Evaluation of the Citalopram levels on QTc Interval in Rats using with Radio-telemetry

Yıl 2022, , 646 - 653, 29.09.2022

Nuşin Harmancı , Çiğdem Toprak , Zuhal Kaltuş , Semra Yiğitaslan , Başar Sırmagül

https://doi.org/10.20515/otd.1083900

Öz

Long QT syndrome is an arrhythmogenic disease characterized by prolonged QT interval. Citalopram (CIT) was reported to prolong QT interval dose-dependently. Omeprazole (OMP), inhibits CIT metabolizing enzyme CYP2C19, thereby increases serum concentrations which may increase the risk of QT prolongation. These are commonly co-prescribed and recent studies have raised the safety concerns about. We aimed to investigate the dose dependent effects of citalopram alone and in combination with OMP. Forty male, Sprague Dawley rats were divided into 5 groups (n=8). CIT (10 mg/kg or 30 mg/kg) was given for 2 weeks alone or in combination with OMP (100 mg/kg) starting from the 2nd week. ECG recordings and blood samples were collected. QT interval significantly increased in all groups compared to control. The plasma level of CIT in the CIT30 group was significantly higher than CIT10 group (p<0.01) and was significantly higher in the CIT10+OMP group than that of the CIT10 group (p<0.01). In treatment groups, the increase in plasma citalopram level correlated positively with the increase in QT (r=0.844, r2=0.713). It was determined that CIT caused prolongation of QT interval, the addition of OMP increased QT interval more, and these increases correlated positively with CIT plasma concentration. Therefore, it would be appropriate to routinely measure CIT plasma levels in addition to ECG, particularly in patients with additional risk factors for QT prolongation.

Anahtar Kelimeler

Citalopram, Electrocardiography, LongQTsyndrome, Radiotelemetry, Therapeutic drug monitoring

Destekleyen Kurum

Financial Support Supported by Eskisehir Osmangazi University Commission of Scientific Researches under the Project Number: 2018/51. Eskisehir/TURKEY

Proje Numarası

Project Number: 2018/51.

Teşekkür

We would like to thank to the Prof. Dr. Ertuğrul Çolak for his contributions to statistical analysis support on this study.

Sıçanlarda Sitalopram Düzeylerinin Qtc Aralığı Üzerine Etkilerinin Radyo-Telemetri Yöntemi ile Değerlendirilmesi

Öz

Uzun QT sendromu, senkop ve ani ölüme neden olabilen QT aralığında uzama ile karakterize aritmojenik bir hastalıktır. Seçici serotonin geri alım inhibitörü olan sitalopram (CIT), en çok reçete edilen antidepresanlardan biridir. CIT'nin doza bağlı olarak QT aralığını uzattığı bildirilmektedir. Bir proton pompası inhibitörü olan omeprazol (OMP), CIT metabolize edici enzim CYP2C19'u inhibe eder, böylece CIT'nin serum konsantrasyonunu artırır ve bu da QT uzaması riskini artırabilir. CIT ve OMP genellikle birlikte reçete edilir ve son çalışmalar CIT ile OMP'nin birlikte kullanılmasıyla ilgili güvenlik endişelerini ortaya çıkarmıştır. Bu çalışmanın amacı, sıçanlarda sitalopramın tek başına ve OMP ile kombinasyon halinde QT aralığı üzerine olan etkilerini doza bağlı olarak araştırmaktır. Kırk adet erkek, Sprague Dawley sıçan 5 gruba ayrıldı (n=8). CIT 10 mg/kg ve 30 mg/kg 2 hafta süreyle oral gavaj yoluyla verildi, 2. haftadan itibaren de iki gruba OMP (100 mg/kg) ile kombine olarak verildi. Kontrol grubu sadece serum fizyolojik aldı. Birinci haftanın ve ikinci haftanın sonunda EKG kayıtları yapıldı ve kan örnekleri alındı. QT aralığı tüm gruplarda kontrol grubuna göre anlamlı olarak arttı. CIT30 grubundaki ilaç plazma düzeyi, CIT10 grubundan önemli ölçüde daha yüksekti (p <0.01). CIT10 + OMP grubunda CIT10 grubuna göre anlamlı derecede yüksekti (p <0.01). Tedavi gruplarında, plazma sitalopram düzeyindeki artış, QT aralığındaki artışla pozitif korelasyon gösterdi (r = 0.844, r2 = 0.713). Sitalopramın sıçanlarda QT aralığının uzamasına neden olduğu, metabolizma inhibitörü OMP eklenmesinin ise ilaç plazma düzeyini daha da arttırdığı. dolayısıyla QT aralığını da daha fazla arttırdığı gösterildi. Ek olarak QT aralığındaki artışların CIT plazma düzeylerindeki artışlar ile pozitif korelasyon gösterdiği belirlendi. Bu nedenle, özellikle QT uzaması için ek risk faktörleri olan hastalarda EKG takibinin ve CIT plazma düzeylerinin rutin olarak ölçülmesinin uygun olacağı görüşündeyiz.

