Beta-adrenergic receptors and reflex tachycardia after single and repeated felodipine administration in essential hypertension.

To verify the possible contribution of beta-adrenergic receptor down-regulation to the reversal of reflex tachycardia during chronic treatment with a dihydropyridine calcium antagonist, 11 hypertensive patients were studied with noninvasive blood pressure (BP) and heart rate (HR) monitoring after a placebo period, and on the first and seventh day of felodipine administration, 5 mg twice daily. Plasma catecholamines and neutrophil beta-adrenergic receptors were measured on the first and seventh day of treatment, immediately before and 2 h after drug administration. The first administration of felodipine was followed by a significant drop in BP (peak reduction in mean BP 24 +/- 7 mm Hg), lasting 6 h and mirrored by reflex tachycardia (peak increase in HR 14 +/- 9 beats/min). On the morning of the seventh day, 12 h after the previous felodipine administration, mean BP (MBP) was 16 mm Hg lower than on the last placebo day, while HR was unchanged. The next administration of felodipine was followed by a smaller drop in BP (MBP - 15 +/- 7 mm Hg; NS vs. placebo), while reflex tachycardia was the same as after acute felodipine (HR 13 +/- 8 beats/min; p less than 0.05 vs. placebo, NS vs. acute administration). Plasma noradrenaline concentration increased after both acute and chronic administration (p less than 0.0001), and preadministration values were highest on day 7 (p less than 0.05). Neutrophil beta-adrenergic receptor density and affinity did not change either acutely or chronically. This study gives both indirect and direct evidence that beta-adrenoceptor down-regulation does not occur during repeated felodipine administration in hypertension. Reflex tachycardia is not abolished, but is reset to lower BP levels.     

Short-term effects of felodipine, a new dihydropyridine, in hypertension.

Felodipine, a dihydropyridine, is a new vasodilating calcium antagonist which lowers blood pressure (BP) by selective action on vascular smooth muscle, especially in the resistance vessels. The effects on BP, heart rate (HR) and tolerance of different single oral doses of felodipine were studied in two series of hypertensive patients. When felodipine was given as single drug to 14 previously untreated hypertensives in a single-blind manner, BP was rapidly reduced by about 15% while HR increased by 25%. Felodipine given in a double-blind manner to eight patients on chronic beta-adrenoceptor blockade reduced BP by some 15-20% compared to placebo, while HR did not change. There was a significant correlation between the pre-treatment mean arterial BP (MAP) and the maximal relative change in MAP, i.e. the higher the initial BP the greater the reduction after felodipine. A significant correlation was also found between the plasma concentration of felodipine and the relative change in MAP. Felodipine was generally well tolerated. When given alone felodipine caused the side effects expected from a pure vasodilator, i.e. headache, flushing and palpitations. When given together with a beta-adrenoceptor blocker, the side effects were much less apparent.     

非洛地平片在人体内药动学与药效学的相关性研究

目的:研究非洛地平片在人体内药动学与药效学的相关性。方法:采用液-质联用法测定10名健康受试者单剂量口服非洛地平10mg后的血药浓度,并以DAS2.0药动学模块程序处理药-时数据及计算药动学参数。分别于服药前及服药后不同时间对收缩压(SBP)、舒张压(DBP)、心率(HR)、平均动脉压(MAP)进行监测。结果:平均药动学参数tmax、Cmax、AUC0～48、AUC0～∞、Ka、t1/2分别为(3.88±0.35)h、(5.94±1.45)μg·L-1、(61.73±15.54)μg·h·L-1、(67.62±16.09)μg·h·L-1、(0.73±0.33)h-1、(15.43±4.15)h,以不同时间血药浓度分别对SBP、DBP、HR和MAP进行回归分析,其相关系数分别为0.614 6、0.985 6、0.907 7和0.568 6。用药2～8 h内DBP下降明显(P<0.05或P<0.01)。结论:非洛地平血药浓度与药效相关,其有效血药浓度约为2.64～5.84μg·L-1,临床应用非洛地平应重点监测DBP、HR。     

