Administration Of Felodipine Research Articles

高血圧症患者に対するＦｅｌｏｄｉｐｉｎｅの長期投与がもたらす糖と脂質の代謝への影響

高血圧症患者に対するＦｅｌｏｄｉｐｉｎｅの長期投与がもたらす糖と脂質の代謝への影響

Treatment of hypertension with felodipine in patients with concomitant diseases.

Coexisting medical conditions often complicate the selection of antihypertensive drugs. Felodipine, a new vascular-selective calcium antagonist with demonstrated antihypertensive efficacy, has not been found to alter lipid profiles in hypertensive patients. Studies in additional patient populations have yielded insights into the effects of the drug on other diseases that may coexist with hypertension. In individuals with stable angina pectoris or congestive heart failure, acute administration of felodipine reduces systemic vascular resistance and increases cardiac output and total coronary blood flow; myocardial contractility is not depressed at doses that produce a clinically significant reduction in vascular resistance. In patients with coronary stenoses, the drug increases vessel diameter in the vicinity of obstructive lesions. Single-dose and long-term studies in patients with exertional angina have found that felodipine reduces anginal frequency and improves exercise tolerance. In patients with congestive heart failure, chronic dosing with felodipine produces a persistent reduction in vascular resistance and an increase in cardiac output, both at rest and during exercise. Symptomatic improvement and increased exercise tolerance have been noted in some studies. In patients with Raynaud's phenomenon, felodipine has been associated with a dose-dependent improvement in symptomatology. Among individuals with exercise-induced bronchospasm, the drug has no effect on resting bronchial tone and may exert some positive effects during exercise. In hypertensive patients with Type II diabetes, felodipine has not been found to raise glucose levels significantly. The data obtained thus far suggest that felodipine is safe for use in hypertensive patients with a variety of concomitant diseases.

Cerebral blood flow in patients with severe hypertension, and acute and chronic effects of felodipine.

To evaluate whether a spontaneous increase in cerebral blood flow (CBF) could be observed in subjects with severe hypertension and to study the effect of a calcium antagonist, felodipine, on blood pressure and CBF after acute and chronic administration. Patients with severe hypertension were recruited at the emergency ward. Patients with previous treatment with calcium antagonists, women of child-bearing potential, severe uraemia, nephrotic syndrome, heart failure, manifest cerebrovascular lesions and pathological liver function tests were excluded. CBF was measured by single-photon emission computed tomography after intravenous administration of xenon-133 before (CBF1) and after intravenous infusion of felodipine, 0.01 mg/min during 40-60 min (CBF2) in 12 patients aged 25-67 years with no antihypertensive treatment except for beta-blockers in four patients and beta-blockers plus a diuretic in one patient. CBF was repeated after 3 weeks of oral therapy with felodipine, 5-10 mg twice a day with the addition of beta-blockers in 10/12 patients (CBF3). During the felodipine infusion blood pressure decreased. There were no neurological symptoms or signs before or during the felodipine administration. CBF1 was within normal limits with no significant differences between previously treated and untreated patients. There was a non-significant tendency to increase in global CBF after felodipine administration, associated with a significant reduction in the physiological side differences in blood flow. In spite of the initially very high blood pressure, no general or focal hyperaemia was observed, and thus no evidence for a 'breakthrough' of the cerebral autoregulation. Felodipine gives a smooth blood pressure reduction with a maintained CBF.

Scintigraphic Evaluation of the Short- and Long-Term Renal Effects of Oral Felodipine Using Technetium-99m-Mercaptoacetyl Triglycine

