessed with each test methods, because coelution with other TCA & metabolites may occur d) imipramine may be displaced from protein-binding sites by plasticizers in collecting devices 4) other labs with Loincs - imipramine in specimen - imipramine in gastric fluid - imipramine in urine Mechanism of action: 1) inhibits serotonin & norepinephrine synaptic re-uptake 2) tricyclic antidepressant

Interactions

drug interactions drug adverse effects (more general classes)

Related

cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2) cytochrome P450 2C19 (cytochrome P450 2C17, cytochrome P450 11A, mephenytoin 4-hydroxylase, cytochrome P450 254C, CYP2C19) cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4) desipramine (Norpramin, Pertofrane)

General

tricyclic antidepressant (TCA)

Properties

MISC-INFO: elimination route LIVER 1/2life 6-24 HOURS therapeutic-range 150-250 NG/ML toxic-range >500 NG/ML protein-binding 76-96% elimination by hemodialysis - peritoneal dialysis - pregnancy-category B safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  5. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 56
  6. Deprecated Reference
  7. Le Noury J et al Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ 2015;351:h4320 PMID: 26376805 - Doshi P No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility. BMJ 2015;351:h4629 PMID: 26377109 http://www.bmj.com/content/351/bmj.h4629 - Henry D, Fitzpatrick T Liberating the data from clinical trials BMJ 2015;351:h4601 PMID: 26377210 http://www.bmj.com/content/351/bmj.h4601