Effect of doxazosin on blood pressure and renal haemodynamics of hypertensive patients with renal failure

Doxazosin, a quinazoline derivative, has alpha 1- adrenoreceptor antagonist properties similar to those of prazosin. This antihypertensive agent has a longer elimination half-life than prazosin. The pharmacokinetic properties of doxazosin are not significantly different in patients with renal insufficiency compared with healthy controls. In this study eight hypertensive patients with renal insufficiency were studied during a two week washout period, followed by a two week single blind placebo phase and an eight week open doxazosin treatment period. Doxazosin was commenced in a dose of 1 mg daily and titrated if necessary, with the dose being doubled every two weeks. In all but one patient doxazosin was successful in controlling the blood pressure. Treatment with doxazosin for eight weeks had no adverse effects on the effective renal plasma flow or glomerular filtration rate of these patients. Six of the eight patients suffered side effects attributable to doxazosin.     

Effect of penbutolol on the hemodynamics in patients with hypertensive disease

It was found that a hypotensive effect of penbutolol used for treatment of 234 patients with hypertensive disease exceeded that of propranolol and developed at a dose of 20-80 mg a day at the end of the 2nd week of treatment. Penbutolol produces a less negative chronotropic effect as compared to propranolol. The excess of penbutolol therapeutic dose leads to the further augmentation of a positive clinical effect.     

Pharmacokinetics of penbutolol and its metabolites in renal insufficiency

Summary The pharmacokinetics of penbutolol, its 4-hydroxylated metabolite and of their conjugates was studied in hypertensive patients with various degrees of renal impairment.A single oral dose of penbutolol 40 mg, was rapidly absorbed after a lag-time of 0.34 h. Its plasma concentration reached a maximum after 0.84 h and then declined bi-exponentially, with an apparent elimination half-life of 21.8 h. The hydroxylation of penbutolol was negligible and conjugation was of major importance for its elimination. Consequently, the kinetics of unchanged penbutolol were not altered by renal impairment. The 48 h-urinary excretion of penbutolol and its metabolites reached 13–14% of the administered dose, which is consistent with extensive metabolism of the drug.After treatment for 30 days with penbutolol 40 mg/d there was no accumulation of the parent drug but the concentration of its conjugates was increased.It is concluded that the dose of penbutolol need not be changed in patients with mild renal insufficiency, 4-hydroxypenbutolol is unlikely to participate in the anti-hypertensive effect of the drug, due to its low concentrations, and biotransformation of penbutolol may be enhanced during chronic treatment.     

美托洛尔对隐匿性肾功能不全的高血压患者肾小球滤过功能的影响

目的:评价β受体阻滞剂美托洛尔单独或与血管紧张素转换酶(ACE)抑制剂贝那普利联合应用对隐匿性肾功能不全的轻、中度高血压患者肾小球滤过功能的影响。方法:73例隐匿性肾功能不全的高血压患者,随机分为美托洛尔(MET)、美托洛尔+贝那普利(MET+BEN)两组,分别应用美托洛尔50～75mg/d或美托洛尔25mg/d+贝那普利5～10mg/d,疗程6个月。血压控制目标为140/90mmHg。治疗前和治疗满6个月时,检测两组患者血尿酸(SUA)血肌酐(Scr)和肾小球滤过率GFR。结果:①治疗后,MET组与MET+BEN组的血压平均水平的差别均无统计学意义(131.3±9.9/71.9±10.5,132.0±10.2/68.9±10.7mmHg,P均>0.05),血压控制达标率亦无显著差别(78.4%,77.8%,P>0.05)。②治疗后MET组血尿酸、肌酐较治疗前升高(439±62,429±57mmol/L,P<0.05;109±17,103±14μmol/L,P<0.01),肾小球滤过率轻度下降(49.9±6.9,52.9±5.8mL/min·1.73m2,P<0.01);③MET+BEN组血尿酸、血肌酐较治疗前降低(417±57,426±62mmol/L,P<0.01;98±12,105±13μmol/L,P<0.01),肾小球滤过率较治疗前升高(54.7±6.2,51.3±5.6mL/min·1.73m2,P<0.01)。④治疗6个月后,MET+BEN组血尿酸、血肌酐均低于MET组(417±57,439±62mmol/L,P<0.01;98±12,109±17μmol/L,P<0.01),肾小球滤过率高于MET组(54.7±6.2,49.9±6.9ml/min·1.73m2,P<0.01)。结论:对合并隐匿性肾功能不全的高血压患者,应避免单独应用美托洛尔,以免加重肾小球滤过功能的损害;而美托洛尔与贝那普利联合应用,可能有益于肾功能的保护。     

