Plasma Concentrations Of Felodipine Research Articles

TRANSDERMAL DELIVERY OF CALCIUM CHANNEL BLOCKER: DEVELOPMENT AND CHARACTERIZATION

Objective: Felodipine, a BCS class II calcium channel blocker, is used in the management of hypertension and angina pectoris. Due to the poor solubility and low bioavailability of the drug, there is a necessity to design an alternative route to achieve a constant plasma concentration of felodipine for its maximum therapeutic utility and can be achieved by transdermal route.Methods: In this study, matrix type transdermal patches were prepared using different combinations of hydrophilic polymer, namely, polyvinylpyrrolidone (PVP) and hydrophobic polymer, namely, ethyl cellulose (EC) by solvent evaporation technique and were subjected for characterization.Results: The Fourier transform infrared studies confirmed the compatibility between drug and polymers. Hydrophilic nature of the polymers greatly influenced physical characteristics and dissolution rate. Equal percentage of PVP and EC yielded patches with good folding endurance. The concentration of plasticizer present in the patches gave them desired folding endurance, and it increased with the presence of hydrophilic polymer. The formulation with highest PVP concentration, F3, exhibited a maximum drug release of 96.23% for 24 hrs. While the formulation with highest EC concentration, F5, exhibited only 74.45% drug release for 24 hrs.Conclusion: From the data, formulation F2 (PVP/EC, 2:1) can be concluded as best formulation due to its desired physical characteristics, good initial drug release, sustained release behavior, and good in vitro permeation. This formulation can be further studied in a clinical scenario.

Pharmacokinetic and Antihypertensive Profile of Amlodipine and Felodipine-ER in Younger Versus Older Patients With Hypertension

To evaluate the impact of age on the pharmacokinetics and blood pressure (BP) responses of a dihydropyridine (DHP) with large versus small first-pass metabolism in hypertensive subjects, younger (n = 28) and older (n = 35) patients with hypertension were randomized to placebo, felodipine-ER 5 mg/d, or amlodipine 5 mg/d. In the young subjects, the first dose of either DHP did not decrease BP and chronic dosing decreased BP by approximately 10 mm Hg, which had disappeared by 24 hours. In the older group, felodipine-ER decreased systolic BP by approximately 10 mm Hg after the first dose and by approximately 20 mm Hg after chronic dosing, which had disappeared after 24 hours. The first dose of amlodipine caused a gradual fall in BP and chronic dosing by approximately 20 mm Hg and still by approximately 10 mm Hg at 120 hours. Older subjects showed approximately 30% higher area under the concentration–time curves and plasma concentrations of felodipine and amlodipine, but (apparent) elimination half-lives did not differ between younger and older subjects. The chronic antihypertensive responses correlated well with both plasma levels and pretreatment BP. Age has only a modest impact on the pharmacokinetics of amlodipine and felodipine-ER but markedly affects the BP response to the first dose of either DHP and the duration of action after chronic dosing of amlodipine.

Bergamottin contribution to the grapefruit juice?felodipine interaction and disposition in humans

Our objectives were to evaluate the contribution of bergamottin to the grapefruit juice-felodipine interaction and to characterize bergamottin disposition. In this study 250 mL grapefruit juice; 2-, 6-, or 12-mg capsules of bergamottin plus water; or water was administered with 5 mg extended-release felodipine to 11 volunteers in a partially randomized, 5-way crossover study. Plasma concentrations of felodipine, its primary metabolite (dehydrofelodipine), bergamottin, and 6',7'-dihydroxybergamottin were determined. Grapefruit juice (containing 1.7 mg bergamottin) increased peak plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) of felodipine by 89% (P < .025) and 54% (P < .025), respectively, compared with water. With 2 mg bergamottin, felodipine C max increased by 33% (P < .05). The increase by bergamottin was markedly variable among individuals (range, -33% to 125%). With 6 mg bergamottin, felodipine C max was enhanced by 35% (P < .025), and with 12 mg bergamottin, felodipine C max increased by 40% (P < .05) and AUC increased by 37% (P < .05) compared with water. Bergamottin measured in plasma after administration of 6 and 12 mg produced C max values of 2.1 and 5.9 ng/mL, respectively, and times to reach C max of 0.8 and 1.1 hours, respectively. The bergamottin metabolite 6',7'-dihydroxybergamottin was detected in plasma of some subjects after bergamottin administration. Bergamottin enhanced the oral bioavailability of felodipine and may cause a clinically relevant drug interaction in susceptible individuals. Grapefruit juice-drug interactions likely also involve other furanocoumarins, possibly acting in combination by additive or synergistic mechanisms. Bergamottin has systemic availability and is metabolized in vivo to 6',7'-dihydroxybergamottin.

