Mild hypertension - current controversies and new approaches Clonidine workshop Titisee 13-15 October 1983 Mild hypertension Current controversies and new approaches Edited byM.A.Weber and C.J.Mathias With an introduction s. by W. Peart Contributions from F. Alhenc-Gelas, L. CeremuiyD.ski, J. G. Collier, J. I. M Drayer, S. S. Franklin, G. P. Guthrie, Jr., K. Hayduk, K. Heilmann, G. Mancia, C. J. Mathias, F. G. McMahon, W. S. Peart, R. J. Polinsky, M. Rowland, M. P. Sambhi, J. E. Shaw, M Tuck, M.A. Weber SteinkopfTVerlag Darmstadt Prof. M. A. Weber Hypertension Center Veterans Administration Center 5901 East 7th Street Long Beach, California 90822 U.S.A. Dr. C. J. Mathias M. B., B. S., D. Phil., M. R. C. P. Senior WelIcome Fellow in Clinical Science, Honorary Consultant Physician and Senior Lecturer in Medicine, Medical Unit St. Mary's Hospital Medical School Norfolk Place, London W2 1PG Great Britain CIP-Kurztitelaufnahme der Deutschen Bibliothek Mild hypertension: current controversies and new approaches / [Clonidine Workshop, TItisee, 13 -15 October 1983]. Ed. by M. A. Weber and C. J. Mathias. With an introd. by W. S. Peart. Contributions from F. Alhenc-Gelas ... - Darmstadt: Steinkopff, 1984.- ISBN-13 :978-3-642-85336-4 e-ISBN-13:978-3-642-85334-0 DOl: 10.1007/978-3-642-85334-0 NE: Clonidine Workshop <1983, Oktober, TItisee>; We ber, Michael A. [Hrsg.]; Alhenc-Gelas, F. [Mitverf.] 1bis work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, re production by photocopying machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law, where copies are made for other than private use, a fee is payable to the publisher, the amount of the fee to be determined by agreement with the pub lisher. Copyright © 1984 by Dr. Dietrich SteinkopffVerlag, GmbH & Co. KG, Darmstadt Softcover reprint of the hardcover 1st edition 1984 Editorial Assistance: Juliane K. Weller - Production: Heinz J. Schafer The use of registered names, trademarks, etc. in this publication does not imply, even in the ab sence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Foreword There is clear evidence that in severe hypertension lowering blood pressure, by drug therapy decreases the incidence of major cardiovascular events. Recent studies suggest that such benefit may also extend to patients with mild to moderate hypertension. The putative benefits of drugs may be offset, however, by their adverse effects and a prime example is the increased incidence of impotence and metabolic disorders in patients on thiazide diuretics. There is, therefore, a real need to look further into the therapy of patients with mild to moderate hypertension. The ideal drug in such patients would oppose the basic mechanisms responsible for the elevation in blood pressure, would prevent counter-regulatory responses and would have minimal side-effects in both the short-term and the long-term, the latter being of particular importance to younger patients. These aspects were considered at the symposium "Mild hypertension. Current con troversies and new approaches" held at Titisee in West Germany, October 13-15 in 1983. The foundation for discussion was set with an exposition of the neural and hormonal regulation of blood pressure in normal man followed by a consideration of the pos~ible pathophysiological mechanisms involved in patients with hypertension. Particular at tention was focused on the central nervous system and on effects governed by activity of the peripheral nervous system as these may well provide further opportunities for logical therapeutic intervention in clinical hypertension. The current management of mild to moderate hypertension was then reviewed. Diuretics, p-adrenergic blockers, centrally acting anti-hypertensives, converting enzyme inhibitors and calcium antag onists were considered in relation to their use as either monotherapy or combina tion therapy. Attention was paid to the management of hypertension in patients with obesity, diabetes mellitus, ischaemic heart disease and the elderly, as in these groups, selective or modified therapeutic approaches may be necessary. The final sessions of the symposium concentrated on novel strategies in therapy, as it was clear that in spite of the availability of potentially effective agents, there were undoubtedly limitations to their use. One approach is to use depot preparations of available drugs, the effects of which have already been well defined. Current research indicates that the transdermal route may offer some advantages in terms of ease of ap plication, duration of action and maintenance of suitable plasma drug concentra tions, particularly for agents whose actions are clearly related to drug concentrations. The first antihypertensive agent available in this form is clonidine, and recent trials with the transdermal form were presented and discussed. Early studies in patients with mild to moderate essential hypertension appear encouraging, but further work is needed both in relation to its effects on the skin and to the definition of its clinical niche in the management of hypertension. v The proceedings of this symposium represent a comprehensive view of the physio logical and biochemical basis of blood pressure control, the possible mechanisms con tributing to essential hypertension, the advantages and disadvantages of currently available drug therapy and a consideration of newer therapeutic approaches. The sym posium. we feel, helped weld together basis concepts with newer therapeutic ideas and we would like to thank Dr. R. K. Rondel for meticulously organizing it and facili tating the editorial work. We hope that these proceedings will be of as much interest and guidance to you as the symposium was to us. Christopher 1. Mathias Medical Unit St. Mary's Hospital Medical School. Norfolk Place London W2 I PG Great Britain Michael A. Weber Hypertension Center Veterans Administration Center Long Beach, Calif. 