Tolerance to the Circulatory Effects of Oral Isosorbide Dinitrate: Rate of Development and Cross–tolerance to Glyceryl Trinitrate
Tolerance to the Circulatory Effects of Oral Isosorbide Dinitrate: Rate of Development and Cross–tolerance to Glyceryl Trinitrate
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对口服硝酸异山梨酯循环效应的耐受性：对三硝酸甘油酯的发展速度和交叉耐受性
DOI：
10.1161/01.cir.61.3.526
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发表时间：
1980
期刊：
影响因子：
37.8
通讯作者：
H. Fung
中科院分区：
文献类型：
--
作者：
U. Thadani;D. Manyari;J. Parker;H. Fung
比较6例患者口服15、30、60、120 mg硝酸异山梨酯后的收缩压(SBP)和心率(HR)的变化。在任何给药剂量后，持续治疗期间的血浆ISDN水平均高于急性治疗期间。ISDN15、30、60和120 mg后2小时立位SBP平均下降，急性期分别为39、42、45和46 mm Hg，持续治疗期间分别为21、20、26和24 mm Hg(p<；0.01)。与安慰剂相比，在急性期给予任何剂量的ISDN后6小时，SBP仍明显降低，但在持续治疗期间则不明显(p<；0.01)。心率仅在急性治疗后显著增加。在另外8名患者中评估了对ISDN耐受性和对硝酸甘油(GTN)交叉耐受性的快速发展。首次给药15 mg后平均收缩压峰值下降36 mm Hg，但每隔6小时给药5次15 mg后收缩压最大下降仅为7 mm Hg(p<；0.001)。用药前首次应用GTN 0.6mgSBP最大降幅为40 mm Hg，连续5天每6小时给药一次，最大降幅仅为10 mm Hg(p<；0.001)。结果表明，在常规治疗过程中，对ISDN的部分循环耐受和对GTN的交叉耐受迅速发展。持续治疗期间血浆ISDN浓度高于急性治疗后，提示人体对硝酸盐的耐受(快速耐受性)是由于终末器官反应的减弱，而不是硝酸盐代谢的加速。
The effects of 15, 30, 60 and 120 mg of isosorbide dinitrate (ISDN) on systolic blood pressure (SBP) and heart rate (HR) were compared after acute oral administration and during sustained therapy four times daily with ISDN in six patients. After any given dose, plasma ISDN levels were higher during sustained therapy than during acute therapy. The average peak reduction in standing SBP occurred at 2 hours after 15, 30, 60 and 120 mg of ISDN; the values were 39, 42, 45 and 46 mm Hg, respectively, after acute therapy and 21, 20, 26 and 24 mm Hg, respectively, during sustained therapy (p < 0.01). Compared with placebo, the reduction in SBP was still apparent 6 hours after any given dose of ISDN during acute but not during sustained therapy (p < 0.01). HR increased significantly only after acute therapy.The rapidity of development of tolerance to ISDN and cross–tolerance to glyceryl trinitrate (GTN) was evaluated in eight other patients. The average peak reduction in SBP after the first dose of 15 mg of ISDN was 36 mm Hg, but after therapy with ISDN every 6 hours, the fifth dose of 15 mg of ISDN produced a peak reduction in SBP of only 7 mm Hg (p < 0.001). The first dose of 0.6 mg GTN before therapy with ISDN produced a peak reduction in SBP of 40 mm Hg, but after therapy with ISDN every 6 hours for 5 days, the same dose of GTN produced a maximum reduction in SBP of only 10 mm Hg (p < 0.001).The results show that partial circulatory tolerance to ISDN and cross–tolerance to GTN developed rapidly during regular therapy with ISDN. The plasma ISDN concentrations were higher during sustained than after acute therapy, suggesting that the tolerance (tachyphylaxis) to nitrates in man is due to the diminution of the end organ response and not to the accelerated metabolism of nitrates.