Verapamil pharmacokinetics and liver function in patients with cirrhosis

In seven patients with liver cirrhosis, verapamil plasma levels were measured in blood drawn simultaneously from the hepatic vein and from an artery during the post-distributive phase after an intravenous bolus infusion of 5 mg of verapamil. In addition the hepatic plasma flow was measured using the indocyanine-green constant infusion technique. From these data the verapamil hepatic clearance and verapamil intrinsic clearance were calculated. The verapamil hepatic clearance was 423 +/- 92 ml/m, the hepatic plasma flow was 819 +/- 318 ml/m, and the verapamil intrinsic clearance was 1431 +/- 961 ml/m. As compared to values reported in the literature, a decrease of the verapamil hepatic clearance by 50% approximately was found, while the hepatic plasma flow was in the normal range and the verapamil intrinsic clearance was reduced by 75%. These data show that in patients with cirrhosis the decrease in verapamil clearance is due to an impairment in the capacity of the liver to remove the drug, and not to a decrease in liver perfusion.     

The calcium-channel blocker, verapamil, does not improve portal pressure in patients with alcoholic cirrhosis.

1. Recently the calcium-channel blocker, verapamil, has been reported to decrease portal pressure in rats with experimental cirrhosis and in patients with liver cirrhosis. 2. In eight patients with alcoholic cirrhosis the effect of verapamil (5 mg i.v.) on systemic and splanchnic haemodynamics was investigated. 3. Mean arterial pressure, wedged hepatic venous pressure, hepatic venous pressure gradient, and verapamil plasma concentrations were measured before and at 10, 20, 30 min following 5 mg i.v. administration of verapamil. At 30-40 min cardiac output, systemic vascular resistance and hepatic blood flow were also measured. 4. Verapamil plasma concentrations averaged 47.9 +/- 52.0, 36.5 +/- 36.3, 31.3 +/- 33.9 ng ml-1 at 10, 20, 30 min respectively: mean arterial pressure and systemic vascular resistance decreased significantly (-9% and -14% respectively), and cardiac index increased significantly (+8%). Wedged hepatic venous pressure and hepatic venous pressure gradient remained unchanged, variations never exceeding 0.2 kPa. Hepatic blood flow increased significantly by 12%. 5. These results show that i.v. administration of 5 mg verapamil does not decrease portal pressure in alcoholic cirrhosis. This lack of effect is probably the consequence of a balance between decrease in porto-hepatic vascular resistance and increase in splanchnic blood inflow.     

Effect of vardenafil, an inhibitor of phosphodiesterase-5, on portal haemodynamics in normal and cirrhotic liver -- results of a pilot study

BACKGROUND: Dysregulation of the cyclic guanosine 3',5' monophosphate-nitric oxide system is in part responsible for portal hypertension in cirrhosis. AIM: To test the effects of inhibitors of phosphodiesterase-5 on portal haemodynamics. METHODS: To 18 healthy subjects and 18 patients with Child A liver cirrhosis, 10 mg of vardenafil, an inhibitor of phosphodiesterase-5, were administered orally. Doppler sonographic measurements of hepatic and splanchnic blood flow, systemic blood pressure and heart rate were recorded before, 1 h after, and 48 h after the application. Vardenafil plasma levels were determined after 1 h. In five patients, invasive registration of free and wedged hepatic vein pressure was performed. RESULTS: Portal venous flow increased in patients from 0.82 +/- 0.30 L/min (mean +/- s.d.) by 26% (CI: 16-37%, P = 0.0004) and in healthy subjects from 0.75 +/- 0.20 L/min (mean +/- s.d.) by 19% (CI: 9-28%; P = 0.0010). Celiac and hepatic artery resistivity indices rose significantly. Systemic blood pressure decreased slightly in patients. The wedged hepatic venous pressure gradient decreased in four of five patients with liver cirrhosis. Vardenafil plasma levels were higher in patients (14 +/- 10 microg/L) than in healthy subjects (9 +/- 6 microg/L; n.s.). CONCLUSIONS: Inhibition of phosphodiesterase-5 increases portal flow and lowers portal pressure by a decrease in sinusoidal resistance and may be a novel therapeutic strategy for portal hypertension.     

