Klockowski P M, Levy G
Department of Pharmaceutics, School of Pharmacy, State University of New York, Amherst.
J Pharmacol Exp Ther. 1988 May;245(2):508-12.
It has been reported that hypovolemia secondary to extensive blood loss alters the functionality of the central nervous system and is associated with changes in the dose requirements or intensity of action of various central nervous system depressants, including a benzodiazepine. To investigate the mechanism(s) of this effect, the influence of experimental hypovolemia on the pharmacodynamics, receptor binding and pharmacokinetics of a benzodiazepine drug was determined. Adult male Sprague-Dawley rats were made hypovolemic by removal of about 30% of their blood over 30 min. An i.v. infusion of desmethyldiazepam (DDZP) was started 30 min later and continued until the animals lost their righting reflex. Compared to results obtained with normal controls, the hypovolemic rats required about one-half the dose of DDZP to produce loss of righting reflex and had significantly lower DDZP concentrations in serum and cerebrospinal fluid at that time. This effect of substantial blood removal could not be reversed by prompt return of the removed blood to the animals. Experimental hypovolemia had no apparent effect on the in vitro binding of tritiated diazepam to benzodiazepine receptor sites in the cerebral cortex of rats. The plasma clearance of DDZP was decreased significantly and the biological half-life was increased in hypovolemic rats compared to normal animals when both received a 30-mg/kg dose by i.v. infusion over 10 min. It is concluded that acute hemorrhagic hypovolemia increases the sensitivity of the central nervous system to the depressant effect of DDZP and decreases the body clearance of that drug in rats. Thus, the pharmacodynamics as well as the pharmacokinetics of a benzodiazepine are altered by hypovolemia.
据报道，大量失血继发的血容量不足会改变中枢神经系统的功能，并与各种中枢神经系统抑制剂（包括苯二氮䓬类药物）的剂量需求或作用强度变化有关。为了研究这种效应的机制，确定了实验性血容量不足对苯二氮䓬类药物的药效学、受体结合和药代动力学的影响。成年雄性Sprague-Dawley大鼠在30分钟内被移除约30%的血液，从而造成血容量不足。30分钟后开始静脉输注去甲西泮（DDZP），并持续输注直至动物失去翻正反射。与正常对照组的结果相比，血容量不足的大鼠产生翻正反射丧失所需的DDZP剂量约为正常对照组的一半，且此时血清和脑脊液中的DDZP浓度显著更低。迅速将移除的血液回输给动物并不能逆转大量失血的这种效应。实验性血容量不足对大鼠大脑皮质中氚标记的地西泮与苯二氮䓬受体位点的体外结合没有明显影响。当正常动物和血容量不足的大鼠均通过10分钟静脉输注给予30mg/kg剂量的DDZP时，血容量不足的大鼠的DDZP血浆清除率显著降低，生物半衰期延长。结论是，急性出血性血容量不足增加了中枢神经系统对DDZP抑制作用的敏感性，并降低了该药物在大鼠体内的清除率。因此，血容量不足会改变苯二氮䓬类药物的药效学和药代动力学。