Anahtar Kelimeler

Elektrokardiyografi, radyotelemetri, sitalopram, terapötik ilaç düzeyi izlemi, uzun qt sendromu

Proje Numarası

Project Number: 2018/51.

Kaynakça

• 1. Basol N, Erbas O. The effects of diltiazem and metoprolol in QTc prolongation due to amitriptyline intoxication. Hum Exp Toxicol. 2016;35(1):29-34.
• 2. Ravichandran S, Srivastav S, Haridas Kamble P, Shukla R, Sharma P, Sharma R. Effect of Vitamin D status on QTc interval in type 2 diabetes mellitus. J Basic Clin Physiol Pharmacol. 2020;32(3):163-7.
• 3. Nakano Y, Wataru S. Syncope in patients with inherited arrhythmias. J Arrhythm. 2017;33(6):572-8.
• 4. Villamanan E, Armada E, Ruano M. [Drug-induced QT interval prolongation: do we know the risks?]. Med Clin (Barc). 2015;144(6):269-74.
• 5. Anys S, Arnaud M, Minois D, Rajalu A, Guyomarch B, Thollet A, et al. Dose response to nadolol in congenital long QT syndrome. Heart Rhythm. 2021.
• 6. Niemeijer MN, van den Berg ME, Eijgelsheim M, Rijnbeek PR, Stricker BH. Pharmacogenetics of Drug-Induced QT Interval Prolongation: An Update. Drug Saf. 2015;38(10):855-67.
• 7. Andrysiak K, Stepniewski J, Dulak J. Human-induced pluripotent stem cell-derived cardiomyocytes, 3D cardiac structures, and heart-on-a-chip as tools for drug research. Pflugers Arch. 2021.
• 8. Shah RR. The significance of QT interval in drug development. Br J Clin Pharmacol. 2002;54(2):188-202.
• 9. Garcia-Rodriguez D, Remior P, Garcia-Izquierdo E, Toquero J, Castro V, Fernandez Lozano I. Drug-induced QT prolongation in COVID-19 pneumonia: influence on in-hospital survival. Rev Esp Cardiol (Engl Ed). 2021;74(1):111-2.
• 10. Golan DE TA, Armstrong EJ, Armstrong AW. . Pharmacology ofSerotonergic and Central Adrenergic Neurotransmission. . In: Lippincott Williams & Wilkins WK, editor. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 3 ed2012. p. 216.
• 11. Prasitlumkum N, Cheungpasitporn W, Tokavanich N, Ding KR, Kewcharoen J, Thongprayoon C, et al. Antidepressants and Risk of Sudden Cardiac Death: A Network Meta-Analysis and Systematic Review. Med Sci (Basel). 2021;9(2).
• 12. FDA. FDA Drug Safety Communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide) [Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-abnormal-heart-rhythms-associated-high-doses-celexa-citalopram.
• 13. Tampi RR, Balderas M, Carter KV, Tampi DJ, Moca M, Knudsen A, et al. Citalopram, QTc Prolongation, and Torsades de Pointes. Psychosomatics. 2015;56(1):36-43.
• 14. Gjestad C, Westin AA, Skogvoll E, Spigset O. Effect of proton pump inhibitors on the serum concentrations of the selective serotonin reuptake inhibitors citalopram, escitalopram, and sertraline. Ther Drug Monit. 2015;37(1):90-7.
• 15. Marstrand P, Christensen AH, Bartels ED, Theilade J. Citalopram and the KCNE1 D85N variant: a case report on the implications of a genetic modifier. Eur Heart J Case Rep. 2018;2(4):yty106.
