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Biomedical subjects

H L Elliott

Publications and source records attributed to H L Elliott.

At least 127 records · Page 7Linked to original sources
PubMed1990

Antihypertensive drugs and blood lipids.

Hypertension frequently coexists with hyperlipidaemia and it has been suggested that the potential benefits of blood pressure reduction may be compromised if lipid levels are not concurrently reduced. In addition, conventional first line antihypertensive drugs (thiazide diuretics and beta-blockers) produce adverse changes in blood lipids which are most apparent in the short-term but do not entirely disappear during chronic treatment. Of the alternative first-line antihypertensive agents, the calcium antagonist and ACE inhibitor drugs are lipid 'neutral' but only the alpha 1-blockers have been associated with favourable effects on the lipid profile.

Benzothiadiazines↗
PubMed1990

The influence of age on the pharmacokinetics and antihypertensive responses to dilevalol.

Age may influence the response to antihypertensive drug treatment either indirectly, by altering the plasma drug concentrations, or directly, by altering the nature and magnitude of the blood pressure reduction. This study investigates the effect of age on the pharmacokinetics and antihypertensive responses following acute and chronic treatment with dilevalol in 18 patients (age range 28-73 years) with essential hypertension. There were no significant age-related changes in pharmacokinetics for either acute or chronic treatment with dilevalol. Correspondingly, there was no evidence of any age-related difference in the antihypertensive response and, in absolute terms, this was slightly greater in the six oldest patients in whom blood pressure fell by 18/10 mmHg, supine, and 16/8 mmHg, erect, after the first dose of dilevalol, compared to 4/3 and 6/3 mmHg, respectively, in the six youngest patients. When allowance was made for the differences in starting (pretreatment) blood pressure, there was no significant difference in the antihypertensive response of the elderly compared to the young patients. This study has shown that the antihypertensive efficacy of dilevalol is not attenuated in the elderly and that there are no age-related differences either in pharmacokinetics or in antihypertensive responsiveness.

Adult↗
PubMed1989

Angiotensin-converting enzyme inhibitors in the elderly.

Although early studies suggested little role for angiotensin-converting enzyme (ACE) inhibitors in older hypertensive patients, more careful evaluation has confirmed their efficacy and good tolerability. Although the elderly tend to have low plasma renin levels, the fall in blood pressure after ACE inhibitors is at least as great (and in several studies greater) than in younger age groups. Because several ACE inhibitors, including captopril and enalaprilat, are eliminated by the kidneys, there are predictable age-related effects on pharmacokinetics. Reduced renal clearance will contribute, at least in part, to the enhanced intensity and duration of action seen in elderly patients. However, not all the effects of age on the kinetics and dynamics of ACE inhibitors are predictable. Studies with perindopril and benazepril in the elderly confirm the efficacy of this group of drugs but highlight other pharmacokinetic differences. ACE inhibitors are effective in reducing blood pressure and can be considered for wider use in elderly hypertensives.

Aged↗
PubMed1989

Predictability of antihypertensive responsiveness and alpha-adrenoceptor antagonism during prazosin treatment.

This study investigates concentration-effect relationships in nine patients who had essential hypertension treated with prazosin. Antihypertensive responsiveness was determined for each individual patient in terms of millimeters of mercury of blood pressure reduction per nanogram per milliliter of plasma prazosin concentration. The principal findings were that there was significant attenuation of antihypertensive responsiveness, from 11.5 mm Hg per nanogram per milliter after the first dose to 8.7 mm Hg per ng/ml after 1 week of treatment with prazosin. Correspondingly, there was significant attenuation of the degree of alpha 1-antagonism as assessed by the pressor response to intravenous phenylephrine. However, there was no significant further attenuation of either assessment during continued treatment for up to 3 months. These findings suggest that after an early adaptation, which occurs within the first week of treatment, there is no long-term attenuation of the antihypertensive effect of prazosin. Despite this initial adaptive change, the magnitude of the long-term antihypertensive effect of prazosin was predictable from the first dose response in individual patients.