Pharmacokinetics of ramipril in hypertensive patients with renal insufficiency

In an open trial, the pharmacokinetics of ramipril and its active metabolite ramiprilat were studied in 25 hypertensive patients with various degrees of renal insufficiency given 5 mg ramipril p.o. for 14 days. Ramipril was rapidly absorbed and reached a peak concentration after 1-2 h. Cmax was greater in patients with severe renal insufficiency, which might indicate a reduced renal elimination rate, although, the rapid decline of the concentration-time curve for ramipril was almost independent of renal function. The mean initial apparent half-lives on Days 1 and 12, respectively, were 2.8 and 3.4 h (Group I: creatinine clearance 5-15 ml/min), 1.8 and 2.3 h (Group II: creatinine clearance 15-40 ml/min), and 1.9 and 1.9 h (Group III: creatinine clearance 40-80 ml/min). No accumulation was observed after multiple dosing. In contrast, the kinetics of its active acid metabolite ramiprilat was significantly influenced by renal function. The mean times to the peak plasma concentration were 5.7 h in Group I, 4.4 h in Group II and 3.8 h in Group III. The initial decline in plasma ramiprilat was dependent upon renal function; the mean initial apparent half-lives (Days 1 and 12, respectively) were 16.0 and 14.8 h (Group I), 10.1 and 9.5 h (Group II) and 10.6 and 8.0 h (Group III). Mean trough concentrations and absolute accumulation also increased with worsening renal function, and the renal clearance of ramiprilat was significantly correlated with the creatinine clearance. The subsequent long terminal phase at low plasma ramiprilat concentrations represented slow dissociation of the ACE-inhibitor complex.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of nifedipine GITS on renal function in hypertensive patients with renal insufficiency

Twelve hypertensive patients with moderately severe renal dysfunction were entered into a protocol to assess the blood pressure and renal effects of the sustained release calcium antagonist, nifedipine GITS (30-180 mg/d given once a day) administered for 5 weeks. Nifedipine GITS monotherapy effectively lowered blood pressure in 50% of the patients. Glomerular filtration rate and effective renal plasma flow were increased 18% and 20%, respectively. The filtration fraction and urinary protein excretion remained unchanged. Changes that were observed in renal function were independent of the blood pressure responses of the patients; there was no correlation between the systemic and renal effect of nifedipine GITS monotherapy. Patients who had a poor systemic blood pressure response exhibited an increase in glomerular filtration rate (+11%) but had a decrease in effective renal plasma flow (-6%); patients who achieved a goal blood pressure response showed increases in both glomerular filtration rate (+35%) and effective renal plasma flow (+40%). These results show that nifedipine GITS monotherapy has the potential to improve renal function abnormalities that are encountered in hypertensive patients with renal disease; the improvement in renal function may be independent of their effect on systemic blood pressure.     

Effects of amlodipine on renal haemodynamics in mild to moderate hypertensive patients

Summary In this study the efficacy and safety of short-term amlodipine administration on renal haemodynamics were evaluated in mild to moderate hypertensive subjects. Our final goal was to evaluate whether the reduced blood pressure induced by treatment was associated with maintenance of renal function.After a run-in period with placebo, 30 hypertensive patients without cardiac or renal diseases were randomly allocated to a double-blind 4 weeks controlled study with amlodipine 10 mg once a day (15 patients) or placebo (15 patients).Renal haemodynamic measurements included effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) by radionuclide study using ¹³¹I-hippuran and ^99mTc, with methods described by Schlegel and Gates, respectively. In addition, effective renal blood flow [ERBF=ERPF/(1-Ht)], filtration fraction (FF=GFR/ERPF) ERPF) and renal vascular resistance (RVR=MBP×80/ERBF) were calculated. Plasma renin activity (PRA), serum aldosterone (ALD) and urinary excretion of sodium (NaU) were evaluated.At the end of amlodipine administration a significant decrease (P<0.001) in SBP, DBP and MBP from baseline values was observed. A significant decrease (P<0.01) in RVR and significant increases (P<0.05) in ERPF, ERBF and in NaU were also found, without relevant changes in GFR, FF, PRA and ALD.No significant variation in clinical and renal measurements was observed in the placebo group.No relevant side effects were observed in either group. In conclusion, amlodipine was effective in lowering blood pressure in mild to moderate hypertension and exerted favourable effects on renal haemodynamics and function.     

