ACE Inhibitors in Hypertension: A Guide for General Practitioners

104 Pages·1992·6.019 MB·English

by  Dr Gillian Strube, Dr George Strube (auth.)

ACE Inhibitors in Hypertension
AGuide for General Practitioners
ACE Inhibitors
in Hypertension
A Guide for
General Practitioners
Dr Gillian Strube
Medical Advisor to West Sussex FHSA
and
Dr George Strube
Medical Audit Facilitator, West Sussex FHSA
SPRINGER SCIENCE+BUSINESS MEDIA, B.V.
British Ubrary Cataloguing in Publication Data
Strube, Gillian
ACE inhibitors in hypertension: a guide for general practitioners.
1. Humans. Circulatory system. Drug therapy
1. Title II. Strube, George
616.1061
ISBN 978-94-010-5737-0 ISBN 978-94-011-3900-7 (eBook)
DOI 10.1007/978-94-011-3900-7
Copyright
e
1992 by Springer Science+Business Media Dordrecht
Origina11y published by Kluwer Academic Publishers in 1992
Softcover reprint of the hardcover 1s t edition 1992
AII rights reserved. No part of this publication may be reproduced, stored in
a retrieval system, or transmitted in any form or by any means, electronic,
mechanical, photocopying, recording or otherwise, without prior permission
from the publishers, Springer Science+Business Media, B.V.
Contents
1 Introduction 1
2 Physiology 3
3 Cardiac and vascular implications ofhypertension:
the need for treatment 17
4 Diagnosis and assessment ofessential hypertension 31
5 The management ofpatientswith hypertension 43
6 The ACE inhibitor drugs: history and pharmacology 55
7 Safetyand side-effects ofACE inhibitors 69
8 Special patientgroups 75
9 Combination therapywith ACE inhibitors 97
10 Conclusion 99
Further reading 101
Index 103
1
Introduction
ACEinhibitorsareoneofthe most excitingand interestingofrecent medical
developments. They fit the patho-physiologica1 processes of cardiovascular
disease with fascinating precision and are a constant stimulus to the
acquisition of greater understanding ofthe mechanisms involved and of the
mode of action of the drugs themselves. There is still much to be learned,
especiallyabout the wider effects ofthedrugs, their precise modeandsite of
action and about differences between the different preparations. ACE
inhibitors are of proven benefit to patients with chronic congestive heart
failure and are the latest in the series of drugs used in the treatment of
hypertension.
Interest in the treatment ofhypertension has paralleled the development
of hypotensive drugs and the realisation that long-term prognosis could be
significantly improved. The treatment of hypertension has progressed in
stages following the development of a succession of increasingly effective
drugs, eachallowingagreater proportionofpatients to be treatedwithfewer
andfewer side-effects.
First, the ganglion-blocking agents such as hexamethonium and guan
ethidine transformed the outlook for patients with malignant hypertension
but proved too unpleasant for routine use in other forms of hypertension.
Next came the rauwolfia group and methyldopa which extended the range of
patients treated and reduced the incidence of stroke in hypertensives. The
major breakthrough in routine long-term treatment of moderate hyper
tension camewith the development ofdesigner drugs and the introduction of
P-blockers. These, used alone and in combination with thiazide diuretics and
with calcium antagonists, still form the basis of the standard treatment in
uncomplicated patients.
However it is by no means a perfect regime. Many people, such as those
suffering from asthma or heart failure, cannot take P-blockers. Some suffer
side-effects. Others, such as diabetics and the elderly, do not benefit overall
becauseofunwelcomesecondaryeffects.
1
ACEINHIBITORSINHYPERTENSION
It is likely that ACE inhibitors will solve the problem of treating
hypertension in most of these patients and therefore have a major role to
playin moderntherapy.
In addition, although the incidence ofstrokeassociated with hypertension
has continued to fall, that ofmyocardial infarction has remained unchanged.
IfACE inhibitorswere found to solve this problem, then they might become
the drugs of first choice in the treatment of the majority of hypertensive
patients.
In this book we remind readers of the renin-angiotensin-aldosterone
system, the pathophysiologyofhypertension and ofwhere ACE inhibitors fit
intothegeneralpicture.
2
2
Physiology
Physiologicalcontrol orblood pressure
If the process and effects of disease are to be understood and remedies
appropriatelyapplied,itis necessarytobearinmindthe normal physiology.
