Erich Keller

Drug dosage in patients during continuous renal replacement therapy : pharmacokinetic and therapeutic considerations

SummaryThe advantages of continuous haemofiltration and haemodialysis over intermittent haemodialysis for the treatment of acute renal failure are well recognised. In intensive care patients, 4 different continuous procedures, arteriovenous and venovenous haemofiltration (CAVH and CVVH) or haemodialysis (CAVHD and CVVHD), are employed. These effective detoxification treatments require knowledge of their influence on drug disposition. Data on kinetics of drugs during continuous treatment are scarce and limited almost exclusively to the oldest and least effective procedure (CAVH). Selected dialysis membranes may adsorb drugs, as in the case of aminoglycosides. In addition, elimination of substances with large molecular weights may vary depending on the pore size of the membrane, as in the case of vancomycin. Thus, even if drug dosages can be based on pharmacokinetic studies, selection of a dialysis membrane not studied may cause unpredictable drug concentrations. With these limitations in mind and considering the available literature on pharmacokinetics in patients with renal failure, general guidelines for drug dosage during continuous renal replacement therapy can be given.In haemofiltration, drug protein binding is the major factor determining sieving, i.e. the appearance of the drug in the ultrafiltrate. In haemodialysis, diffusion is added to ultrafiltration, and therefore the saturation of the combined dialysate and ultrafiltrate will decrease further with increasing dialysate flow rate. In continuous haemofiltration or haemodialysis the extracorporeal clearance can be calculated by multiplying the saturation value (estimated or, better, measured) with the ultrafiltrate and dialysate flow rate. Dividing the extracorporeal clearance by the total clearance (including the nonrenal clearance) gives the fraction of the dose removed due to extracorporeal elimination. Whether dosage recommendations available for anuric patients have to be modified or not can be decided on the basis of this value. In case of high nonrenal clearance, the degree of saturation is without clinical significance. Based on these considerations guidelines have been constructed for the effect of extracorporeal elimination on more than 120 different drugs commonly used in intensive care patients.

Pharmacokinetics of gabapentin in subjects with various degrees of renal function

The pharmacokinetics of oral gabapentin (400 mg) was studied in normal subjects and in subjects with various degrees of renal function. Sixty subjects participated in this three‐center study. None of the subjects were receiving hemodialysis. Plasma and urine samples were collected for up to 264 hours after dosing, and concentrations of gabapentin were determined by high performance liquid chromatography. Apparent oral plasma clearance (CL/F) and renal clearance (CLR) of gabapentin decreased and maximum plasma concentration, time to reach maximum concentration, and half‐life values increased as renal function diminished. Gabapentin CL/F and CLR were linearly correlated with creatinine clearance. Total urinary recovery of unchanged drug was comparable in all subjects, indicating that the extent of drug absorption was unaffected by renal function. There was no evidence of gabapentin metabolism even in subjects with severe renal impairment. In summary, impaired renal function results in higher plasma gabapentin concentrations, longer elimination half‐lives, and reduced CL/F and CLR values. Based on pharmacokinetic considerations, it appears that the dosing regimen of gabapentin in subjects with renal impairment may be adjusted on the basis of creatinine clearance.

Influence of hepatic cirrhosis and end-stage renal disease on pharmacokinetics and pharmacodynamics of furosemide

SummaryAfter rapid intravenous injection of furosemide 40 mg (Fu), plasma levels were determined in 7 healthy volunteers, 8 patients with liver cirrhosis with ascites and 7 patients with end-stage renal disease (ESRD). The diuretic response was evaluated by measuring the urinary excretion of sodium and potassium and the urine volume. The mean elimination half life (tF1/2+) of Fu averaged 51±7.7 (±SD) min in healthy subjects, 52±7.7 min in cirrhosis and 200±57 min in ESRD. The non-renal clearance (Clnr) in healthy subjects (56±28 ml/min) corresponds to the total plasma clearance in functionally anephric patients (54±18 ml/min). In cirrhosis there was no significant change in the disposition parameters of Fu in comparison to the healthy volunteers, but there was a significant reduction in urine sodium and volume, whereas potassium excretion remained unchanged. Fu “excretion rate — response” curves showed diminished tubular sensitivity to Fu in cirrhosis.

Disposition and diuretic effect of furosemide in the nephrotic syndrome.

