The Role of the Adenosine Receptors and Endogenous Adenosine in the Cardiovascular Toxic Effects Induced by the Citalopram Overdose In Rats.

Amaç: Antidepresan ilaçlar tüm dünyada ve ülkemizde en sık rastlanan zehirlenme etkenlerinden biridir. Ülkemizde yapılan çalışmalarda zehirlenmeye neden olan antidepresanlar içinde selektif serotonin re-uptake inhibitörleri (SSRİ)'nin ikinci sıklıkta yer aldığı bildirilmektedir. Yapılan çalışmalarda yüksek dozda alındığında rutin kardiyak monitörizasyon gerektiren tek SSRI grubu antidepresanın sitalopram olduğu vurgulanmıştır. Sitalopramın yüksek dozuna maruz kalımda serotonin sendromu, nörotoksisite ve kardiyak toksisite (bradikardi, hipotansiyon, QT ve QRS genişlemesi) görülebileceği bildirilmiştir. Adenozinin kardiyovasküler sistem etkilerini A1, A2a ve A2b reseptörleri üzerinden gösterdiği bilinmektedir. Adenozin, A1 reseptörleri üzerinden, negatif kronotrop, negatif dromotrop ve negatif inotrop etki ile kardiyak depresyon oluşturur. Bu çalışma sitalopram zehirlenmesinde oluşan kardiyovasküler toksik etkilerin mekanizmasında selektif adenozin reseptör antagonistlerinin ve endojen adenozinin etkisinin araştırılması amacıyla planlanmıştır. Gereç ve Yöntem: Çalışmamız iki protokolden oluşmaktadır. Protokol 1'de sitalopramın kardiyovasküler toksik etki oluşturan dozu 4 mg/kg/dk olarak bulundu (n=18). Sıçanlar 4 gruba randomize edildi. Stabilizasyon sonrasında tüm gruplara sodyum kromoglikat (A3 reseptör antagonisti, 20 mg/kg, i.v) uygulandı. 1.gruba %5 dekstroz (n=7), 2.gruba DPCPX (8- Cyclopentyl-1,3-Dipropylxanthineæ selektif A1 reseptör antagonisti, 20 ?g/kg/dk, n=7), 3.gruba CSC (8-(3-chlorostyryl) caffeineæ selektif A2a reseptör antagonisti, 24 ?g/kg/dk, n=7), 4.gruba %10 DMSO (n=3) 20 dk. infüzyonla verildi. Takiben her gruba 4 mg/kg/dk sitalopram 60 dk. infüzyonla verildi. Protokol 2'de sıçanlar üç gruba randomize edildi. Grup 1 (kontrol)'e sitalopram verilmeden (4 mg/kg/dk-60 dk, n=8) 1 saat önce %5 dekstroz intraperitoneal (i.p) olarak verildi. Grup 2 (n=8) ve grup 3'e (n=8) ilaç infüzyonuna başlamadan 1 saat önce EHNA (Erythro-9-(2-hydroxy-3-nonyl) adenine, adenozin deaminaz inhibitörü, 10 mg/kg i.p) ve NBTI (S-(4-nitrobenzyl)-6-thioinosine, adenozin transport inhibitörü, 1mg/kg i.p) verildi. Stabilizasyon periyodunu takiben grup 2'ye %5 dekstroz, grup 3'e sitalopram 60 dk. boyunca infüzyonla verildi. Deneye başlamadan önce ve deney sonunda sıçanlardan kan alınarak plazma adenozin düzeyleri HPLC (high pressure liquid chromotography) ile ölçüldü. Her iki protokolde de ortalama arteriyel basınç (OAB), kalp atım hızı (KAH), QRS, QT ve yaşam süreleri kaydedildi. İstatistiksel analizde grup içinde tekrarlayan ölçümlerde ANOVA'yı takiben Tukey-Kramer çoklu karşılaştırma testleri, gruplararasında ANOVA'yı takiben Tukey-Kramer çoklu karşılaştırma testleri, yaşam analizinde Kaplan-Meier kullanıldı. P Bulgular: Çalışmanın birinci kısmındaæ %5 dekstroz grubunda sitalopram infüzyonuæ OAB ve KAH'da 20. dakikadan itibaren anlamlı azalma (OAB için tüm dakikalarda p 0.05). DPCPX grubu %5 dekstroz grubuna göre, QT süresinde sitalopramın oluşturduğu uzamayı 20. dakikadan itibaren anlamlı şekilde engelledi (p 0.05). Gruplarda deney süresince ölüm kaydedilmedi. Çalışmanın ikinci kısmındaæ sitalopram infüzyonu plazma adenozin düzeyini değiştirmedi (p>0.05). EHNA/NBTI verilen gruplarda plazma adenozin düzeylerinde istatistiksel olarak anlamlı artış oluştu (p 0.05). Sonuç: Çalışmanın ilk kısmında yüksek doz sitalopramın oluşturduğu QT uzaması selektif adenozin A1 reseptör antagonisti DPCPX tarafından engellendi. Bu sonuç, sitalopram zehirlenmesinde oluşan QT uzamasının mekanizmasında endojen adenozinin ve/veya adenozin A1 reseptör stimülasyonunun rol oynadığını düşündürmektedir. Çalışmanın ikinci kısmında yüksek doz sitalopram plazma adenozin düzeylerini artırmadı. Yüksek doz sitalopram, EHNA/NBTI'a bağlı artan endojen adenozinin oluşturduğu kardiyovasküler etkileri artırdı. Bu sonuçlar sitalopramın ve adenozinin oluşturduğu kardiyovasküler etkilerde benzer mekanizmaların rol oynadığını düşündürmektedir. Sonuç olarak yüksek doz sitalopram plazma adenozin düzeylerini artırmaksızın, endojen adenozine duyarlılığı artırarak ve/veya direkt adenozin A1 reseptörlerini stimüle ederek kardiyovasküler toksik etki oluşturabilir. Anahtar Kelimeler: Adenozin, adenozin reseptör antagonistleri, sitalopram zehirlenmesi, QT uzaması, QRS uzaması ve hipotansiyon. Objective: The antidepressant drugs are one of the most common causes of poisonings all