Karl-Ludwig Schulte

Clinical pharmacokinetics of angiotensin converting enzyme (ACE) inhibitors in renal failure.

SummaryArterial hypertension occurs frequently in patients with chronic renal failure. Antihypertensive treatment of arterial hypertension with angiotensin converting enzyme (ACE) inhibitors has been shown to be effective with a low incidence of adverse effects compared with other drug classes. Furthermore, treatment with ACE inhibitors may slow the progression of renal function impairment in certain groups of patients, such as those with diabetes.Most ACE inhibitors are prodrugs which are converted by hepatic esterolysis to an active diacid metabolite. Only captopril and lisinopril have sufficient oral bioavailability and are given as active drugs. ACE inhibitors can be subdivided into 3 classes with regard to the active group: the majority of ACE inhibitors are carboxyl-containing drugs, a new class of ACE inhibitors possess a phosphoryl-group and captopril and related compounds are sulfhydryl-containing drugs.The predominant elimination pathway of ACE inhibitors is excretion via the kidneys. Therefore, renal insufficiency is associated with reduced elimination of most ACE inhibitors and, thus, altered pharmacokinetic properties. This is most evident in chronic renal failure when glomerular filtration rates (GFR) are <30 to 40 ml/min (1.8 to 2.4 L/h). As renal clearance decreases, the peak plasma concentration and area under the plasma concentration-time curve of the active drugs or diacids are increased and time to peak concentrations and half-life are prolonged. However, there are large between-drug differences in the changes in pharmacokinetic parameters, resulting in different degrees of drug accumulation after consecutive administration. This leads, for example, to high accumulation rates for drugs such as lisinopril, or cilazaprilat. In contrast, fosinopril, which is also excreted to a large extent by the hepatobiliary pathway, does not seem to accumulate in renal failure.In general, pharmacokinetics and conversion of prodrugs seem to be slightly affected in chronic renal failure; however, these changes do not appear to be clinically relevant. Efficiency of clearance for prodrugs or active drugs and their respective metabolites by haemodialysis or peritoneal dialysis varies considerably. For some ACE inhibitors, such as captopril or enalapril, the high elimination fraction by haemodialysis necessitates a supplemental dose after dialysis. Other ACE inhibitors, such as quinapril or cilazapril, are only poorly eliminated by haemodialysis or peritoneal dialysis.Dosage recommendations for treatment with ACE inhibitors in chronic renal failure depend on the specific pharmacokinetic properties of the various agents. For most ACE inhibitors, dosage adjustment is recommended in moderate and severe impairment of renal function, with resultant dosages being 25 to 50% of those recommended for patients with normal renal function.

Antihypertensive and metabolic effects of diltiazem and nifedipine.

The antihypertensive effect of diltiazem (180-270 mg/day) and nifedipine (40-60 mg/day) in slow-release forms was assessed over 8 weeks in a double-blind parallel study in 40 subjects with essential hypertension at rest and during exercise. Blood pressure was comparably reduced in both groups at rest as well as during exercise. The responder rates (greater than or equal to 10% reduction in diastolic blood pressure) after 8 weeks of therapy were 53% at rest and 75% during exercise in the diltiazem group and 78% and 50%, respectively, in the nifedipine group. Diltiazem decreased heart rate by 8% (p less than 0.01), while nifedipine did not affect it. As a consequence, myocardial oxygen consumption, as judged by the pressure-rate product, was reduced by diltiazem. Resting plasma norepinephrine levels were increased significantly after 8 weeks of diltiazem therapy. Plasma epinephrine, renin, aldosterone, glucose, insulin, and lactate and routine laboratory parameters were unchanged at the end of the study. No significant changes in total cholesterol and triglyceride levels were observed after 8 weeks. Whereas therapy with diltiazem resulted in an 8% fall in low density lipoprotein cholesterol after 8 weeks (p less than 0.05), nifedipine induced a drop in very low density lipoprotein cholesterol (p less than 0.05) after 8 weeks of therapy. We conclude that both diltiazem and nifedipine are effective antihypertensive agents lacking undesirable metabolic side effect. Diltiazem, however, had the advantage of lowering heart rate and myocardial oxygen consumption.

