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Effects of single-dose and short-term oral captopril on hepatic blood flow and haemodynamics in mild to moderate hypertensive patients

University of British Columbia

The angiotensin converting enzyme inhibitor, captopril has been extensively used in the treatment of mild to moderate hypertension and congestive heart failure. Although the haemodynamic changes associated with acute and/or chronic captopril therapy have been extensively studied, there is conflicting information of its influence on hepatic blood flow (QH). Most of the human studies have been investigated the influence of captopril on after single-dose administration and very few data are available on its effects after chronic therapy. The most frequently used method to estimate is based on the hepatic clearance of indocyanine green (ICG) from the blood. This thesis reports i) the effects of single-dose (100 mg) and two-weeks (100 mg/day) captopril treatment on QH, assessed by ICG clearance, in six mild to moderate hypertensive male subjects, ii ) the changes in the area under the serum concentration-time curve (AUC) and plasma clearance (ClpICG) of ICG, iii ) the changes in blood pressure, heart rate and splanchnic vascular resistance (SVR) before and after acute and short-term captopril therapy, iv) the effects of postural change from sitting to upright on ClpICG and QH blood pressure, heart rate and SVR before and after two-weeks captopril therapy, v) the effects of acute and two-weeks captopril treatment on some important pharmacokinetic parameters of unchanged captopril. There were two study days two-weeks apart (day 1 and day 14). was estimated at baseline seated, upright, reseated and 1 hour after captopril dosing on the first study day. The same procedures were repeated in the same patients following 14 days captopril therapy. The serum concentration of ICG was determined by spectrophotometric analysis following intravenous ICG dose of 0.45 mg/kg. There was a slight ~ 5% and ~ 6% decrease, but, no significant change in ClpICG and QH, respectively, whether expressed in absolute terms or per unit body weight or body surface area, following the initial and terminal doses of captopril. A significant 25%-29% (p = 0.04) increase in ICG plasma clearance after two-weeks captopril treatment was observed in all of the four study phases (seated, upright, reseated and post-captopril) as compared to control values. Liver blood flow increased substantially, in the four study phases, in the range from 21% to 25% (p = 0.06) after 14 days treatment with captopril. Systolic and diastolic blood pressures were reduced significantly after the initial dose of captopril from 160.5 ± 5.3 and 103.3 ± 1 mm Hg to 132.4 ± 9.3 mm Hg (p < 0.005) and 86.6 ± 6.3 mm Hg (p<0.05), respectively, with peak reduction 3 hours after captopril dosing. Treated baseline systolic and diastolic blood pressures on day 14 were « 15 and ~ 11 mm Hg lower than the pretreatment values (p < 0.005 and p < 0.05, respectively). The reduction in blood pressure after two-weeks captopril treatment was sustained for 20 hours post-dose. The absolute decrease in systolic and diastolic blood pressures, 3 hours after the terminal captopril dose, was 31.7 ± 6.6 mm Hg (19.7%) and 20.4 ± 8.0 mm Hg (19.8%), respectively (p < 0.005), as compared to pretreatment values. Heart rate remained unaltered after the acute doses of captopril and decreased slightly = 3 beats/ min after two-weeks captopril therapy. Despite the significant reduction in systolic and diastolic blood pressures, SVR was unaffected by the acute doses of captopril. In contrast, after two-weeks captopril therapy SVR decreased as an average by 19% ± 3% (p = 0.125). Postural change from sitting to upright significantly decreased ClpICG by ~ 25% (p = 0.005) and 27% (p = 0.001) on day 1 and 14, respectively. Similarly, significantly decreased by ~ 23% (p = 0.008) and = 25% (p = 0.003) during upright posture before and after two-weeks captopril therapy, respectively. There was a slight increase in diastolic blood pressure (= 5- 7 mm Hg) in upright position on both study days. A significant increase in heart rate of 4 and 6 beats/min (p < 0.025) was observed on standing before and after captopril. The SVR increased in upright position by 31.0% (p < 0.05) and 33.3% (non-significant), before and after two-weeks captopril treatment, respectively, as compared to seated values. In agreement with previous studies, the serum concentration of unchanged captopril increased rapidly after captopril administration. Peak serum concentration (Cmax) unchanged captopril was 697.2 ± 192.8 ng/ml (mean ± SEM) and the time required to reach Cmax (tmax) ~ 76 minutes after a single captopril dose. The Cmax after the terminal dose of two-weeks captopril treatment was 870.5 ± 85.9 ng/ml which is ~ 25% (non-significant) larger than that after the initial dose and was reached ~ 52 minutes following drug administration. In conclusion, despite the fact that captopril has no apparent acute effect on as measured I hour post-dose, there is a substantial chronic increase in on continued captopril administration in patients with mild/moderate hypertension. Acute and short-term administration of captopril does not interfere with the homeostatic responses to postural change. The decrease in SVR on continued therapy may suggest an important antihypertensive mechanism of captopril. The captopril induced increase in after prolonged therapy should be considered when captopril is coadministered with high-clearance drugs, because systemic availability. hence, therapeutic effect may be altered.

Thesis/Dissertation

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2009-01-09

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http://hdl.handle.net/2429/3474

Pharmaceutical Sciences

University of British Columbia

UBCV

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