CITALOPRAM

7.5 SERUM/PLASMA/BLOOD CONCENTRATIONS

7.5.2 TOXIC CONCENTRATIONS

A. ADULT

1. An overdose of 840 milligrams in an adult resulted in death. At necropsy, citalopram concentration was 6.1 micrograms/gram femoral vein blood (Ostrom et al, 1996).
2. A combined overdose of trimipramine and citalopram in an adult female resulted in postmortem femoral blood levels of 2.33 mg/kg and 4.81 mg/kg, respectively (Musshoff et al, 1999).

7.7 LD50/LC50

A. ANIMAL DATA

§ LD50 - (IP) MOUSE - 179 mg/kg (RTECS, 2000)

B. HUMAN DATA

§ TDLo - (ORAL) HUMAN: 4571 mcg/kg/8 days

§ intermittent sleep, headache and

§ nausea/vomiting reported (RTECS, 2000)

8.0 KINETICS

8.1 ABSORPTION

A. ORAL

1. Bioavailability is estimated to be 100% (Kragh-Sorensen, 1981; Milne & Goa, 1991).
2. Citalopram is well absorbed following oral administration; peak serum levels occur within 2 to 4 hours (Overo, 1978; Kragh-Sorensen et al, 1981; Sweetman, 2000).

8.2 DISTRIBUTION

8.2.1 DISTRIBUTION SITES

A. PROTEIN BINDING

1. It has been estimated that approximately 50% of citalopram is bound to plasma proteins (Milne & Goa, 1991).

8.2.2 DISTRIBUTION KINETICS

A. VOLUME OF DISTRIBUTION

1. Citalopram is widely distributed throughout the body with an apparent volume of distribution of 15 L/kg (Kragh-Sorensen et al, 1981; Milne & Goa, 1991; Sweetman, 2000).

8.3 METABOLISM

8.3.1 METABOLISM SITES AND KINETICS

A. THERAPEUTIC DOSE

1. Citalopram is metabolized in the liver primarily via N-demethylation, deamination, and N-oxidation to less lipophilic compounds which are more readily excreted by the kidney (Milne & Goa, 1991; Sweetman, 2000).

8.3.2 METABOLITES

A. THERAPEUTIC DOSE

1. Several metabolites of citalopram have been identified which are also serotonin reuptake inhibitors: desmethylcitalopram (primary metabolite), didesmethylcitalopram, and citalopram-N-oxide (Milne & Goa, 1991; Baettig et al, 1993; Oyehaug & Ostensen, 1984; Overo, 1982).

a. The metabolites appear to be less potent. They are present in lower concentrations in the plasma and enter the brain less readily (Milne & Goa, 1991).

8.4 EXCRETION

8.4.1 KIDNEY

A. Approximately 12% to 13% of a dose of citalopram is excreted as unchanged drug in the urine (Oyehaug & Ostensen, 1984; Milne & Goa, 1991; Sweetman, 2000).

8.4.3 BILE

A. Citalopram is mainly excreted (85%) via the liver (Sweetman, 2000).

8.5 ELIMINATION HALF-LIFE

8.5.1 PARENT COMPOUND

A. THERAPEUTIC DOSE

1. Elimination half-life of citalopram is approximately 33 hours (Kragh-Sorensen et al, 1981; Sweetman, 2000); the elderly may have a longer half-life (Overo et al, 1985).