Relation of regression of left ventricular hypertrophy to changes in ambulatory blood pressure after long-term therapy with perindopril versus nifedipine

Casual as well as ambulatory 24-hour blood pressure (BP) and echocardiographic parameters were studied in 40 patients with untreated or insufficiently treated mild to moderate essential hypertension. Left ventricular (LV) hypertrophy was assessed before and after 24 weeks of therapy with either the converting enzyme inhibitor perindopril or the calcium antagonist nifedipine. The design was a double-blind parallel study with a placebo run-in period. Patients received a daily oral dosage of either 4 to 8 mg of perindopril or 40 to 80 mg of nifedipine in slow-release form. A diuretic (25 mg/day of hydrochlorothiazide) was added in nonresponders (greater than 90 mm Hg casual diastolic BP). Once-daily perindopril and twice-daily nifedipine comparably reduced both casual and ambulatory BP throughout 24 hours (p less than 0.01) without affecting 24-hour heart rate. Six subjects withdrew from the nifedipine group and 4 from the perindopril group. After 12 and 24 weeks of therapy, LV hypertrophy was significantly reduced by both agents. Before active treatment was begun, LV mass index was more closely correlated to 24-hour (p less than 0.001) than to casual BP. This correlation disappeared after treatment with both agents. The correlation between ambulatory systolic day-time BP and LV mass was only still present (r = 0.54; p less than 0.05) after 24 weeks of treatment with nifedipine. It is concluded that regression of LV hypertrophy during converting enzyme inhibition or calcium antagonism may be partly independent of dosage and magnitude of 24-hour BP decrease.

Functional versus structural changes of forearm vascular resistance in hypertension.

Structural changes in resistance vessels have been considered an important factor in triggering and maintaining chronic hypertension in humans and in experimental animals. To determine whether the increased forearm vascular resistance observed following vasodilator maneuvers in hypertensive patients is predominantly due to structural or to functional changes, we examined the influence of different vasodilator stimuli on forearm blood flow and blood pressure in 22 male patients with established essential hypertension and in 22 age-matched normotensive men (age range, 28-52 years). Blood pressure was measured directly, and blood flow was measured by venous occlusion plethysmography. The maneuvers applied were 1) arterial occlusion combined with handgrip exercise and local heating, 2) intra-arterial infusion of the calcium entry blocker nifedipine, 3) intra-arterial infusion of the nonspecific vasodilator sodium nitroprusside, 4) arterial occlusion initiated after intra-arterial infusion of nifedipine. Vascular resistance during vasodilation induced by arterial occlusion or infusion of nifedipine or sodium nitroprusside remained significantly higher in the hypertensive than in the normotensive subjects. However, the maximal vasodilation achieved by the combination of arterial occlusion and nifedipine resulted in a similar resistance in both groups (1.6 +/- 0.2 in the hypertensive vs 1.4 +/- 0.2 mm Hg/ml/min/100 ml tissue in the normotensive subjects. These data suggest that there is an important functional component of the elevated resistance in patients with essential hypertension.

Color-Coded Duplex Sonography for Noninvasive Diagnosis and Grading of Renal Artery Stenosis

The accuracy of color-coded duplex sonography (CCDS) in screening hypertensive patients for renal artery stenosis (RAS) was assessed using a semi-quantitative waveform analysis. Our special aims were to separate between moderate and high grade stenoses and to evaluate the accuracy of the method in imaging both the whole course of the renal arteries and accessory renal arteries. Included in the prospective, angiographically controlled study were 135 consecutive patients with 268 renal arteries, of which 195 arteries (73%) could be visualized both proximally and distally by CCDS. Only three of 15 accessory renal arteries could be identified by CCDS. In 42 RAS > or = 50% sensitivity of CCDS was 93%, specificity 92%, and overall accuracy 92%. The sensitivity in identifying RAS > or = 75% was 92%, and none of the high grade stenoses were missed. Because of difficulties in visualizing the middle portion of the renal artery, we carefully examined this part of the artery in 116 additional patients. Whereas the proximal and the distal parts could be visualized in 77% of the renal arteries, signals from the middle third could be derived only in 60% on the right, and in 39% on the left side. Provided that the renal arteries were visualized both proximally and distally, a hemodynamically effective RAS could be excluded with high probability. Moreover, exact grading of high-grade stenoses was possible in all cases but one. An advantage of CCDS over conventional duplex sonography appears to be the time-saving examination. Since a low prevalence of RAS impairs the positive predictive value of CCDS, the examination should be reserved for patients with a strong clinical suspicion of renovascular hypertension.

Clonidine suppression test revisited.

