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clomipramine (Anafranil)

Tradename: Anafranil. Indications: 1) obsessive compulsive disorder 2) depression 3) panic attacks 4) cataplexy [6] Contraindications: 1) recent myocardial infarction 2) do not use with 14 days of MAO inhibitor Dosage: Start 25 mg PO QD, max 250 mg/day. May be given as single dose QHS. Tabs: 25, 50, 75 mg. Pharmacokinetics: 1) well absorbed after oral administration 2) extensive 1st pass metabolism - metabolized by cyt P450 1A2, cyt P450 2C19, cyt P450 2D6, cyt P450 3A4 [5] 3) active metabolite desmethyl-clomipramine 4) 8-OH-clomipramine & 8-OH-desmethyl-clomipramine may have biological activity 5) metabolism is highly variable 6) 1/2life 20-30 hours [2] 7) effects usually seen in 4-8 weeks of therapy, but may occur within 2-3 weeks Adverse effects: 1) common (> 10%) - anticholinergic side effects - dizziness, dry mouth, constipation, tachycardia, increased intraocular pressure, urinary retention - headache - increased appetite & weight gain - nausea - weakness - unpleasant taste 2) less common (1-10%) - blurred vision, confusion, delirium, hallucinations, 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 (LFTs) allergic reactions, photosensitivity 4) other [2] - overdose results in prolongation of the QT interval Drug interactions: 1) serotonin syndrome may occur with concurrent administration of other serotonergic agents 2) MAO inhibitors 3) potential additive effects with alcohol, CNS depressants, anticholinergic agents & sympathomimetics 4) clomipramine blocks the uptake of guanethidine & clonidine 5) neuroleptics may inhibit metabolism & lead to higher concentrations of active metabolite desmethyl- clomipramine 6) any drug which inhibits cyt P450 1A2, cyt P450 2D6 or cyt P450 3A4 can increase clomipramine levels 7) any drug which induces cyt P450 1A2, cyt P450 2D6 or cyt P450 3A4 can diminish clomipramine levels Laboratory: 1) specimen: serum, plasma (EDTA), whole blood, urine 2) methods: a) serum/plasma: HPLC, GLC, GC-MS, RIA b) whole blood: HPLC, GLC, GC-MS c) urine: HPLC, RIA 3) interferences: -> desmethyl & 2-OH metabolites may interfere with parent compound in HPLC assays Mechanism of action: 1) inhibits re-uptake of serotonin & norepinephrine 2) antagonizes dopaminergic neurotransmission 3) inhibits cyt P450 2D6 [5]

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 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

General

tricyclic antidepressant (TCA)

Properties

MISC-INFO: elimination route LIVER 1/2life 15-62 HOURS therapeutic-range 100-250 NG/ML protein-binding 90-98% elimination by hemodialysis - hemoperfusion - peritoneal dialysis - pregnancy-category C D 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 - not on National VA formulary
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  5. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  6. Deprecated Reference