P van Brummelen

Nifedipine: Kinetics and dynamics in healthy subjects

Kinetics and pharmacologic effects of three formulations of nifedipine were examined in six healthy young men in a crossover design. Each subject received intravenous nifedipine, 0.015 mg/kg body weight, 20 mg in a capsule, and 20 mg in a slow‐release tablet. Changes in heart rate (HR), blood pressure, heart dimensions, and plasma norepinephrine levels (PNE) were examined serially. Plasma concentrations of nifedipine (Cp) and urinary metabolite concentrations were measured by liquid chromatography. After intravenous injection the elimination t½ was 1.7 ± 0.4 hr, systemic clearance was 26.7 ± 5.4 l/hr, and volume of distribution was 0.8 ± 0.2 l/kg. After the capsule, Cp rose rapidly, to a maximum concentration (Cmax) of 117 ± 15 ng/ml at a maximum time (tmax) of 1.4 ± 0.5 hr. After the sustained release tablet tmax was 4.2 ± 0.7 hr and Cmax was 26 ± 10 ng/ml. Nifedipine bioavailability was 56% ± 25% for the capsule and 52% ± 13% for the tablet, but there were large interindividual differences. Urinary excretion was 58% ± 13% 24 hr after intravenous injection, and after 32 hr was 55% ± 13% after capsules and 32% ± 8% after tablets. HR increased briefly after intravenous injection and after capsules (15 to 20 bpm), but not significantly after tablets. Diastolic blood pressure (DBP) fell briefly after capsules (8 to 10 mm Hg), but there was a sustained effect after tablets. Cardiac dimensions were unchanged. PNE levels paralleled plasma drug levels in the three experiments. There was a hyperbolic correlation between nifedipine Cp and changes in DBP (r2 = 0.86), with a minimal effective concentration of about 15 ng/ml. It is concluded that nifedipine kinetics correlate directly with the effect on blood pressure and HR. Side effects from a high Cmax can be avoided with the tablet. It is likely that twice‐daily dosing will induce a continued effect.

Liquid chromatographic determination of nifedipine in plasma and of its main metabolite in urine.

A high-performance liquid chromatographic method was developed for the assay of nifedipine in plasma and its main metabolite (M-I) in urine. After liquid-liquid extraction nifedipine was chromatographed in a reversed-phase system with ultraviolet detection at 238 nm. The method was sensitive to 2 ng nifedipine per ml plasma and the standard curve was linear to at least 400 ng/ml. Standard deviations did not exceed 8.5%. There was no interference with photodecomposition products or metabolites. M-I was determined in urine after liquid-liquid extraction by ion-pair chromatography with ultraviolet detection at 290 nm. The method was sensitive to 0.02 micrograms M-I per ml urine and the standard curve was linear to at least 5 micrograms/ml. Standard deviations did not exceed 5.0%. The methods were used to study nifedipine disposition in healthy volunteers.

Adrenergic activity and peripheral hemodynamics in relation to sodium sensitivity in patients with essential hypertension.

In 25 outpatients with essential hypertension, sodium sensitivity, defined as the difference in mean arterial pressure (delta MAP) between 2 weeks of high-sodium (300 mmol per day) and 2 weeks of low-sodium (LS) intake (50-100 mmol per day), was studied in relation to the plasma norepinephrine (NE) level, NE release, and pressor response to intravenous NE. In addition, forearm blood flow (FBF) was measured by plethysmography. There were two control periods of regular sodium intake, one of 4 weeks duration at the beginning of the study and one of 2 weeks duration at the end. The delta MAP ranged from +18 to -8 mm Hg. The eight patients in whom delta MAP was greater than 10 mm Hg were regarded as salt-sensitive. When compared with salt-insensitive subjects, salt-sensitive patients had higher plasma NE levels in the control period (p less than 0.05) and after 2 weeks of HS intake (p less than 0.01). Sodium sensitivity was directly related to the change in plasma NE between the HS and LS periods (p less than 0.001). The NE release decreased in salt-insensitive subjects whereas it increased in salt-sensitive patients between the LS and HS periods. Changes in NE release were directly related to sodium sensitivity (p less than 0.05). The pressor response to NE was not significantly influenced by changes in sodium intake. The FBF fell in salt-sensitive patients and increased in salt-insensitive subjects between the LS and HS periods. Sodium sensitivity was directly related to the change in forearm vascular resistance (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Nifedipine: kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration

The pharmacokinetics and hemodynamic effects of nifedipine were studied in patients with liver cirrhosis and in age‐matched healthy control subjects. In a randomized order each subject received nifedipine by intravenous infusion (4.5 mg in 45 minutes) and as a tablet (20 mg). After intravenous nifedipine patients had a longer elimination t½ (420 ± 254 vs. 111 ± 22 minutes; P < 0.01), a greater volume of distribution (1.29 ± 0.60 vs. 0.97 ± 0.42 L/kg), and a lower systemic clearance (233 ± 109 vs. 588 ± 140 ml/min; P < 0.001). Plasma protein binding of nifedipine was lower in the patients (P < 0.001). After oral nifedipine systemic availability was much higher in patients (90.5% ± 26.2% vs. 51.1% ± 17.1%; P < 0.01) and maximal in patients with a portacaval shunt. Blood pressure decreased and heart rate increased after intravenous nifedipine and these effects could be fitted to plasma concentrations by a sigmoidal model. Maximal effects on heart rate and diastolic blood pressure were not different in liver cirrhosis. When free drug levels were considered, the concentrations corresponding to half the maximal effect were also not different. Blood pressure changes with oral nifedipine were comparable with those after intravenous infusion. We conclude that in patients with liver cirrhosis the pharmacokinetics of nifedipine are considerably altered; dose reduction is recommended when such patients need oral nifedipine.