over the world. In our country, the selective serotonin re-uptake inhibitors (SSRI) are the second most frequent reasons of the antidepressant toxicity. It was reported that citalopram is the only SSRI which requires routine cardiac monitoring in overdose. Serotonine syndrome, neurotoxicity and cardiac toxicities (bradycardia, hypotension, QT and QRS prolongations) can be seen with the citalopram overdose. Adenosine shows its well known cardiovascular effects by A1, A2a and A2b receptors. Activation of A1 receptors depresses the heart by negative inotropic, chronotropic and dromotropic effects. The aim of this study is to clarify the role of adenosine receptors and/or endogenous adenosine in the mechanism of the cardiovascular toxic effects induced by citalopram overdose. Materials & Methods: This study consists of two protocols. In the first protocol, the cardiovascular toxic dose of the citalopram was found as 4 mg/kg/min (n=18). The rats were randomized into four groups. After the stabilization period, sodium cromoglycate (A3 receptor antagonist, 20 mg/kg, i.v) was administered to all groups. 5% dextrose was administered to the first group (n=7), DPCPX (8-Cyclopentyl-1,3-Dipropylxanthineæ selective adenosine A1 receptor antagonist, 20 ?g/kg/dk, n=7) was administered to the second group, CSC (8-(3-chlorostyryl) caffeineæ selective adenosine A2a receptor antagonist, 24 µg/kg/min, n=7) was administered to the third group and 10% DMSO (n=3) was administered to the fourth group for 20 minutes. Following the infusions, we administered 4 mg/kg/min citalopram for 60 minutes. In the second protocol, the rats were randomized into three groups. 5% dextrose was administered intraperitoneally (i.p) 1 hour before the beginning of the citalopram infusion (4 mg/kg/min, for 60 minutes, n=8). EHNA (Erythro-9-(2-hydroxy-3-nonyl) adenine, 10 mg/kg, i.p) and NBTI (S-(4-nitrobenzyl)-6-thioinosine,1mg/kg, i.p) were administered 1 hour before the drug infusions. After the stabilization period, 5% dextrose and citalopram was administered for 60 minutes to the second and the third group, respectively. We collected blood from the rats before and after the experiment to measure the basal plasma adenosine levels by HPLC. Mean arterial pressure (MAP), heart rate (HR), QT and QRS durations and survival times were recorded during the experiments for both protocols. Statistical analysis of data within groups was evaluated by repeated measures ANOVA followed by Tukey's multiple comparison tests. To analyze the differences among the groups, ANOVA and Tukey's multiple comparison tests were performed. Duration of survival was compared using survival analysis based on the Kaplan Meier procedure. For all studies, p values of Results: In the first protocol, the citalopram infusion in the dextrose group, caused a significant decrease in the MAP and HR after the 20th minute (in MAP p 0.05). It was determined that DPCPX infusion significantly prevented the prolongation of the QT duration induced by citalopram after 20th minute when compared to the control group (p 0.05). All rats completed the experiment alive. In the second protocol, plasma adenosine concentrations did not change significantly after citalopram infusion (p>0.05). In the other two groups pretreated with EHNA/NBTI, plasma adenosine concentrations showed a significant increase at the end of the experiment. (p 0.05). Conclusion: In the first protocol, the prolongation of the QT duration induced by citalopram was prevented by DPCPX (selective adenosine A1 receptor antagonist) infusion significantly. According to this result, it can be suggested that the endogenous adenosine and/or adenosine A1 receptor stimulation may be responsible for the QT prolongation induced by citalopram. In the second protocol, the citalopram in overdose did not increase the plasma adenosine concentrations. Citalopram in overdose potentialized the cardiovascular effects induced by the increased endogenous adenosine concentrations after EHNA/NBTI administration. It can be suggested according to these results, adenosine and citalopram use the similar mechanisms in the cardiovascular effects. As a result, citalopram in overdose without any increase in the adenosine plasma concentrations, may cause to cardiovascular toxic effects by increasing the sensitivity to endogenous adenosine and/or direct stimulation of the adenosine A1 receptors, Keywords: Adenosine, adenosine receptor antagonists, citalopram toxicity, QT prolongation, QRS prolongation and hypotension