12.0 REFERENCES

12.2 GENERAL BIBLIOGRAPHY
1. AHA (American Heart Association): Guidelines for cardiopulmonary resuscitation and emergency cardiac care. JAMA 1992; 268:2171-2302.
2. AMA Department of Drugs: Drug Evaluation Subscription. American Medical Association, Chicago, IL, 1991.
3. American Heart Association & International Liaison Committee on Resuscitation. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation, 2000; suppl 8:1-383.
4. Anon: Danish University Antidepressant Group: Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology 1986; 90:131-138.
5. Barceloux D, McGuigan M, Hartigan-Go K: Position statement: cathartics. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Clin Toxicol 1997; 35:743-752.
6. Benitz WE & Tatro DS: The Pediatric Drug Handbook, 2nd ed. Year Book Medical Publishers, Chicago, IL, 1988.
7. Benitz WE & Tatro DS: The Pediatric Drug Handbook, 3rd ed. Mosby-Year Book Inc, Chicago, IL, 1995.
8. Bouchard JM, Delaunay J, Delisle JP et al: Citalopram versus maprotiline: a controlled, clinical multicentre trial in depressed patients. Acta Psychiatr Scand 1987; 76:583-592.
9. Brown TM, Skop BP & Mareth TR: Pathophysiology and management of the serotonin syndrome. Ann Pharmacother 1996; 30:527-533.
10. Burrows GD, McIntyre IM, Judd FK et al: Clinical effects of serotonin reuptake inhibitors in the treatment of depressive illness. J Clin Psychiatry 1988; 49(suppl):18-22.
11. Chamberlain JM, Altieri MA, Futterman C et al; A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care, 1997; 13:92-94.
12. Christensen P, Thomsen HY, Pedersen OL et al: Orthostatic side effects of clomipramine and citalopram during treatment of depression. Psychopharmacology 1985; 86:383-385.
13. Chyka PA & Seger D: Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Clin Toxicol 1997; 35:721-736.
14. de Wilde J, Mertens C, Overo KF et al: Citalopram versus mianserin: a controlled, double-blind trial in depressed patients. Acta Psychiatr Scand 1985; 72:89-96.
15. Dursun SM, Burke JG, Nielsen F et al: SSRI-related toxic serotonin syndrome: improvement of discontinuation of treatment and propranolol. Eur Psychiatr 1997; 12:321-323.
16. FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. Fed Register 1985; 50:2244-2262.
17. Giang DW & McBride MC: Lorazepam versus diazepam for the treatment of status elipticus. Pediatr Neurol 1988; 4:358-361.
18. Gillman PK: Ecstasy, serotonin syndrome and the treatment of hyperpyrexia (letter). MJA 1997; 167:109-111.
19. Glassman AH: Citalopram toxicity (letter). Citalopram toxicity. Lancet 1997; 350:818.
20. Goldberg RJ & Huk M: Serotonin syndrome from trazodone and buspirone (letter). Psychosomatics 1992; 33:235-236.
21. Graham PM: Successful treatment of the toxic serotonin syndrome with chlorpromazine (letter). Med J Australia 1997; 166:166-167.
22. Gravem LF, Amthor KF, Astrup C et al: A double-blind comparison of citalopram (Lu 10-171) and amitriptyline in depressed patients. Acta Psychiatr Scand 1987; 75:478-486.
23. Grundemar L, Wohlfart B, Lagerstedt C et al: Symptoms and signs of severe citalopram overdose. Lancet 1997; 349:1602.
24. Guze BH & Baxter LR Jr: The serotonin syndrome: case responsive to propranolol (letter). J Clin Psychopharmacol 1986; 6:119-120.
25. Hoes MJAJM: Mirtazapine as treatment for serotonin syndrome. Pharmacopsychiatry 1996; 29:81.
26. Kasper S, Fuger J & Moller HJ: Comparative efficacy of antidepressants. Drugs 1992; 43(Suppl 2):11-23.
27. Keren A, Tzivoni D, Gavish D et al: Etiology, warning signs and therapy of torsade de pointes: a study of 10 patients. Circulation 1981; 64:1167-1174.
28. Kline SS, Mauro LS, Scala-Barnett DM et al: Serotonin syndrome versus neuroleptic malignant syndrome as a cause of death. Clin Pharmac 1989; 8:510-514.
29. Kragh-Sorensen P, Overo KF, Petersen OL et al: The kinetics of citalopram: single and multiple dose studies in man. Acta Pharmacol Toxicol 1981; 48:53-60.
30. Lahat E, Goldman M, Barr J et al: Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomized study. BMJ 2000; 321:83-86.