• 16. MHRA. Citalopram and escitalopram: QT interval prolongation [Available from: https://www.gov.uk/drug-safety-update/citalopram-and-escitalopram-qt-interval-prolongation.
• 17. Dean L, Kane M. Omeprazole Therapy and CYP2C19 Genotype. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kane MS, Kattman BL, et al., editors. Medical Genetics Summaries. Bethesda (MD)2012.
• 18. Lozano R, Bibian C, Quilez RM, Gil J, Constante Y, Garcia-Arilla E. Clinical relevance of the (S)-citalopram-omeprazole interaction in geriatric patients. Br J Clin Pharmacol. 2014;77(6):1086-7.
• 19. Wu WT, Tsai CT, Chou YC, Ku PM, Chen YC, You SL, et al. Cardiovascular Outcomes Associated With Clinical Use of Citalopram and Omeprazole: A Nationwide Population-Based Cohort Study. J Am Heart Assoc. 2019;8(20):e011607.
• 20. Nyakas C, Prins AJA, Bohus B. Age-related alterations in cardiac response to emotional stress: Relations to behavioral reactivity in the rat. Physiology & behavior. 1990;47(2):273-80.
• 21. Funk KA, Bostwick JR. A comparison of the risk of QT prolongation among SSRIs. Ann Pharmacother. 2013;47(10):1330-41.
• 22. Adeyemi O, Parker N, Pointon A, Rolf M. A pharmacological characterization of electrocardiogram PR and QRS intervals in conscious telemetered rats. J Pharmacol Toxicol Methods. 2020;102:106679.
• 23. Bora S, Erdogan MA, Yigitturk G, Erbas O, Parlak I. The Effects of Lipid Emulsion, Magnesium Sulphate and Metoprolol in Amitriptyline-Induced Cardiovascular Toxicity in Rats. Cardiovasc Toxicol. 2018;18(6):547-56.
• 24. Mori S, Hori A, Turker I, Inaji M, Bello-Pardo E, Miida T, et al. Abnormal Cardiac Repolarization After Seizure Episodes in Structural Brain Diseases: Cardiac Manifestation of Electrical Remodeling in the Brain? J Am Heart Assoc. 2021;10(9):e019778.
• 25. Jebali H, Ghabi H, Mami I, Fatma LB, Smaoui W, Kaab BB, et al. Evaluation of electrocardiographic findings before and after hemodialysis session. Saudi J Kidney Dis Transpl. 2020;31(3):639-46.
• 26. Sener MT, Anci Y, Kalkan K, Kir MZ, Emet M. How valuable is P-wave dispersion in the determination of carboxyhemoglobin levels? Hum Exp Toxicol. 2014;33(5):466-72.
• 27. Antoniou CK, Dilaveris P, Manolakou P, Galanakos S, Magkas N, Gatzoulis K, et al. QT Prolongation and Malignant Arrhythmia: How Serious a Problem? Eur Cardiol. 2017;12(2):112-20.
• 28. McClelland J, Mathys M. Evaluation of QTc prolongation and dosage effect with citalopram. Ment Health Clin. 2016;6(4):165-70.
• 29. FDA. Citalopram (marketed as Celexa) Information. 2015.
• 30. Waring WS, Graham A, Gray J, Wilson AD, Howell C, Bateman DN. Evaluation of a QT nomogram for risk assessment after antidepressant overdose. Br J Clin Pharmacol. 2010;70(6):881-5.
• 31. Engebretsen KM, Harris CR, Wood JE. Cardiotoxicity and late onset seizures with citalopram overdose. J Emerg Med. 2003;25(2):163-6.
• 32. Kanjanauthai S, Kanluen T, Chareonthaitawee P. Citalopram induced torsade de pointes, a rare life threatening side effect. Int J Cardiol. 2008;131(1):e33-4.
