Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four pharmacons were tested on an acute portal pressure lowering effect in an experimental animal model with 25 normal and 25 rats with Thioacetamide-toxic liver cirrhosis. Invasive measurements of arterial and portal pressure were made under Hexobarbital-Sodium anaesthesia during 30 minutes after pharmacon application. The portal pressure of cirrhotic rats was under basic conditions 9.5 +/- 1.5 mm Hg and significant higher as in normal animals (5.3 +/- 0.9 mm Hg, p less than 0.01). After 10 mg/kg body mass Propranolol the portal pressure decreased in both animal groups small but not significantly over the whole measurement time. 1 mg/kg Verapamil lowered arterial middle pressure significantly, but increased portal pressure at all 15-20% in both animal groups. Application of 0.1 mg/kg Prazosin decreased the arterial middle pressure at all 5-15% and the portal pressure at all 20-30% in both study groups (both significantly). For Canrenoat-Potassium (20 mg/kg) no clear effect could by evaluated on portal pressure. The model of Thioacetamide-toxic cirrhosis of the rat offers conditions like cirrhosis in human medicine in order to study the effects of portal pressure lowering pharmacons. Propranolol and Prazosin decrease portal pressure and should by further investigated.
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PMID:[Pharmacological lowering of portal pressure in normal rats and in experimental liver cirrhosis]. 181 60

Verapamil and nifedipine are the most frequently used calcium channel blocking agents in Sweden at present time. The pharmacokinetics of verapamil has been described both in healthy volunteers as well as in patients with supraventricular arrhythmias, angina pectoris, liver cirrhosis, hypertrophic cardiomyopathy or hypertension. Intravenous pharmacokinetics of nifedipine has been investigated in healthy volunteers and oral pharmacokinetics in healthy volunteers as well as in patients with hypertension. The pharmacokinetics of verapamil and of one of its metabolites, norverapamil, is changed after multiple oral dosing as has been described in patients with supraventricular tachyarrhythmias, angina pectoris or in patients with essential hypertension. Plasma concentration-effect relationships have been established for verapamil in different clinical situations and in a few cases also for nifedipine. An update of the pharmacokinetics of these two important calcium channel blocking agents is presented.
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PMID:Pharmacokinetics of calcium channel blocking agents. 294 Jul 99

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.
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PMID:The calcium-channel blocker, verapamil, does not improve portal pressure in patients with alcoholic cirrhosis. 317 67

We studied the effects of a series of 16 vasodilators on the intrahepatic vasoconstriction induced by norepinephrine in the isolated perfused rat liver. The vasodilators were nonselective alpha-adrenergic antagonists (phentolamine, ifenprofil, isoxsuprine and buflomedil), a nonselective beta-adrenergic antagonist (propranolol) and an agonist (isoproterenol), an alpha 2-adrenergic agonist (clonidine), calcium channel blockers (verapamil and diltiazem), nitrovasodilators (nitroglycerin, sodium nitroprusside), papaverine and other unclassified vasodilators, some of them with rheological properties (diazoxide, vincamine, cinepazide, naftidofuryl and pentoxifylline). The most potent drugs were ifenprofil, phentolamine, isoxsuprine, clonidine, sodium nitroprusside and buflomedil. Diazoxide, papaverine, pentoxifylline and trinitrine were less powerful. Verapamil, diltiazem, propranolol, isoproterenol, vincamine, cinepazide and naftidofuryl were ineffective. We conclude that different classes of pharmacological agents have significant vasodilatory properties on the hepatic microvasculature. This offers interesting perspectives in the treatment of cirrhosis and stressful states where high levels of circulating norepinephrine may contribute to the altered liver perfusion.
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PMID:Effect of vasodilators on hepatic microcirculation: a study of the inhibition of norepinephrine-induced vasoconstriction in the isolated perfused rat liver. 335 3

