Power B M, Forbes A M, van Heerden P V, Ilett K F
Department of Intensive Care, Sir Charles Gairdner Hospital, Nedlands, Australia.
Clin Pharmacokinet. 1998 Jan;34(1):25-56. doi: 10.2165/00003088-199834010-00002.
Critically ill patients exhibit a range of organ dysfunctions and often require treatment with a variety of drugs including sedatives, analgesics, neuromuscular blockers, antimicrobials, inotropes and gastric acid suppressants. Understanding how organ dysfunction can alter the pharmacokinetics of drugs is a vital aspect of therapy in this patient group. Many drugs will need to be given intravenously because of gastrointestinal failure. For those occasions on which the oral route is possible, bioavailability may be altered by hypomotility, changes in gastrointestinal pH and enteral feeding. Hepatic and renal dysfunction are the primary determinants of drug clearance, and hence of steady-state drug concentrations, and of efficacy and toxicity in the individual patient. Oxidative metabolism is the main clearance mechanism for many drugs and there is increasing recognition of the importance of decreased activity of the hepatic cytochrome P450 system in critically ill patients. Renal failure is equally important with both filtration and secretion clearance mechanisms being required for the removal of parent drugs and their active metabolites. Changes in the steady-state volume of distribution are often secondary to renal failure and may lower the effective drug concentrations in the body. Failure of the central nervous system, muscle, the endothelial system and endocrine system may also affect the pharmacokinetics of specific drugs. Time-dependency of alterations in pharmacokinetic parameters is well documented for some drugs. Understanding the underlying pathophysiology in the critically ill and applying pharmacokinetic principles in selection of drug and dose regimen is, therefore, crucial to optimising the pharmacodynamic response and outcome.
重症患者会出现一系列器官功能障碍，常常需要使用多种药物进行治疗，这些药物包括镇静剂、镇痛药、神经肌肉阻滞剂、抗菌药物、强心药和胃酸抑制剂。了解器官功能障碍如何改变药物的药代动力学是该患者群体治疗的一个重要方面。由于胃肠道功能衰竭，许多药物需要静脉给药。在可以采用口服途径的情况下，生物利用度可能会因胃肠蠕动减弱、胃肠道pH值变化和肠内营养而改变。肝肾功能障碍是药物清除率的主要决定因素，因此也是个体患者稳态血药浓度、疗效和毒性的主要决定因素。氧化代谢是许多药物的主要清除机制，人们越来越认识到重症患者肝细胞色素P450系统活性降低的重要性。肾衰竭同样重要，因为清除母体药物及其活性代谢产物需要滤过和分泌清除机制。稳态分布容积的变化通常继发于肾衰竭，可能会降低体内有效的药物浓度。中枢神经系统、肌肉、内皮系统和内分泌系统功能障碍也可能影响特定药物的药代动力学。一些药物的药代动力学参数变化的时间依赖性已有充分记录。因此，了解重症患者潜在的病理生理学并在选择药物和给药方案时应用药代动力学原理对于优化药效学反应和治疗结果至关重要。
