Hl Elliott

Enhanced Pressor Response to Angiotensin I in Normotensive Men With the Deletion Genotype (DD) for Angiotensin-Converting Enzyme

The insertion (I)/deletion (D) polymorphism of the human angiotensin-converting enzyme gene has emerged as a genetic risk factor for ischemic heart disease. However, the functional consequences of this polymorphism in humans are not known. Ten normotensive men with the DD genotype and 10 with the II genotype participated in a study in which pressor responses to stepwise infusions of incremental doses of angiotensin I (Ang I) and Ang II and Ang II production during Ang I infusion were measured. Pressor responses were expressed as PD20, which reflects the angiotensin dose required to raise mean blood pressure by 20 mm Hg. The PD20 for Ang I in subjects with the DD genotype was significantly lower than that in II genotype subjects (8.8 versus 14.8 ng/kg per minute, P = .0091), whereas the PD20 for Ang II between the two groups did not differ significantly. The ratio of PD20 for Ang I and Ang II in DD subjects was significantly lower than that in II subjects (0.85 versus 0.96, P = .0452), and the venous levels of Ang II during Ang I infusion in DD subjects were significantly higher than those in II subjects (P < .01). Our study has shown increased pressor responsiveness to Ang I, probably as a consequence of the generation of increased Ang II levels, in subjects homozygous for the DD allele of the angiotensin-converting enzyme gene. This result may be relevant to the reported adverse cardiovascular risk conferred by the D allele, as it provides a mechanistic rationale for the association between this polymorphism and cardiovascular disease.

White-coat hypertension as a cause of cardiovascular dysfunction

BACKGROUNDnThe increasing use of 24 h ambulatory blood pressure monitoring has allowed diagnosis of white-coat hypertension, in which blood pressures are higher on clinic measurements than on ambulatory monitoring. Treatment is not generally thought to be necessary for this disorder. However, there is evidence that patients with white-coat hypertension develop renal impairment and left ventricular hypertrophy. We undertook this study to assess whether white-coat hypertension, in the absence of cardiovascular structural abnormalities, is associated with cardiovascular functional abnormalities.nnnMETHODSnCardiovascular function was assessed by ultrasonography in three groups of patients classified as normotensive, persistently hypertensive, or white-coat hypertensive (23, 20, and 22 patients, respectively) on the basis of ambulatory blood pressure monitoring, carried out for 28 h with recordings taken every 15 min during the day and every 20 min during the night, and clinic measurements, made with a semi-automatic oscillometric device.nnnRESULTSnSimilar abnormalities of diastolic left ventricular function were identified in the patients with persistent hypertension and those with white-coat hypertension; both groups differed in these indices from the normotensive group (E/A ratios 0.94 [SD 0.23], 1.06 [0.21], and 1.24 [0.31] respectively; ANOVA p < 0.005). In addition, the white-coat and persistently hypertensive groups, when compared with the normotensive group, showed similar abnormalities of elasticity, compliance, and stiffness (stiffness index 4.32 [1.90], 4.53 [1.38], and 3.27 [0.95] respectively; ANOVA p < 0.05) of the large arteries.nnnINTERPRETATIONnFunctional cardiovascular abnormalities were identified in white-coat hypertensive patients who had no identifiable structural abnormalities. Such functional abnormalities can be reversed by antihypertensive treatment. We propose that patients with white-coat hypertension might benefit from antihypertensive treatment as well as those with persistent hypertension. This hypothesis should be addressed in prospective clinical trials.

Enalapril clinical pharmacokinetics and pharmacokinetic-pharmacodynamic relationships. An overview.

SummaryThe conventional pharmacokinetic profile of the angiotensin converting enzyme (ACE) inhibitor, enalapril, is a lipid-soluble and relatively inactive prodrug with good oral absorption (60 to 70%), a rapid peak plasma concentration (1 hour) and rapid clearance (undetectable by 4 hours) by de-esterification in the liver to a primary active diacid metabolite, enalaprilat.Peak plasma enalaprilat concentrations occur 2 to 4 hours after oral enalapril administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life 2 to 6 hours) and a subsequent prolonged phase (elimination half-life 36 hours), the latter representing equilibration of drug from tissue distribution sites. The prolonged phase does not contribute to drug accumulation on repeated administration but is thought to be of pharmacological significance in mediating drug effects.Renal impairment [particularly creatinine clearance <20 ml/min (<1.2 L/h)] results in significant accumulation of enalaprilat and necessitates dosage reduction. Accumulation is probably the cause of reduced elimination in healthy elderly individuals and in patients with concomitant diabetes, hypertension and heart failure.Conventional pharmacokinetic approaches have recently been extended by more detailed descriptions of the nonlinear binding of enalaprilat to ACE in plasma and tissue sites. As a result of these new approaches, there have been significant improvements in the characterisation of concentration-time profiles for single-dose administration and the translation to steady-state. Such improvements have further importance for the accurate integration of the pharmacokinetic and pharmacodynamic responses to enalapril(at) in a concentration-effect model. This model is able to characterise the concentration-effect relationship in individual recipients of the drug and predict the antihypertensive responses to dosage alterations.Therapeutic use of enalapril has recently expanded to include heart failure. In this condition, responses to enalapril may be mediated by different effector systems in different organs and may occur at different concentration ranges to those observed during treatment of hypertension. However, similar concentration-effect analyses are still relevant. After almost 15 years of clinical use, the therapeutic applicability of enalapril continues to expand and detailed pharmacokinetic description of the agent remains an integral component of this expansion.