Effects of calcium antagonism on the resting and exercise-stimulated renin-aldosterone axis

The effect of short-term calcium antagonism with felodipine on blood pressure and on some biochemical plasma variables such as catecholamines, renin and aldosterone was studied in 10 normal volunteers at rest and during incremental bicycle exercise. At rest, diastolic blood pressure was slightly decreased during felodipine, whereas systolic pressure and heart rate were not significantly changed. The plasma noradrenaline concentration and plasma renin activity were increased during felodipine treatment; the plasma adrenaline and aldosterone concentrations on the contrary, were not significantly changed. The rises in plasma renin activity, plasma aldosterone and plasma adrenaline and noradrenaline concentrations produced by exercise were not significantly affected by felodipine. The plasma calcium concentration was significantly higher during felodipine treatment than during placebo and this was accompanied by an increased urinary calcium excretion. It is concluded that the rise in plasma renin activity during calcium antagonism with felodipine is not accompanied by a significant increase in plasma aldosterone. Furthermore, the present data suggest that, at least during exercise, calcium antagonism does not interfere with the mechanisms underlying the exercise-induced activation of renin and aldosterone release.     

Antihypertensive efficacy of the calcium-antagonist felodipine in patients with persisting hypertension on beta-adrenoceptor blocker therapy. The Canadian Felodipine Study Group.

1. The antihypertensive efficacy of two different doses of the calcium antagonist felodipine was evaluated in patients with hypertension persisting despite beta-adrenoceptor blocker therapy. Following a single-blind placebo period of 4 weeks, patients were randomized to placebo (n = 36), felodipine 5 mg twice daily (n = 39) and felodipine 10 mg twice daily (n = 35) for another 4 weeks. beta-adrenoceptor blocker therapy remained unchanged throughout the study. 2. Effects on blood pressure (BP) were evaluated after the first dose and after chronic dosing at 2 h after dosing and the end of the dosing interval (12 h). 3. Felodipine decreased systolic and diastolic BP by 30-35/20-25 mm Hg at 2 h. These decreases were similar after acute and chronic treatment. Twelve hours after dosing, decreases of 15-20/10-15 mm Hg were observed compared to 10/5 mm Hg on placebo, and half of the patients still had a controlled BP (supine diastolic BP less than 90 mm Hg). BP responses were rather similar for both doses of felodipine at 2 and 12 h. 4. Multiple regression analysis showed that both initial BP level and plasma felodipine concentrations were significant predictors of the BP response to felodipine, but age was not. 5. Adverse effects attributed to felodipine were mainly related to vascular symptoms (primarily flushing and ankle swelling); these occurred in about 30% of patients, and were pronounced in three patients (4%). 6. Felodipine is therefore highly effective in lowering BP of hypertensive patients on chronic beta-adrenoceptor blocker therapy, with no evidence for a gradual lowering of the BP or for development of tolerance. Both initial BP level and plasma concentrations are better indicators of antihypertensive efficacy of this calcium antagonist than age.     

Catecholamines, renin-angiotensin-aldosterone, and cardiovascular response during exercise following acute and long-term calcium antagonism with felodipine in essential hypertension

Studies were performed in nine patients with essential hypertension to explore the effect of the calcium antagonist felodipine on the exercise-induced responses of the sympathetic and renin-angiotensin-aldosterone systems as well as of blood pressure and heart rate. The patients were subjected to an individually graded submaximal work test (bicycling) after administration of placebo and a single dose of felodipine (10 mg) in a double-blind design and following long-term (8 weeks) felodipine treatment (10 mg twice daily). After a single dose of felodipine sitting preexercise blood pressure was decreased, whereas heart rate, plasma noradrenaline, adrenaline, renin activity, and angiotensin II increased. After long-term felodipine treatment blood pressure was reduced, heart rate was unchanged, and plasma noradrenaline and renin activity increased. The exercise-induced increases in plasma catecholamines, renin activity, angiotensin II, aldosterone, blood pressure, and heart rate were similar after acute and long-term felodipine administration as compared with placebo. In conclusion, acute and long-term felodipine treatment influences neither reflex activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system nor the cardiovascular responses to physical exercise in patients with essential hypertension.     

