H. J. Gilfrich

The enantiomers of phenprocoumon: Pharmacodynamic and pharmacokinetic studies

The pharmacodynamics and pharmacokinetics of the optical enantiomers of phenprocoumon were studied in 5 normal subjects and compared to the racemic mixture. Each subject received a single oral dose of 0.6 mg /kg of racemic, S (−), and R (+) phenprocollmon. S (−) phenprocoumon was 1.6 to 2.6 times as potent as R (+) phenprocollmon when the area under the effect/time curve was used to quantify the total anticoagulant effect per dose. Comparing the plasma concentrations that elicited the same anticoagulant effect, S (−) phenprocoumon was 1.5 to 2.5 times as potent as R (+) phenprocoumon. The anticoagulant activity of the racemic mixture was between that of the enantiomers. There was no distinct difference in the rate of elimination between the enantiomers. The apparent volume ()f distribution and the plasma clearance for S (−) phenprocoumon were less than those for R (+) phenprocoumon. When the binding of the enantiomers to human serum albumin was compared, S (−) phenprocoumon was more highly bound than R (+) phenprocoumon. The protein binding of racemic phenprocoumon was between that of the enantiomers. The results show that S (−) phenprocoumon is a more potent anticoagulant than R (+) phenprocoumon and that the pharmacokinetic d~fferences between the enantiomers are due mainly to differences in their distribution.

Dose-response relationships and plasma concentrations of digitalis glycosides in man.

SummaryAn inter-individual, randomized, double-blind study of digitoxin (Dt) and β-acetyl digoxin (D) was performed in 120 healthy male volunteers. Groups of 10 persons each received orally D 0, 0.1, 0.2, 0.3, 0.4, 0.5 or 0.6 mg and Dt 0.04, 0.08, 0.12, or 0.16 mg daily for 7 days; Loading doses were given for the first three days. Plasma levels were measured with an86Rb-erythrocyte assay 24 h after the last dose. ECG, carotid artery pulse and phonocardiogram were recorded prior to (b) and 24 h after (a) the last dose. QTc, amplitude of T-waves in V2 to V6, electromechanical systole (QS2c) and left ventricular ejection time (LVETc) were measured. The differences between a and b (Δ-values) reflect glycoside-induced changes in heart function. The plasma glycoside concentrations depended on dose and ranged from 0 to 2.4 ng/ml for D and from 0 to 42 ng/ml for Dt. QTc, QS2c, and LVETc were significantly shortened by the glycosides and typical parallel, sigmoid, log dose-response curves were obtained for the Δ-values. Dt was 3.8-times as potent as D in diminishing these parameters. The maximal effect of the two glycosides was almost identical at the highest doses: Δ-QTc=−45 ms, Δ-QS2c=−25 ms, Δ-LVETc=−12.5 ms. The latter two parameters showed a plateau of maximum efficacy. Both glycosides caused significant flattening of T-waves, Dt being 7.2-times as potent as D. Significant relationships between plasma concentration and cardiac effects were observed (p<0.001)−Δ-QTc (D: r=0.7; Dt: r=0.77), Δ-QS2c (D: r=0.7; Dt: r=0.75), and Δ-LVETc (D: r=0.46; Dt: r=0.43); D correlated less well than Dt with the flattening of T (r=0.46; r=0.76, respectively). The most important conclusions were that: Dt was about 4-times as potent as D in influencing cardiac performance; the effects of D and Dt on systolic time intervals reached a plateau at “therapeutic” doses; Dt induced more pronounced flattening of the T-wave than D; and plasma glycoside levels within the “therapeutic” range corresponded to observed effects on the heart.

Interruption of the enterohepatic circulation of phenprocoumon by cholestyramine.