Comparison of the effects of penbutolol and propranolol on glomerular filtration rate in hypertensive patients with impaired renal function.

Penbutolol and propranolol were administered orally in a dosage of 40 mg once daily and 80 mg twice daily, respectively to 12 patients with hypertension and impaired renal function. Both drugs caused a significant decrease in mean arterial pressure and heart rate. Serum creatinine concentration increased significantly by 10% during therapy with propranolol without concomitant decrease in creatinine clearance. No such effect was seen with penbutolol. GFR measured with [125I]-iothalamate showed no significant changes with both drugs.     

Effect of cilazapril in hypertensive patients with renal impairment.

The aim of the study was to evaluate the clinical and renal hemodynamic effects of cilazapril in 10 hypertensive patients with moderate-to-severe chronic renal failure (creatinine clearance 14-50 ml/min). After 2 weeks of placebo, cilazapril 0.5 mg/day was given, and the dose was increased up to 5 mg/day if sitting diastolic blood pressure (SDBP) was not normalized (less than or equal to 90 mm Hg). Once a normal SDBP value was achieved, the patients remained on the given dose regimen for 6 months. After this period SDBP decreased from 107 +/- 2 to 95 +/- 2 mm Hg (p less than 0.001). At the end of treatment, glomerular filtration rate (GFR) remained unchanged in five patients, improved in four patients, and slightly decreased in one patient, the slope from baseline being 0.137 and the variation of GFR per unit of GFR at baseline being between -0.20 and 0.47. Likewise, effective renal plasma flow increased not significantly, showing considerable variability. Urinary protein excretion was reduced significantly from 2.51 +/- 0.75 to 0.51 +/- 0.10 g/L (p less than 0.05), suggesting that converting enzyme inhibition may exert a renal protective effect. In conclusion, it appears that cilazapril does not induce functional damage in the kidney of predialysis hypertensives.     

Pharmacokinetics of piroximone after oral and intravenous administration to patients with renal insufficiency.

The pharmacokinetics of piroximone (PI) were determined in patients with renal failure (inulin clearance less than 50 ml min-1 per 1.73 m2) using two protocols: (a) 10 patients received a single i.v. infusion of 0.5 mg kg-1 PI and the data were compared with those from seven healthy subjects receiving the same regimen; (b), a single oral dose of either 25 or 50 mg PI was given to 20 patients. PI concentrations were assayed by h.p.l.c. in plasma and urine over 48 h. After i.v. administration to healthy subjects PI was distributed rapidly and eliminated with a mean half-life of 1.3 +/- 0.2 h. The urinary recovery of unchanged PI was 64% of the dose. In the patients the extent of renal elimination of PI was decreased (-78%) in relation to the degree of renal insufficiency as assessed by inulin clearance (r = 0.97, P < 0.0001). Mean Cmax, AUC and t1/2,z values after i.v. infusion were increased by 47%, 127% and 77%, respectively, in comparison with healthy subjects. Similar results were obtained after oral administration. Until chronic dosing studies are undertaken, PI dosage should be adapted in relation to renal function.     

Pharmacokinetics of a fixed combination of sotalol and hydrochlorothiazide in hypertensive patients with moderate renal insufficiency

Summary Decreased elimination of a combined formulation of Sotalol (160 mg) and hydrochlorothiazide (25 mg) was found in patients with moderate renal insufficiency. Very slight accumulation of sotalol and hydrochlorothiazide was observed, so it appears unnecessary to reduce the dosage in patients with a creatinine clearance of 30 ml/min or more.     