Ischemic and Nonischemic Tissue Concentrations of Felodipine After Coronary Venous Retroinfusion During Myocardial Ischemia and Reperfusion

Summary: Tissue and plasma concentrations of felodipine, a dihydropyridine (DHP) calcium antagonist, retroinfused through the coronary venous system were studied in 27 pigs. The animals underwent 45-min myocardial ischemia followed by 4-h reperfusion. Felodipine (7 nmol/kg body weight) was administered in the coronary vein for 30 min, 5 min before reperfusion. Concentrations of felodipine in the ischemic and nonischemic myocardium and in plasma were determined by gas chromatography. In the ischemic area, felodipine concentration at start of reperfusion was 304 ± 285, 171 ± 160, and 52 ± 47 nmol/kg (mean ± SD) in the subepicardial, midmyocardial, and subendocardial layer, respectively. Corresponding concentrations in the nonischemic area were 15 ± 13, 17 ± 14, and 16 ± 15 nmol/kg (p < 0.05 vs. ischemic area). Subepicardial concentration was highest at start of reperfusion, whereas concentrations in other layers peaked at the end of retroinfusion. The transmural concentration gradient of felodipine in the ischemic area decreased progressively during the reperfusion period. The nonischemic tissue concentration increased slightly during the reperfusion period. The plasma concentration was very low throughout the study (peak = 3.2 ± 1.4 nM at 30 min). Coronary venous retroinfusion of felodipine resulted in profound accumulation of the drug, specifically in ischemic myocardium. The plasma concentration was low and did not affect systemic hemodynamics. Coronary venous retroinfusion is considered an advantageous technique for selective drug delivery.

Ischemic and Nonischemic Tissue Concentrations of Felodipine After Coronary Venous Retroinfusion During Myocardial Ischemia and Reperfusion

Tissue and plasma concentrations of felodipine, a dihydropyridine (DHP) calcium antagonist, retroinfused through the coronary venous system were studied in 27 pigs. The animals underwent 45-min myocardial ischemia followed by 4-h reperfusion. Felodipine (7 nmol/kg body weight) was administered in the coronary vein for 30 min, 5 min before reperfusion. Concentrations of felodipine in the ischemic and nonischemic myocardium and in plasma were determined by gas chromatography. In the ischemic area, felodipine concentration at start of reperfusion was 304 +/- 285, 171 +/- 160, and 52 +/- 47 nmol/kg (mean +/- SD) in the subepicardial, midmyocardial, and subendocardial layer, respectively. Corresponding concentrations in the nonischemic area were 15 +/- 13, 17 +/- 14, and 16 +/- 15 nmol/kg (p < 0.05 vs. ischemic area). Subepicardial concentration was highest at start of reperfusion, whereas concentrations in other layers peaked at the end of retroinfusion. The transmural concentration gradient of felodipine in the ischemic area decreased progressively during the reperfusion period. The nonischemic tissue concentration increased slightly during the reperfusion period. The plasma concentration was very low throughout the study (peak = 3.2 +/- 1.4 nM at 30 min). Coronary venous retroinfusion of felodipine resulted in profound accumulation of the drug, specifically in ischemic myocardium. The plasma concentration was low and did not affect systemic hemodynamics. Coronary venous retroinfusion is considered an advantageous technique for selective drug delivery.

Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine--and its potential clinical relevance.

The effect of drinking grapefruit juice on the acute pharmacokinetic and haemodynamic actions of the dihydropyridine calcium antagonist felodipine given as a 5 mg plain tablet has been studied in nine, healthy, middle-aged males. Compared to water, grapefruit juice caused an increase in Cmax from mean 6 to 16 nmol.l-1, and in the AUC from 23 to 65 nmol.h.l-1. The change in AUC corresponded to an increase in the systemic availability of felodipine from 15 to 45%, assuming no change in its clearance. This change was probably caused by inhibition of the oxidation of felodipine to the inactive dehydrofelodipine by flavonoids in grapefruit juice. The interaction with grapefruit juice is believed to be a class effect for the dihydropyridines, as oxidation of the dihydropyridine ring to the corresponding pyridine derivative is a major metabolic route for all these drugs. The higher plasma concentrations of felodipine taken with grapefruit juice resulted in a greater change in blood pressure measured in the morning 3 h after dosing (-9%) than did water (0%).