Pharmacokinetic interaction between verapamil and metoprolol in the dog. Stereochemical aspects.

The effect of verapamil co-administration on the hepatic first-pass clearance of metoprolol was investigated in dogs. Plasma concentration-time course of metoprolol enantiomers and urinary recovery of oxidative metabolites were determined after a single iv (0.51 mg/kg) and an oral (1.37 mg/kg) dose of deuterium-labeled pseudoracemic metoprolol, with or without concomitant administration of racemic verapamil (3 mg/kg). Verapamil inhibited both the systemic and oral clearance of metoprolol by about 50-70%. The first-pass effect of metoprolol was completely abolished after co-administration of verapamil, reflecting a marked alteration in the degree of hepatic extraction of metoprolol from intermediate to low. The hepatic clearance of metoprolol was slightly (S)-enantioselective (R/S ratio = 0.89 +/- 0.04) in control dogs. Inhibition of hepatic clearance of metoprolol by verapamil was selective towards (S)-metoprolol, such that the enantioselectivity in hepatic clearance toward (S)-metoprolol disappeared following verapamil co-administration (R/S ratio = 1.01 +/- 0.05). Urinary metabolite profiles indicated that O-demethylation and N-dealkylation were the major pathways of oxidative metabolism in the dog. alpha-Hydroxymetoprolol was a minor metabolite in urine. N-Dealkylation showed a strong preference for (S)-metoprolol, whereas O-demethylation and alpha-hydroxylation exhibited a modest selectivity toward (R)-metoprolol; hence, the slight (S)-enantioselectivity in the overall hepatic clearance. Comparison of metoprolol metabolite formation clearances in the absence or presence of verapamil co-administration showed that all three oxidative pathways were inhibited by 60-80%. The greater inhibition of hepatic clearance observed with (S)-metoprolol as compared to (R)-metoprolol was attributed to a significant (S)-enantioselective inhibition in the O-demethylation of metoprolol by verapamil.     

Hepatic Blood Flow Measurements and Indocyanine Green Kinetics in a Chronic Dog Model

The objective of this study was to compare hepatic blood flow measurements using ultrasonic flow probes and ICG in a conscious dog model and to evaluate whether ICG can be used to estimate relative change in hepatic blood flow. Seven mongrel dogs (3 M, 4 F, BW = 21 ± 1.8 kg, Hct = 0.39 ± 0.05) were used in the study. Catheters were surgically inserted into carotid artery and portal, hepatic and jugular vein. Transit-time ultrasonic flow probes were implanted around the portal vein and hepatic artery. After two weeks of recovery, a single i.v. bolus dose of ICG (0.5 mg/kg) was administered to each dog. The disposition profiles for ICG in the four catheters were measured for 15 minutes and the hepatic blood flow reading from the probes recorded. Jugular vein ICG blood clearance (Cl = 5.9 ± 1.1 ml/min/kg) was low compared to the electronically measured hepatic blood flow rate (Q = 27.8 ± 9.1 ml/min/kg). Extraction ratios (E = 0.15 ± 0.05) estimated using data from the inlet and the outlet of the liver were consistent with the clearance values, suggesting that ICG is not highly extracted by dog livers. Three dogs were used in experiments where liver blood flow was increased by food intake. Consistent with characteristics of low extraction ratio drugs, ICG was insensitive to blood flow changes while there was an overall increase in electronically measured liver blood flow of 30%. Therefore, ICG is a poor indicator of hepatic blood flow and the present dog model permits continuous and reliable measurements of hepatic blood flow and can be a useful tool in studying the effects of hepatic hemodynamics on pharmacokinetics.     