肾动脉支架术对轻中度肾功能不全合并肾动脉狭窄患者肾功能的影响

目的研究肾动脉支架术对轻中度肾功能不全合并肾动脉狭窄患者肾功能的影响。方法选取2015年1月~2016年1月在我院已经进行过肾动脉支架手术的轻中度肾功能不全合并肾动脉狭窄的280例患者,在手术前和手术后分别对这280例患者进行血压测试、血肌酐(Scr)以及肾小球滤过率等指标进行为期1年的跟踪观察记录,分别记录患者手术前、手术后3个月、手术后6个月以及手术后1年三种不同指标的值,并对三种指标进行统计分析和检验。结果经过肾动脉支架手术后,轻中度肾功能不全合并肾动脉狭窄患者的肾功能有了明显改善,血压值恢复正常率显著高于肾动脉支架手术前,血肌酐值与手术前差异有统计学意义,肾小球滤过率也比手术前有很大的改善,这三组指标较手术前差异有统计学意义(P0.05)。结论肾动脉支架术能够有效的治疗轻中度肾功能不全合并肾动脉狭窄疾病且有显著疗效,能够使患者重新恢复到健康,在临床治疗中值得推广和应用。     

Pharmacodynamics and pharmacokinetics of oral nitrendipine solution in hypertensive patients with advanced renal failure

Summary Nitrendipine solution 5 mg·ml^–1 in the dose of 5 mg was given orally to 20 patients with chronic renal failure and elevated diastolic blood pressure (110 mmHg), of whom 10 were on maintenance haemodialysis (endogenous creatinine clearance <5 ml·min^–1) and 10 were at the predialysis stage (endogenous creatinine clearance 5–20 ml·min^–1).The aim of the study was to investigate the influence of kidney function and/or dialysis treatment on the pharmacokinetic and pharmacodynamic profile of a solution of nitrendipine and to assess its antihypertensive efficacy.After 10 min there was a significant reduction in blood pressure from 188/113 to 173/100 (patients not dependent on dialysis) and from 197/112 to 161/94 mmHg (patients dependent on dialysis). The maximum fall in blood pressure (approximately 30%) was attained after 90 min in the dialysis patients and after 120 min in the non-dialysis group. Blood pressure increased again about 3 h after the administration of nitrendipine but it was still below baseline after 12 h. The terminal elimination half-life (4.1 h in the dialysis patients and 3.6 h in non-dialysis patients) was similar to that observed in patients with normal renal function. The pharmacokinetics of nitrendipine did not differ between the dialysis and non-dialysis groups. There was a correlation between plasma concentration and the blood pressure reduction. The maximum plasma concentration of nitrendipine was reached after 0.5 h (median) and did not differ between the two groups. The mean maximum plasma concentration was 14.8 g·1^–1 in the study population as a whole, with comparable means in the dialysis (17.3 g·1^–1) and non-dialysis (12.4 g·1^–1) groups.The nitrendipine solution proved to be effective in lowering acutely elevated blood pressure in patients with advanced renal failure and renal hypertension, and was well tolerated. The pharmacokinetics was not affected by renal impairment or by dialysis.     

慢性肾功能不全患者肾穿刺活检的风险与价值研究

目的回顾性分析慢性肾功能不全（CRI）患者经皮肾穿刺活检（PRB）的风险与价值。方法对符合条件的50例CRI患者进行PRB,行光镜、免疫组化染色和选择性电镜检测,观察肾穿刺组织肾小球个数、病理类型、诊断以及穿刺并发症。结果肾组织标本合格率为96%。病理类型前三位为增生性肾小球硬化症21例（42%）,IgA肾病（IgAN）9例（18%）,狼疮性肾炎（LN）8例（16%）。PRB后修改诊断5例（10%）,明确病因3例（6%）,诊断修正率为16%,根据病理结果决定治疗方案16例（32%）,治疗方案修正率为26%。并发症以镜下血尿最常见,共48例（98%）,肾周小血肿11例,肾周大血肿2例,腹膜后血肿1例。结论原发性肾脏疾病肾穿后病理结果多为慢性病变,大部分患者的诊断治疗方案不受肾穿刺病理结果的影响,且肾周血肿出现机率较多且较大,偶可合并腹膜后血肿,但狼疮性肾炎表现为慢性肾衰时其肾脏病理的活动指数仍较高,少数病例肾脏病理显示新月体肾炎,仍需应用免疫抑制剂以改善预后。     