Adrenergic alpha-Antagonists↗
PubMed1989

Pressor responsiveness, age and hypertension.

It has long been accepted that enhanced vascular reactivity is an integral part of the hypertensive state. This study investigates pressor responsiveness to the selective alpha 1-adrenoceptor agonist, phenylephrine, in 62 normotensive and hypertensive subjects aged 20-70 years. Since blood pressure increases with age, it is possible that effects attributed specifically to blood pressure will be confounded by age. The present study showed no correlation between responsiveness and starting blood pressure. However, responsiveness was positively correlated with age. These results suggest that it may be an oversimplification to attribute increased vascular responsiveness to the hypertensive state.

Adult↗
PubMed1989

Prediction of response to antihypertensive therapy with enalapril and nifedipine.

We evaluated the usefulness of an integrated concentration-effect modelling technique in predicting the long-term response to antihypertensive therapy with enalapril and nifedipine. Two groups of essential hypertensives were given monotherapy with 20 mg nifedipine twice a day (n = 14) or 20 mg enalapril once a day (n = 13), and were studied following the administration of the drugs and after at least 6 weeks' treatment. For both drugs the predicted responses (predose and 4 h postdose) were in close agreement with the observed responses. With enalapril the observed and predicted profiles over a 12-h study period were well correlated in all subjects. In contrast, with nifedipine, although there was generally good agreement, the model over-predicted the profile of response in one patient and under-predicted the profile in one patient. Thus, there is evidence that application of concentration-effect analysis is useful in predicting the steady-state antihypertensive effect from the first dose-response to the drug.

Blood Pressure↗
PubMed1989

Hypercholesterolaemia in treated hypertensives: a controlled trial of intensive dietary advice.

We evaluated dietary counselling by dietitians in hypercholesterolaemic hypertensives over 6 months. A total of 141 patients were randomly assigned to intensive advice or usual care. Body weight fell significantly in the intervention group, but did not in the controls. There was a modest but significant fall in total cholesterol from 7.1 to 6.8 and 7.1 to 6.9 mmol/l in the diet and the control groups, respectively (4 and 3%). A similar pattern emerged from the triglyceride measurements. Low-density lipoprotein fell in both groups, but only achieved significance (P less than 0.05) in the intervention group. High-density lipoprotein did not change. There was a more marked change in cholesterol when serum levels during the study were compared with the previous annual review. These falls occurred after selection for the study but before random allocation to groups. They are unlikely to reflect regression to the mean as the lipids were stable for 2 or more years before the study, but may reflect spontaneous changes in diet after the patients were labelled hypercholesterolaemic. Dietary advice can lower total cholesterol but the magnitude of this decrease is small. Additional approaches are likely to be required to reduce plasma cholesterol to a normal range.

Antihypertensive Agents↗
PubMed1989

Calcium antagonists in the treatment of hypertension and angina pectoris in the elderly.

Calcium antagonist drugs are widely used in the treatment of hypertension and ischemic heart disease in middle-aged and elderly patients. There are reports that both the pharmacokinetics and pharmacodynamics of these drugs may be affected by increasing age, but the clinical relevance of any age-related changes remains unclear. There is evidence of significant age-related differences in pharmacokinetics that mainly reflect reduced drug clearance in the elderly, leading to higher plasma drug levels. However, calcium antagonist drugs demonstrate wide intersubject variability in pharmacokinetics, particularly in the elderly, and this often obscures any age-related differences. Increased antihypertensive responsiveness has been reported in the elderly, but there is other evidence to suggest that this may not be an independent age-related effect. If allowance is made for differences in pretreatment blood pressure and plasma drug concentrations, there is no confirmatory evidence of an age-related preferential antihypertensive action. Similarly, there is no evidence that the elderly are more susceptible to the adverse pharmacological effects of calcium antagonist drugs. For example, studies of the cardiac conduction effects of verapamil have failed to show an increased effect in the elderly. In fact, young subjects appear to be more likely to develop significant prolongations of atrioventricular conduction. Thus, although there are age-related differences in the clinical pharmacology of calcium antagonist drugs, there is no evidence to suggest that this affords any specific additional beneficial or adverse impact on their therapeutic usefulness.