The short- and long-term effect of felodipine on renal perfusion and tubular function was investigated using a new renal tubular imaging agent, 99mTc-mercaptoacetyl triglycine (99mTc-MAG3). Twelve patients with essential hypertension (mean age = 49 +/- 8 years) were studied. Renal scintigraphies with 180 MBq 99mTc-MAG3 were performed at baseline, at the 2nd hour following oral administration of 5 mg felodipine and 4 weeks later on 5-10 mg daily felodipine therapy. The time-activity curves of each kidney were obtained following background subtraction. The 99mTc-MAG3 clearance value was measured for each kidney. In addition, perfusion index (PI), reno index, time to maximum, half-maximum and two thirds of maximum activity values of each kidney were calculated. Systolic and diastolic blood pressures were significantly lowered with long-term administration of felodipine (from 159 +/- 12/105 +/- 5 to 141 +/- 11/87 +/- 7 mm Hg, p = 0.01 and p = 0.002, respectively). Heart rate did not change significantly. Initially, a decrease in PI indicating an increase in renal blood flow (from 246 +/- 96 to 194 +/- 54, p = 0.01) was observed, whereas no change was noted during the chronic administration (to 230 +/- 69, p = NS). Total clearance of 99mTc-MAG3 was decreased nonsignificantly following the initial dose of felodipine (from 361 +/- 93 to 351 +/- 91 ml/min, p = NS). During long-term therapy, felodipine did not alter the perfusion and tubular function of the kidneys. Our results indicated that felodipine causes a significant increase in renal blood flow initially, even with a nonsignificant change in systemic blood pressure.

Vasodilators inhibit acute alpha 1-adrenergic receptor-induced trophic responses in the vasculature.

Cardiovascular hypertrophy plays an important role in the development and maintenance of hypertension. Hyperactivity of the sympathetic nervous system may be one of the initiating factors responsible for the stimulation of growth processes involved in these structural alterations. We have used a well-established early biochemical marker of cellular growth processes, induction of ornithine decarboxylase (ODC), to determine whether alpha 1-adrenergic receptor-induced vascular trophic responses are dependent on arterial pressure elevation. Hydralazine or felodipine were coadministered to control the alpha 1-adrenergic receptor agonist-induced rise in mean arterial pressure (MAP). Methoxamine (2, 5, or 10 mg/kg s.c.) increased the average MAP (up to 20 mm Hg) and vascular ODC activity (up to ninefold) above control rats over 4 hours. Concomitant administration of hydralazine (0.5, 1.25, or 5 mg/kg s.c.) or felodipine (100 or 250 micrograms/kg s.c.) with methoxamine (10 mg/kg) attenuated the alpha 1-adrenergic receptor-induced activation of ODC in the aorta and mesenteric resistance vasculature, as well as the MAP increases. Vasodilators alone did not lower basal vascular ODC activity. The major findings include: 1) alpha 1-adrenergic receptor activation dose-dependently induces vascular ODC activity concomitantly with MAP elevation, 2) vasodilators inhibited both the alpha 1-adrenergic receptor-induced MAP increases and the activation of mesenteric vascular and aortic ODC, and 3) the stimulus-response correlation between MAP elevation and mesenteric (r = 0.78) and aortic (r = 0.92) ODC activation was characterized by a logistic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Felodipine (once daily) versus nifedipine (four times daily) for Prinzmetal's angina pectoris

In 30 consecutive patients with Prinzmetal's angina pectoris, the antiischemic effect of felodipine, a new long-acting vasoselective calcium antagonist, administered at doses of 10 and 20 mg once daily was compared with that of the wellestablished therapeutic regimen with nifedipine administered at a dose of 20 mg 4 times daily. Twenty-four-hour Holter monitoring was performed during a 2-day placebo run-in and at the end of each of 3 consecutive 6-day periods during which the 3 active treatments were administered in randomized sequence. Three patients withdrew, whereas 27 completed the study. The therapeutic regimens tested proved to be similarly effective; primary end points (ischemic episodes recorded by Holter monitoring, and anginal attacks reported on diary cards) occurred in 5 patients (19%) during nifedipine treatment, and in 7 (26%) and 3 (11%) during felodipine treatment with 10 and 20 mg, respectively (p = not significant). The distribution of residual ischemic episodes demonstrated that treatment with felodipine once daily provides 24-hour antiischemic protection. Twenty-six patients were followed up with 20 mg of felodipine once daily for a mean of 6 ± 5 months, and 21 of them (81%) remained free of symptoms and Holter-recorded ischemic attacks. It is concluded that for Prinzmetal's angina pectoris, 24-hour antiischemic protection may be achieved with administration of felodipine once daily. The availability of a simplified therapeutic approach may constitute a real advantage in terms of patient compliance and improving the quality of life.

β-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.