Acute and chronic effect of verapamil on estimated hepatic blood flow were investigated in 12 patients with HBsAg-positive cirrhosis and portal hypertension. Acute administration of verapamil results in a significant increase (8%) in estimated hepatic blood flow (p less than 0.05). However, after chronic continued administration of verapamil, the mean value of estimated hepatic blood flow remains unchanged vis-a-vis basal values. Acute and chronic use of verapamil significantly reduced the hepatic venous pressure gradient for about an average of 20% at 1 hr after drug administration (p less than 0.05) and 18% 2 weeks later (p less than 0.05). This drop was associated with a significant reduction in hepatic vascular resistance by 39% at 1 hr later and by 37% 2 weeks later. Furthermore, the drop in hepatic vascular resistance was independent of any verapamil-induced changes in systemic hemodynamics. Verapamil significantly increased the indocyanine green plasma clearance and extraction ratio after acute or chronic use of the drug. We conclude that in patients with HBsAg-positive cirrhosis, the mechanism of verapamil in reducing the hepatic venous pressure gradient is predominantly by inducing a drop in hepatic portal vascular resistance.
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PMID:Effects of verapamil on estimated hepatic blood flow in patients with HBsAg-positive cirrhosis. 340 2

The calcium antagonists diltiazem, nifedipine and verapamil are widely used in the treatment of coronary heart disease, arterial hypertension, certain supraventricular tachyarrhythmias and obstructive hypertrophic cardiomyopathy. During recent years their pharmacokinetic properties and metabolism have been studied in more detail. Although these 3 calcium antagonists exhibit great diversity in chemical structure, they exhibit common pharmacokinetic properties. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. Their systemic plasma clearances are high and dependent on liver blood flow. Therefore, their bioavailabilities (diltiazem 40 to 50%; nifedipine 40 to 50%; verapamil 10 to 30%) are low despite almost complete absorption following oral administration. During long term treatment, oral clearance decreases and bioavailability increases due to saturation of hepatic first-pass metabolism. Pronounced intra- and inter-individual variations in clearance and bioavailability are observed. In patients with liver cirrhosis the various pharmacokinetic parameters are grossly altered. Clearance decreases, elimination half-life is substantially prolonged, and bioavailability more than doubles. In addition, the volume of distribution increases. Whereas renal disease has no impact on the pharmacokinetics of diltiazem and verapamil, elimination half-life of nifedipine increases in relation to the degree of renal impairment due to an increase in volume of distribution. Systemic clearance, however, remains unchanged. The data so far available indicate that the plasma concentrations of these drugs correlate with both their electrophysiological and haemodynamic effects. However, no effective therapeutic plasma concentration range has been firmly established. As reliable clinical end-points are available for dose titration of calcium antagonists, it is doubtful whether therapeutic drug monitoring will be of great value. Calcium antagonists are often administered in combination with a variety of other drugs. Thus, the potential for both pharmacodynamic and pharmacokinetic drug interaction exists. The interaction between digoxin and these drugs is of clinical importance. Verapamil and diltiazem cause a significant increase in plasma digoxin concentrations. In contrast, nifedipine does not lead to a significant increase in the plasma digoxin concentration. The mechanism responsible for this interaction is inhibition of both renal and non-renal digoxin clearance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Clinical pharmacokinetics of verapamil, nifedipine and diltiazem. 354 36

The effect of the calcium channel blocking agent, verapamil, on microcirculatory patterns and hepatic function was investigated in the perfused liver of cirrhotic rats. Compared with controls, cirrhotic livers had higher vascular resistance, increased intrahepatic shunting, and smaller extravascular albumin space and larger extravascular sucrose space, as determined by a multiple-indicator dilution technique. Hepatic function, estimated by determining propranolol and antipyrine extraction, was markedly reduced in cirrhotic livers. Portal pressure was then reduced 25% either pharmacologically by verapamil or hydrodynamically by lowering inflow. Verapamil decreased vascular resistance by 22%. This was associated with a 38% reduction in intrahepatic shunting and a 62% increase in extravascular albumin space. Hydrodynamically lowering pressure had no or adverse effects. The verapamil-induced improvement in microcirculatory characteristics was associated with a significant improvement in oxygen consumption (+21%) and antipyrine clearance (+20%). We conclude that the microvascular distortions of liver cirrhosis in the rat are partially reversible by vasodilators like verapamil.
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PMID:Verapamil favorably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver. 373

