Shammas F V, Dickstein K
Cardiology Department, Central Hospital in Rogaland, Stavanger, Norway.
Clin Pharmacokinet. 1988 Aug;15(2):94-113. doi: 10.2165/00003088-198815020-00002.
Pharmacokinetics is the study of the effect that the body has on drug absorption, distribution, metabolism and excretion. The pharmacokinetics of a specific drug are assessed by the volume of distribution, bioavailability, clearance and elimination half-life. Elimination half-life is directly related to the volume of distribution and inversely related to clearance. Any 1 or more of these parameters may be altered by physiological changes such as ageing, or disease states such as congestive heart failure. Congestive heart failure is associated with hypoperfusion to various organs including the sites of drug clearance, i.e. the liver and kidneys. It also leads to organ congestion as seen in the liver and gut. The main changes in drug pharmacokinetics seen in congestive heart failure are a reduction in the volume of distribution and impairment of clearance. The change in elimination half-life consequently depends on whether both clearance and the apparent volume of distribution change, and the extent of that change. Pharmacokinetic changes are not always predictable in congestive heart failure, but it seems that the net effect of reduction in the volume of distribution and impairment of clearance is that plasma concentrations of drugs are usually higher in patients with congestive heart failure than in healthy subjects. The changes in pharmacokinetics assume importance only in the case of drugs with a narrow therapeutic ratio (e.g. digoxin) and some of the antiarrhythmics such as lignocaine (lidocaine), procainamide and disopyramide. This necessitates reduction in both the loading and maintenance doses. Prolongation of the elimination half-life leads to delay in reaching steady-state, and therefore dose increments must be made more gradually. Plasma concentration measurements of the drugs concerned are a good guide to therapy and help to avoid toxicity. Pharmacokinetic changes are of less importance in the case of drugs with immediate clinical response, e.g. diuretics and intravenous vasodilators such as nitrates and phosphodiesterase inhibitors. The dose in the latter group can be titrated to the desired effect. Not all adverse reactions to drugs that may occur in heart failure are the result of alterations in pharmacokinetics; rather, some may be due to important drug interactions. An interaction may occur directly e.g. reduction of renal clearance of digoxin by captopril and quinidine; or indirectly, e.g. through diuretic-induced hypokalaemia, which exacerbate arrhythmias associated with digoxin and antiarrhythmics such as quinidine and procainamide.
药代动力学是研究机体对药物吸收、分布、代谢和排泄的影响。特定药物的药代动力学通过分布容积、生物利用度、清除率和消除半衰期来评估。消除半衰期与分布容积直接相关，与清除率成反比。这些参数中的任何一个或多个可能会因生理变化（如衰老）或疾病状态（如充血性心力衰竭）而改变。充血性心力衰竭与包括药物清除部位（即肝脏和肾脏）在内的各种器官灌注不足有关。它还会导致肝脏和肠道等器官充血。充血性心力衰竭中药物药代动力学的主要变化是分布容积减少和清除功能受损。消除半衰期的变化因此取决于清除率和表观分布容积是否都发生变化以及变化的程度。充血性心力衰竭中的药代动力学变化并不总是可预测的，但分布容积减少和清除功能受损的净效应似乎是充血性心力衰竭患者的血浆药物浓度通常高于健康受试者。药代动力学变化仅在治疗窗较窄的药物（如地高辛）以及一些抗心律失常药物（如利多卡因、普鲁卡因胺和丙吡胺）的情况下才显得重要。这就需要减少负荷剂量和维持剂量。消除半衰期延长会导致达到稳态的延迟，因此剂量增加必须更加缓慢。相关药物的血浆浓度测量是治疗的良好指导，有助于避免毒性。对于具有即时临床反应的药物（如利尿剂和静脉血管扩张剂，如硝酸盐和磷酸二酯酶抑制剂），药代动力学变化的重要性较小。后一组药物的剂量可以根据所需效果进行滴定。并非所有心力衰竭中可能发生的药物不良反应都是药代动力学改变的结果；相反，有些可能是由于重要的药物相互作用。相互作用可能直接发生，例如卡托普利和奎尼丁降低地高辛的肾清除率；或间接发生，例如通过利尿剂引起的低钾血症，这会加剧与地高辛以及奎尼丁和普鲁卡因胺等抗心律失常药物相关的心律失常。