The effect of cholestyramine (12 gm/day divided into 3 doses) on the pharmacokinetics and pharmacodynamics of a single intravenous dose (30 mg) of phenprocoumon was studied in 6 normal subjects. Cholestyramine treatment led to an increase in the rate of elimination of phenprocoumon in all. Total clearance increased 1.5‐ to 2‐fold. The total anticoagulant effect per dose was considerably reduced during treatment with cholestyramine. Binding studies in vitro showed that phenprocoumon is strongly bound to cholestyramine and that at a given cholestyramine concentration the percentage of phenprocoumon bound remained constant over a large concentration range of phenprocoumon. The results suggest that phenprocoumon undergoes extensive enterohepatic recycling in man which can be effectively interrupted by cholestyramine.

Digoxin and digitoxin elimination in man by charcoal hemoperfusion.

ZusammenfassungBisher gibt es keine allgemein anwendbare kausale Therapie lebensbedrohlicher Digitalis-Intoxikationen. Daher wurde in vitro und in vivo beim Menschen untersucht, ob die Hämoperfusion mit beschichteter Aktivkohle toxikologisch relevante Mengen von Herzglykosiden zu eliminieren vermag. Bei einer Blutumlaufgeschwindigkeit von 100 ml/min betrug in vitro die Digoxin-Clearance durch Hämoperfusion 51±8 ml/min, im Vergleich zu 24,3±11,3 ml/min durch die Hämodialyse. Für Digitoxin fand sich eine Clearance von 31,7±13,4 ml/min durch Hämoperfusion, während bei Hämodialyse kein meßbarer Anteil des Glykosids eliminiert wurde.Diese Clearence-Werte lassen erwarten, daß die Herzglykoside durch die Hämoperfusion aus dem Blut eliminiert werden, ohne daß allerdings durch die in vitro-Untersuchung eine Aussage möglich ist, ob toxische Glykosidkonzentrationen im Gewebe hierdurch gesenkt werden können.Bei 2 Patienten, bei denen aus anderen Gründen eine Hämoperfusion durchgeführt wurde, wurde Digoxin nach einer Bolusinjektion von 0,5 mg mit einer konstanten Geschwindigkeit von 0,125 ml/h infundiert und der Effekt der Hämoperfusion ermittelt. Bei einer mittleren Digoxin-Clearance von 77 ml/min wurden durch eine 4- bzw. 6-stündige Hämoperfusion nur 5% und 4,5% der applizierten Dosis eliminiert. Dahingegen wurden bei gleichem Vorgehen bei 2 anderen Patienten im Mittel 24% der verabreichten Digitoxin-Dosis durch eine 4- bzw. 6stündige Hämoperfusion eliminiert, obwohl die Digitoxin-Clearance deutlich unter der Digoxin-Clearance lag. Die geringe Effektivität der Hämoperfusion bei der Digoxinelimination ist auf das große Verteilungsvolumen dieses Glykosids zurückzuführen, welches durch hohe Gewebe-und niedrige Plasmakonzentrationen gekennzeichnet ist. Andererseits ist die gute Wirkung der Hämoperfusion in der Elimination von Digitoxin auf das deutlich kleinere Verteilungsvolumen zurückzuführen und läßt den Einsatz der Hämoperfusion bei lebensbedrohlicher Digitoxin-Intoxikation sinnvoll erscheinen.SummarySince there is no widely used causal means of reducing the severity of massive digitalis intoxication the capability of hemoperfusion with coated activated charcoal to remove toxicologically relevant amounts of digoxin and digitoxin was evaluated in vitro and in man. At a blood flow rate of 100 ml/min the digoxin clearance by hemoperfusion in vitro was 51±8 ml/min in comparison to 24.3±11.3 ml/min by hemodialysis. The average hemoperfusion clearance of digitoxin was 31.7±13.4 ml/min, whereas almost no digitoxin was removed by hemodialysis. These clearance values point to the ability of hemoperfusion of eliminating digitalis glycosides from the blood. They do not clarify the essential question whether it is possible to lower the toxic concentrations in the tissues.In two patients being on hemoperfusion for other reasons, 0.5 mg digoxin were injected intravenously as a bolus 1 h prior to the beginning of hemoperfusion and 0.125 mg/h were infused continuously over 4h simultaneously with hemoperfusion. By an average digoxin clearance of 77 ml/min, only 5 and 4.5% of the dose given were removed by this procedure. In 2 patients receiving digitoxin under the same trial conditions an average of 24% of the digitoxin load were eliminated by 4 to 6 h hemoperfusion period although the clearance values obtained were below the clearance for digoxin.The lack of effectiveness in eliminating toxicological relevant amounts of digoxin is due to the quite high distribution volume which results in high tissue concentrations and low blood concentrations of the drug. On the other hand the effective removal of digitoxin is due to the appreciably smaller distribution volume and suggests that hemoperfusion may be a valuable method of rapid reversal of advanced digitoxin toxicity in man.