Contribution of the liver to overall elimination of propranolol

The pharmacokinetics of propranolol have been studied in pentobarbitone-anesthetized dogs after both systemic and portal venous administration. The results confirm that after systemic venous administration hepatic extraction is high, averaging 69–92% at one circulation, and that hepatic clearance accounts for 74–102% of the whole body elimination; thus the clearance of propranolol is chiefly dependent on hepatic blood flow. The kinetics differed when propranolol was given into the hepatic portal vein in a logarithmically declining fashion. Extraction of propranolol was initially complete in some dogs, but subsequently more propranolol left the liver in venous blood than entering via arterial and portal venous blood. These findings are interpreted as evidence for saturation of propranolol extraction by the liver.     

Effect of nadolol on liver haemodynamics and function in patients with cirrhosis.

Beta-adrenoceptor blockers used in the medical management of portal hypertension decrease liver blood flow. The sporadic onset of hepatic encephalopathy during propranolol treatment was ascribed to this decrease. The aim of the present study was to evaluate the effect of chronic treatment with nadolol on liver blood flow and liver function. Nadolol, a non-cardioselective beta-adrenoceptor blocker, has been reported to be as powerful as propranolol in decreasing portal pressure. Before and after 1 month of treatment with nadolol at a dose reducing heart rate by 25%, in 15 cirrhotic patients with portal hypertension, the following parameters were determined: hepatic venous pressure gradient, hepatic blood flow, galactose eliminating capacity, aminopyrine metabolic activity, ICG clearance and intrinsic hepatic clearance. Hepatic venous pressure gradient and hepatic blood flow were decreased by nadolol. However liver function was not affected by the drug. We conclude that, despite a lowered hepatic blood flow, liver function is not affected by 1 month of nadolol treatment.     

THE INFLUENCE OF LIDOCAINE AND VERAPAMIL ON HAEMODYNAMIC PARAMETERS AFTER INTRAVENOUS ADMINISTRATION OF MIDAZOLAM IN RABBITS

Cardiac arrhythmia can be a serious complication during general anaesthesia of patients suffering from cardiac arrhythmias and using antiarrhythmic drugs. The aim of the present experiments was to establish the way in which lidocaine and verapamil influence haemodynamic parameters of rabbits after midazolam anaesthesia. The experiments were performed on rabbits. Heart rate was counted according to ECG. Blood pressure was measured directly in the carotid artery. Cardiac output, stroke volume, and total peripheral resistance were estimated using the method of human 125J albumin dilution. Midazolam caused a gradual fall of arterial blood pressure till 30 min of the experiment. The decrease of blood pressure in the first 45 min of the experiment might be a result of decreasing peripheral resistance, and after 60 min should be rather attributed to a decrease of cardiac output and stroke volume. Lidocaine did not change the influence of midazolam on the blood pressure and heart rate. The consequence was a decrease of blood pressure after midazolam and lidocaine administration. Combined administration of midazolam and lidocaine decreased the influence of both midazolam and lidocaine on the total peripheral resistance. An injection of midazolam with verapamil resulted in a significant decrease of blood pressure. Combined administration of midazolam and verapamil caused a significant decrease of heart rate as compared with the initial value and administration of midazolam alone.     

原发性肝癌双介入化疗栓塞肝血流的测定

目的探讨肝动脉门静脉双介入化疗栓塞方法治疗原发性肝癌肝血流的变化。方法原发性肝癌50例分为肝动脉泵+门静脉泵灌注化疗(A组)25例,肝动脉泵化疗(B组)25例,观察彩超、增强CT、核素显像对原发性肝癌血流的变化。结果 A组92.0%高于B组84.0%(χ2=3.79,P<0.05);彩超发现肿块共56个,超声造影检出肿块54个,增强CT检出肿块55个。三者比较差异无统计学意义;术后门静脉血流量(1303.6±98.6)mL/min低于术前(1552.7±72.3)mL/min(t=2.345,P<0.05);术后脾静脉血流量(8073.8±30.6)mL/min高于术前(1055.9±29.8)mL/min(t=2.345,P<0.05);不同显像方法阳性率比较差异无显著性意义。结论肝动脉门静脉双介入化疗栓塞治疗原发性肝癌是安全有效的方法。     