The effects of verapamil on portal pressure, microsomal liver function and extravascular albumin space were investigated in rats rendered cirrhotic by chronic exposure to phenobarbital and carbon tetrachloride. Verapamil significantly decreased splenic pulp pressure by 28% (P less than 0.05). In cirrhotic animals it improved liver function, measured by the aminopyrine and caffeine breath tests, by 36% (P less than 0.025) and 53% (P less than 0.05), respectively. The extravascular albumin space, an important determinant of drug clearance, was measured by a multiple indicator dilution technique. It was significantly larger in verapamil treated than in untreated cirrhotics (4.41 +/- 1.06 vs 2.73 +/- 0.79 ml/g; P less than 0.01). We conclude that verapamil has significant potential as a portal antihypertensive agent and its value in treating cirrhosis in man should be explored by controlled studies.
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PMID:Chronic verapamil administration lowers portal pressure and improves hepatic function in rats with liver cirrhosis. 374 84

An understanding of the pharmacokinetics of the calcium antagonists (slow-channel blocking drugs) is essential in order to design appropriate dosage regimens which will provide optimum therapeutic efficacy with these agents. This review summarises and evaluates the current state of knowledge of the absorption and disposition characteristics of the 3 most extensively used calcium antagonists in cardiovascular therapeutics: verapamil, diltiazem and nifedipine. While an extensive literature regarding the kinetics of verapamil exists, reports dealing with diltiazem and nifedipine are limited. This is, in part, due to difficulties in developing simple, specific and sensitive analytical procedures. All 3 drugs undergo extensive metabolism in the liver. Metabolites of verapamil (norverapamil) and diltiazem (desacetyldiltiazem) accumulate in the plasma of patients and have been shown to produce some effects similar to those of their parent compounds. The bioavailability of diltiazem and nifedipine has not been well studied, and no investigations of the absolute bioavailability of these compounds have been reported. However, the bioavailability of verapamil has been studied extensively; about 22% of an orally administered dose of verapamil is systemically available. Bioavailability is increased when liver function is impaired, such as in patients with hepatic cirrhosis. The high first-pass extraction of verapamil has been suggested to be stereoselective, with preferential elimination of the (-) isomer. The plasma concentration-time curves of verapamil and diltiazem have been studied following oral administration. The elimination half-lives of verapamil and diltiazem are about 8 and 5 hours, respectively. All 3 drugs are highly protein-bound in the plasma. Several other drugs have the ability to displace verapamil from plasma protein binding sites, but the clinical significance of this interaction is doubtful. Other drug interactions have been investigated with these agents. Verapamil causes digoxin plasma levels to rise during concomitant administration, but no drugs have been shown to alter the disposition of verapamil. Diazepam affects the plasma levels of diltiazem leading to a decrease. The mechanism of this interaction has not been reported, but an effect on bioavailability has been suggested. Age has been shown to be a factor in the disposition of both diltiazem and verapamil. Older patients tend to have lower clearances of these 2 drugs than do younger patients. It has also been shown that hepatic cirrhosis leads to a decreased clearance of verapamil. Plasma level monitoring may be helpful for adjusting doses of both verapamil and diltiazem, despite the absence of a definition of therapeutic plasma concentrations. These agents all have low, and highly variable, systemic availability, and plasma concentrations cannot be predicted after oral administration.
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PMID:Calcium antagonists. Pharmacokinetic properties. 633 96