Patient compliance.
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Drug Administration Schedule↗
Biomedical subjects
P A Meredith
Publications and source records attributed to P A Meredith.
Low-dose verapamil in middle-aged and elderly patients with angina pectoris: no evidence of increased susceptibility to the cardiac effects.
This study investigated the cardiac responses and pharmacokinetics following the acute and chronic administration of verapamil in 14 middle-aged and elderly patients with ischemic heart disease (age range 42-76 years). There were small significant reductions in heart rate during chronic treatment, but there were no significant effects on the PR intervals following either single intravenous administration or after 4 weeks continued treatment. Left ventricular ejection fractions at rest or exercise were not significantly changed following either acute intravenous (rest 33%; exercise 38%) or chronic oral dosing with verapamil (rest 35%; exercise 43%) when compared with placebo (rest 34%; exercise 42%). There were no independent age-related effects on these indices of cardiac function, nor on apparent liver blood flow, nor on blood pressure and heart rate. The plasma clearance of verapamil was reduced from 1.3 l/min after acute dosing to 0.8 l/min during chronic treatment, but there was no significant independent age-related effect. The results of this study suggest that middle-aged and elderly patients with ischemic heart disease do not show enhanced cardiovascular responses to low doses (5 mg intravenously and 80 mg tid orally) of the calcium antagonist drug, verapamil.
Administration, Oral↗
Antihypertensive drugs: individualized analysis and clinical relevance of kinetic-dynamic relationships.
Individualized approaches to antihypertensive therapy are being widely advocated. Ideally these should incorporate rational prospective methods for drug and dosage selection but progress has been hampered by the paucity of information about dose- (and plasma concentration-) response relationships. However, in several recent clinical studies, concentration-effect analysis has been used to characterize kinetic-dynamic relationships in individual patients for a range of antihypertensive drugs. This approach provides an integrated mathematical description of drug response which has potential utility for quickly identifying poor or nonresponders and for determining individual dose requirements for optimum longterm blood pressure control.
Antihypertensive Agents↗
Dose responses and pharmacokinetics for the angiotensin converting enzyme inhibitor quinapril.
Single doses of the angiotensin converting enzyme (ACE) inhibitor quinapril were administered to salt replete normotensive men to investigate pharmacokinetics and dose responses. Maximal ACE inhibition was produced by the 2.5, 5, and 20 mg doses (but not by 0.5 mg), but there was evidence of dose-dependency only for the duration of ACE inhibition. Quinaprilat was detectable in plasma up to 72 hours after all doses and the terminal phase half-life was calculated at 26 +/- 7 hours. Although there were dose-related increases in area under the curve (AUC), the relationships between dose and both AUC and maximum concentration were nonlinear. These findings suggest that quinapril displays the same prolonged terminal phase half-life that is characteristic of other ACE inhibitor drugs. The failure of doses above 2.5 mg to produce any further increase in the magnitude of ACE inhibition is consistent with an maximum effect dose-response relationship, with the obvious implication that higher doses will increase only the duration not the magnitude of response.
Adult↗
An additive or synergistic drug interaction: application of concentration-effect modeling.
Although a conventional pharmacokinetic analysis can identify the pharmacokinetic component in a drug interaction, the pharmacodynamic component is less accessible and, ideally, should be evaluated over a range of doses. The potential of integrated concentration-effect modeling to avoid such multiple-dose studies has been evaluated in this study of the hypotensive effect of the combination of prazosin and verapamil, which has previously been shown to be more than simply additive. Characterization of the blood pressure responses (by concentration-effect modeling) revealed that for supine diastolic blood pressure, responsiveness was significantly higher at 3.3 +/- 0.5 mm Hg per ng/ml when prazosin was combined with verapamil (p less than 0.01) compared with 2.4 +/- 0.5 and 2.4 +/- 0.4 mm Hg per ng/ml, respectively, for standard doses and augmented doses of prazosin alone. These findings suggest that there are both pharmacokinetic and pharmacodynamic components in the interaction between prazosin and verapamil and illustrate the applicability of concentration-effect modeling for investigating drug interactions.
Adult↗
Combination of nifedipine and doxazosin in essential hypertension.