Aged↗
PubMed1989

The pharmacokinetics and angiotensin converting enzyme inhibition dynamics of cilazapril in essential hypertension.

1. In a double-blind, placebo controlled, crossover study 12 patients with essential hypertension received single doses of 5, 10 and 20 mg of cilazapril. 2. Peak plasma levels of cilazaprilat and the 24 h areas under curve were directly proportional to dose. 3. The elimination half-life during the first 8 h was about 1.7 h. 4. From 24 h onwards there was a prolonged terminal elimination phase with a half-life of about 40 h, and strict dose proportionality of plasma concentrations was not maintained. 5. The pharmacokinetics of cilazaprilat and the pharmacodynamics of plasma ACE inhibition were well described by a one compartment model with saturable binding to ACE. 6. The coefficients of the model which related to plasma ACE and its interaction with cilazaprilat were in good agreement with model independent observations. 7. The values for kinetic and dynamic parameters in hypertensive patients were comparable with those reported for healthy volunteers.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

The influence of cilazapril on indices of autonomic function in normotensives and hypertensives.

1. In two single dose studies, acute blood pressure reduction with cilazapril was not associated with any significant change in supine or erect heart rate in either normotensives or hypertensives. 2. To investigate the lack of reflex cardioacceleration, a series of autonomic function tests was undertaken when there was maximum ACE inhibition, maximum evidence of angiotensin II withdrawal and the lowest blood pressure. 3. There was no evidence that cilazapril had any significant impact on indices of sympathetic nervous activity or the integrity of baroreflex mechanisms. 4. The results for the bradycardic response to apnoeic facial immersion, suggested enhanced parasympathetic activity, consistent with the withdrawal of the vagolytic actions of angiotensin II. 5. These results suggest that the absence of a heart rate response to ACE inhibition is not related to a profound sympatho-inhibitory effect or an impairment of baroreflex function. While there is some evidence of enhanced cardiac parasympathetic tone it seems unlikely that this is the sole explanation for the lack of cardioacceleration.

Adult↗
PubMed1989

Concentration-effect relationships and individual responses to doxazosin in essential hypertension.

1. This study investigates aspects of the pharmacokinetics, pharmacodynamics and concentration-effect relationships in 10 patients with essential hypertension during acute and chronic treatment with doxazosin, an alpha 1-adrenoceptor antagonist. 2. Following the first dose of doxazosin (2 mg) there were significant reductions in blood pressure, increases in heart rate and in plasma noradrenaline, and parallel rightward shifts of the phenylephrine pressor response curves, consistent with alpha-adrenoceptor antagonism. There was no significant change in the pressor response to angiotensin II. 3. Using an integrated kinetic-dynamic model, individual blood pressure responsiveness was characterised as the fall in blood pressure (mm Hg) per unit drug concentration. Responsiveness to the first dose of doxazosin was directly correlated with the responsiveness after 1 and 6 weeks treatment although there was a systemic reduction (of approximately 30%) which occurred during the first week of treatment. 4. Neither the acute nor long-term responsiveness to doxazosin was related to age, plasma renin activity, plasma noradrenaline or the pretreatment sensitivity to phenylephrine. There was a significant relationship between responsiveness and the height of the initial (pretreatment) blood pressure. 5. Integration of pharmacokinetic and pharmacodynamic data provides a reproducible index of responsiveness which can be used to investigate the consistency of the long-term anti-hypertensive response, to identify factors which influence the magnitude of the response, and to optimise the choice of dose and dose interval.

