Short-term effects of felodipine in hypertensive type II diabetic males on sulfonylurea treatment.

OBJECTIVES: To study the effects on blood pressure and glucose homeostasis of felodipine, a calcium antagonist. DESIGN: A double-blind randomized cross-over study comparing felodipine ER and placebo. SETTING: A university centre of diabetic care in Malmö, Sweden. SUBJECTS: Seventeen hypertensive type II diabetic males on oral sulfonylurea (glibenclamide) treatment. INTERVENTIONS: Four-week treatment periods separated by a 2-week wash-out period. Felodipine 10-20 mg once daily was given. MAIN OUTCOME MEASURES: Blood pressure, heart rate, HbA1c and response to oral glucose tolerance test; glucose, insulin and c-peptide. Measured before randomization and at the end of each double-blind treatment period. RESULTS: Blood pressure was significantly reduced during felodipine treatment and heart rate slightly increased. Felodipine did not influence insulin or c-peptide levels. There was no significant change in glucose levels but an increase in HbA1c. CONCLUSION: The study demonstrated that felodipine is an effective agent for type II diabetic patients on glibenclamide treatment. The effect on HbA1c is noteworthy even if not of clinical significance in the short term. Controlled long-term studies in diabetic patients are needed to fully evaluate antihypertensive agents.

Plasma concentration--effect relationships for felodipine: a meta analysis.

The plasma concentration versus antihypertensive effect relationship for the calcium antagonist felodipine was investigated in 67 patients with hypertension and 21 healthy subjects by use of the Emax model. No consistent effect of felodipine on blood pressure was observed in the healthy subjects. In patients with hypertension the plasma drug concentration and blood pressure versus time curves mirrored each other, indicating a close relationship between concentration and effect. The maximum effect (Emax) model fitted the diastolic blood pressure data of most patients, but the model was less often applicable in patients with low initial diastolic blood pressure levels. The average Emax values and the plasma felodipine concentration needed to obtain 50% of Emax for the patients with hypertension were 29 mm Hg and 8 nmol/L, respectively. The Emax values increased with increasing initial diastolic blood pressure levels but were similar in patients with high and low plasma felodipine concentrations. Age had negligible influence on the antihypertensive response to felodipine when compensation was made for the plasma concentrations.

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 pharmacokinetics and plasma concentration vs effect relationships.

UNLABELLED: Felodipine was completely absorbed from an oral solution (OS), as well as from the conventional (CT) and extended release (ER) tablets. The time to peak plasma concentration increased in the order OS < CT < ER. Peak plasma felodipine concentrations were significantly lower and trough concentrations higher when felodipine was administered in the ER-tablet compared with CT and oral solution. The variability in plasma felodipine concentration during the dose interval, expressed as the fluctuation index, increased in the order ER o.d. < CT b.i.d. < CT o.d. The distribution of the AUC of plasma felodipine concentrations vs time determined in 140 individuals was unimodal, indicating that genetic factors are unlikely to influence the metabolism of felodipine to any clinically significant extent. With increasing age the plasma concentrations and the terminal half-life of felodipine increased, whereas the plasma clearance and the ratio of the AUC of the primary pyridine metabolite to that of unchanged drug decreased. The time to maximum plasma felodipine concentration, the bioavailability and the volume of distribution were not consistently influenced by age. Body weight, body mass index and concomitant intake of beta-blockers had negligible influence on the pharmacokinetics of felodipine. The pharmacokinetics in the limited number females did not differ substantially from that of the males in our investigation. No consistent effect on blood pressure was seen in healthy subjects after administration of felodipine. In hypertensive patients, however, there was a good relationship between plasma felodipine concentration and antihypertensive effect. There was no hysteresis for the reduction in blood pressure. The relationship between plasma felodipine concentration and antihypertensive effect could, in most patients, be described by a modified Emax model. The average Emax value was estimated to be approximately 30 mmHg. Placebo correction decreased the magnitude of the blood pressure reduction. The Emax estimates increased with increasing initial blood pressures whereas age had a negligible effect. Patients with high and low plasma felodipine concentrations had similar Emax values. The EC50 values were not influenced by any of these factors. The Emax model used was less suitable for patients with low initial blood pressure levels. IN CONCLUSION: The plasma concentration vs time profile of felodipine is modified by using different pharmaceutical formulations, without loss of bioavailability. As a group, the elderly have higher total concentrations of unchanged felodipine in plasma compared with young individuals. The variation in plasma concentrations between individuals is, however, only partially explained by age. There is a good and direct relationship between felodipine plasma concentrations and antihypertensive effects in hypertensive patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Felodipine in the treatment of hypertensive type II diabetics: effect on glucose homeostasis.

The effect of felodipine on glucose tolerance was evaluated in 18 male type II diabetic patients treated with diet alone, who were hypertensive despite beta-blocker treatment. The study was a double-bind cross-over comparison of placebo and felodipine in addition to beta-blockade. Oral glucose tolerance tests were performed at randomization and at the end of each 4-week double-blind treatment period. The doses of felodipine given were 5 mg b.i.d. for 2 weeks followed by 10 mg b.i.d. for a further 2 weeks. Blood pressure was significantly reduced during felodipine treatment, whereas heart rate remained unaltered. HbA1c and fasting insulin levels did not change during the treatment periods. Fasting and maximal blood glucose levels were not altered between any of the treatment periods. However, there was a small but statistically significant increase (median increase 4%) in the area under the glucose concentration vs. time curve after felodipine as compared to placebo treatment. This increase was not considered to be clinically significant in the short term, but the finding merits further investigation in a rigorous long-term study.

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.

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%.

Plasma concentration profiles and antihypertensive effect of conventional and extended-release felodipine tablets.

1. The rate and extent of felodipine absorption from an oral solution, conventional and extended-release tablets were investigated in two groups of healthy volunteers (n = 18 + 15). 2. The antihypertensive effect of felodipine conventional tablets twice daily (n = 71) and extended-release tablets once daily (n = 76) were compared in a parallel-group study in hypertensive patients. 3. As from a solution, felodipine was completely absorbed from the two solid dosage forms. The rate of absorption increased in the order extended-release tablets, conventional tablets, solution. 4. The extended-release tablet gave more sustained plasma concentrations than the conventional tablet. 5. The extended-release tablet given once daily gave similar blood pressure control to the conventional tablet given twice daily.

The effect of felodipine on cold-induced digital vasospasm.

Felodipine, a calcium antagonist with pronounced vascular selectivity, was given to 10 patients with cold-induced, digital vasospasm. Placebo and increasing doses of felodipine (2.5, 5, and 10 mg b.i.d.) were given for 2 weeks each. There was a significant decrease in systemic, but not in digital, blood pressure and a significant increase in heart rate during felodipine treatment. The subjective rating of symptoms improved significantly on all doses. No significant effect on cold-induced digital vasospasm during local cooling to 15 and 10 degrees C was registered. Typical side effects of calcium-entry blockers were reported. Moreover, two postmenopausal women reported recurrence of menstrual bleeding and one woman reported vaginal hemorrhagic discharge during treatment. In conclusion, felodipine, although causing a significant, symptomatic relief, had no significant effect on cold-induced digital vasospasm when objective measures were used.