Pharmacodynamic and pharmacokinetic interactions have been reported when an alpha 1-antagonist is combined with a calcium antagonist. We evaluated the clinical usefulness of the combination of nifedipine (20 mg twice daily, b.i.d.) and doxazosin (2 mg once daily, o.d.) in hypertensive patients in whom blood pressure (BP) control was suboptimal after doxazosin (group A) or nifedipine (group B) as monotherapy and investigated the underlying kinetic and dynamic interactions, including changes in vascular responsiveness to i.v. infusions of angiotensin II (ANGII) and phenylephrine (PE). The combination was well tolerated and associated with further significant reductions in BP. After 4 weeks of combined therapy, average supine BP over 8 h was 122/77 in group A and 137/80 in group B as compared with 140/86 and 150/88 mm Hg, respectively, during monotherapy + placebo. The combination attenuated both phenylephrine and ANG-induced pressor responses: e.g., the mean PD15 values (dose of agonist required to increase systolic BP by 15 mm Hg) for group A at 1.5-3 h were 3.5 micrograms/kg/min for PE and 7.5 ng/kg/min for ANGII as compared with 2.9 and 2.3, respectively, during treatment with doxazosin and placebo. There was no evidence of a significant kinetic interaction between the two drugs and, in particular, addition of nifedipine had no effect on the steady-state kinetics of doxazosin. In conclusion, doxazosin and nifedipine are an effective antihypertensive combination in patients who require treatment with more than one drug.
Aged↗
Neurohormonal and blood pressure responses to low-dose infusion of an orally active renin inhibitor, Ro 42-5892, in salt-replete men.
Renin inhibitors are an alternative means of blockade of circulating and tissue-based renin-angiotensin systems (RAS). We studied a new renin inhibitor, Ro 42-5892, by low-dose (0.1 mg/kg) intravenous (i.v.) infusion in 10 min (fast) or 6 h (slow) or placebo in a double-blind cross-over study to assess the relationship between drug concentration and response. Fasting salt-replete normotensive male volunteers (n = 9) aged 18-32 years were studied supine. There were no significant changes in blood pressure (BP) or heart rate (HR) between drug and placebo infusion. Drug concentration peaked (482 +/- 140 ng/ml) at the end of the fast infusion or showed a sustained plateau (25.9 +/- 6.1 ng/ml) with the slow infusion (mean time to peak 121 +/- 99 min). Both fast (135.2 +/- 26 ng/ml/h2) and slow (121.0 +/- 31.1 ng/ml/h2) infusions had similar area under the curve (AUC)0-24-values. Plasma renin activity (PRA) was dramatically reduced by both strategies, but AUC0-10 for PRA was significantly less for slow (1.7 +/- 0.6 ngAI/ml/h2) than fast (4.9 +/- 2.5 ngAI/ml/h2) infusions. Mean peak plasma active renin (AR) concentration was increased by both fast (102.2 +/- 65.9 pg/ml) and slow (195.2 +/- 110.5 pg/ml) infusions as compared with placebo (49.9 +/- 18.6 pg/ml). Similarly, AUC0-10 for AR was greater for slow (990.2 +/- 582.1 pg/ml/h) than fast (512.4 +/- 189.4 pg/ml/h) infusions. Plasma angiotensin-converting enzyme (ACE) activity was unaltered. Our results indicate that protracted low concentrations of Ro 42-5892 may provide more effective and long-lasting inhibition of renin.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
The effect of saturation of ACE binding sites on the pharmacokinetics of enalaprilat in man.
1. Eight healthy male volunteers received oral enalapril, 10 mg, in the presence and absence of pretreatment with captopril, 50 mg, twice daily for 5 days. 2. Enalaprilat pharmacokinetics were characterised after both doses of enalapril to investigate the effect of saturating ACE binding sites by pretreatment with captopril. 3. The pharmacokinetics of enalaprilat were best described by a one compartment model with zero order input incorporating saturable binding to plasma and tissue ACE. 4. Values of AUC (0.72 h) for enalaprilat were 419 +/- 97 and 450 +/- 87 ng ml-1 h in the presence and absence of captopril, respectively. The difference was not statistically significant nor were there any other differences in model parameters. 5. Induction of ACE by captopril resulting in an increase in the number of ACE binding sites, may have obscured any effect of captopril on the occupancy of ACE binding sites by enalapril.