肝癌及门静脉癌栓血供灌注特征的彩超与超声造影研究

目的探讨彩超(CDUS)与超声造影(CEUS)对不同类型肝癌及门静脉癌栓(PVTT)的血供灌注特征及临床价值。方法应用CDUS及CEUS对经临床证实的369例437个不同类型肝癌病灶及合并的PVTT进行血供灌注特征和血流动力学变化的研究分析。结果①肝癌血供灌注呈多样性:肝动脉血供为主型占72.8%(318/437),肝动脉和门静脉双重血供型占16.7%(73/437),肝动脉和门静脉双重血供兼动静脉瘘型占8.2%(36/437),门静脉血供为主型占2.3%(10/437)。②PVTT血供灌注也呈多样性,即肝动脉血供型或双重血供型。③肝癌血供的CEUS初始强化形态与肿瘤血管分布状态密切相关。结论 CEUS可明确判定肝癌及合并的PVTT的血供灌注特征,对肝癌的诊断、鉴别诊断及治疗方案的选择有重要的临床价值。     

Characteristics of liver circulation and the outflow of bile and lymph in acute carbon tetrachloride poisoning]

In acute tests set up on 13 dogs the pressure and blood flow in the portal vein and hepatic artery, the pressure in the inferior vena cava along with lymph- and bile currents were registered following intraportal introduction of CCI4. Subject to determination were also the resistance of venous and arterial hepatic vessels and of the splachnic zone, as well as the summary blood flow. The rising pressure and diminished blood flow in the portal vein were found to be the result of the growing resistance of venous vessels in the liver. Falling pressure and reduced blood flow in the hepatic artery bore witness to the general toxic effect of CCl4 on the animal organism. Increased portal pressure and disturbed permeability of biological membranes was attended by a greater lymph outflow. The inhibition of bile secretion came as a result of hypoxic and toxic damage of the liver.     

猪肝脏体外不同灌流系统建立和评价

目的：探讨体外肝脏灌流系统中的影响因素，建立稳定有效的体外肝脏灌流系统。方法：根据灌流和氧合的方式建立不同的体外猪肝脏灌流系统，随机分为3组(每组n=4)。A组单独灌流门静脉，氧合灌流液；B组同时灌流门静脉和肝动脉，共同氧合门静脉和肝动脉的灌流液；C组同时灌流门静脉和肝动脉，分别氧合门静脉和肝动脉的灌流液。观察体外肝脏灌流时间、胆汁分泌量、病理变化和血液动力学等指标。结果：A组的灌流时间明显低于B组和C组。在1，3，6h的时间点A组胆汁分泌量、血液动力学等指标和B、C组比较差异有统计学意义。在12h时间点B组和C组胆汁分泌量和血液动力学的差异也有统计学意义。结论：同时灌流门静脉和肝动脉，分别氧合门静脉和肝动脉灌流液的灌流系统更稳定，对体外肝脏功能的维持效果较好。     

彩色多普勒超声检查在肝癌肝动脉化疗栓塞术疗效评价中的价值

目的:探讨彩色多普勒超声检查在原发性肝癌(HCC)经肝动脉化疗栓塞术(TACE)疗效评定中的价值.方法:对72例原发性肝癌患者TACE术前、术后7天、术后30天行彩色多普勒超声检查,观察肿瘤大小及内部回声改变、肿瘤血供情况、记录肝动脉血流、门静脉血流动力学改变.结果:原发性肝癌TACE术后肿瘤显著缩小、血供明显减少,肝动脉峰值流速、平均流速明显下降,门静脉血流速度增快.结论:彩色多普勒超声检查能判断肝癌术前术后肿瘤大小及血流灌注状态,是目前检验肝癌TACE术疗效评定的有效影像学检查方法之一.     

Do beta blockers differ in their effects on hepatic microsomal enzymes and liver blood flow?

