(Frohlich, Tarazi & Dustan , 1969; Lund-Johan sen , 1977). How successful is a
therap y whic h renders suc h a pat ient normotensive by making his cardiac output
abnorma lly low while leaving tot al peripheral resis ta nce ina ppropria tely high? Ju st
this situation ob tai ns duri ng chronic the rapy of hypert en sion wit h f}-ad renocep tor
antago nists (Lund -Jo hansen, 1979 ). What are the co nsequences of a chronica lly
subnorma l cardiac output which inev itabl y must be associated with hypo perfusion of
at least some tissue s (Trap-Je nse n, Clau sen & Noer, 1975; Bau er & Brooks, 1979 )?
Similar qu estion s must be as ked abo ut chronic ha emodynamic dysfunction s and
about other abnormalities, suc h as hyperreninaem ia, adrene rgic hyperactivit y,
hyperuricaem ia, hypokalaemia and disturban ces of ca rbohydrate or lipid
metabolism , caused by any anti hypertensive drug which 'successfull y' reduces blood
pr essure. Conver sely we must inquire int o po ssible beneficial results of chronic
therapy with some drugs th at ma y not be related solely to blo od pressure reduction,
such as a po ssible 'ca rdioprotective' effect of ß-adrenoceptor antagonists (Zanchetti,
1977). The an swers to th ese qu estion s will have an im porta nt impact on
th e indi vidu alization oftherap y.
extent this approach is feasible and is being used to good ad vantage by some
pract ition ers. Some pati ent character istics, suc h as age and pr essure levels , are
a lways at hand. U nfortuna te ly, clinical 'guess timates' of whic h pr esso r mechanism s
a re mainl y responsibl e for blood pr essure elevat ion in any give n patient a re
A qu antitati ve charac teriza tio n of hype rtensive mechanism s might theoret icall y
ma ke it possible to predict whic h drug or combi na tio n of drugs would lower the
bloo d pr essure of eac h pat ient most read ily, restore normal haem od ynamics, neural
and endocri ne function most effectively and be associat ed with th e fewest side effects
resulting from disturban ces in circulat ory homeostasis. On e wo uld choose a drug
which co rrects the disturbances resp on sible for a pat ien t' s hypertension and not one
whic h redu ces blood pressure by crea ti ng addi tiona l, th ou gh co untera cti ng,
abnorma lities . However , th is approach appea rs to be in confl ict with the size of the
hypert ensive population , since it is not feasible to qu antitat e th e pressor mechanism s
in million s of pati ents. Nor is such exact cha rac terizatio n necessary for the vas t
rnajority of mild hyperten sive pati ents who se blood pr essure is satisfactorily
controlIed by ad mi nistration of one or two appropriat ely chose n and logically
hype rtensive mechanism s remains to be established. On e pr edictable problem lies in
repeat edl y. The next th ree pap ers will examine pr agmatic a nd conceptual
approaches to antih yperten sive th erapy in the context of haemodynamics, of the
renin-an giot ensin- aldosterone system and ofadrenergic mech ani sm s.
Do sage schedules and pharmacokinetics
Wh en it co mes to establish ing th e optim al do se of an anti hypertensive drug, th e
app roac h inevi ta bly has to be pr agmatic. The best do sage schedule for a given patient
of any anti hyperte nsive agent ca n be and must be det ermined by titrat ing the do se
against that patient's blood pressure response and against undesirable side effects.
Failure on the part of physicians to accomplish this laborious chore is probably
responsible for more therapeutic failures than any other factor. If the dose is left
inappropriately low, the drug may be mistakenly considered ineffective. If it is
increased too rapidly or pushed too high the patient may be falsely considered
Because the pharmacodynamic determination ofmagnitude and duration ofaction
ofantihypertensive drugs is so eminently feasible, pharmacokinetic considerations or
studies are not needed for the overwhelming majority of patients. Since good c1inical
endpoints of drug action are intrinsicalIy superior to pharmacokinetic data,
determination of concentrations of antihypertensive drugs in blood or other body
fluids have little to offer as guides to drug dosage . Furthermore, the concentration of
many ofthese drugs in the blood correlates poorly, only briefly or not at alI with the
intensity of their pharmacological action (Israili, 1979). The reasons for this lack of
correlation include formation of active metabolites (hydralazine, methyldopa,
certain ß-adrenoceptor antagonists), retention at the site of action (reserpine,
guanethidine, some vasodilators), slow reversibility of drug-induced relaxation of
arterial smooth muscle (diazoxide), irreversible enzyme inhibition (monoamine
oxidase inhibitors), cumulation of effect (diuretics) and many others. After a single
dose ofmany antihypertensive drugs the half-time ofthe return ofblood pressure to
pretreatment levels greatly exceeds the plasma half-life of the drug. For some drugs
this discrepancy becomes even more prominent after repeated dosing. Thus, the
duration ofthe blood pressure lowering effect of a single dose of an antihypertensive
drug may be much shorter than that observed after each dose du ring chronic therapy.