Catecholamines and the renin-angiotensin-aldosterone system during treatment with felodipine ER or hydrochlorothiazide in essential hypertension.

The neurohumoral responses after 10 mg of felodipine extended release (ER), a new dihydropyridine calcium antagonist, and 25 mg of hydrochlorothiazide (HCTZ) were compared in a randomized, double-blind, crossover trial in 28 mild to moderate hypertensives. Antihypertensive drugs were gradually discontinued. Felodipine ER, 10 mg was given once daily for 2 weeks; after another washout period of 1 week, patients were switched to 25 mg of HCTZ once daily and vice versa. Blood pressure (BP) was measured at baseline, 2.5 h after medication, and after 2 weeks of treatment (24 h postdosing) using an oscillometric device. Felodipine ER and HCTZ both lowered BP effectively. However, felodipine ER was superior in reducing systolic and diastolic BP during the short term and medium term. Treatment with felodipine ER over 2 weeks increased sympathetic outflow as indicated by elevated plasma norepinephrine levels, whereas plasma epinephrine was mainly unaffected, as were plasma renin and aldosterone levels. On the other hand, 25 mg of HCTZ increased plasma renin and aldosterone, but left catecholamines unchanged. Despite persistent increased sympathetic activity, the reduction in BP in this study was more pronounced after felodipine ER as compared to HCTZ. The lack of a difference between heart rates under both medications after 2 weeks of treatment suggests a resetting of the baroreflex by felodipine ER and furthermore that the increased norepinephrine levels may not be clinically relevant, but demonstrate the maintained baroreflex activity. HCTZ, in doses as low as 25 mg, is still capable of stimulating the renin-angiotensin-aldosterone system.     

Acute haemodynamic and humoral responses to felodipine and metoprolol in mild hypertension

Summary Oral administration of felodipine to 10 patients with mild essential hypertension acutely reduced systemic vascular resistance (SVR) by 40% after 30 min. The change in SVR was significantly related to age (r=–0.74). The reduction in the intraarterially measured brachial artery pressure was limited to 15/13 mmHg, due to a rise in cardiac output (CO). The tachycardia was sustained for 90 min, as was an elevation of plasma noradrenaline. There was a transient increase in stroke volume, associated with a reduction in pulmonary capillary wedge pressure, which was at least partly due to a reduced intravascular volume. In contrast to SVR, pulmonary vascular resistance was not affected by felodipine. Addition of intravascular metoprolol after 90 min decreased HR and CO and augmented SVR. The felodipine-induced rise in plasma renin activity (PRA) of 100% was completely reversed by metoprolol. Plasma angiotensin II (PA II) rose by 15% during felodipine, whereas plasma aldosterone concentration (PAC) was not affected. Thus, actuely administered felodipine was a potent dilator of systemic but not of pulmonary arterioles, it stimulated the sympathetic nervous system, and reduced left ventricular filling pressure. The rise in plasma renin did not result in a higher plasma aldosterone level, due partly to reduced generation of angiotensin II.     

Glucose tolerance in hypertensive patients during treatment with the calcium antagonist, felodipine.

1 Twelve non-diabetic hypertensive male patients insufficiently controlled by a diuretic were included in a double-blind, randomised study. In addition placebo or felodipine was given for 4 weeks followed by a 2 week wash-out period, after which the alternative treatment was given for another 4 weeks. At the end of each treatment period an oral glucose tolerance test (OGTT) was performed and blood pressure, plasma noradrenaline and felodipine levels were measured. 2 There was no change in either glucose, insulin or glucagon levels during the OGTT after felodipine compared with placebo. Blood pressure was significantly reduced during the dosage interval of felodipine (12 h). Plasma noradrenaline increased significantly after felodipine. Side effects were few. 3 In a separate open study 58 hypertensive patients were treated with felodipine in addition to a diuretic and a beta-adrenoceptor blocker for up to 1 year. There were no significant changes in fasting blood glucose levels during the study.     