Disposition of azapropazone in chronic renal and hepatic failure.

SummaryThe disposition of azapropazone 600 mg i.v. was investigated in 6 healthy subjects, 13 patients with cirrhosis and 8 patients with renal failure. In healthy subjects the elimination half-life was 12.2±2.1 h (mean ± SD), the volume of distribution 10.6±3.31 and the total clearance was 597±135 ml·h−1. Renal clearance accounted for about 62% of the total clearance. The free fraction of azapropazone in the plasma was 0.0045±0.0006. The patients with cirrhosis were divided into Group I with modest and Group II with severe impairment of liver function. In Group I the total clearance of azapropazone was not significantly different from that in healthy subjects. There was a 2.5-fold increase in its free fraction in plasma, and a reduction in the free drug clearance to about half that in healthy subjects. In Group II patients total clearance was reduced to about 20% of normal. This was partly due to reduced non-renal clearance but mainly to impaired renal clearance of azapropazone. The diminished renal clearance was considered at least in part to represent a drug-induced impairment of renal function, as there was a concomitant reduction in creatinine clearance. The free fraction of azapropazone in the plasma was markedly enhanced (>0.02), and simultaneously, free drug clearance was drastically reduced, to about 2% of that in healthy subjects. In patients with renal failure the total clearance was diminished, depending on the degree of impairment of kidney function. Anephric patients were estimated to have about one third of the total clearance in normal subjects. The free fraction of azapropazone in the plasma was increased in 4 of the 8 patients. It is concluded that patients with cirrhosis and modest impairment of liver function may require about half the normal dose of azapropazone, since free drug clearance is reduced by about 50%. Patients with severe impairment of liver function are expected to be highly susceptible to dose-related side effects, since the pronounced increase in the free fraction in plasma and the decreases in renal and non-renal clearance lead to marked reduction in free drug clearance and so to accumulation of free drug in the body. In patients with renal failure the dose of azapropazone should be reduced according to the degree of impairment of kidney function and plasma protein binding of the drug.

Pharmacokinetics of triamterene after i.v. administration to man: Determination of bioavailability

SummaryWith a new formulation, which made intravenous infusion of triamterene (TA) possible, plasma levels and urinary excretion rates of TA and its main metabolite (OH-TA-ester) were measured in a randomized, cross-over trial in 6 healthy volunteers given triamterene 10 mg i.v. and 50 mg p.o. TA and OH-TA-ester were determined by densitometric measurement of native fluorescence after thin layer chromatography. Distribution volumes of the central compartment of TA and OH-TA-ester were 1.49 l/kg and 0.11 l/kg, respectively. Terminal half-lives were 255 min for TA and 188 min for OH-TA-ester after i.v. administration. For TA total plasma clearance was 4.5 l/min and renal plasma clearance 0.22 l/kg. The formation of OH-TA-ester was very rapid and the concentration of the metabolite exceeded that of TA at all times. After i.v. administration the urinary recovery of TA and OH-TA-ester was 4.4% and 50.9%, respectively. The bioavailability of TA was 52%, corresponding to absorption of 83%. TA is partly eliminated by a first-pass-effect. The main metabolite of TA is OH-TA-ester, which is pharmacologically active.