Plasma levels and diuretic response were determined in seven healthy subjects and six patients with severe nephrotic syndrome (NS) after 40 mg furosemide (Fu). Mean apparent volume of distribution and distribution volume at steady state of the groups did not differ. Total Fu clearance was higher in NS (251 ± 54 ml/min) than in healthy subjects (174 ± 32 ml/min) (P < 0.01), a difference that correlated with the nonrenal clearance of 56 ± 28 ml/min in healthy subjects and 154 ± 45 ml/min in patients with NS (P < 0.001). Normal β‐elimination half‐life of 51 ±7.7 min was 37 ± 6.2 min (P < 0.001) in NS. Mean normal Fu protein binding of 98.6 fell to 97.2%, with decreasing plasma albumin levels. After 40 mg IV Fu, sodium and volume excretion decreased in NS (P < 0.001 and P < 0.005). In patients Na+/Fu excretion rate ratios showed “tubular resistance” to Fu over the time when large amounts of Fu were excreted. The reduced diuretic response to Fu in NS is taken to be mainly a consequence of its impaired renal excretion.

Rebound of plasma vancomycin levels after haemodialysis with highly permeable membranes

SummaryVancomycin is usually given only once a week to haemodialysis (HD) patients. If highly permeable dialysis membranes are used, however, high clearance values have been reported, so the aim of the study was to determine whether high clearance of vancomycin resulted in sufficient drug elimination to induce subtherapeutic plasma levels after one week. In 18 chronic HD patients, treated with polysulfone dialyzers (1.2 m2), the pharmacokinetics of vancomycin were studied after administration of 1 g. Concentrations were determined by fluorescence polarisation immunoassay.At a blood flow of 219 ml·min−1, HD clearance of vancomycin was 62.3 ml·min−1. Immediately after dialysis plasma concentrations were 38% lower than predialysis levels. However, marked rebound in the vancomycin level was observed 5 h later, resulting in plasma levels only 16% lower than prior to dialysis. 3 HD treatments in 1 week removed about one third of the initial dose. After one week 15 of 18 patients still had a therapeutic plasma level (>5 μg·ml−1).In conclusion, polysulfone membranes show high clearance of vancomycin. However, transfer of drug from blood to dialysate appears to be faster than from tissues to blood. Because of a marked rebound in plasma level after treatment, therapeutic drug concentrations will still be present in most patients after one week.

Effect of Nifedipine and Captopril on Glomerular Hyperfiltration in Normotensive Man

Glomerular hyperfiltration and hypertension induced by extensive loss of renal parenchyma are suspected to accelerate progression of renal failure. Amino acid infusion or protein ingestion also modify renal hemodynamics and increase glomerular filtration rate (GFR). This phenomenon was used to study the influence of two commonly used antihypertensive agents, captopril and nifedipine, on renal hemodynamics at rest and during glomerular hyperfiltration. Thirteen healthy volunteers were studied on three separate days (days A, B, and C) in random sequence: inulin and p-amino hippurate (PAH) clearance were measured first under glucose infusion and afterwards under stimulation by amino acid infusion (0.35 mmol/kg/min; 4 mg/kg/min). Day A served as a control, where no medication was given. On day B, 10 mg nifedipine, and on day C, 25 mg captopril, were administered orally before study. Without premedication (= day A, control) GFR increased from 108.0 +/- 6.9 mL/min (SEM) to 131.7 +/- 7.0 mL/min (P less than 0.05). On day B (nifedipine), GFR before stimulation by amino acids was already elevated to 121.8 +/- 4.2 mL/min (P less than 0.05 compared with day A) and increased to 132.6 +/- 6.3 mL/min with infusion of amino acids, thus to the same range as on day A without medication. On day C, after captopril, GFR did not increase with infusion of amino acids (from 112.5 +/- 7.2 to 117.3 +/- 6.3 mL/min). Our results indicate the calcium channel antagonist nifedipine and the angiotensin-converting enzyme (ACE) inhibitor captopril differ in their effect on intrarenal hemodynamic parameters. Nifedipine induces hyperfiltration at rest and allows maximal hyperfiltration to develop under amino acid infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraperitoneal and intravenous cefoperazone kinetics during continuous ambulatory peritoneal dialysis