Adult↗
Clinical pharmacokinetics of amlodipine.
Amlodipine is a dihydropyridine calcium antagonist drug with distinctive pharmacokinetic characteristics which appear to be attributable to a high degree of ionisation. Following oral administration, bioavailability is 60 to 65% and plasma concentrations rise gradually to peak 6 to 8h after administration. Amlodipine is extensively metabolised in the liver (but there is no significant presystemic or first-pass metabolism) and is slowly cleared with a terminal elimination half-life of 40 to 50h. Volume of distribution is large (21 L/kg) and there is a high degree of protein binding (98%). There is some evidence that age, severe hepatic impairment and severe renal impairment influence the pharmacokinetic profile leading to higher plasma concentrations and longer half-lives. There is no evidence of pharmacokinetic drug interactions. Amlodipine shows linear dose-related pharmacokinetic characteristics and, at steady-state, there are relatively small fluctuations in plasma concentrations across a dosage interval. Thus, although structurally related to other dihydropyridine derivatives, amlodipine displays significantly different pharmacokinetic characteristics and is suitable for administration in a single daily dose.
Absorption↗
The influence of age on the pharmacokinetics of verapamil.
The influence of age on the pharmacokinetics of verapamil at steady state has been studied in 74 individuals, age range 19-79 years, including healthy normotensive volunteers and patients with essential hypertension. The peak plasma concentrations (Cmax) of verapamil were significantly higher in older subjects (r = 0.24; P = 0.03) and there was a non-significant age-related decrease in clearance/F and a non-significant increase in elimination half-life. These results suggest that increasing age is associated with changes in the pharmacokinetics of verapamil but these changes are small and unlikely to be of clinical significance.
Adult↗
The interactions between nisoldipine and two beta-adrenoceptor antagonists--atenolol and propranolol.
1. The interactions between the dihydropyridine calcium antagonist nisoldipine and two beta-adrenoceptor blocker drugs (atenolol and propranolol) were investigated in two groups of healthy normotensive subjects. 2. The steady state plasma concentrations of both beta-adrenoceptor blockers were significantly altered by the addition of nisoldipine: for propranolol there were significant increases in Cmax, by about 50%, and in AUC by about 30% and for atenolol there was a significant increase in Cmax, by about 20%. 3. The addition of nisoldipine was also associated with significant changes in apparent liver blood flow (measured by indocyanine green clearance) from 1.4 to 2.4 l min-1 in the atenolol group and from 1.3 to 2.3 l min-1 in the propranolol group. 4. Both nisoldipine-beta-adrenoceptor blocker combinations were associated with small enhanced blood pressure reductions e.g. from 104/60 with atenolol alone to 98/50 mm Hg with the combination but there was no alteration to the extent of beta-adrenoceptor blockade (as assessed by bicycle ergometry). 5. This pharmacodynamic profile in healthy normotensives is consistent with the known therapeutic efficacy of such combination treatments in patients with hypertension and angina. 6. It is suggested that there is a pharmacokinetic component to the efficacy of this type of combination, perhaps reflecting vasodilator-induced changes in drug absorption and/or hepatic extraction.
Adult↗
A dose-ranging study of UK-68,798, a novel class III anti-arrhythmic agent, in normal volunteers.
1. UK-68,798, a novel class III anti-arrhythmic agent was administered intravenously to twelve healthy volunteers in a placebo controlled, double-blind, dose-escalating study. 2. Doses of 5 and 10 micrograms kg-1 of UK-68,798 selectively and significantly prolonged the QT interval, with mean maximum changes of 35 and 107 ms respectively, without affecting other ECG intervals. 3. There were dose-related increases in AUC but clearance (23 l h-1), terminal elimination half-life (8 h) and volume of distribution (245 l) were found to be independent of dose with low levels of intra- and inter-patient variability. 4. UK-68,798 has electrophysiological effects indicative of selective class III anti-arrhythmic activity and merits further assessment in clinical studies.
Adult↗
The effects of age on the pharmacokinetics, antihypertensive efficacy and general tolerability of dilevalol.