西尼地平与非洛地平治疗高血压病疗效及对自主神经功能的影响

目的 比较原发性高血压患者使用西尼地平与非洛地平的降压效果及对自主神经功能的影响。方法 轻中度原发性高血压患者随机分为西尼地平组(n=38，西尼地平10mg，每日1次)与非洛地平组(n=36，非洛地平5mg，每日1次)，治疗3个月后，比较两组血压与心率的改变，用动态心电图进行能量光谱分析。结果 西尼地平与非洛地平均有良好降压作用，但西尼地平对心率无明显的影响，而非洛地平增加心率，并使白天与夜晚R-R间期低频／高频(LF/HF)比率明显增加，西尼地平仅在白天有增加。结论 西尼地平对轻中度原发性高血压有良好降压疗效，且不增加交感神经活性，为有利于防止心脏事件发生的新型钙通道阻滞剂。     

Abrupt withdrawal of beta-blocking agents in patients with arterial hypertension. Effect on blood pressure,heart rate and plasma catecholamines and prolactin

Summary Chronic treatment with beta-blockers was interrupted abruptly in six patients with arterial hypertension. Three patients, who had experienced symptoms during a previous withdrawal, again complained of transient palpitations, tremor, sweating, headache and general malaise. A significant increase in standing blood pressure (BP) and heart rate (HR) was noted after 24 h. The standing HR reached a maximum after 48 h and had decreased significantly on the 7th day (p<0.005). There was a strong tendency to greater increase in standing BP and HR in the patients who experienced symptoms than in those who did not. Plasma concentrations of noradrenaline, adrenaline and prolactin did not change significantly. Thus, beta-blocker withdrawal symptoms are reproducible and are indicative of a transient sympathetic hyperresponse. The increased activity is not likely to be caused by increased production of circulating catecholamines, but rather by increased sensitivity of the beta-receptor.     

Systemic and renal hemodynamic effects of single oral doses of felodipine in patients with refractory hypertension receiving chronic therapy with beta-blockers and diuretics

In 12 patients with primary hypertension (World Health Organization stage 2) inadequately controlled by chronic standard triple therapy, hydralazine was replaced by felodipine, a new vasodilating dihydropyridine derivative, and the acute effects of the drug on central and renal hemodynamics were monitored. Following baseline measurements, an oral solution of felodipine (0.075-0.1 mg/kg) was given. Fifteen minutes after intake of felodipine, a significant hypotensive response was observed, and the maximal response (23% reduction of mean arterial pressure) occurred after 30 min. There was a linear relationship between the changes in mean arterial pressure and log plasma concentration of felodipine. Cardiac output (dye dilution) increased during maximal blood pressure reduction, from 5.3 +/- 1.0 to 6.6 +/- 2.4 L/min (p less than 0.01), partly because of increased heart rate from 57 +/- 4 to 65 +/- 9.1 beats/min (p less than 0.01) and partly because of increased stroke volume from 93 +/- 14 to 104 +/- 33 ml (p less than 0.05). Renal plasma flow (para-aminohippuric acid clearance) increased significantly (p less than 0.05) from 343 +/- 138 to 391 +/- 154 ml/min, while glomerular filtration rate ([51Cr]EDTA clearance) did not change. Arteriovenous noradrenaline difference increased 36% during felodipine therapy, when corrected for blood flow increase. We conclude that felodipine is a calcium inhibitor with potent vasodilating properties.     

The effect of 8 weeks treatment with the calcium antagonist felodipine on blood pressure, heart rate, working capacity, plasma renin activity, plasma angiotensin II, urinary catecholamines and aldosterone in patients with essential hypertension.