The effects of three beta blockers on liver blood flow and hepatic enzyme activity were investigated. Eight healthy subjects received placebo, 100 mg metoprolol, 40 mg nadolol, and 60 mg propranolol orally three times a day for four days in a randomized block design. On the fourth day of each treatment, beta blockade was measured by inhibition of exercise-induced tachycardia and apparent liver blood flow was measured by indocyanine green clearance. Plasma concentrations of the beta blockers were measured 2 hours after the early morning dose. Metoprolol produced the greatest inhibition of exercise tachycardia. All three drugs appeared to reduce liver blood flow, but this was only statistically significant in the case of propranolol. Enzyme inhibition occurred but to a varying extent. Propranolol produced a 36 per cent fall in antipyrine clearance (P less than 0.1) while metoprolol and nadolol both caused a 12 per cent reduction (P less than 0.05 and P = 0.06, respectively). Wide interindividual variation in the plasma concentrations of the drugs limit interpretation, but the results suggest that at the doses used, metoprolol and nadolol may be less likely to cause significant drug interaction by enzyme inhibition than propranolol.     

彩色多普勒检测肝外阻塞性黄疸肝脏血流动力学改变

目的：应用彩色多普勒研究阻黄患者肝血流动力学的改变。方法：用彩色多普勒检测阻黄患者１８例（对照组正常人１０名）的门静脉、肝动脉管径,门静脉血流速度,肝动脉收缩期峰值速度（Ｖｍａｘ）,舒张末期峰值速度（Ｖｍｉｎ）及其时间平均速度（Ｖｍｅａｎ）和其阻力指数（ＲＩ）。结果：阻黄时,门静脉管径及其流速、流量与正常人比较无统计学意义（Ｐ＞０．０５）;肝动脉管径明显扩张,肝动脉流速、流量与正常人比较有统计学意义（Ｐ＜０．０５）。肝动脉阻力指数与正常人比较无统计学意义（Ｐ＞０．０５）。结论：阻黄时,肝脏血流量明显增多,门静脉血流量与正常人无明显差异。     

Disagreement between acute and chronic haemodynamic effects of nadolol in cirrhosis: a pathophysiological interpretation

BACKGROUND: The acute effects of beta-blockers may be different from chronic; mechanisms underlying this difference are poorly elucidated. AIM: To assess portal pressure and its pathophysiological determinants after acute and chronic administration of nadolol. METHODS: In 24 patients with cirrhosis and portal hypertension hepatic venous pressure gradient, portal blood flow and resistance to portal blood flow were measured before, 60-90 min after acute administration of nadolol, and after 1 month. Patients were good-responders if hepatic venous pressure gradient was < or =12 mmHg, or decreased by at least 20%. RESULTS: Eleven and 13 patients were good- and poor-responders to acute administration, respectively. Acute poor-responders showed a lower decrease in portal blood flow (P = 0.04) and a less evident decrease in mean arterial pressure (P < 0.001). Eleven and 13 patients were good- and poor-responders to chronic administration, respectively. Chronic poor-responders showed a larger increase in resistance to portal blood flow compared with good-responders (P = 0.01). Disagreement between acute and chronic effects was seen in 12 patients: six were acute good-responders chronic poor-responders and six were acute poor-responders chronic good-responders. Acute good-responders chronic poor-responders patients had the smallest decreases in portal blood flow and in mean arterial pressure after acute administration, while acute poor-responders chronic good-responders showed the largest (P = 0.05 and 0.01). CONCLUSIONS: Disagreement between acute and chronic effects of nadolol on hepatic venous pressure gradient is common. The mechanism responsible is complex, the acute effect being mainly modulated by arterial hypotension and the chronic effect by changes in portal resistance.     