31. Lazzara R: Amiodarone and torsade de pointes (editorial). Ann Intern Med 1989; 111:549-551.
32. Mattioni TA, Zheutlin TA, Sarmiento JJ et al: Amiodarone in patients with previous drug-mediated torsade de pointes: long-term safety and efficacy. Ann Intern Med 1989; 111:574-580.
33. Mills KC: Serotonin syndrome: a clinical update. Med Toxicol 1997; 13:763-783.
34. Milne RJ & Goa KL: Citalopram: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness. Drugs 1991; 41:450-477.
35. Moyer B, Shrading W & Burkhart KK: Celexa(R) for Celebrex(R)? A case of medication sample error. Int J Med Toxicol 2000; 3:7.
36. Musshoff F, Schmidt P & Madea B: Case report: Fatality caused by a combined trimipramine-citalopram intoxication. Forensic Sci International 1999; 106:125-131.
37. Neuvonen PJ, Pohjola-Sintonen S, Tacke U et al: Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide-clomipramine overdoses (letter). Lancet 1993; 342:1419.
38. Nyth AL & Gottfries CG: The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. A nordic multicentre study. Br J Psychiatry 1990; 157:894-901.
39. Nyth AL, Gottfries CG, Lyby K et al: A controlled multicenter clinical study of citalopram and placebo in elderly depressed patients with and without concomitant dementia. Acta Psychiatr Scand 1992; 86:138-145.
40. Olin B (Ed): Facts and Comparisons. Facts and Comparisons, Inc, St. Louis, MO, 1995.
41. Ostrom M, Anders E, Thorson J et al: Fatal overdose with citalopram (letter). Lancet 1996; 348:340.
42. Overo KF, Toft B, Christophersen L et al: Kinetics of citalopram in elderly patients. Psychopharmacology 1985; 86:253-257.
43. Overo KF: Kinetics of citalopram in man; plasma levels in patients. Neuro-Psychopharmacol & Biol Psychiat 1982; 6:311-318.
44. Oyehaug E & Ostensen ET: High-performance liquid chromatographic determination of citalopram and four of its metabolites in plasma and urine samples from psychiatric patients. J Chromatography 1984; 308:199-298.
45. Pedersen OL, Kragh-Sorensen P, Bjerre M et al: Citalopram, a selective serotonin reuptake inhibitor: clinical antidepressive and long-term effect - a phase II study. Psychopharmacology 1982; 77:199-204.
46. Personne M, Persson H & Sjoberg G: Citalopram toxicity (letter). Lancet 1997; 350:519.
47. Perticone F, Ceravolo R, Cuccurullo O et al: Prolonged magnesium sulfate infusion in the treatment of ventricular tachycardia in acquired long QT syndrome. Clin Drug Inverst 1997; 13:229-236.
48. Power A: Citalopram in overdose may result in serious morbidity and death. BMJ 1998; 316:307-308.
49. Product Information Ativan(R), 1999, Wyeth-Ayerst Co, Philadelphia, PA
50. Product Information: Ativan(R), lorazepam. Wyeth, Philadelphia, PA, 1991.
51. RTECS: Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health, Cincinnati, Ohio (Internet Version). Micromedex, Inc, Englewood, CO, 1998.
52. RTECS: Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health, Cincinnati, Ohio (Internet Version). Micromedex, Inc, Englewood, CO, 2000.
53. Scott R, Besag FMC, Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
54. Smith WM & Gallagher JJ: "Les torsades de pointes": an unusual ventricular arrhythmia. Ann Intern Med 1980; 93:578-584.
55. Sternbach H: The serotonin syndrome. Am J Psychiatr 1992; 149:1410-1411.
56. Sweetman S (Ed), Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic version, Micromedex, Englewood, CO, 2000.
57. USP DI Volume I Drug information for the health care professional. 20th edition, 2000; Micromedex Inc, World Color Book Services, Taunton, MA.
58. Vale JA: Position Statement: gastric lavage. American Academy of Clinical Toxicology/European Association of Poisons Centres and Clinical Toxicologists. Clin Toxicol 1997; 35:711-719.
59. Vukmir RB: Torsades de pointes: a review. Am J Emerg Med 1991; 9:250-255.

13.0 AUTHOR INFORMATION

13.1 CONTRIBUTOR(S) TO THIS DOCUMENT

A. Original publication: 02/98
B. Most recent revision: 01/01
C. List of contributors:

§ 1. Katherine M Hurlbut, MD

§ 2. POISINDEX(R) Editorial Staff

13.4 SPECIALTY BOARD

A. Specialty Board: CNS DRUGS (MG2120)

End of Document