Clinical Pharmacology of Prazosin and Phentolamine in Patients with Heart Failure

&NA; In a controlled crossover study we assessed the effects of an initial single oral dose of 150 mg phentolamine or 2 mg prazosin on the haemodynamics and plasma concentrations of noradrenaline in 12 patients with mild to moderate cardiac dysfunction in cardiomyopathy (NYHA Classes I‐III). Nine of these patients continued chronic oral treatment with either 300‐450 mg phentolamine or 7.5‐15 mg prazosin for a period of 4‐6 weeks each in randomised order. The effects on both haemodynamics and plasma noradrenaline were essentially the same under the treatment with both drugs. The acute effect on reduction of exercise‐induced elevation of diastolic pulmonary artery pressure was abolished after chronic treatment. However, significant increase in stroke volume—on average, from 83 ± 7.2 to 100 ± 6.0 ml (phentolamine) and 99 ± 6.7 ml (prazosin)—occurred only after chronic treatment. Increased sympathetic activity, as expressed in plasma noradrenaline concentrations, was similar under both phentolamine and prazosin. There was no direct evidence for the clinical relevance of the more pronounced presynaptic &agr;‐blockade with phentolamine as compared with the almost pure postsynaptic &agr;‐blocking properties of prazosin. Development of tolerance seemed to occur with both drugs; however, haemodynamic benefit in terms of increased stroke volume could only be achieved after chronic treatment.

Pharmakokinetik von Triamteren bei Probanden und Patienten mit Leber- und Nierenfunktionsstörungen

The knowledge about the pharmacokinetics of triamterene (TA) was limited until recently. The metabolic pathway of TA is the formation of p-hydroxytriamterene (OH-TA), which is subsequently conjugated with active sulfate to form p-hydroxytriamterene sulfuric acid ester (OH-TA-ester). The phase-II-metabolite is surprisingly pharmacologically active. TA and its metabolites were measured concomitantly by a specific and sensitive tlc-method. The i.v. kinetics of TA were determined after application of a newly developed lactic acid solution of the drug. Comparing these data with results after oral application of TA the bioavailability of TA was 52% and the extent of absorption 83%. The bioavailability of different dosage forms was correlated with in vitro-tests. In liver disease the pharmacokinetics of TA are markedly altered. While in cirrhosis the hydroxylation of TA was decreased, the biliary excretion of this agent was strongly reduced in hepatitis. In renal disease the excretion of TA and OH-TA-ester was reduced proportional to the reduction of endogenous creatinine clearance. In older patients the elimination of TA was impaired.SummaryThe knowledge about the pharmacokinetics of triamterene (TA) was limited until recently. The metabolic pathway of TA is the formation of p-hydroxytriamterene (OH-TA), which is subsequently conjugated with active sulfate to form p-hydroxytriamterene sulfuric acid ester (OH-TA-ester). The phase-II-metabolite is surprisingly pharmacologically active. TA and its metabolites were measured concomitantly by a specific and sensitive tlc-method. The i.v. kinetics of TA were determined after application of a newly developed lactic acid solution of the drug. Comparing these data with results after oral application of TA the bioavailability of TA was 52% and the extent of absorption 83%. The bioavailability of different dosage forms was correlated with in vitrotests. In liver disease the pharmacokinetics of TA are markedly altered. While in cirrhosis the hydroxylation of TA was decreased, the biliary excretion of this agent was strongly reduced in hepatitis. In renal disease the excretion of TA and OH-TA-ester was reduced proportional to the reduction of endogenous creatinine clearance. In older patients the elimination of TA was impaired.