The effect of 8 weeks treatment with the calcium antagonist felodipine--a new long-acting dihydropyridine derivative--in a dose of 10 mg twice daily was studied in 10 male patients with essential hypertension, WHO grade I-II, aged 25-62 years. Diastolic blood pressure was reduced in supine and upright position. Systolic blood pressure was reduced only in the upright position. Heart rate was unchanged in the supine and decreased in the upright position. During dynamic exercise blood pressure was reduced. The maximal working capacity decreased, whereas the maximal heart rate attained was unchanged. Twenty-four hour urinary noradrenaline excretion, plasma renin activity and 24 h urinary aldosterone excretion were increased. Plasma angiotensin II and 24 h urinary adrenaline excretion were unchanged. In conclusion, felodipine is an effective long-acting blood pressure lowering drug with minor side effects. After 8 weeks on felodipine treatment heart rate was not increased, although the activity of the sympathetic nervous system and the renin-aldosterone system seemed enhanced.     

Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers

Objective: This study was performed to assess whether coadminstration with grapefruit juice significantly affects the pharmacokinetics of amlodipine, a dihydropyridine class calcium antagonist with slow absorption, distribution and low plasma clearance. The primary objective was to evaluate whether short exposure to grapefruit juice could affect the metabolism of amlodipine to an extent similar to that previously demonstrated for other dihydropyridines (e.g. felodipine, nisoldipine, nitrendipine). Methods: Twelve healthy male volunteers followed a randomised, open crossover study design, comparing the effect of a single oral dose of amlodipine (5 mg) taken together with a glass of grapefruit juice (250 ml) vs water. Blood samples to determine plasma concentration were taken and blood pressure (BP) and heart rate (HR) were measured throughout the study. Results: When amlodipine was coadministered with grapefruit juice, C_max was 115% and AUC(0–72 h) was 116% compared with water, but t_max was not significantly changed. There were no significant differences in BP and HR between the two treatments. A small decrease in diastolic BP, however, was observed in both treatments 4–8 h after drug administration, coinciding with C_max, but this was normalised after 12 h. The BP reduction seen was compensated by a slight increase in HR, which remained throughout the study. Conclusion: An interaction between grapefruit juice and amlodipine was demonstrated. The haemodynamic data showed that a dose of 5 mg was sufficient to achieve a BP reduction in healthy subjects, but the increase in amlodipine plasma concentration seen after intake of grapefruit juice was too small to significantly affect BP or HR. The clinical significance of this food/drug interaction, however, cannot be ignored since there is considerable variation between individuals and a more extensive intake of grapefruit juice might give more pronounced effects. Received: 7 November 1995/Accepted in revised form: 27 March 1996     

Plasma concentration-effect relationships of intravenous and extended-release oral felodipine in hypertensive patients.

Felodipine, a dihydropyridine calcium antagonist, was given double-blind in a crossover design comparing once-daily doses of 20 mg felodipine extended-release (ER) tablets with placebo in 12 hypertensive patients. A 2-h intravenous infusion was given after a placebo washout. After oral felodipine, blood pressure (BP) was significantly lower than after placebo, both after the first dose and after 2 weeks of treatment. Supine BP 24 h after the first dose of placebo and felodipine was 159/97 and 153/92 mm Hg (p less than 0.01/0.05), respectively. Corresponding BPs at 2 weeks were 158/99 and 144/89 mm Hg (p less than 0.01/0.01). Approximately 75% of the maximal and 60% of the trough effect at steady state were obtained already after the first dose. The plasma concentration (CpF) vs. time curve after felodipine ER was relatively flat. After oral felodipine, a linear correlation was found between BP reduction and logarithmic CpF. After intravenous administration, CpF correlated well with a hyperbolic function. These data indicate that there is an almost linear relation between BP reduction and log CpF in the range from 2-20 nmol/L, and that little additional effect is to be expected above approximately 20 nmol/L. No hysteresis was found for the relationship between CpF and BP reduction. The absolute bioavailability of felodipine ER was 22%.     