1. This study investigated the influence of age on the pharmacokinetics, pharmacodynamics, general tolerability and concentration-effect relationships in 18 patients with essential hypertension (age range 23-73 years) during treatment with dilevalol, a non selective beta-adrenoceptor antagonist with vasodilator properties. 2. There were no significant age-related changes in pharmacokinetics for either acute or chronic treatment with dilevalol, although there were significant changes in elimination half-life from 7.8 to 11.7 h (P less than 0.05) and in AUC from 261 to 352 ng ml-1 h (P less than 0.005) following translation from acute to chronic dosing. 3. In absolute terms, dilevalol treatment (as compared with placebo) produced numerically larger falls in average blood pressure in the six oldest as compared with the six youngest patients: for example, supine blood pressure fell by, respectively, 29/15 and 10/7 mm Hg during chronic treatment. 4. Using an integrated kinetic-dynamic model, blood pressure responsiveness was characterised by relating the fall in blood pressure (mmHg) to the plasma drug concentrations in each individual patient. No independent age-related effect was demonstrated. There was a significant relationship between response and the height of initial blood pressure which tended to be higher in the elderly patients. 5. Patient tolerability was generally satisfactory and there was no differential age-related effect. 6. This study has shown that the antihypertensive efficacy of dilevalol is not attenuated in the elderly and that there are no significant age-related differences in pharmacokinetics or pharmacodynamics.
Adult↗
Studies with abanoquil (UK-52,046) a novel quinoline alpha 1-adrenoceptor antagonist: II. Duration of action, pharmacokinetics and concentration-effect relationships in normotensive subjects.
1. This study further examines the quinoline-derivative abanoquil with particular respect to the duration of its alpha 1-adrenoceptor antagonist activity and its concentration-effect relationship following a single intravenous bolus dose of 0.5 micrograms kg-1 in young, normotensive males. 2. alpha 1-adrenoceptor antagonism (as assessed by phenylephrine pressor responses) was detectable for up to 12 h post dosing: at 12 h there was a significant 1.5-fold rightward shift (95% CI: 2.2 to 1.1) of the pressor dose-response curve for diastolic blood pressure. 3. Despite evidence of substantial alpha 1-adrenoceptor antagonism abanoquil had no significant effect on blood pressure, supine and erect, but there were small and statistically significant increments in heart rate. 4. The degree of alpha 1-adrenoceptor antagonism was related to whole blood concentrations abanoquil: the PD-ratios of phenylephrine pressor responses performed at 1, 6, and 12 h post dosing were significantly correlated with log drug concentrations (r = 0.57 for systolic (P less than 0.05) and r = 0.78 for diastolic blood pressure (P less than 0.005). 5. In conclusion, abanoquil produced significant alpha 1-adrenoceptor antagonism which was related to circulating drug concentrations. The absence of other significant cardiovascular effects suggests that abanoquil warrants further clinical study as an antiarrhythmic agent.
Adrenergic alpha-Antagonists↗
The description and prediction of antihypertensive drug response: an individualised approach.
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Adrenergic alpha-Antagonists↗
The effect of renal impairment on the pharmacokinetics and metabolism of bopindolol.
The pharmacokinetics of the non-selective beta-adrenoceptor antagonist, bopindolol, have been studied in 18 hypertensive patients with varying degrees of renal impairment following single and multiple oral dosing. Bopindolol, which undergoes extensive hepatic metabolism, was found to accumulate in patients with chronic renal failure but the disposition in patients on regular haemodialysis did not differ significantly from patients with normal renal function. The mechanism underlying these changes in pharmacokinetics is not clear but suggests the presence of metabolic inhibitors in uraemic plasma which are removed by regular haemodialysis.
Adrenergic beta-Antagonists↗
The clinical consequences of the absorption, distribution, metabolism and excretion of amlodipine.
By comparison with other calcium antagonist drugs, amlodipine has unique pharmacokinetic properties that are probably attributable to its chemical structure and positive ionic charge at physiological pH. Thus, amlodipine undergoes gradual absorption from the gastro-intestinal tract and is widely distributed throughout body tissues. It is cleared only slowly by metabolism in the liver and so has a long elimination half-life, which makes it suitable for single daily dosing. During steady-state administration there are only small peak-to-trough variations in plasma drug levels and in clinical use these pharmacokinetic properties appear to be associated with a smoother pharmacodynamic effect and a reduced incidence of (early) vasodilator side effects.
Amlodipine↗
Dose-response clarification in early drug development.
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Antihypertensive Agents↗