Effect of penbutolol on lidocaine kinetics

The effect of penbutolol (Betapressin), a stereospecific beta-adrenergic antagonist, on the pharmacokinetics of a single dose of intravenous lidocaine was evaluated in seven healthy volunteers. Subjects received a single 100-mg lidocaine intravenous dose of lidocaine hydrochloride, once in the control state and a second time during coadministration of penbutolol, 60 mg daily. Lidocaine volume of distribution was significantly increased during penbutolol treatment (4.9 vs 3.4 l/kg, p less than 0.005), resulting in a significant prolongation of elimination half-life (2.5 vs 2.0 h, p less than 0.025). The mechanism of the distributional shift is not established, but may result from a change in the pattern of peripheral blood flow and therefore the profile of tissue uptake of lidocaine. Total metabolic clearance of lidocaine, however, was not significantly altered by penbutolol (23.0 vs 19.4 ml/min/kg). The present study of healthy volunteers suggests that penbutolol increases lidocaine volume of distribution. If the finding also applied to patients, a higher loading dose of lidocaine might be necessary.     

Alprazolam kinetics in patients with renal insufficiency

Alprazolam kinetics following a single 1.0-mg oral dose of alprazolam were compared between seven dialysis-dependent patients with chronic renal failure and seven healthy controls matched for age, sex, and weight. There were no significant differences between patients and controls in alprazolam half-life (11.5 vs. 11.3 hours) or clearance of total drug (1.14 vs. 1.26 ml/min/kg). However, alprazolam free fraction was increased in renal failure patients (35.7% vs. 31.9% unbound, p less than 0.005). Free clearance of alprazolam averaged 23% lower in patients (3.2 vs. 4.1 ml/min/kg), but the difference was not significant. Renal insufficiency has a quantitatively small influence on alprazolam pharmacokinetics.     

Pharmacokinetics and haemodynamics of candesartan cilexetil in hypertensive patients on regular haemodialysis

AIMS: The pharmacokinetic profile of candesartan cilexetil might be altered in patients with end-stage renal disease (ESRD). No data are available about the pharmacokinetics and haemodynamics of the angiotensin II receptor antagonist candesartan cilexetil in ESRD patients on regular haemodialysis (HD). METHODS: We performed a repeated dose study (8 mg candesartan cilexetil once daily) in eight male HD patients over a treatment period of 5 days with an additional observation period of 3 days. RESULTS: Pharmacokinetic analysis with nonlinear mixed effects modeling (NONMEM) over the whole treatment period revealed a dependency of the volume of distribution on body weight and of the metabolic clearance on age and body weight in the studied population. No significant drug elimination by HD was observed. The estimated metabolic and intercompartmental clearances were 83 ml min-1 (CV 39%) and 9.9 ml min-1, respectively. The unexplained random variability of the final two compartment model was 30%. In one patient with adult polycystic kidney disease oral clearance decreased during the observation period, attributable to a significant increase in bioavailability. Maximum observed changes in blood pressure were -50/-27+/-14/8 mmHg on day 5 with haemodialysis therapy as compared with changes in blood pressure of -14/-12+/-14/8 mmHg on day 1 without haemodialysis treatment. The observed maximum decrease in systolic blood pressure correlated with the amount of ultrafiltration during the HD session on day 5 (r=0.70, P<0.05). In two patients, one of whom was binephrectomized, severe hypotensive episodes were observed during this HD session. CONCLUSIONS: HD does not influence the elimination kinetics of candesartan. The observed inter- and intraindividual variability of oral clearance and the pronounced influence of HD-induced volume contraction on the haemodynamic effects of candesartan makes it mandatory to carefully monitor HD patients treated with candesartan cilexetil.     

