警惕!氨茶碱与这些抗菌药合用会致命!

2021-10-14 关0027 MedSci原创

茶碱类药物主要用于治疗慢性阻塞性肺疾病和支气管哮喘,对支气管平滑肌有直接松弛作用,为常用的支气管扩张药。此外,茶碱类药物还能够兴奋呼吸中枢、增强膈肌收缩力、强心利尿、降低毛细血管张力并减少血管渗出。

茶碱类药物主要用于治疗慢性阻塞性肺疾病、支气管和哮喘,对支气管平滑肌有直接松弛作用,为常用的支气管扩张药。此外,茶碱类药物还能够兴奋呼吸中枢、增强膈肌收缩力、强心利尿、降低毛细血管张力并减少血管渗出。氨茶碱为茶碱与乙二胺的复盐,含茶碱77%~83%。该药碱性较强,局部刺激性大,口服易引起胃肠道刺激症状。氨茶碱的有效血药浓度范围较窄,浓度过高易出现恶心、呕吐、心悸等毒性反应,而血药浓度过低无平喘作用。

 

氨茶碱进入体内后被迅速吸收,释放出茶碱,茶碱可被人肝微粒体细胞色素P450同工酶CYP3A4、CYP1A2代谢。而支气管哮喘患者在应用茶碱的同时需要联合应用抗菌药,某些抗菌药就是通过影响P450同工酶的作用而影响茶碱代谢,进而影响茶碱的血药浓度。

 

1.氨茶碱与大环内酯类药物

 

大环内酯类抗生素为14~16元环的内酯化合物,可与CYP3A4酶进行N-脱甲基化,其代谢物与酶形成稳定化合物,使酶失去活性,进而影响茶碱代谢。

 

研究显示,14元环的红霉素、克拉霉素对茶碱药动学参数影响最显著,且联合用药时间越长,剂量越大,发生茶碱中毒的风险越高。与罗红霉素、乙酰螺旋霉素、麦迪霉素联用,均可使茶碱血药浓度升高。

 

2.氨茶碱与林克霉素、克林霉素

 

林可霉素、克林霉素可抑制P450酶活性,降低茶碱清除率、使茶碱血药浓度升高。

 

3.氨茶碱与四环素类

 

四环素为 P450 酶抑制剂, 可抑制茶碱代谢,使其药理作用和毒性反应增强。急性心肌梗死伴低血压患者, 禁忌两药联用。

 

4.氨茶碱与喹诺酮类

 

喹诺酮类可选择性抑制与茶碱代谢有关的P450同工酶,抑制茶碱的脱甲基化和羟化过程,引起剂量依赖性茶碱代谢抑制,血药浓度升高。

 

研究认为,依诺沙星、环丙沙星和氟罗沙星可降低茶碱的清除率,培氟沙星与诺氟沙星可抑制茶碱代谢,使得茶碱血药浓度显著升高,所以在治疗过程中,尽量避免两药联用,必要时可减少茶碱用量,监测茶碱血药浓度。

 

5.氨茶碱与抗真菌药

 

咪唑类抗真菌药是P450酶抑制剂,氟康唑、酮康唑和伊曲康唑与茶碱联用时,通过药酶抑制作用降低茶碱清除率,使其血药浓度增高,出现茶碱中毒的风险。

 

两性霉素B有药酶诱导作用,与茶碱合用,可使茶碱血药浓度降低,停用两性霉素B后,茶碱浓度上升,因此,两药合用时, 适当增加茶碱剂量。

 

6.氨茶碱与氯霉素

 

氯霉素为肝药酶抑制剂,可延缓氨茶碱在体内的代谢清除,血药浓度升高,半衰期延长,曲线下面积增大,合用时应注意调整氨茶碱的剂量。

 

7.氨茶碱与抗结核药

 

异烟肼是肝药酶抑制剂,可抑制P450酶活性, 与氨茶碱联用时可抑制其在肝脏中的代谢,导致氨茶碱血药浓度增高,甚至出现中毒症状。

 

利福平是P450同工酶诱导剂,通过诱导P450酶活性,加速茶碱的代谢和清除,使茶碱血药浓度下降,半衰期缩短,进而影响药物的生物效应。停服利福平,可能引起氨茶碱血药浓度回升,导致毒性反应。

 

8.氨茶碱与磺胺类

 

磺胺类药物的蛋白结合率高,与茶碱联用时,使茶碱从蛋白结合部位置换出来, 游离型茶碱浓度升高,毒性增加。

 

文献报道,4例患者联用氨茶碱与磺胺甲基异唑(SMZ)后,茶碱血药浓度升高,停用SMZ后血药浓度下降。因此,联合用药时应注意调整茶碱剂量。

 

9.氨茶碱与氨基糖苷类

 

氨茶碱可促进庆大霉素在肾小管的重吸收,碱化尿液, 增强其抗菌作用,同时增加耳、肾毒性。因此,两药联用时,应减少庆大霉素的使用剂量。

 

10.氨茶碱与头孢菌素类

 

头孢呋肟、头孢噻肟可使氨茶碱血药浓度明显升高,增强其毒副作用, 而头孢噻肟、头孢呋肟血药浓度却明显降低,两药不宜合用。

 

综上,氨茶碱与抗菌药物联用时表现出不同的相互作用,引起茶碱血药浓度的升高或降低,导致毒性反应或疗效降低,因此,在使用过程中应及时调整剂量,密切监测血药浓度,避免不良事件的发生。

 

参考文献:

1. 戴光强总主编. 医学继续教育系统丛书.医院药学分册(进展篇).合肥:安徽科学技术出版社, 2001 :235

2. 贾公孚, 谢惠民. 药物联用禁忌手册[J]. 中国协和医科大学出版社, 2001.

3. 陈顺烈, 林永祥, 蒋三员, 等. 氨茶碱的药物相互作用. 中国医院药学杂志, 1988, 8 ( 10) : 441

4. 国家药典委员会. 中华人民共和国药典(二部)临床用药须知. 北京:化学工业出版社,2005.

5. Boyce EG, Dukes GE, Rollins DE, et al. Theeffect of rifampin on theophylline kinetics. J Clin Pharmacol 1986, 26: 696.

6. 陈刚, 治疗药物监测, 北京:人民军医出版社,1988, 359.

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