Serum cefoperazone (CFP) kinetics after a 1‐gm dose added to the peritoneal dialysate were followed in seven patients undergoing continuous ambulatory peritoneal dialysis (CAPD). In a randomized order five of the seven patients received 1 gm IV CFP. Serum samples were collected over 10 hr during one dialysate exchange interval. CFP concentrations were determined by HPLC. After intravenous dosing CFP mean peak and 6‐hr serum concentrations were 104.2 ± 29.1 µg · ml−1 and 8.5 ± 3.8 µg · ml−1, mean body clearance was 80 ± 20 ml · min−1, and mean apparent volume of distribution was 14.6 ±3.2 l. The elimination rate constant (kel) varied from 0.29 to 0.38 hr−1 and was almost identical to kel derived from intraperitoneal application (range 0.29 to 0.42 hr−1). Instillation of CFP with the peritoneal dialysate resulted in a rapid rise of serum levels (Tmax = 1.9 ±0.7 hr; absorption rate constant ka = 0.68 ± 0.11 hr−1), and sufficient CFP concentrations (Cmax =33.2 ± 5.3 µg · ml−1), were maintained over 6 hr (C6hr = 17.3 ± 5.8 µg · ml−1). Mean systemic availability of intraperitoneal CFP was 95% ± 12%. Intraperitoneal administration of CFP in patients undergoing CAPD resulted in serum levels of CFP adequate for systemic treatment of bacterial infections.

Effect of antihypertensive drugs on glomerular hyperfiltration and renal haemodynamics: Comparison of captopril with nifedipine, metoprolol and celiprolol

SummaryGlomerular hyperfiltration and hypertension may contribute to the progression of chronic renal insufficiency regardless of the underlying disease. Protein restriction and antihypertensive treatment are used to slow the decline in renal function. However, little is known about the interaction of protein loading and antihypertensive treatment on glomerular haemodynamics in humans. This paper compares the renal haemodynamic effects ofβ-adrenoceptor blockers with those of the calcium channel antagonist nifedipine and the ACE inhibitor captopril on resting glomerular filtration and during glomerular hyperfiltration. In two separate studies the effects of nifedipine, captopril, metoprolol, and celiprolol on renal haemodynamics have been investigated. In two groups of healthy volunteers (n =13) inulin and PAH clearances were measured, first under fasting conditions and afterwards during aminoacid infusion.In fasting subjects nifedipine and metoprolol induced glomerular hyperfiltration, while celiprolol and captopril did not significantly affect GFR. Without premedication, and also after nifedipine, metoprolol and celiprolol, the aminoacid infusion significantly increased the GFR. After premedication with captopril, however, aminoacid-induced hyperfiltration was prevented. In fasting subjects captopril, celiprolol and metoprolol elevated PAH clearance. With our without premedication aminoacid infusion increased renal plasma flow compared to baseline on the control day.We conclude that in healthy subjects, acute administration of antihypertensive drugs results in different renal haemodynamic responses. In contrast to captopril and celiprolol, nifedipine and metoprolol induce glomerular hyperfiltration like protein loading. Thus, they may counteract the renal haemodynamic effects of protein restriction. Celiprolol behaves similarly to captopril, since it increases renal perfusion without inducing glomerular hyperfiltration, a pattern which might reflect lower glomerular pressure. Only captopril, however, was able to prevent glomerular hyperfiltration induced by aminoacids.If these observations are confirmed during chronic treatment of patients with impaired renal function, they may suggest that certain antihypertensive drugs reverse, while others seem more likely to support the effect of protein restriction on renal haemodynamics and on the progression of renal disease.

Drug therapy during continuous arteriovenous hemofiltration

Since the first description of continuous arteriovenous hemofiltration as a method of emergency fluid removal (Kramer et al. 1977), this measure has gained wide acceptance predominantly as a supportive treatment of acute renal failure in critically ill patients. It has been shown that the machinefree hemofiltration allows liberal parenteral nutrition without the risk of fluid overload. In addition it has some capacity to remove uremic toxins. The method can be applied without sophisticated apparative equipment and without trained dialysis personal being familiar with the problems of extracorporal circulation.

Disposition of hydrochlorothiazide (Hct) during phenytoin (Ph) treatment

SummaryPlasma levels and urinary recovery of Hct were determined in seven healthy male volunteers. 75 mg Hct were administered as a tablet in a randomised fashion with or without phenytoin pretreatment (300 mg/d). Bioavailability of Hct showed considerable intra- and interindividual variation (32–87% and 42–77% respectively), but phenytoin did not influence the disposition parameters of the diuretic.ZusammenfassungBei 7 gesunden Freiwilligen wurden Plasmaspiegel und Urinausscheidung von Hydrochlorothiazid gemessen. In randomisierter Reihenfolge wurden 75 mg Hydrochlorothiazid mit und ohne vorausgegangener 6tägiger Phenytoin-Therapie (300 mg/die) oral verabreicht. Es fanden sich große intra- und interindividuelle Unterschiede in der Bioverfügbarkeit von HCT (32–87% bzw. 42–77%), Phenytoin zeigte jedoch keinen Einfluß auf die Dispositionsparameter des Diuretikums.