Twenty-four hour blood pressure profiles in hypertensive patients following various formulations and dosage regimens of felodipine

The blood pressure lowering capacity of felodipine administered either as extended release tablets once or twice daily or as plain tablets twice daily has been compared in a double-blind, three-way cross-over study in 16 hypertensive patients. All the patients were on long-term treatment with 10 or 20 mg felodipine daily and other antihypertensive therapy (mainly beta-blockers) was allowed if it was kept unchanged. Non-invasive blood pressure and heart rate recordings were obtained throughout 24 hour periods using an Accutracker ambulatory system. The 24 h mean systolic and diastolic blood pressures after extended release tablets o.m. did not differ significantly from those after extended release tablets b.d. or plain tablets b.d. There was a tendency for the extended release tablets given o.m. to reduce blood pressure somewhat more in the morning, and for the extended release tablets b.d. to reduce blood pressure more during the night than the other treatments. Mean 24 h heart rate after all treatments was comparable. Manual recordings confirmed these results. Blood pressure was well-controlled throughout the 24 h period by all three treatments. The extended release tablets tended to give less extreme plasma concentrations of felodipine. This may be of value for patients with adverse vasodilator effects. For a majority of hypertensive patients the adequacy of blood pressure control and the simplicity of once daily dosing will favour the extended release tablet given once daily.

Felodipine Clinical Pharmacokinetics

Absorption of felodipine is rapid and complete. A pronounced first-pass metabolism results in a bioavailability of 15%, irrespective of the oral formulation used. The peak plasma concentrations and area under the plasma concentration-time curve are linearly related to the dose. The variability in plasma concentrations is wide, and individualization of the dosage is recommended. Plasma felodipine concentrations are increased in the elderly, and in patients with congestive heart failure or liver cirrhosis; in these patients felodipine should be started at a low dosage. Food intake has no clinically significant effect on felodipine absorption. Serum digoxin concentrations are increased by felodipine in plain tablet form, but not when it is administered as extended release tablets. Activators, inducers and inhibitors of the cytochrome P450 system affect the plasma concentrations of felodipine. No displacement reactions with high affinity protein binding drugs have been observed. There is a significant correlation between plasma concentration and haemodynamic effect. The mean elimination half-life of 24h together with the extended release formulation of felodipine favours once-daily dosage in patients with hypertension.

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.

The influence of infusion rate on the hemodynamic effects of felodipine

The hemodynamic effects of the calcium entry blocker felodipine were studied during and after different infusion rates. Eight healthy normotensive volunteers had their individual pharmacokinetics of felodipine determined, and they subsequently entered a double-blind, randomized, crossover study. Individualized infusions of felodipine were given by a computerized infusion pump to reach plasma concentrations of 6 ng/ml (15.6 nmol/L) after 20 minutes, to be sustained for 8 hours (fast infusion) or the same plasma concentration after 8 hours (slow infusion). Control infusions with saline and vehicle were given. Blood pressure, heart rate, ECG conduction times, and baroreceptor sensitivity by the Valsalva test were measured, as well as the plasma concentrations of felodipine. The infusion system used produced the expected plasma concentration-time profiles with higher plasma concentrations after the fast infusion until 8 hours. Both slow and fast infusion increased heart rate (p less than 0.05) and produced a similar decrease in diastolic blood pressure (p less than 0.05). Slow infusion therefore reduced blood pressure more effectively. The tachycardia after the fast infusion was more pronounced during the first hour of the infusion but was indistinguishable from the slow infusion later, when plasma concentrations were still significantly different. Baroreceptor responsiveness was diminished by both felodipine treatments. There was no obvious difference in side effects caused by the two infusion regimes. The initial tachycardia after felodipine can be diminished by a slow rate of administration of the drug with a similar effect on blood pressure.

