Meredith P A, Elliott H L
University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland.
J Cardiovasc Pharmacol. 1993;22 Suppl A:S6-8.
Although it has long been recognized that many antihypertensive drugs exhibit large intersubject variability in their disposition characteristics, the concept that this translates into a high variability in response has largely been ignored. Thus, too often in the past, research into antihypertensive drugs has ignored the importance of underlying plasma drug concentrations and has sought to attribute the variability in antihypertensive response to factors such as age and plasma renin activity. In studies with hypertensive patients in which pharmacokinetic and pharmacodynamic indices have been integrated, we have demonstrated that the intersubject variability in the pharmacokinetics of verapamil, nifedipine, enalapril, and amlodipine is directly related to the variability in blood pressure response at steady state. The characteristic low variability in the peak and predose, steady-state plasma concentrations associated with amlodipine are reflected in a correspondingly low variability in the blood pressure response. In addition, using the trough-to-peak, steady-state, blood pressure response as an index of 24-h duration of action, amlodipine exhibited significantly higher values with lower variability (66 +/- 11%) when compared to verapamil (47 +/- 13%), nifedipine (48 +/- 9%) and enalapril (44 +/- 15%). Concentration-effect analyses of all four drugs revealed that the antihypertensive response could be related to circulating drug concentrations and that the response following administration of the first dose correlated well with the response following long-term treatment.
尽管早就认识到许多抗高血压药物在处置特征方面存在较大的个体间差异，但这种差异转化为反应的高度变异性这一概念在很大程度上被忽视了。因此，过去对抗高血压药物的研究常常忽视血浆药物浓度的重要性，并试图将抗高血压反应的变异性归因于年龄和血浆肾素活性等因素。在对高血压患者进行的药代动力学和药效学指标综合研究中，我们已经证明维拉帕米、硝苯地平、依那普利和氨氯地平药代动力学的个体间差异与稳态血压反应的变异性直接相关。氨氯地平相关的峰浓度和给药前稳态血浆浓度具有低变异性的特点，这相应地反映在血压反应的低变异性上。此外，以谷峰稳态血压反应作为24小时作用持续时间的指标，与维拉帕米（47±13%）、硝苯地平（48±9%）和依那普利（44±15%）相比，氨氯地平的值显著更高且变异性更低（66±11%）。对所有四种药物的浓度效应分析表明，抗高血压反应可能与循环药物浓度有关，并且首剂给药后的反应与长期治疗后的反应相关性良好。