The pharmacodynamic and pharmacokinetic profiles of controlled-release formulations of felodipine and metoprolol in free and fixed combinations in elderly hypertensive patients

AIMS: The aims of this study were to study the efficacy and tolerability of felodipine extended release (ER) 5 mg and metoprolol controlled release (CR/ZOC) 50 mg given as a fixed combination (Logimax) or as a free combination in elderly (age greater than 60 years) hypertensive patients, using ambulatory blood pressure (BP) monitoring. A secondary aim was to relate the efficacy of the free and fixed combinations with pharmacokinetic profiles. METHODS: This was a double-blind, placebo-controlled randomised three-way crossover multi-centre study. BP was measured for 26 h using ambulatory blood pressure monitoring (ABPM), which was performed on the last day of the three treatment phases. RESULTS: Mean sitting BPs, measured during the trough period with ABPM, were significantly lower with both the free and fixed combinations of metoprolol and felodipine than placebo (141/83 mmHg free, 140/83 mmHg fixed, 156/93 mmHg placebo). The mean BPs measured over 24 h using ABPM were 143/82 mmHg, 140/82 mmHg and 158/93 mmHg for the free, fixed and placebo treatment arms, respectively. The trough-to-peak ratios (T:P) were 75% and 79% for the systolic BP and 70% and 70% for the diastolic BP for the free and fixed combinations, respectively. Pharmacokinetic evaluation revealed identical plasma concentration-time curves for felodipine given as the free or fixed combination. Comparison of the plasma concentration-time curves for metoprolol revealed a delay in the release rate from the fixed combination formulation. No significant differences in BP control between the active treatments were noted during this period. Of 26 patients entered into the study, 3 withdrew during active phase for non-drug-related reasons. No patient withdrew from active treatment due to treatment-related adverse events. The frequency of adverse event reporting for the fixed combination of felodipine and metoprolol was similar to that for placebo (60% and 58%, respectively). CONCLUSION: The results suggest that once-daily dosing with either the free or fixed combination of felodipine 5 mg and metoprolol 50 mg produces a significant sustained reduction in systolic and diastolic BP with similar plasma concentration profiles over a 24-h period.     

Baroreceptor activity in man during administration of the calcium channel blocker felodipine

The mechanisms responsible for the resetting of the baroreceptor reflex during long-term administration of 1,4 dihydropyridine calcium channel blockers are incompletely understood. The present study investigated the effect of 10 mg per day of felodipine on arterial blood pressure (BP), heart rate (HR), urinary norepinephrine, and cardiac beta-1-receptor sensitivity in 10 healthy volunteers. Blood pressure heart rate and urinary norepinephrine were determined during control and on days 1,4, and 14 of felodipine administration. Dose response curves of intravenous bolus injections of isoproterenol were performed on the same days to measure cardiac beta-1-receptor sensitivity. Felodipine significantly reduced the blood pressure from 131 +/- 6/74 +/- 3 mm Hg (mean +/- s.e.m.) to 123 +/- 6/65 +/- 2 mm Hg on day 1 (p less than 0.01). The blood pressure remained decreased during the entire protocol. The initial increase in the heart rate (62 +/- 5 to 67 +/- 4 min-1) remained elevated on day 4 and returned within the control range by day 14 (63 +/- 4 min-1) in spite of unchanged felodipine plasma levels (1.71 +/- 1.13 ng/ml (day 1) and 1.66 +/- 0.66 ng/ml (day 14). Urinary norepinephrine rose significantly with short-term felodipine administration (62 +/- 12 versus 50 +/- 6 micrograms/24 h; p less than 0.01). With long-term felodipine administration this value returned to pretreatment levels (55 +/- 12 micrograms/24 h). Cardiac beta-1-receptor sensitivity was not changed at any point of the protocol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma concentration-effect relationship of felodipine intravenously in patients with congestive heart failure