Felodipine in the treatment of patients with severe hypertension and impaired renal function

Twenty-three patients with severe hypertension and impaired renal function were included in an open study of the efficacy and tolerance of felodipine treatment over 6 months. All patients were previously treated with a diuretic, a beta blocker, and a vasodilator, and eight of them also received an ACE inhibitor. At the start of felodipine treatment the previously used vasodilator was withdrawn. In nine patients the concomitant antihypertensive treatment was reduced during the study. The glomerular filtration rate (GFR), as 51Cr EDTA clearance, was determined before and at the end of the study. The blood pressure (BP) and heart rate (HR) were recorded at all clinical visits in the morning 12 hours after the evening dose of felodipine and 2 hours after the morning dose. Plasma concentrations of felodipine were measured at every visit before the morning dose and 2 hours after dose. The BP was reduced after felodipine was substituted for the previously used vasodilator. A significant additional anti-hypertensive effect was recorded 2 hours after the dose and amounted to -37 +/- 22/-15 +/- 12 mmHg (p = 0.0001/p = 0.0002) at 6 months. The effect measured 12 hours after the dose was less pronounced and was -11 +/- 28/-6 +/- 10 mmHg (p = 0.15/p = 0.03). Mean GFR was unchanged during the study, 38 +/- 19 versus 38 +/- 19 ml/min (n = 16). There was a sixfold interindividual variation in the trough plasma concentrations at steady state at the same drug dosage. Higher plasma concentrations seemed to be required to achieve the same antihypertensive effects as in patients with less severe hypertension and normal renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Clinical pharmacokinetics of felodipine. A summary.

Felodipine is completely absorbed from the gastrointestinal tract. However, the amount reaching the systemic circulation is reduced to about 15% because of first-pass degradation. The bioavailability is constant within the dose interval of 5 to 40mg orally. The frequency histogram of the area under the plasma concentration-time curve (AUC) seems to be normally distributed. The disposition of felodipine is independent of the administered dose over the intravenous dose interval (1-3 mg). The plasma concentration-time curve declines in 3 distinct phases. The mean elimination half-life of felodipine is approximately 25h. Felodipine is extensively distributed to extravascular tissues. The volume of distribution of felodipine is about 10 L/kg, implying that less than 1% of the amount of drug in the body is localised in the blood. Felodipine is more than 99% bound to plasma proteins. Mean total clearance from the blood is 1 to 1.5 L/min and, therefore, felodipine is considered a high clearance drug. Felodipine is metabolised completely and no unchanged drug is eliminated in the urine. The first step in the metabolism involves oxidation to the corresponding pyridine derivative by the cytochrome P-450 system. Identified metabolites in plasma and urine are devoid of vasodilating activity. Long term treatment, and the presence of hypertension and impaired renal function do not affect the disposition of felodipine. Elderly people may have higher plasma levels than the young and middle-aged. Impaired liver function significantly decreases systemic clearance. Cimetidine and food affect felodipine kinetics, but with negligible clinical implications. Therapeutic concentrations of felodipine do not interact with highly protein-bound drugs and these drugs have no effect on the binding of felodipine to human plasma proteins in vitro. Plasma levels of digoxin and metoprolol tended to increase during felodipine treatment. There is a significant correlation between plasma concentrations of felodipine and haemodynamic effects in both healthy subjects and hypertensive patients during short term as well as during long term treatment.

Antihypertensive Effects and Pharmacokinetics of Felodipine Combined with a β-Blocker and a Diuretic

The antihypertensive effect of felodipine, a new calcium antagonist with dihydropyridine structure, was investigated in 25 patients with essential hypertension that was not controlled on standard triple therapy (a beta-blocker, a diuretic, and a vasodilator). After substituting the previous vasodilator with felodipine, blood pressure was reduced and remained well controlled during a 2 year follow-up period. After about 1 1/2 years of treatment, felodipine was compared double-blind with placebo in a subgroup of 10 patients while keeping the same beta-blocker and diuretic therapy. Compared with the placebo, felodipine lowered blood pressure during a 12 h interval, which supports a twice-daily dosage in clinical practice. Determination of the plasma concentrations of felodipine during steady-state conditions showed a mean elimination half-life of 23.4 +/- 11.1 h. During long-term therapy, tolerance was good, and felodipine seems to be a safe and efficient antihypertensive agent in combination with a beta-blocker and a diuretic in patients whose hypertension is not adequately controlled on standard triple therapy.