90822 U.S.A. VI Contents v Foreword .. Introduction: Some neurological aspects of blood pressure control W. S. Peart ................. . Central and peripheral control of blood pressure Chairman: M. A. Weber Central nervous system control of blood pressure R. J. Polinsky . . . . . . . . . . . . . . . 11 Discussion . . . . . . . . . . . . . . . . 23 Blood pressure control and the peripheral sympathetic nervous system C. J. Mathias 24 Discussion . . . . . . . . . . . . . . . . . . . . . . 31 Baroreflex function and centrally acting antihypertensive drugs G. P. Guthrie, Jr. 34 Discussion . . . . . . . . . . . . . . . . . . . . 42 Haemodynamic effects of antihypertensive agents in man G. Mancia and A. Zanchetti 43 Discussion . . . . . . . . . . . . . . . . . . . . 50 Vascular autonomy and its relation tuthe action of antihypertensive drugs J. G. Collier 51 Discussion . . . 59 General discussion 60 Therapeutic consequences Chairman: S. S. Franklin Therapeutic decisions in mild hypertension: an introductory overview S. S. Franklin . . . . . . . . . . . . . . . . . . . . . . . . 65 When to treat? Recent trials in mild hypertension. Epidemiological data and conclusions K. Hayduk . . . . . . . . .... . . . . . . . . . . . . . . . . . . 72 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Current assessment of the stepped-care treatment of mild hypertension: diuretics, beta-blockers, vasodilators versus c10nidine M. P. Sambhi 78 Discussion . . . . . . . . . . . . . . 86 VII Use of centrally-acting agonists in the treatment of mild hypertension in the elderly patient J.I. M. Drayer, M. A. Weber 88 Discussion . . . . . . . . 94 Sympathetic nervous system activity in the obese hypertensive patient: potential role for central alpha-adrenoreceptor agonists M. Tuck . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . 108 Oonidine for treating patients with mild hypertension and angina pectoris T. Zaleska, L. CeremuZyllski ................... 109 New pharmacological approaches in the treatment of mild hypertension. The potential role of converting enzyme inhibitors and calcium blocking agents F. Alhenc-Gelas, P. Corvol, J. Menard 118 Discussion . . . . 125 General discussion. . . . 127 Advances in treatment Chairman: M. P. Sambhi Rate-controlled drug delivery and the reduction of risk K. Heilmann . . . . . . . . . . . . . . . . . . 131 Oonidine rate - controlled system: technology and kinetics J. E. Shaw, D. Enscore, L. Chu .......... . 134 Discussion . . . . . . . . . . . . . . . . . . . . . 141 Absorption of clonidine from a transdermal therapeutic system when applied to different body sites K. Hopkins, L. Aarons, M. Rowland 143 Discussion . . . . . . . . . . . 147 Oinical experience with clonidine TIS F. G. McMahon, R. Michael, A. Jain, J. R. Ryan 148 Discussion . . . . . . . . . . . . . . . . 152 Clinical effectiveness of the transdermal route of antihypertensive treatment M. A. Weber, J. I. M. Drayer, J. L. Lipson, D. D. Brewer. . 153 Discussion . . . . . . . . . . . . . . . . . . . . . 158 Roundtable discussion on the use of transdermal medication: clinical characteristics and skin reactions 159 Panel discussion: the role of clonidine in the treatment of mild hypertension. 163 Concluding remarks W.S.Peart . 167 Participants. 169 Subject Index 171 VIII Introduction: Some neurological aspects of blood pressure control w. S. Peart It may at first seem strange that in a meeting on mild hypertension many of the papers should concern the nervous system. Such an emphasis arises naturally, however, from the recent resurgence of interest in the neurological control of the circulation. This in troductory paper aims to pin-point some of the important neurological considerations and thus to form a framework for a more detailed discussion of the treatment of mild hypertension by subsequent contributors. History Our understanding of the role of the nervous system in cardiovascular control has de veloped over some 140 years (see review by Peart 1979). The term 'vasomotor nerves' was first used by Stelling in 1840 and their action on blood vessels was confrrmed by the studies of Claude Bernard, Waller and Brown-Sequard in the 1850's. By the latter half of the 19th century growing knowledge of physiological chemistry and endocri nology had led to the ready acceptance of the concept that organs could release /mb stances into the circulation. The demonstration by Oliver and Schafer of the pressor ef fects