The Effects of the Adenosine Receptor Antagonists on the Reverse of Cardiovascular Toxic Effects Induced by Citalopram In-Vivo Rat Model of Poisoning

Background: Citalopram is a selective serotonin reuptake inhibitor that requires routine cardiac monitoring to prevent a toxic dose. Prolongation of the QT interval has been observed in acute citalopram poisoning. Our previous experimental study showed that citalopram may be lead to QT prolongation by stimulating adenosine A1 receptors without affecting the release of adenosine. Aims: We examined the effects of adenosine receptor antagonists in reversing the cardiovascular toxic effects induced by citalopram in rats. Study Design: Animal experimentation. Methods: Rats were divided into three groups randomly (n=7 for each group). Sodium cromoglycate (20 mg/kg) was administered to all rats to inhibit adenosine A3 receptor mast cell activation. Citalopram toxicity was achieved by citalopram infusion (4 mg/kg/min) for 20 minutes. After citalopram infusion, in the control group (Group 1), rats were given an infusion of dextrose solution for 60 minutes. In treatment groups, the selective adenosine A1 antagonist DPCPX (Group 2, 8-cyclopentyl-1,3-dipropylxanthine, 20 μg/kg/min) or the selective A2a antagonist CSC (Group 3, 8-(3-chlorostyryl)caffeine, 24 μg/kg/min) was infused for 60 minutes. Mean arterial pressure (MAP), heart rate (HR), QRS duration and QT interval measurements were followed during the experiment period. Statistical analysis was performed by ANOVA followed by Tukey’s multiple comparison tests. Results: Citalopram infusion reduced MAP and HR and prolonged the QT interval. It did not cause any significant difference in QRS duration in any group. When compared to the control group, DPCPX after citalopram infusion shortened the prolongation of the QT interval after 40, 50 and 60 minutes (p<0.01). DPCPX infusion shortened the prolongation of the QT interval at 60 minutes compared with the CSC group (p<0.05). CSC infusion shortened the prolongation of the QT at 60 minutes compared with the control group (p<0.05). Conclusion: DPCPX improved QT interval prolongation in citalopram toxicity. The results of this study show that mechanism of cardiovascular toxicity induced by citalopram may be related adenosine A1 receptor stimulation. Adenosine A1 receptor antagonists may be used for the treatment of citalopram toxicity