Attenuation of renal ischaemic injury by felodipine

Felodipine is a vasodilating calcium channel blocker of the dihydropyridine type. The effects of felodipine on post-ischaemic renal function were evaluated in rats subjected to bilateral renal artery occlusion for 30 or 60 min. In a first set of experiments the recovery of renal function after 30 or 60 min of renal artery occlusion was followed intermittently for 16 days by endogenous creatinine clearance. Renal function was better preserved in rats given felodipine (45 nmol/kg i.v.) during the occlusion period than in vehicle-treated control rats. The survival rate after 60-min occlusion was 11% in controls but 70% in the felodipine-treated rats. After occlusion for 30 min the survival rate was similar in the two groups, but renal function recovered faster in the felodipine group than in the controls. In a second series, acute renal damage was evaluated by the extent of erythrocytes trapped in the kidney after 30-min reperfusion following 60-min renal artery occlusion. Felodipine administration (45 nmol/kg) during the occlusion reduced renal damage compared with vehicle controls. Kidney weight and systemic haematocrit were also better maintained in the felodipine-treated rats. Furthermore, renal damage was reduced by the t-butyl analogue or felodipine. H 186/86, which is devoid of vasodilatory effects. The results demonstrate that treatment with the vasodilator calcium channel blocker felodipine protects the kidney from ischaemic/reperfusion injuries. The tissue protection is not related to the haemodynamic effects alone, since the haemodynamically inactive dihydropyridine H 186/86 also reduced the extent of renal damage. An additional antiperoxidant or scavcnger-like effect inherent in the dihydropyridine molecule is suggested.

Determination of felodipine and its metabolites in plasma using capillary gas chromatography with electron-capture detection and their identification by gas chromatography—mass spectrometry

A novel method for the determination of felodipine and its metabolites in plasma by capillary gas chromatography (GC) with electron capture detection was developed. Felodipine and its oxidized metabolite were assayed by capillary GC after solid-phase extraction with the aid of a cool on-column injection technique. Acid metabolites, methyl monoacid and ethyl monoacid and diacid, were extracted with diethyl ether and propylated with 1- n-propyl-3- p-tolyltriazene before being submitted to capillary GC. These methods were very sensitive and useful for the pharmacokinetic study of felodipine. Felodipine and its metabolites were identified by GC—mass spectrometry. The mass spectral patterns of the peaks of extracts from human plasma samples after oral administration of felodipine were in good agreement with those of reference compounds.

Acute and chronic efficacy of felodipine in congestive heart failure

In 13 patients with congestive heart failure we tested the acute hemodynamic effects of 5 vs. 10 mg felodipine tablets, in a double-blind, cross-over study. One hour after felodipine 5 mg, echocardiographic ejection fraction (%), cardiac index (thermodilution-ml/min/m 2), and pulmonary wedge pressure (mm Hg) significantly changed (from 21 ± 2 to 26 ± 2, 2350 ± 150 to 2790 ± 160, 24 ± 4 to 17 ± 4) while they remained steady after felodipine 10 mg. The greatest stroke index increases were associated with felodipine 5 mg in 12 patients and 10 mg in 1 patient. Therefore we evaluated (open study) the long-term (2 months-1 year) clinical and hemodynamic efficacy following the treatment with the acutely most effective dose (twice daily). After 2 months ejection fraction, cardiac index and pulmonary wedge pressure were respectively 24 ± 2, 2550 ± 150, and 18 ± 4 (12 hours after the last drug administration, n = 11, P < 0.02 from baseline). These parameters further increased one to two hours after the following administration of felodipine. Clinical improvement (reduction of 1 functional class, according to the New York Heart Association) was observed in 8 13 patients. These 8 patients participated to the one year follow-up. In 5 patients follow-up was interrupted because of acute cardiovascular events. However, before study interruption (5 patients) or ending (3 patients) clinical status did not worsen and ejection fraction remained higher than in the pretreatment period. Therefore, low dose felodipine might be used in the treatment of congestive heart failure.