• 33. Blaschke D, Parwani AS, Huemer M, Rolf S, Boldt LH, Dietz R, et al. Torsade de pointes during combined treatment with risperidone and citalopram. Pharmacopsychiatry. 2007;40(6):294-5.
• 34. Tarabar AF, Hoffman RS, Nelson L. Citalopram overdose: late presentation of torsades de pointes (TdP) with cardiac arrest. J Med Toxicol. 2008;4(2):101-5.
• 35. de Gregorio C, Morabito G, Cerrito M, Dattilo G, Oreto G. Citalopram-induced long QT syndrome and torsade de pointes: role for concomitant therapy and disease. Int J Cardiol. 2011;148(2):226-8.
• 36. Deshmukh A, Ulveling K, Alla V, Abuissa H, Airey K. Prolonged QTc interval and torsades de pointes induced by citalopram. Tex Heart Inst J. 2012;39(1):68-70.
• 37. Rasmussen SL, Overo KF, Tanghoj P. Cardiac safety of citalopram: prospective trials and retrospective analyses. J Clin Psychopharmacol. 1999;19(5):407-15.
• 38. Weeke P, Jensen A, Folke F, Gislason GH, Olesen JB, Andersson C, et al. Antidepressant use and risk of out-of-hospital cardiac arrest: a nationwide case-time-control study. Clin Pharmacol Ther. 2012;92(1):72-9.
• 39. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89(11):1363-72.
• 40. Sanguinetti MC, Mitcheson JS. Predicting drug-hERG channel interactions that cause acquired long QT syndrome. Trends Pharmacol Sci. 2005;26(3):119-24.
• 41. Perez-Riera AR, Barbosa-Barros R, Daminello Raimundo R, da Costa de Rezende Barbosa MP, Esposito Sorpreso IC, de Abreu LC. The congenital long QT syndrome Type 3: An update. Indian Pacing Electrophysiol J. 2018;18(1):25-35.
• 42. Su S, Sun J, Wang Y, Xu Y. Cardiac hERG K(+) Channel as Safety and Pharmacological Target. Handb Exp Pharmacol. 2021.
• 43. Sicouri S, Antzelevitch C. Sudden cardiac death secondary to antidepressant and antipsychotic drugs. Expert Opin Drug Saf. 2008;7(2):181-94.
• 44. Vieweg WV, Hasnain M, Howland RH, Hettema JM, Kogut C, Wood MA, et al. Citalopram, QTc interval prolongation, and torsade de pointes. How should we apply the recent FDA ruling? Am J Med. 2012;125(9):859-68.
• 45. Liu P, Han D, Sun X, Tan H, Wang Z, Liu C, et al. Prevalence and risk factors of acquired long QT syndrome in hospitalized patients with chronic kidney disease. J Investig Med. 2019;67(2):289-94.
• 46. Ueda N, Yoshimura R, Umene-Nakano W, Ikenouchi-Sugita A, Hori H, Hayashi K, et al. Grapefruit juice alters plasma sertraline levels after single ingestion of sertraline in healthy volunteers. World J Biol Psychiatry. 2009;10(4 Pt 3):832-5.
• 47. Brosen K, Naranjo CA. Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol. 2001;11(4):275-83.
• 48. Rasmussen BB, Brosen K. Is therapeutic drug monitoring a case for optimizing clinical outcome and avoiding interactions of the selective serotonin reuptake inhibitors? Ther Drug Monit. 2000;22(2):143-54.
• 49. Benazzi F. A "therapeutic window" with citalopram in a case of depression. Pharmacopsychiatry. 1996;29(1):42.