Cardiovascular medication exposures and poisonings in Izmir, Turkey: a 14-year experience.

Cardiovascular medications (CVMs) are frequently prescribed for cardiovascular diseases. The unconscious use of cardiovascular drugs may lead to severe clinical manifestations, even to death, especially when in overdose. The objective of this study is to clarify the profile of CVM exposures admitted to Department of Emergency Medicine in Dokuz Eylul University Hospital (EMDEU) between 1993 and 2006. Case demographics, type of the medication, route and reason for exposure, clinical effects and outcome were recorded. Related to the CVM exposures, 105 poisoning cases were admitted. Mean age of children and adults were 12.8 +/- 1.0 and 30.1 +/- 1.8, respectively. Females were dominating (77.1%). Poisoning by accident occurred mainly among children in the 0-6 age group (64.3%) and suicide attempt was predominant in the 19-29 age group (47.8%). The most common ingested CVMs admitted to EMDEU were calcium channel blockers (19.7%), beta-blockers (17.3%), angiotensin converting enzyme inhibitors and diuretics (11.8%). Most of the patients were asymptomatic (59.1%). Frequently observed symptom was altered consciousness (18.6%). Antihypertensive drugs are responsible for the most of the CVM exposures. Prospectively designed multi-centered studies are needed to reflect the epidemiological properties of cardiovascular drug exposures throughout our country and would be very valuable for the determination of preventive measures

Adenosine Mediated-Cardiovascular Toxicity in Amitriptyline Poisoning Rats

This study was designed to clarify the contribution of endogenous adenosine in the amitriptyline-induced cardiovascular toxicity mechanisms. Rats (n =24) were randomized into three groups. Control group received 5% dextrose i.p 1 hour ago before the amitriptyline infusion (0.94 mg/kg/min/60 minutes). Other rats pretreated 1 hour prior to experimental protocol with EHNA (inhibitor of adenosine deaminase, 10 mg/kg i.p) and NBTI (inhibitor offacilitated adenosine transport, 1mg/kg i.p). After EHNA/NBTI administrations, Group 2 received 5% dextrose, while Group 3 received amitriptylineinfusion. Mean arterial pressure (MAP), heart rate (HR), QT and QRS durations were recorded. Plasma adenosine concentrations were measured(HPLC). In the control group, plasma adenosine concentrations significantly increased after amitriptyline infusion (p &lt; 0.05). In EHNA/NBTI administered groups, plasma adenosine concentrations significantly increased (P &lt; 0.001). In the control group, amitriptyline infusion caused a significantdecrease in the MAP, HR and prolongation in QT and QRS durations after 10th min. (P &lt; 0.001). In EHNA/NBTI administered group, a significantdecrease was found in the MAP (after 30th min.) and HR (after 40th min.) and prolongation in the QRS at 60th min.(p &lt; 0.05). Amitriptyline infusionfollowing EHNA/NBTI administrations, caused a significant decrease in the MAP, HR and prolongation in the QT and QRS durations after 10th min. (P&lt; 0.001). In EHNA/NBTI administered groups, amitriptyline-induced MAP (P &lt; 0.01, after 20th min) and HR reductions (p &lt; 0.05, after 40th min) andQRS prolongations (p &lt; 0.05, after 10th min) were more significant than dextrose-induced reductions and prolongations. These results indicated thatamitriptyline enhanced plasma levels of adenosine and potantialized cardiovascular effects of endogenous adenosine.</p