Acute effects on exercise tolerance of felodipine and diltiazem, alone and in combination, in stable effortangina

The acute effects on exercise tolerance and electrocardiographic ischaemia of felodipine and diltiazem, alone or in combination, were investigated in 12 patients with documented stable effort-induced angina pectoris. After being withdrawn from their previous antianginal treatments, patients received a single oral dose of felodipine 10 mg, diltiazem 60 mg, their combination or placebo on four different days, according to a double-blind, 4 x 4 latin-square design. Exercise time to ischaemic threshold (ST-segment depression = 1 mm) and to peak exercise was significantly prolonged by the felodipine-diltiazem combination (492 and 504 s, respectively) against placebo (301 and 370 s, both P less than 0.01), felodipine alone (381 and 428 s, both P less than 0.01) and diltiazem alone (367 and 422 s, both P less than 0.01). The effects on total work followed a similar pattern. In comparison with placebo, the administration of felodipine and diltiazem alone significantly increased exercise duration as well as total work to ischaemic threshold and to peak exercise, with no differences between the two drugs. Systolic blood pressure during exercise was not affected by any of the treatments. However, in comparison with both placebo and diltiazem, the combination induced an increase (P less than 0.01) in heart rate during exercise. One patient suffered from symptomatic hypotension with the combination, and another had sinus tachycardia after felodipine. In conclusion, the acute concomitant administration of felodipine and diltiazem in patients with stable effort angina induces a marked improvement in exercise tolerance in comparison with placebo, felodipine alone and diltiazem alone. However, the benefit/risk profile of such a combination requires further, long-term investigation.

Felodipine in chronic stable angina: a randomized, double-blind, placebo-controlled, crossover study

To investigate the antianginal efficacy and tolerability of felodipine, a new dihydropyridine calcium antagonist, 20 patients with stable exertional angina, not completely controlled by beta-blocker monotherapy, entered a randomized, double-blind, placebo-controlled, crossover study. Patients on standard beta-blocker therapy, who had at least 3 weekly anginal episodes and a reproducible exercise test (stopped for angina and ECG signs of ischaemia) at the end of 2 weeks placebo treatment, were eligible for the study. They were randomized to one sequence of treatment: felodipine 5 mg twice daily for 2 weeks followed by placebo for a further 2 weeks, or vice versa. Beta-blocker treatment was unchanged throughout the study. A treadmill test was carried out at the end of each crossover period, 2-4 h after drug administration. The number of anginal attacks and nitroglycerin consumption was recorded on a diary card. At rest, felodipine significantly (P less than 0.05) reduced standing systolic but not diastolic blood pressure. Heart rate was not modified by the active treatment. At ischaemic threshold and at peak exercise, heart rate, systolic blood pressure and rate-pressure product remained unchanged. Exercise duration was increased by felodipine (P less than 0.01) and maximal ST change was reduced (P less than 0.01). Time to 1 mm ST depression was prolonged non-significantly by felodipine (basal 5.7 +/- 1.5, felodipine 7.4 +/- 2.0, placebo 6.6 +/- 1.5 min). The number of patients who stopped exercise due to angina and ST change was 20/20 at baseline, 16/20 with placebo and 10/20 with felodipine. Felodipine significantly reduced weekly anginal episodes (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute effects of felodipine and nifedipine on hepatic and forearm blood flow in healthy men

The acute effects of oral administration of felodipine 10 mg and nifedipine 10 mg on heart rate, blood pressure, forearm blood flow and hepatic blood flow were studied in nine healthy men. Both drugs caused an increase in heart rate of 16 and 7 beats.min-1, respectively. Hepatic blood flow was significantly increased by 1.2 and 0.41.min-1 after felodipine and nifedipine. There was also a decrease in diastolic blood pressure, 10 and 5 mm Hg, respectively, after felodipine and nifedipine. The forearm blood flow was increased by about 30 ml.100 ml-1.min-1 after felodipine, but nifedipine had no effect. The haemodynamic effects were most pronounced 50 min after drug administration.

Renal failure in haemorrhagic shock in dogs: Salutary effects of the calcium entry blocker felodipine