Aged↗
PubMed1989

Pharmacokinetic-pharmacodynamic relationships of alpha-adrenoceptor antagonists.

Competitive alpha1-adrenoceptor antagonists are effective in the treatment of both hypertension and cardiac failure. Prazosin has both a short half-life and a short duration of action, but other related quinazoline derivatives, such as doxazosin and terazosin, have pharmacokinetic and pharmacodynamic profiles which make them potentially suitable for once-daily administration. Acute reductions in blood pressure have been correlated with plasma concentrations of prazosin but in most instances, particularly during long term therapy, there is no simple, direct relationship between drug concentration and the fall in blood pressure. Using integrated pharmacokinetic-pharmacodynamic analysis, correlations have been described not only for reductions in blood pressure during short and long term treatment but also for alpha1-adrenoceptor antagonist activity. Furthermore, this integrated approach defines the drug concentration-effect relationship in individual subjects and provides a mathematical description of response that is potentially useful for investigating the factors (both kinetic and dynamic) which influence the inter- and intrasubject variability in antihypertensive effect of alpha-adrenergic blockers. Preliminary data suggest that the long term response to treatment with prazosin and doxazosin is mainly dependent upon the height of the pretreatment blood pressure and the response to the first dose.

Adrenergic alpha-Antagonists↗
PubMed1989

Pressor responsiveness in essential hypertension and the effects of treatment with an alpha blocker, calcium antagonist or ACE inhibitor.

We have studied the contribution of neurohumoral and structural factors to pressor responsiveness and peripheral resistance in mild/moderate hypertension. Pressor responses to intravenous infusions of phenylephrine (an alpha1 agonist) and angiotensin II were studied in groups of patients with essential hypertension before and after treatment, for 6 weeks with either nifedipine (20 mg bid), enalapril (20 mg daily) or doxazosin (2 mg daily). All drugs lowered blood pressure to a similar extent. Pressor responsiveness to both phenylephrine and angiotensin II showed wide intersubject variation when expressed as the dose of agonist required to raise mean arterial pressure by 20 mmHg (PD20). A group of age-matched normotensive controls showed a similar PD20 for phenylephrine to hypertensives. Angiotensin 11 sensitivity was greater in hypertensives. Drug treatment had different effects in hypertensive patients. Doxazosin, an alpha blocker, reduced the responsiveness to phenylephrine but had no effect on responses to angiotensin II. Nifedipine attenuated responses to both agonists while treatment with enalapril increased responsiveness to both phenylephrine and angiotensin II. We have not found evidence of systematic differences in alpha 1 receptor responses in hypertensives and different "vasodilator" drugs can lower blood pressure with widely different effects on adrenergic and non-adrenergic vascular responses.

Adrenergic alpha-Antagonists↗
PubMed1989

Clinical pharmacological evaluation of calcium antagonists and other drugs modifying myogenic tone in essential hypertension.

The factors determining the acute and long-term response to calcium antagonists have been studied in controlled trials in essential hypertension. The importance of dose and plasma level in determining the response has been confirmed. The blood pressure response has been modelled and mathematically described, with drug concentrations related to blood pressure falls by linear or Emax (maximum fall in blood pressure) models. The acute response predicted the response after 6 weeks of treatment. Neither age nor plasma renin activity independently influenced the response to calcium antagonists. The level of pretreatment blood pressure (starting blood pressure) was positively related to indices of response. In similar studies with other drugs modifying myogenic tone, while vascular reactivity to selective agonists was reduced, enhanced or unchanged, blood pressure falls were related to plasma levels in all cases.

Blood Pressure↗
PubMed1989

Treatment of high blood pressure--the effect on coronary morbidity and mortality.