Systemicblood pressureis a productofleftventricularoutput (LVO) and
systemicvascular resistance(SVR), alsocalledperipheralresistance.
LVO x SVR = BP
ThisisOhm'slawwhichstatesthat
Flow(LVO) = pressure (BP)
resistance(SVR)
The SVR is dependent on the diameter of the arterioles. In health, this
depends solely on the tone of smooth muscle in the arterioles which is
controlledbythe homeostaticmechanismsdescribedbelow.
IftheSVR rises, the blood pressure rises, as long as the left ventricle can
keep the output the same. The blood pressure also rises ifthe cardiacoutput
increasesbuttheperipheralresistancestaysthesame.
There are often changes in both parameters. For instance, during
exercise, the peripheral resistance falls due to arteriolar dilatation and
increased blood flow toskeletal muscles but the cardiacoutput risesso much
that the blood pressure rises. Thisissuch a consistent response that it canbe
used as a measure ofleft ventricular function. If, during an exercise test, the
blood pressure fails to rise, this is taken as evidence of poor left ventricular
function and isapoor prognosticsign.
The status quo is maintained by a complex system of inter-related
feedback mechanisms known as homeostaticmechanisms.
3
ACEINHIBITORSINHYPERTENSION
These include the autonomic nervous system (with its two components,
the sympathetic and parasympathetic systems) and the renin-angiotensin
system. Both of these involve circulating and local, tissue-based humoral
agents.
Theautonomicnervoussystem
The behaviour ofthe cardiovascular system isregulated, to agreatextent, by
the competing or balancing effects of the sympathetic and parasympathetic
divisionsoftheautonomicnervoussystem.
Thesympatheticnervoussystem
Sympathetic activity is increased by exercise, by stress and by a fall in
systemic blood pressure, detected by baroreceptors in the carotid sinus and
aorticarchandtransmittedbythe nervesofthesympatheticnervoussystem.
These effects are mediated by catecholamines, such as noradrenaline,
whichare producedatsympatheticnerveendingsand intheadrenal medulla.
The production of catecholamines by the adrenal medulla is also
increasedbyhighlevelsofangiotensinII (p. 10).
The effects of increased sympathetic tone are complex. They can be
divided into a and Padrenergic effects, some of which are shown in Table
2.1.
Table2.1 Somea andPadrenergiceffects
a effects peffects
Vasoconstriction Vasodilatation
Intestinalmuscle Heart: increasedforce and
relaxation rate;arrhythmias
Pupillarydilatation Bronchialrelaxation
Noradrenaline +++ +
Adrenaline + +++
The a and Peffects can be further subdivided into at' a , PI and P effects
2 2
(Figures2.1 and2.2).
4
"'Cl~oCIl 5o0<
t
y
Effects vasoconstriction vasoconstriction+vasodilatation(byinhibitionofnor adrenalinerelease) myocardialcontractilit ratetheart bronchodilatation vasodilatation
_ _ - -
_ _ - -
_ _
_
_ s
s _ arl onchi eriole
ole he br art
rs eri
pto art 0
e 0
c ~
e 2
R P
p, pz
m
a
e
r
st
< <: < nalineblood
odamdrein em
-- --I --I/ Ainblostre.......A oussyst
- - - N < v
-- -- -- )a er
-- -- -- nd cn
--- --- --- gla heti
0 0 0 ) al at
n p
Ch Ch Ch dre ym
A A A A s
f
o
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ct
e
f
f
e
es) e p
ne n d
holierv nali an
cn e a
cord Acetylergic oradr 2.1
n N e
nal =oli = ur
Spi ACh(ch NA Fig
VI
ACEINHIBITORSINHYPERTENSION
~
Leftventricularoutput } t
and/or --~.~. BP --....,~~ sympathetic tone i
peripheral resistance~ t
~
effects a effects
~ i
Leftventricular .... ---- {contractilit¥
outputi heartrate T
\ i
arteriolartone
BPi .~... -------- peripheral resistance i
Figure2.2 Sympatheticcontrolofblood pressure
Sympathetic activity causes increases in myocardial contractility (strength
ofcontraction), heart rate and blood pressure and therefore in cardiac work.
It increases coronary perfusion bycausingdilatation ofthe coronaryarteries.
It therefore demands increased work at the same time as providing the
wherewithallfor ittobedone.
P-Blocking drugs interfere with these effects to varying degrees, reducing
heart rate, blood pressure and myocardial contractility. This explains their
tendency to precipitate or exacerbate heart failure in susceptible patients and
reduce peripheralperfusion.
Parasympatheticnervoussystem
Parasympathetic (vagal) tone is increased by a rise in blood pressure,
detected by baroreceptors in the carotid sinus and aortic arch, by depression
or lethargy and by fear or pain (vaso-vagal attack). It causes bradycardia by
slowing conduction at the S-A node and thus reduces cardiac output and
blood pressure (Figures2.3-2.5).
6