BACKGROUND The diagnosis of pheochromocytoma may be difficult because the clinical picture is variable. OBJECTIVE The purpose of this paper is to report our experience and to review the published data on the diagnostic significance and risks of the clonidine suppression test in the diagnosis of pheochromocytoma. PATIENTS AND METHODS 114 patients were evaluated for pheochromocytoma using the clonidine suppression test. RESULTS The diagnosis was established in four patients. Overall accuracy of the test in our own series was 98% when the normal response to clonidine was defined as total plasma catecholamines of less than 500 ng/L, or less than 70% of the baseline value. No serious complication was noted. CONCLUSION Our data and the published series demonstrate that the clonidine suppression test is accurate and safe in patients with suspected pheochromocytoma.

Hyperreninemia and Secondary Hyperaldosteronism in a Patient with Pheochromocytoma and von Hippel-Lindau Disease

In a 21-year-old Caucasian women with von Hippel-Lindau disease, norepinephrine-producing adrenal pheochromocytoma was identified as the underlying cause of severe hypertension. She was found to have extremely elevated levels of circulating renin and aldosterone, and she was markedly hypokalemic. Administration of captopril further enhanced renin secretion, while her blood pressure improved. The patient became normokalemic following tumor removal, and her blood pressure decreased to normal levels with reestablishment of normal circadian blood pressure rhythm. This case demonstrates that, in the absence of renovascular or malignant hypertension, pheochromocytoma can be the underlying cause for the clinical syndrome of hypertension associated with severe hypokalemia and hyperreninemic hyperaldosteronism.

24-hour noninvasive oscillometric blood pressure monitoring: evaluation of the antihypertensive circadian profile of nitrendipine.

The understanding of blood pressure (BP) and heart rate (HR) variation, circadian changes, and the responses to nonclinical situations has been improved by automated ambulatory recordings. The antihypertensive efficacy of a once-daily regimen (10/20 mg) of nitrendipine was evaluated in detail using the lightest available portable device equipped with an oscillometric blood pressure (BP) recorder (SpaceLabs 90202, weight 480 g) devoid of any electrode. A good antihypertensive effect throughout the day in 20 outpatients could be demonstrated. No significant change of BP could be found in early morning and wake-up period; HR was not significantly affected after 6 weeks of oral therapy.

Circadian antihypertensive profile of carvedilol (BM 14190).

Summary: Carvedilol (BM 14190) is a new potent and well‐tolerated &bgr;‐adrenoceptor antagonist with vasodilating properties. Acute clinical studies have confirmed its efficacy as an antihypertensive agent. The present double‐blind, randomized, metoprolol‐controlled, longterm study reports the therapeutic results of carvedilol in essential hypertensive patients. Compared with placebo, carvedilol significantly reduces blood pressure after oral administration of 50 mg on a single and twice daily regimen. The antihypertensive effect was acute in onset, comparable in supine and standing position, and exercise‐induced hypertension and tachycardia were significantly reduced. Indirect automatic 24 h blood pressure monitoring reliably confirmed clinic blood pressure and demonstrated a good antihypertensive effect of carvedilol after a single oral administration throughout daily activities and sleeping periods.

Effects of diltiazem alone and combined with mefruside on cardiovascular response at rest and during exercise, carbohydrate metabolism and serum lipoproteins in patients with systemic hypertension

The antihypertensive effects of the calcium antagonist diltiazem, both alone and combined with the diuretic mefruside, were assessed over 14 months in 36 patients with essential hypertension. Patients received 180 or 270 mg/day; those with inadequate response were given 270 mg/day plus mefruside, 20 mg/day. Both monotherapy and combination therapy significantly reduced blood pressure (BP) at rest and during exercise. However, adding mefruside did not significantly decrease BP below that achieved with diltiazem alone. After 14 months of therapy, the percentage of responders (patients with at least 10% reduction in diastolic BP at rest) was 64% for all patients, 100% (by definition) for those receiving diltiazem alone and 47% for those receiving the combination. Diltiazem decreased heart rate by 6% (4 beats/min at rest) (p less than 0.05). Combined therapy with mefruside did not further reduce heart rate. There were few adverse effects and no undesirable metabolic effects with either monotherapy or combined therapy. Plasma renin activity, aldosterone levels, carbohydrate metabolism, serum lipoprotein levels and routine laboratory test results were unchanged in both groups at the end of the study. Thus, diltiazem is an effective antihypertensive agent and apparently the combination of diltiazem and mefruside does not potentiate the antihypertensive effect of diltiazem alone during long-term therapy.