Congestive heart failure

Summary: We determined hemodynamics and myocardial lactate extraction in 11 patients with severe coronary disease after 0.010 (D1), 0.015 (D2), and 0.025 nmol/min (D3) of the arteriolar dilator felodipine during pacing-induced angina pectoris. Plasma concentrations of felodipine after the 3 doses were 12 (5), 25 (6) and 43 (8) nmol/ L, respectively. At corresponding pacing rates, mean blood pressure fell from 126 (24) to 90 (15) mm Hg at D3 (p < 0.01) and pulmonary capillary wedge pressure was reduced from 14 (10) to 9 (8) mm Hg (p < 0.05). Cardiac output increased at all three doses (p < 0.01). The reduction of systemic vascular resistance at D3 was 49% (p < 0.01) and of coronary vascular resistance 35% (p < 0.05). At D1, there was no change in lactate extraction, while 8/10 lactate producers improved at D2 and D3. ST depression was diminished at all three doses (p < 0.05) at the control pacing rate. During maximal pacing rate at D3, the myocardial oxygen consumption was 14% above control level (N.S.). Thus, felodipine was beneficial in most patients at higher dosage. Ventricular unloading and improved coronary perfusion might explain some of these positive effects.

Systemic and Renal Hemodynamic Effects of Single Oral Doses of Felodipine in Patients with Refractory Hypertension Receiving Chronic Therapy with β-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.

Felodipine. A calcium-inhibiting vasodilator in refractory hypertension.

12 patients with primary hypertension not adequately controlled on combined treatment with diuretics, beta-adrenergic blocking drugs and hydralazine were included in the study. The patients were hospitalised and hydralazine discontinued. The diuretic and beta-blocking medication was given about 1 hour prior to the short term experiments and, following baseline measurements, an oral solution of felodipine (0.075-0.1 mg/kg) was ingested. Cardiac output was measured (dye dilution technique) and continuous monitoring of intra-aortic blood pressure (brachial artery) was performed. In 10 patients, changes in renal plasma flow (para-aminohippuric acid clearance) and glomerular filtration rate (51Cr-EDTA-clearance) were followed over a short period, and in 6 patients repeated after 5 to 7 months. Plasma renin activity (radioimmunoassay of angiotensin I) was followed, as was plasma concentration of felodipine. A significant hypotensive response was seen only 15 minutes after intake of felodipine. The maximal response occurred after 30 minutes when mean arterial blood pressure was reduced by 24% (from 132 to 102 mm Hg). There was a linear relationship between the change in mean arterial blood pressure and log plasma concentration of felodipine. Cardiac output increased from 5.1 +/- 1.5 to 6.6 +/- 2.6 L/min (p less than 0.01), partly because of increased heart rate from 56 +/- 7.9 to 65 +/- 9.5 beats/min (p less than 0.01) and partly due to increased stroke volume from 93 +/- 25 to 103 +/- 34 ml/beat (p less than 0.05). Renal plasma flow increased significantly (p less than 0.05) from 343 +/- 138 ml/min to 391 +/- 154 ml/min and 400 +/- 149 ml/min, while glomerular filtration rate did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemodynamic effects of single-dose felodipine in normal man.

The haemodynamic effects of an oral solution of 15 mg felodipine were studied in 8 healthy males. Maximal plasma concentrations of felodipine were seen 30 to 40 minutes after administration, when significant decreases in diastolic and mean blood pressures were noted. Heart rate increased maximally by 45% after 30 minutes, accompanied by a 57% increase in cardiac output and 175% increase in forearm blood flow. Total peripheral resistance decreased by 40% and forearm vascular resistance by 66%. Apparent hepatic blood flow was unchanged.

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.

Felodipine ? A new vasodilator, in addition to ?-receptor blockade in hypertension

In a double-blind, cross-over trial, 10 men with primary hypertension, not adequately controlled with a beta-blocker alone, were also given felodipine or placebo for periods of one week. Placebo was administered single-blind for 2 weeks and 1 week, respectively, before randomization and between treatments. The dose of felodipine ranged from 6.25 mg to 25 mg. The addition of felodipine resulted in a pronounced (20%), statistically significant reduction in blood pressure (BP) and a small but significant increase in heart rate (HR). The effects were seen within 1-2 h and were maximal after 3-4 h. During steady state treatment the duration of BP reduction was at least 12 h. No orthostatic reaction was seen. There was a significant correlation between the plasma concentration of felodipine and change in BP. The most frequently reported side-effects were headache and ankle oedema, the latter probably being due to pronounced pre-capillary vasodilatation. There was no weight increase and thus no indication of general water retention. No clinically significant change in laboratory variables and no influence on the P-Q time were seen. Thus, felodipine in combination with a beta-blocker seems to be a useful addition to the treatment of hypertensive patients whose BP is not adequately controlled with a beta-blocker alone.