Transthoracic electrical impedance during extracorporeal hemodialysis in acute respiratory failure (“Shocked lung syndrome”)

The alteration (ΔZ0) of transthoracic electrical impedance (TEI) during extracorporeal hemodialysis (EHD) was investigated in two Groups of patients with acute renal and acute respiratory failure, that differed with respect to the severity of respiratory insufficiency. Group I had moderate respiratory failure (FiO20.31±0.10, Pa0284±14 mmHg), and Group II had severe respiratory failure (Fi020.75±0.17, PaOO77±14 mmHg). There was a significant correlation between increase in TEI (ΔZ0) and decrease in body weight (ΔBW) in each individual patient, but the slope of regression lines was remarkably flattened in Group II. In Group I, ΔTEI was 1.9±0.9 Ω, the calculated TEI for 500 gr decrease in BW (ΔZ0–500 gr) was 0.59±0.21 Ω, and a significant correlation existed between pooled data of ΔZ0 and ΔBW. In Group II TEI increased less significantly, ΔTEI was 0.6±0.3 Ω (P<0.001), ΔZ0–500 gr was 0.26±0.27 Ω (P<0.01), and there was no correlation between pooled data of ΔZ0 and ΔBW. Increase of TEI in Group II could be completely attributed to increase in hematocrit. It is concluded that patients of Group I with acute renal failure and moderate respiratory failure lost intrathoracic fluid during EHD, whereas patients of Group II with severe respiratory failure did not. TEI during EHD may serve as a test for detection of fixed fluid within the pulmonary interstitium indicating a poor prognosis of the acute respiratory failure.

Magnesium concentration in saliva — an indicator of digitalis toxicity

SummaryIn a prospective study salivary magnesium was measured by atomic absorption spectrophotometry in 168 patients on chronic digoxin therapy. Magnesium concentration in saliva was correlated with clinical data and plasma digoxin levels. A significant elevation in salivary magnesium concentration was caused by digoxin therapy (0.58±0.39 mmol/l,n=93) in comparison to patients with no digitalis treatment (0.17±0.07 mmol/l,n=35). Magnesium concentrations in saliva were significantly higher in toxic patients (1.1±0.68 mmol/l,n=32) than in non-toxic patients. Possibly toxic patients showed a magnesium level of saliva of 0.63±0.39 mmol/l (n=40). In 89% of the intoxicated patients salivary magnesium concentrations were higher than 1.0 mmol/l. The overlap of magnesium between toxic and nontoxic patients was less as compared to calcium and potassium concentrations in saliva. No changes were noted in serum magnesium levels. Magnesium concentration in saliva was influenced by chronic digoxin therapy only. No significant increase of magnesium in saliva was observed within 24 h after i.v. injection of 1.0 mg digoxin in four healthy volunteers. It is concluded that salivary magnesium concentration is a valid method for monitoring digoxin therapy in addition to plasma digoxin levels.ZusammenfassungIm Rahmen einer prospektiven Studie zum Problem der Digitalisintoxikation wurde die Speichelkonzentration von Magnesium bei 168 Patienten unter chronischer Digoxintherapie zugleich mit der Messung der Plasmakonzentration von Digoxin und der Erfassung klinischer Daten untersucht. Die Bestimmung erfolgte mit Hilfe der Atomabsorptionsspectrophotometrie. Die Magnesiumkonzentration im Speichel war bei Patienten ohne Digitalisintoxikation signifikant höher (0,58±0,34 mmol/l,n=96) als bei Patienten ohne Digoxin (0,15±0,07 mmol/l,n=32). Patienten mit fraglicher Überdosierung wiesen einen Magnesiumspiegel im Speichel von 0,63±0,39 mmol/l (n=40) auf. Bei 89% der intoxikierten Patienten war die Magnesiumkonzentration im Speichel höher als 1,0 mmol/l. Die Überlappung der Magnesiumkonzentration bei nicht intoxikierten und intoxikierten Patienten war geringer als für Calcium und Kalium im Speichel beobachtet. Eine signifikante Änderung des Serummagnesiumspiegels wurde nicht gefunden. Die Magnesiumkonzentration im Speichel wurde ausschließlich durch die chronische Digoxingabe beeinflußt. Es wird gefolgert, daß die Bestimmung von Magnesium im Speichel eine wertvolle Ergänzung zur Erfassung des Digitalisierungsgrades darstellt.