Pharmacodynamic modeling of the antihypertensive response to amlodipine

The distinctive pharmacokinetic characteristics of amlodipine, particularly the long half‐life, are presumed to translate directly to a prolonged duration of action, but the concentration‐effect relationship for the antihypertensive response has not been clearly established. In this study of 12 patients with essential hypertension, treatment with 5 mg amlodipine once daily has been evaluated with use of an integrated pharmacokinetic‐pharmacodynamic model to calculate individual patient responsiveness for the decrease in blood pressure per unit change in drug concentration. Amlodipine concentrations were well correlated with the placebo‐corrected reductions in blood pressure in individual patients and responsiveness, for example, for erect systolic blood pressure was − 3.1 ± 0.9 mm Hg/ng/ml. By characterizing the concentration‐effect relationships in individual patients, this study has confirmed that the plasma concentration–time profile is an appropriate index of the effect‐time profile, as reflected by an antihypertensive response that is sustained throughout 24 hours with relatively little trough‐to‐peak variability.

Absence of an effect of mianserin on the actions of clonidine or methyldopa in hypertensive patients

SummaryThe concurrent administration of tricyclic antidepressants has been shown in man to result in a clinically significant impairment of the antihypertensive effect of clonidine. This interaction is thought to be related to competition for central α2 receptors where clonidine acts as an agonist and the tricyclics act as antagonists. Although it seems to cause less cardiovascular effects than tricyclic antidepressants, the tetracyclic antidepressant, mianserin also has been reported to be an α receptor antagonist and may, therefore, also interfere with the antihypertensive activity of centrally-acting drugs. This study investigates the effects of acute and chronic mianserin administration in patients with essential hypertension established on long term treatment with either clonidine or methyldopa. The first dose of mianserin was not associated with an increase in blood pressure and during a further two weeks of mianserin therapy there were no significant alterations in blood pressure, supine or erect. Similarly, mianserin did not alter heart rate either after acute or after chronic administration. Mianserin itself had a sedative effect but there was no interference with the sedation attributable to clonidine or methyldopa. Mianserin caused no reduction in salivary flow and did not influence the reduced saliva production caused by clonidine. Both clonidine and methyldopa are associated with a reduction in sympathetic outflow but there was no evidence in this study of any further change in plasma noradrenaline or 24 h urinary catecholamine excretion. This study demonstrates that if mianserin is given acutely or chronically, it does not interfere with the effects of the centrally acting antihypertensive drugs, clonidine and methyldopa. Mianserin may therefore be a suitable antidepressant for patients receiving these antihypertensive agents if drug treatment for depression is indicated.

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.

Concentration-effect relationships and implications for trough-to-peak ratio

The guidelines on trough-to-peak ratio identified an index of the duration of action of an antihypertensive drug (relative to its dosage interval) to prevent the use of inappropriately large doses of drug simply to extend the apparent duration of action. In some instances, however, trough-to-peak ratio may be dose-dependent and this analysis examines the contribution that the underlying concentration-antihypertensive effect relationship makes to the dose dependency of trough-to-peak ratio. Where this concentration-effect relationship is essentially linear the trough-to-peak ratio is almost invariably dose-independent. In contrast, where the relationship is identified as being of a sigmoid-Emax type the trough-to-peak ratio is likely to be dose-dependent. The nature of the concentration-effect relationship also influences the duration of action beyond the dosage interval whereby linear drugs are superior to Emax drugs by virtue of the greater persistence of the antihypertensive effect.

Differential effects of ACE inhibiting drugs: Evidence for concentration‐, dose‐, and agent‐dependent responses

Clinical Pharmacology and Therapeutics (1993) 53, 622–629; doi:10.1038/clpt.1993.82

Moxonidine: pharmacology, clinical pharmacology and clinical profile.

Management strategies in hypertension evolve in response to an increased understanding of underlying pathophysiological processes and developments and refinements in drug treatments. Recent research has identified the regulatory role of the imidazoline (I1) receptor in sympathetic outflow and blood pressure regulation and this has led to the development of moxonidine, a highly selective centrally acting antihypertensive agent. At a practical level, moxonidine is suitable for single daily dosing in hypertension. Furthermore, in comparative studies moxonidine has a low incidence of symptomatic adverse effects comparable, for example, to that of the ACE inhibitor drugs, captopril and enalapril. The antihypertensive efficacy of moxonidine has now been established in a series of comparative clinical trials against all other first-line antihypertensive drug classes but, in line with current concepts, it may be necessary to look beyond blood pressure reduction. For example, centrally acting agents are known to be effective for promoting the regression of LV hypertrophy and studies in hypertensive patients have shown that antihypertensive treatment with moxonidine successfully leads to significant reductions in LV mass indices. Furthermore, there is now evidence that moxonidine has a beneficial effect on insulin sensitivity such that there are likely to be improvements in the overall metabolic profile. Thus, the clinical characteristics of moxonidine indicate that it is well suited for consideration among the first-line antihypertensive treatment choices.

Calculation of trough-to-peak ratio in the research unit setting. Advantages and disadvantages.

The trough-to-peak ratio for the response to an antihypertensive drug is a clinically meaningful parameter but only when the calculation has been derived from an appropriate and scientifically robust study. Since the methodological details have not been defined by any regulatory authority, several possible approaches have developed. The major apparent advantages of the intensive study of individual patients in the research unit setting are that the conditions of measurement can be standardized and an accurate account can be taken of the circadian variations in the responses to placebo and active drug treatment. The principal disadvantage is that it is an artificial environment that may, or may not, be directly relevant to routine clinical circumstances. Nevertheless, the values obtained with this approach to date are directly comparable to values obtained by the alternative approaches, such as ambulatory blood pressure measurements (provided that those are also well-conducted studies). Thus, using the trough-to-peak ratio not only appears valid but also permits the detailed study of individual patients and also lends itself to the incorporation of additional and confirmatory clinical pharmacological assessments.