Nifedipine, relationship between pharmacokinetics and pharmacodynamics

The availability of specific chemical assays and the development of appropriate biological models have made it feasible to study the relationship between the pharmacokinetics and the pharmacodynamics of nifedipine, a relationship that is presumed to be sigmoidal for most effects. In healthy volunteers the haemodynamic effects of a single dose of nifedipine are markedly influenced by the pharmaceutical preparation and the rate of drug input. When the plasma concentration of nifedipine increases rapidly, such as after an intravenous bolus injection or rapidly disintegrating capsules, there is a marked increase in heart rate and little or even no effect on blood pressure. On the other hand, when the drug is given as a slow intravenous infusion or as a sustained release tablet and when the capsules are taken together with food, the decrease in blood pressure is accompanied by few or no changes in heart rate. Furthermore, it has been shown that not only haemodynamic effects of nifedipine, but also oesophageal motor function may be used as a quantifiable pharmacological effect. For patients with angina pectoris, a plasma concentration range that is associated with optimal treatment has not been defined, since large inter-individual variations in the nifedipine plasma concentration were observed in effectively treated patients. For patients with hypertension, significant sigmoidally shaped correlations between blood pressure reduction and nifedipine plasma concentrations following single or multiple doses have been demonstrated. The concentration-effect parameters were very similar to those found for normotensive subjects. After 6 weeks of treatment the potency of the drug had decreased, which might indicate the development of some tolerance. In patients with severe renal impairment, the maximal effect of nifedipine on diastolic blood pressure was more than doubled, which cannot be explained by differences in pharmacokinetics; therefore these patients appear to be more sensitive at the pharmacodynamic level. In patients with liver cirrhosis, the pharmacokinetics of nifedipine were quite different due to reduced protein binding and reduced enzyme activity; in patients with a portacaval shunt, considerable increased bypassing of the liver during the first pass after oral administration was observed. When corrected for free drug concentrations, the concentration-effect relationship for these patients is essentially the same as that found for healthy subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Nifedipine: influence of renal function on pharmacokinetic/hemodynamic relationship.

The hemodynamic effects and kinetics of nifedipine were examined in four groups of five subjects with different degrees of impaired renal function. In a randomized order, each subject received nifedipine by an intravenous infusion (4.5 mg in 45 minutes) and by mouth as a sustained‐release tablet (20 mg). Plasma concentrations of nifedipine and urinary metabolite excretion were measured by liquid chromatography. Heart rate, blood pressure, forearm blood flow, and plasma norepinephrine levels were examined serially. After intravenous nifedipine infusion, the elimination t½ was 106 ± 24 minutes in controls and increased gradually across the groups to 230 ± 94 minutes in the group with severe renal impairment. In these same groups, the volume of distribution at steady state was 0.78 ± 0.23 and 1.47 ± 0.24 L/kg, but total systemic clearance did not differ. Plasma protein binding decreased from 96.0% ± 0.5% in controls to 93.5% ± 0.4% in severe renal insufficiency. Except for systemic clearance, kinetics were closely related to creatinine clearance, as was the urinary excretion of the main nifedipine metabolite. Except for systemic availability, which tended to decrease, the kinetics of nifedipine tablets were not influenced by the degree of renal failure. Hemodynamic effects after intravenous nifedipine could be fit to plasma concentrations under a sigmoidal model. When compared with control values, the maximal effect on diastolic blood pressure was more than doubled in severe renal failure. The inverse correlation between maximal effect on diastolic blood pressure and creatinine clearance (r = − 0.68) was independent of pretreatment values. Neither free drug levels corresponding to 50% of the maximal effect on diastolic blood pressure nor the slope of the concentration‐effect curve was influenced by the degree of renal impairment. The maximal effect on forearm blood flow tended to increase in renal failure, whereas the effect on heart rate was unchanged. Blood pressure changes after oral nifedipine were of the order of those after intravenous infusion. We conclude that, although nifedipine kinetics differ in patients with renal failure, these changes do not explain the greater blood pressure lowering effect.