Established drugs used in the treatment of hypertension have reduced stroke but have had disappointingly little impact on coronary artery disease and its complications. This could be due to inadequate falls in blood pressure (or excessive falls). It is possible that the role of blood pressure in ischaemic heart disease has been over-estimated compared to other risk factors. Alternatively, the drugs used previously may have adversely affected other factors. Mortality in treated hypertensives remains higher than normotensives but so does their blood pressure. The blood pressure on treatment is a much better predictor of outcome than initial blood pressure. This suggests that improved blood pressure control may be desirable. In our hospital-based hypertension clinic many patients have more than one risk factor. In spite of intensive efforts between 1980 and 1988, smoking habits changed little and serum cholesterol and random blood glucose actually rose. Cholesterol is high in our population of hypertensive patients and the mean (+/- SD) rose from 6.4 +/- 1.3 to 6.6 +/- 1.3 (n = 127; P less than 0.01). These observations highlight the importance of a multiple risk factor approach. The benefits of alternative drugs which can lower total cholesterol and/or low-density lipoprotein (LDL) and/or raise high-density lipoprotein (HDL) deserve study in this population. A final possibility is that the widely observed association between hypertension and ischaemic heart disease is not causal (or is weak compared to other risk factors). If a common underlying mechanism caused both atheroma and hypertension then reduction of blood pressure would not be expected to reverse atheroma and its complications. At present this possibility cannot be excluded.

Antihypertensive Agents↗
PubMed1988

The combination of prazosin and verapamil in the treatment of essential hypertension.

An exaggerated fall in blood pressure has been reported with the combination of an alpha 1-blocker and a calcium antagonist. This study investigated, in a placebo-controlled, randomized crossover trial, the clinical usefulness of the combination of prazosin (2 mg b.i.d.) and verapamil (160 mg b.i.d.). Therapeutic efficacy was monitored at regular outpatient visits: average supine and erect blood pressures were, respectively, 175/99 and 176/103 mm Hg with placebo, 160/91 and 164/96 mm Hg with single drug treatment, and 152/84 and 152/89 mm Hg with combination therapy. This significant and clinically useful reduction in blood pressure had an overall magnitude of approximately 28/18 mm Hg (supine) and 29/19 mm Hg (erect). Further measurements were made during a series of intensive study days, and the most important additional finding was a pharmacokinetic interaction that resulted in increased peak concentrations and bioavailability of prazosin. In conclusion, the combination of prazosin and verapamil proved effective in the treatment of 12 patients with essential hypertension who had been poorly responsive to conventional treatment with a beta-blocker and thiazide diuretic.

Adult↗
PubMed1988

Relationship between plasma prazosin concentration and alpha-antagonism in humans: comparison of conventional and rate-controlled (Oros) formulations.

A single-dose comparative evaluation in young normotensive men of the plasma concentrations and alpha-adrenoceptor antagonism after conventional prazosin and a new slow-release formulation (Oros) is described. Whereas conventional prazosin (2 mg) produced a maximum reduction in erect blood pressure at 3 hours (80/46 mm Hg compared with 110/65 mm Hg with placebo), the lowest blood pressure of 94/48 mm Hg with Oros prazosin (5.5 mg) was not observed until 8 hours after administration. Twenty-four hours after Oros prazosin, prazosin was still detectable in plasma and erect blood pressure was reduced to 107/58 mm Hg compared with 110/71 mm Hg after placebo. alpha 1-Antagonism (assessed by the pressor responses to intravenous phenylephrine) was maximal, with a 4.8-fold shift in dose-response 24 hours after Oros prazosin, and persisted at least until 30 hours after administration, with a 2.3-fold shift. There were significant correlations between alpha 1-antagonism and plasma prazosin concentrations for both Oros and conventional prazosin. The slopes of these relationships were significantly different, but this is thought to be consistent with the differences in the rates of drug release from the two formulations. Overall this study provides further evidence in humans that the duration and extent of the alpha 1-antagonism and the blood pressure response reflect the plasma prazosin concentrations. Additionally these data suggest the potential suitability of this type of a slow-release formulation for single daily administration.

Adult↗