Arterial-venous blood alcohol concentration gradients

Arterial and venous blood alcohol concentration (BAC)-time courses were completely defined in the peripheral circulations, both during and after the constant rate infusions of ethanol via the cephalic vein or hepatic artery in the dog. These BAC data were characterized by the following trends. (1) A much faster rise in the blood alcohol curve, as well as a higher peak BAC was found using the shorter infusion time. (2) During infusion, the alcohol concentration was higher in arterial or arterialized blood than venous blood when infusion was via the cephalic vein. (3) Peak BAC was higher in the femoral artery than the femoral vein whether infusion was via the cephalic vein or hepatic artery. (4) Peak BAC was higher in the hepatic artery or portal vein than the hepatic vein when infusion was via the cephalic vein. When administration was directly into the liver, the peak BAC in the hepatic vein was higher than the portal vein. (5) After infusion ceased, there was an arterial-venous inversion; peripheral arterial ethanol concentrations were significantly less (p<0.001)than corresponding venous concentrations; with cephalic vein administration, a hepatic vein-portal crossover was observed, the reverse being true when ethanol was administered via the hepatic artery. In either case, the BAC was observed to be higher in the hepatic artery than the portal vein or hepatic vein throughout the sampling period. (6) BAC was observed to be higher for the same sampling times at the respective sites when ethanol was administered directly into the liver. While the methodology in this study is prohibitive for human experimentation, correlations may be extended to man. The elaboration of the arterial-venous concentration differences for ethanol should prove beneficial in revealing the relationships among the doses of alcohol, the circulating blood ethanol concentrations, and physiological and psychomotor test parameters in man.This work was supported in part by a grant from The University of Connecticut Research Foundation.Abstracted in part from a dissertation by J. L. Rheingold submitted to The University of Connecticut in partial fulfillment of the Doctor of Philosophy degree requirements.     

哌唑嗪预防食管胃静脉曲张破裂再出血的临床对照研究

目的探讨哌唑嗪预防肝硬化食管胃静脉曲张破裂出血复发的效果及其作用机制。方法对 35例治疗组患者和 35例对照组患者进行前瞻性对照研究 ,在用药前后用彩色多普勒超声仪检测其门静脉系统血流动力学的变化 ,并动态监测患者的血压、心率、肝肾功能及食管胃静脉曲张破裂出血复发情况。结果用药 10天后治疗组门静脉血流量、脾静脉血流量显著下降 ,于 4周后门静脉血流量、脾静脉血流量、门静脉内径、脾静脉内径 ,分别下降为 10 5 1 3± 378 5ml min ,5 4 8.3± 331.1ml min ,1.3± 0 .4cm ,0 .9± 0 .2cm ,与用药前比较差异有显著性 ,临床上未见明显副反应 ;随访 2年 ,对照组再出血率和病死率均显著高于治疗组 ,两组中Child -pughC级患者的病死率无显著性差异。结论哌唑嗪预防食管胃静脉曲张破裂出血的复发是安全有效的 ,值得在临床进一步研究和试用。     

THE EFFECT OF VASOPRESSIN ON HEPATIC ARTERY FLOW IN THE RAT

The effects of vasopressin infusion on hepatic artery flow was studied in rats. Hepatic artery ligation followed by the infusion of vasopressin (0.08 microU/g body weight per min) decreases portal venous flow and liver blood flow. Vasopressin infusion results in an increase in hepatic artery flow and liver blood flow both of which are abolished by subsequent hepatic artery ligation. The increase in hepatic artery flow and the decrease in portal venous flow following the infusion of vasopressin is discussed in relation to the management of patients presenting with bleeding oesophageal varices.     

Verapamil pharmacokinetics and apparent hepatic and renal blood flow.

The effect of acute and continued administration of verapamil on pharmacokinetics and regional blood flow has been studied in eight normotensive subjects. Continued administration resulted in a significant decrease in verapamil clearance, compared to that following acute dosing, as assessed by increases in both terminal elimination half-life (from a mean +/- s.d. of 5.2 +/- 2.3 h to 6.7 +/- 2.0 h) and AUC (from a mean +/- s.d. of 800 +/- 353 ng ml-1 h to 1455 +/- 244 ng ml-1 h). The relative clearance of norverapamil was not changed. Acute administration of verapamil resulted in a significant increase (P less than 0.005) in apparent liver blood flow which with continued administration fell significantly (P less than 0.01) towards placebo values. Effective renal plasma flow similarly increased with acute verapamil administration (P less than 0.05) and with chronic administration reduced again to be not significantly different from placebo. Acute and chronic verapamil administration did not significantly alter glomerular filtration rates. These results suggest that there may be a relationship between the acute increase in liver blood flow and the relatively increased clearance of verapamil following acute dosing.