Influence of single- and multiple-dose omeprazole treatment on nifedipine pharmacokinetics and effects in healthy subjects

SummaryThe effects of single dose (20 mg) and short-term (20 mg/day for 8 days) oral treatment with omeprazole on the pharmacokinetics and effects of oral nifedipine (10 mg capsule) and on gastric pH have been investigated in a randomized, double-blind, placebo-controlled cross-over study in 10 non-smoking healthy male subjects.The single dose of omeprazole had no significant effect on any pharmacokinetic parameter of nifedipine, nor on gastric pH, or blood pressure or heart rate.Short-term omeprazole treatment increased the AUC of nifedipine by 26% (95% confidence interval 9–46%), but all other pharmacokinetic parameters of nifedipine, including elimination half-life, Cmax, tmax, and recovery of the main urinary metabolite, were not significantly changed. The median gastric pH during the absorption phase of nifedipine was increased by short-term omeprazole (pH 4.2) compared to placebo treatment (pH 1.4). Blood pressure and heart rate did not differ between treatments.The interaction between nifedipine and omeprazole is not likely to be of major clinical relevance.

Nifedipine kinetics and dynamics during rectal infusion to steady state with an osmotic system

Nifedipine steady‐state kinetics and dynamics were investigated in a placebo‐controlled study of six healthy subjects. Nifedipine was given rectally through an osmotic system at a zero‐order rate for 24 hr. Steady‐state plasma concentrations of approximately 20 ng/ml were achieved within 6 to 8 hr. Nifedipine lowered diastolic blood pressure (DBP) and increased forearm blood flow (FBF) and plasma norepinephrine concentration. On the other hand, heart rate (HR) and systolic blood pressure were not affected. Changes in DBP and FBF were closely related to nifedipine plasma concentrations during and immediately after the infusion period. Our data indicate that nifedipine lowers blood pressure in subjects with normotension and that it is possible by infusing the drug at a relatively low rate to dissociate its effect on blood pressure from that on HR.

Norepinephrine removal and release in the forearm of healthy subjects.

The relevance of local removal and release of norepinephrine (NE) for antecubital venous plasma NE concentration was studied in 22 healthy subjects. Arterial and venous plasma NE and forearm blood flow were measured during intra-arterial infusion of two doses of NE, intra-arterial NE infusion with two doses of sodium nitroprusside, intravenous infusion of NE with intra-arterial infusion of four doses of sodium nitroprusside, and lower body negative pressure of -20 mm Hg for 15 minutes. The venous plasma NE concentration-time curves during the infusions of the two doses of NE indicated first-order kinetics for forearm extraction: forearm NE extraction rate during the low dose infusion was 67 +/- 4.1% (SEM) and correlated with basal forearm blood flow (r = -0.64, p less than 0.03, n = 12). Local sodium nitroprusside-induced vasodilatation during the intra-arterial and intravenous NE infusions was accompanied by dose-dependent decreases in forearm extraction rates for NE and epinephrine. During lower body negative pressure, taking into account the high basal forearm extraction rate for NE, local and systemic release of NE was indicated by increases in arterial and venous plasma and the venous-arterial plasma NE concentration difference (p less than 0.05 for all). These data show that removal of NE from forearm circulation is a process with a high extraction ratio obeying first-order kinetics and that this extraction process inversely relates to forearm blood flow. Thus, antecubital venous plasma NE is likely to be derived mainly from local release and not from the arterial plasma NE input.

Does regional norepinephrine spillover represent local sympathetic activity

Regional spillover of norepinephrine (NE), based on isotope dilution and single-compartment steady-state kinetics, is considered one of the best parameters for estimating organ sympathetic activity. However, the effects of local changes in clearance of NE on the spillover have not yet been investigated. We studied local NE kinetics and clearance in the forearm of 10 healthy subjects using intra-arterial infusions of NE, tritiated NE, the neuronal uptake inhibitor desipramine, and tyramine, which competes with NE for the neuronal uptake carrier. Before and during complete blockade of neuronal uptake by desipramine the venous concentrationtime curves for tritiated NE and for NE released by tyramine were biexponential, consistent with the presence of (at least) two compartments for circulating tritiated NE and for locally released NE. The time constants for tyramine-induced release of NE and, in the same subjects during desipramine infusion, for tritiated NE were almost equal at the same level of forearm blood flow. This argues against possible diffusion or transport differences for NE to and from the circulation and the synapse. The regional intrinsic clearance capacity (a measure of the maximal ability of an organ to irreversibly remove drug by all pathways in the absence of any flow limitations) for NE decreased in the forearm by 65% (p<0.01) during neuronal uptake blockade by desipramine; the forearm clearance decreased by 59% (p<0.001), whereas the spillover rate of NE increased from 33±5 to 63±11 pmol-min1 (p<0.05). Nitroprussideinduced increments in blood flow increased the spillover of NE from 18±4 to 35±6 pmolmin1 (/7<0.01); the clearance of circulating NE also increased (by 58%, p<0.05), and the intrinsic clearance capacity remained unchanged. This demonstrates that regional spillover of NE is markedly influenced by local changes in clearance and flow. The new parameter plasma appearance rate of NE is proposed. Although also derived from isotope dilution, this parameter may better approximate the regional entry of NE into the blood pool than spillover. This is corroborated by the nonsignificant changes of plasma appearance rate of NE during our desipramine and nitroprusside infusions. {Hypertension 1991;18:56-66