Pharmacokinetics of flutamide in patients with renal insufficiency

AIMS: The aim of this study was to determine the pharmacokinetic parameters of flutamide, a nonsteroidal antiandrogenic compound, and its pharmacologically active metabolite, hydroxyflutamide, in renal insufficiency. Haemodialysis (HD) clearance of flutamide and hydroxyflutamide was also determined. METHODS: Pharmacokinetic parameters were assessed for flutamide and hydroxyflutamide in 26 male subjects with normal renal function (creatinine clearance by 24 h urine collection, CLcr, greater than 80 ml min(-1) 1.73 m(-2); n=6) or reduced renal function; CLcr=50-80 (n=7), 30-49 (n=3), 5-29 (n=4), and <5 ml min(-1) 1.73 m(-2)-HD (n=6), following a single, oral 250 mg flutamide dose. Subjects undergoing HD received a second 250 mg dose of flutamide 4 h prior to HD; blood and dialysate were collected during HD to determine dialysability of flutamide and hydroxyflutamide. RESULTS: Cmax, tmax, AUC, t1/2, and renal clearance of flutamide and hydroxyflutamide did not differ between groups. Less than 1% of the dose appeared in dialysate as hydroxyflutamide. No serious adverse events were observed. CONCLUSIONS: Renal function did not affect flutamide nor hydroxyflutamide disposition. HD did not alter hydroxyflutamide pharmacokinetics. Dosing adjustments for renal impairment or HD are not indicated for flutamide.     

Pharmacokinetics of loratadine in patients with renal insufficiency

The disposition of loratadine, a new orally active histamine H1 receptor antagonist and its primary metabolite descarboethoxyloratadine were characterized in adult volunteers with normal renal function (group I), patients with chronic renal failure, i.e., creatinine clearance less than 30 mL/min (group II), as well as chronic hemodialysis patients (group III). The effect of hemodialysis on the disposition of loratadine and descarboethoxyloratadine was also assessed. Subjects in groups I and II were given a single oral 40 mg dose of loratadine while the patients in Group III received two single 40 mg doses of loratadine (during an interdialytic period and just prior to hemodialysis). Loratadine was rapidly absorbed and the decline of plasma concentrations after attainment of the Cmax was biexponential in all subjects. No significant differences in t1/2 beta were observed between the three groups (8.7 +/- 5.9, 7.6 +/- 6.9, 8.6 +/- 1.6 hrs: in groups I, II, and III, respectively). The apparent total body clearance and apparent volume of distribution of loratadine also did not differ significantly among the three groups. No significant differences in the Cmax or tmax of the metabolite were observed. The metabolite AUC infinity 0 however was significantly greater in group II subjects: (212.4 +/- 37.8, 469.5 +/- 95.4, 325.2 +/- 114.6 ng.hr/mL; groups I, II, and III, respectively). No significant relationship was observed between the terminal elimination half-life of loratadine or descarboethoxyloratadine and creatinine clearance. Hemodialysis augmented endogenous clearance by less than 1%. The disposition of loratadine is not significantly altered in patients with severe renal insufficiency nor is hemodialysis an effective means of removing loratadine or descarboethoxyloratadine from the body.     

Stereoselective pharmacokinetics of oral nitrendipine in elderly hypertensive patients with normal and impaired renal function

Summary The pharmacokinetics of the enantiomers of nitrendipine has been studied in seven elderly patients with chronic renal failure (CRF) and in six control subjects (mean creatinine clearance 30 and 97 ml·min^–1 respectively). Racemic nitrendipine 20 mg was given once daily for seven days and the pharmacokinetics of the enantiomers over the last dosage interval were determined using a stereospecific assay.In both groups nitrendipine exhibited stereoselective pharmacokinetics (AUC, C_max), but the half-lives of the enantiomers did not differ in individual subjects. As an index of stereoselectivity, the mean S/R ratio of AUCs in control subjects (2.07) was not significantly different from the ratio in patients with CRF (2.68).The mean AUCs of (S)- and (R)-nitrendipine during the last dosage interval were increased in CRF by 132% and 85%, respectively. The observed doubling of the half-lives and the increases in C_max did not reach significance because of the large variability in each group.Thus, the pharmacokinetics of oral nitrendipine is altered in CRF, but there was no change in the stereoselectivity of its pharmacokinetics.