The efficacy of felodipine, a dihydropyridine calcium entry blocker to restore renal function was investigated in Wiggers model of haemorrhagic shock. Mongrel dogs were anaesthetized with sodium pentobarbital and subjected to haemorrhagic shock by allowing the animals to bleed into a reservoir. After maintaining the hypotensive state (mean blood pressure 40-45 mm Hg) for a period of 150 min, the blood was reinfused and the recovery of the various parameters were monitored for an additional 120 min. These studies were conducted in three different groups of dogs: (A) Solvent control, (B) Felodipine 0.01 mumol/kg i.v., administered 10 min prior to reinfusion of the blood, and (C) Felodipine 0.01 mumol/kg i.v., administered prior to haemorrhage. In all the three groups arterial blood pressure returned to similar basal levels following reinfusion. Felodipine administration prior to haemorrhage or before reinfusion (Group B and C) resulted in a 80-95% recovery in the renal blood flow, 60-65% in the glomerular filtration rate, 150-300% in the urine volume and 80-100% in the urinary sodium and potassium excretions. In the vehicle-treated control group, despite a 45% recovery in the renal blood flow, renal function was not restored following reinfusion. The observations made in these studies suggest that felodipine, an arteriolar dilator which also possesses natriuretic properties, could be clinically useful in the treatment of renal failure in haemorrhagic shock. Prevention of cellular calcium overload during ischaemia and reperfusion by this dihydropyridine derivative, may account for its ability to preserve vascular as well as tubular function.

Histological and in vitro studies supporting decreased uteroplacental blood flow as explanation for digital defects after administration of vasodilators

In a recent study, the vasodilating drugs nifedipine, nitrendipine, felodipine, and hydralazine induced phalangeal defects in rabbits, when given on day 16 of pregnancy. Histologically, the changes were characterized by disturbed chondrogenesis. In order to elucidate mechanisms behind the defects, the fetal concentration of felodipine was measured, and the fetal limb plates were examined histologically, at 0, 2, 4, 8, 12, and 24 hours after single oral administration of felodipine (12 mumol/kg) on day 16 in pregnant rabbits. The effects of nifedipine, nitrendipine, and felodipine were also investigated in an in vitro system, in which chick embryonic mesenchymal limb bud cells differentiated into chondrocytes. In this system, no inhibition of chondrogenesis was observed below concentrations 3 x 10(5) M. At this concentration, unspecific cytotoxicity was found. The highest fetal concentrations of felodipine were more than 500 times lower than what was required for in vitro toxicity. Histologically, the digital areas of the limb plates showed extensive edema and dilatation of marginal sinus within 2 hours. After 8 hours, rupture of the thin-walled vessels occurred with hemorrhages. Finally, small necroses and blisters were observed. Similar early changes have been reported in experiments where digital defects were induced by clamping uterine vessels. This study thus indicates that the phalangeal defects after administration of high doses of vasodilators are secondary to pharmacological action (associated with a significant reduction in the uteroplacental blood flow), and not a direct effect on fetal chondrogenesis.

The effects of Ca2+ antagonists and hydralazine on central 5‐hydroxytryptamine biochemistry and function in rats and mice

1. The effects of calcium antagonists on behaviour mediated by 5-hydroxytryptamine (5-HT) have been studied in rats and mice together with an investigation of the effects of these drugs on 5-HT synthesis in rat brain and endogenous 5-HT release from brain slices. 2. Administration of felodipine (35 mg kg-1 i.p.) to rats pretreated with tranylcypromine (20 mg kg-1, i.p.) resulted in the animals displaying the complete 5-HT-mediated behavioural syndrome (including head weaving, reciprocal forepaw treading and hind limb abduction) 75 min later. No evidence was obtained for the rate of 5-HT synthesis in brain regions differing between control and felodipine-treated rats. 3. Pretreatment with felodipine (10 or 35 mg kg-1) enhanced the 5-HT-mediated behavioural syndrome induced by injection of tranylcypromine and L-tryptophan. The rate of 5-HT accumulation in the brain was similar in both groups. Administration of Bay K 8644 (1 mg kg-1, i.p.) did not prevent the enhanced behaviour induced by felodipine (10 mg kg-1). 4. The 5-HT behavioural syndrome induced by injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was unaltered by either acute injection of felodipine (35 mg kg-1) or administration of felodipine twice daily for 3 days. 5. Felodipine (10 microM), verapamil (10 microM) and Bay K 8644 (10 microM) did not alter either basal release of endogenous 5-HT from slices prepared from frontal cortex or hind brain, or release following addition of K+ at a concentration of 20 mM, or 35 mM. 6. Verapamil (25mgkg-', i.p.), nicardipine (25mgkg-1, i.p.) and nifedipine (20mgkg-1, i.p.) all markedly inhibited the 5-HT2 receptor-mediated head twitch response in mice produced by injection of 5- methoxy-N,N-dimethyl-tryptamine (5-MeODMT). Felodipine had the same effect with an ED50 of 2.6mgkg-'. Bay K 8644 did not reverse this effect. Both verapamil (IC50:2.5 microM) and nicardipine (IC50:8 microM) were 5-HT2 antagonists as indicated by inhibition of [3H]-ketanserin binding in mouse frontal cortex. However felodipine and nifedipine antagonized 5-HT2 receptor binding only in the millimolar range.7. Hydralazine (5mg kg 1, i.p.) induced the 5-HT behavioural syndrome in tranylcypromine pretreated rats, enhanced the tranylcypromine/L-tryptophan behavioural syndrome, inhibited 5-MeODMT-induced head twitch behaviour in mice and was not a 5-HT2 receptor antagonist. 8. These data indicate that at a high dose, Ca2+ antagonists produce complex changes in 5-HT function in rodents which are similar to those produced by lithium administration. The data with hydralazine suggest that the effects seen are not related to an action at Ca2 + channels.