of an intravenous injection of an adrenal gland extract was of particular impor tance. Adrenaline was the first hormone to be purified (Abel and Crawford 1899), and subsequently to be synthesized (Stolz 1904; Dakin 1905). At this time Elliott first sug gested that a sympathetic impulse might liberate adrenaline at the nerve ending, to act on the blood vessels. In 1907 Langley postulated the existence of a receptive area on muscle which would respond to the substance liberated from what we now know to be cholinergic nerve endings. Barger and Dale (1910) investigated the relationship be tween the Elliott hypothesis and the group of amines that they were then synthesizing and studying pharmacologically. In his retrospective assessment of their work, Dale (1965) remarked that he was too concerned with pointing out the differences between sympathetic action and the action of adrenaline to notice that noradrenaline fitted the requirements for the sympathetic neurotransmitter. It was not until Loewi (1921) dem onstrated 'Acceleranstoff', released by stimulating the vasomotor nerves to the heart, that the chemical theory of neurotransmission received wide support. Although Can non and Rosenblueth were still referring to the humoral effects of sympathetic nerve stimulation under the headings of sympathin E and I as late as 1933, by 1934 Bacq had suggested - on a critical assessment of previous work - that noradrenaline was likely to be the substance involved. In 1946 von Euler extracted noradrenaline from the splenic nerves. At that time, working in Gaddum's laboratory, I .showed by parallel pharmaco logical assay that the substance that appeared in blood after sympathetic nerve stimu lation was noradrenaline (Peart 1949). The assessment of the activity of the sympathetic nervous system as opposed to its basic physiological mechanism, has followed two main lines. The fust has attempted to corre late sympathetic nerve action with the appearance of noradrenaline in the blood stream and its metabolic products in the urine. The second has been an increasingly detailed study of sympathetic fibres and terminals. The latter approach has been the more re warding. Since it has been applied centrally within the nervous system, as well as at the periphery, it has led to a much greater understanding of the mode of action of many different drugs. We know much more about the intimate workings of the synapse, how ever, than we do about the overall function of the sympathetic nervous system. Von Euler (1956) was one of the first to study patients with autonomic insufficiency. He and his colleagues showed two main abnormalities. A fluorescence method of catechol de termination (von Euler and Fioding 1956) showed these patients to have very low blood levels when either lying or standing. This was matched by very low levels of both free and conjugated forms of adrenaline and noradrenaline in the urine. At this time the full pattern of metabolic products in the urine was not known, but I remember us ing these observations in the diagnosis of patients with phaechromocytoma. The rat blood pressure preparation was used as the final assay of free amines. More recently, Mathias et al. (1975), working with patients with transected cervical cords, have dem onstrated the failure of very low plasma noradrenaline levels to rise on tilting. These patients are, of course, without higher sympathetic outflow. Patients with phaeo chromocytomas have a gross excess of catechols in the plasma. They may be differen tiated from patients with other forms of hypertension by plasma assay. This has become a standard investigation in phaeochromocytoma along with assessment of the marked increase of metanephrines in the urine (Manger and Gifford 1977). Plasma catechol levels must be regarded as a very crude guide to the level of sympathetic nervous ac tivity because of various factors which have emerged in relation to the release and sub sequent fate of noradrenaline. This is particularly the case at the intermediate levels of sympathetic activity which are most interesting with respect to the control of the circu lation. Sympathetic pharmacology Figure 1. is a diagram showing our present understanding of sympathetic pharmacolo gy at both peripheral and central levels (see Stjarne et aI. 1981 for background referen ces). All the factors which affect the release of noradrenaline into the synaptic cleft may be classified as either stimulators or inhibitors. The major final event whereby a vesicle containing noradrenaline and other substances attaches itself to the membrane and liberates its contents by exocytosis, has been shown to depend upon the centry of cal cium ions into the nerve ending. Once in the cleft, noradrenaline may follow a number of courses. • It may attach to the alpha -receptor on the effector cell. l • It may re-enter the nerve ending (uptake 1), there to be metabolized by monoamine oxidase (MAO) to 3: 4 dihydroxymandelic acid and subsequently to VMA (vanilyl mandelic acid); this re-uptake can be blocked by cocaine. • It may diffuse in the cleft to stimulate alpha -prejunctional receptors which inhibit 2 the release of noradrenaline. 2