The Description and Prediction of Antihypertensive Drug Response

Donnelly, Richard (1988) The Description and Prediction of Antihypertensive Drug Response. PhD thesis, University of Glasgow.

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In recent years there has been a tendency to move away from a standardised stepped care regimen for treating patients with hypertension and to adopt instead a more flexible approach in which antihypertensive treatment is tailored to the needs of individual patients. A wider choice of drugs is now available and some of the newer agents such as calcium antagonists, ACE inhibitors and alpha1 adrenoceptor antagonists represent reasonable alternatives to a diuretic or beta blocker as first-line treatments. An individualised approach to treatment is a laudable goal but factors which determine the response to antihypertensive therapy - both kinetic and dynamic - are not clearly understood and at present we are unable to predict which patients will respond to which drugs. An additional problem is that very little is known about dose-effect relationships for antihypertensive drugs -information which would constitute a basis for optimising drug therapy prospectively in individual patients. It has been suggested that for a number of antihypertensive drugs no predictable concentration-effeet relationship exists but this probably reflects the negative findings of those previous studies which considered the response for groups of subjects rather than for individuals. In a series of single blind studies 46 patients with mild to moderate essential hypertension received treatment with placebo for 2 weeks followed by nifedipine, or enalapril, or doxazosin, or ketanserin. Each active treatment was administered as monotherapy for 4-6 weeks and patients attended for a series of 8-hour study days to evaluate the effects of placebo, 1st dose and chronic (1-6 weeks) therapy. At frequent intervals during each study day, and at 24 hours after dosing, blood pressure and heart rate were recorded and venous blood samples collected for measurement of plasma drug concentration. Additional blood samples were obtained for plasma renin activity, aldosterone and catecholamines. Pressor responsiveness to intravenous infusions of the selective alpha1 agonist phenylephrine (PE) and the non-adrenergic vasoconstrictor angiotensin II (All) was measured on each study day. The pharmacokinetics and pharmacodynamic effects were evaluated after acute and chronic treatment. Drug concentration-effect analysis was used to characterise the antihypertensive response of each individual patient in terms of kinetic as well as dynamnic parameters and to describe the temporal discrepancy for the plasma concentration-effect relationship (Keq). In each study there was no simple direct relationship between plasma drug concentration and the placebo-corrected fall in blood pressure. However, using the integrated kinetic-dynamic model drug levels were well correlated with reductions in both systolic and diastolic blood pressure in individual patients. The kinetic-dynamic relationships for nifedipine, doxazosin and ketanserin were most appropriately described by the simpler linear model and responses of individual patients were characterised in terms of the fall in blood pressure per unit drug concentration. For example, responsiveness to nifedipine (m), as the mean of the group, was -0.48 following the first dose, -0.45 after 1 week and -0.49 mmHg systolic/ng/ml after 6 weeks. There was an average reduction of 30% in the responsiveness to doxazosin during chronic treatment compared with single dose administration: for example, the mean responsiveness for the group was -2.1 following the first dose and -1.4 mmHg systolic/ng/ml after 6 weeks. There was a similar reduction in responsiveness to ketanserin from -0.47 to -0.25 mmHg systolic/ng/ml after 1 month and additionally there was a significant increase in Keq from 0.49 (1st dose) to 1.86 hours -1 (1 month). The pharmacokinetics and kinetic-dynamic relationships of enalapril were different in several respects compared with the other three drugs. A conventional pharmacokinetic model did not satisfactorily describe all the features of the disposition, particularly the accumulation of enalaprilat during chronic therapy. An alternative approach using a physiologically realistic model which assumes saturable binding of the drug to ACE was most appropriate for characterising both the kinetics and the concentration-effcet relationships. In the case of enalapril, but with none of the other drugs, the linear concentration-effect model was inferior to the full Langmuir (Emax) equation for describing the kinetic-dynamic relationships. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Pharmacology, Medicine
Date of Award: 1988
Depositing User: Enlighten Team
Unique ID: glathesis:1988-77757
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 11:53
Last Modified: 14 Jan 2020 11:53

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