Hemodynamic Effects of Calcium Antagonists with High or Low Vascular Selectivity

Infusion of felodipine and verapamil in increasing doses to anesthetized spontaneously hypertensive rats induced a progressive fall in arterial blood pressure (BP). To estimate the cardiac action of the different drugs, we also measured changes in cardiac output (CO) and velocity of flow (dF/dT) by a Doppler flow probe placed on the ascending aorta. Infusion of verapamil induced a parallel decrease in mean arterial BP, CO, and cardiac inotropy (as estimated by max. dF/dT). In contrast, upon felodipine administration, the decrease in arterial BP was accompanied by an initial small rise in dF/dT. A decrease in dF/dT was observed only after high doses of felodipine, which caused pronounced levels of hypotension.

Renal Effects of Felodipine

The dihydropyridine calcium channel antagonist felodipine has a wide spectrum of effects on the kidney. From a variety of studies in normotensive and hypertensive animals and human subjects, felodipine produces a decrease in renal vascular resistance that, although predominantly dependent on the decrease in mean arterial pressure (MAP), may be associated with an increase in renal blood flow (RBF). The glomerular filtration rate (GFR) is unchanged. In response to acute felodipine administration, the significant diuresis and natriuresis observed is caused by a direct inhibitory effect on net renal tubular sodium and water reabsorption. While the acute natriuretic response to felodipine administration is modulated by compensatory adaptations over the remainder of the 24-h period and during chronic treatment, the negative sodium balance established is sustained over the duration of the treatment. Renal sodium and water retention are not observed and there is little effect on renal potassium handling. As a vasodilator antihypertensive agent, felodipine produces renal vasodilatation (normal or increased but not decreased RBF) without adverse effects on the GFR or renal sodium and water retention.

Absorption of theophylline is reduced by felodipine administration

Absorption of theophylline is reduced by felodipine administration

Haemodynamic effects and pharmacokinetics of felodipine at rest and during exercise in hypertensive patients treated with metoprolol or atenolol.

A study has been performed in thirteen patients with essential hypertension, WHO Class I-II, and a diastolic blood pressure greater than or equal to 95 mmHg, on beta-blocker (metoprolol or atenolol) monotherapy, who were also given felodipine 10 mg b.d. for 28 days. The acute and steady state blood pressure response at rest and during exercise, and the pharmacokinetics of felodipine and metoprolol, were examined. Felodipine in combination with the beta-blocker reduced the systolic and diastolic blood pressures acutely and at steady-state. The duration of the effect was longer at steady-state. There was a significant correlation between the plasma concentration of felodipine and the change in blood pressure. The increase in systolic blood pressure during exercise was of the same magnitude before and after felodipine administration. No change in resting supine heart rate was found after the administration of felodipine. There was no significant differences in the pharmacokinetics of felodipine during long-term treatment, except for the trough plasma concentration, which was increased at steady-state, even though cumulation of felodipine and its metabolite did not occur. There was a significant decrease in the maximal plasma concentration and AUC of metoprolol after 28 days of treatment with felodipine, but its elimination half-life was not changed. The adverse reactions reported during this study were those generally seen after dihydropyridines and, except for two patients who were withdrawn after the first study day, the effects were well tolerated.