The pharmacodynamics of felodipine were analyzed in patients with congestive heart failure in a randomized, double-blind, placebo-controlled study. Felodipine at a dose of 1 mg (n = 11) or placebo (n = 12) was given intravenously during a 60-min period. Hemodynamic measurements and plasma samples were obtained every 15 min during a 2-hour period. An increase in heart rate (HR, +8%, p less than 0.01) and cardiac output (CO, +36%, p less than 0.001), and a decrease in mean arterial pressure (MAP, -24%, p less than 0.001) and systemic vascular resistance (SVR, -46%, p less than 0.001), were found. Pulmonary artery, right atrial, wedge pressure, and stroke-work index did not change. Linear regression analysis showed a significant correlation between felodipine plasma levels and changes in HR (r = 0.71, p less than 0.05), MAP (r = 0.94, p less than 0.01), CO (r = 0.73, p less than 0.05), and SVR (r = 0.88, p less than 0.01). A strong hyperbolic correlation was demonstrated between individual plasma levels and changes in MAP (r = 0.97, p less than 0.001). Hysteresis analysis showed that plasma levels are directly related to the concentration at the receptor site. A clockwise hysteresis was found in HR, CO, and SVR, but not in MAP. It is concluded that changes in flow and resistance are based on a physiological adjustment, a baroreflex-mediated response to vasodilation induced by felodipine, resulting in MAPs that remain closely related to felodipine plasma levels over a wide range.     

Long-term clinical, hemodynamic, angiographic, and neurohumoral responses to vasodilation with felodipine in patients with chronic congestive heart failure.

Twenty patients on conventional therapy for severe congestive heart failure (CHF) were randomly assigned to adjunctive treatment with felodipine (n = 10) or placebo (n = 10) and followed over a 6-month period. Baseline clinical, hemodynamic, angiographic, and neurohumoral estimates of CHF were comparable in the two treatment groups. These estimates remained virtually unchanged at 6 months in patients on placebo therapy, but circulating noradrenaline levels were further augmented. In patients on felodipine therapy, substantial reductions in left ventricular end-systolic pressure, mean arterial pressure, and systemic vascular resistance were observed at 6 months. This afterload reduction led to a preferential increment in the stroke volume (36%) which increased cardiac output (30%), whereas heart rate tended to decrease. The improved hemodynamics during felodipine treatment were paralleled by marked improvements in the angiographic left ventricular ejection fraction and regional segmental wall motion score. The enhanced contractile state of the left ventricle was accompanied by significant reductions in the augmented plasma levels of catecholamines, and the patient clinical status improved. The 6-month mortality rate in the 20 patients was 40% and indicated a closer relation to baseline noradrenaline plasma levels than to hemodynamic or angiographic estimates of CHF. Despite the limited number of patients, the long-term clinical efficacy of felodipine is thus evidenced in patients with CHF and is related to sustained arteriolar dilatation and improved neurohumoral profile by this vasoselective calcium antagonist.     

A population study of the pharmacokinetics of felodipine.

1. The pharmacokinetics of felodipine was studied after continuous oral administration of 5 or 10 mg conventional tablets to a population of 140 male and female Caucasian subjects, of which 67 were hypertensive patients and 73 were healthy volunteers. In addition, 42 of these individuals received felodipine intravenously. 2. With increasing age the area under the felodipine plasma concentration vs time curve (AUC), the maximum plasma concentration (Cmax), and the terminal elimination half-life of felodipine increased, while the plasma clearance of felodipine decreased. The bioavailability and steady state volume of distribution and the time to Cmax were not consistently influenced by age. 3. The ratio of the AUC of the primary pyridine metabolite of felodipine and that of unchanged drug decreased with increasing age. 4. Neither Cmax, AUC nor the half-life of felodipine were related to body mass index. 5. The distribution of AUC for felodipine, as well as the ratio of the AUC of this first metabolite to that of unchanged felodipine, was unimodal. Thus, the presence of a sizable group of individuals, with a clinically significant different metabolism of 1,4-dihydropyridine due to genetic factors is unlikely. 6. The pharmacokinetics of felodipine did not seem to differ between hypertensive patients and healthy volunteers, when adjusted for age. Neither was there a difference between patients taking beta-adrenoceptor antagonists and those who did not. 7. As a group the elderly had higher total concentrations of unchanged felodipine in plasma compared with younger individuals. The variation in plasma concentrations of felodipine between individuals is, however, only partially explained by age. In clinical practice this emphasizes the need for dose titration of felodipine.