It also has become c1ear that after blood pressure reduction with some drugs,
particularly if treatment has been prolonged, the reduced pressure greatly outlasts
any operativeness in the body of the original hypotensive drug effect, This is welI
illustrated by the observation that in some patients, weeks or months are required for
the blood pressure to return to pretreatment level s when alI antihypertensive drugs
are discontinued (Dustan, Page, Tarazi & Frohlich, 1968; Lutterodt, Natel &
regression during therapy of structural blood vessel abnormalities or 'resetting'
towards normal of control mechanisms. In any case , the time course of blood
pressure reduction in such patients cannot possible bear any relation to the
pharmacokinetic fate ofthe drug used in therapy.
With very few exceptions, pharmacokinetic studies are oflittle use and not needed
for the management ofhypertensive patients. Dosage schedules must be individualIy
adjusted in many patients, but the patient's therapeutic response is both the only
reliable and the simplest guide.
Bauer, J. H. & Brooks, C. S. (1979). The long-terrn effect of propranolol therapy on renal
function. Am. J. Med. , 66,405-410.
Doyle, A. E. (1980). Errors in the treatment ofhypertension. Drugs, 19, 181-189.
Dustan, H. P., Page, I. H., Tarazi, R. C. & Frohlich, E. D. (1968). Arterial pressure responses to
discontinuing antihypertensivedrugs. Circulation , 37, 370-379.
Frohlich, E. D., Tarazi, R. C. & Dustan, H. P. (1969). Re-examination ofthe hemodynamics of
hypertension. Am. J. med. Sei; 257,9-23.
Israili, Z. H. (1979). Correlation of pharmacologic effectswith plasma levelsofantihypertensive
drugs in man. Ann. Re v. Pharmae. Toxieol.. 19,25-52.
INDlVIDUALlZATION OF ANTIHYPERTENSIVE TREATMENT 255
Joint National Committee (1977). Report of the joint national committee on detection,
evaluation, and treatment ofhigh blood pressure. J. Am. med. Ass.. 237,255-261.
Koch-Weser, J. (1973). Correlation of pathophysiology and pharmacotherapy in primary
hyperten sion. Am. J. Cardiol., 32,499-510.
Koch-Weser, J. (1974). Vasodilator drugs in the treatment ofhypertension . Arch. Int. Med., 133,
Koch-Weser, J. (1979). Treatment of hypertension in the elderly. In Drugs and the Elderly, ed.
Crooks, J. & Stevenson, I. H., pp. 247-262 . London : Macmillan Press.
Lund-Johansen, P. (1977). Hemodynamic alterations in hypertension - spontaneous changes
and efTects of drug therapy. A review. Acta med. Scand. , 603, 1-14.
Lund-Johansen, P. (1979). Hemodynamic consequences of long-term beta-blocker therapy: A
5-year follow-up study ofatenolol. J. Cardiova sc. Pharmac., 1,487-496.
Lutterodt, A., Nattel , S. & McLeod, P. J. (1980). Durat ion of antihypertensive efTect ofa single
daily dose ofhydrochlorothiazide. Clin. Pharmac. Ther., 27,324-327.
Pickering, G. (1978). Hypertension in general practice. J. Roy. Soc. Med. , 71,885-889.
Simon, A. c., Safar, M. A., Levenson, J. A., Kheder, A. M. & Levy, B. I. (1979). Systolic
hypertension : Hemodynamic mechanisms and choice of antihypertensive treatment. Am.
Tarazi , R. c., Magrini, F. & Dustan , H. P. (1975). The role of aortic distensibi1ity in
·hypertension. In Recent Advances in Hyp ertension, ed. Milliez, P. & Safar, M., pp 133-142.
Trap-Jensen, J., Clausen, J. P. & Noer, I. (1975). Regional hemodynamic changes during
exercise in essential hypertension before and after prolonged beta-receptor blockade.
Scand. J. clin. lab. Invest., 35, 143-160.
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Cardioprotective Action of Beta-Blockers, ed. Gross, F., pp 28-37 . Bem: Hans Huber
DOES THE ASSAY OF CATECHOLAMINE
W. H. BIRKENHÄGER & P. W. DE LEEUW
Department of lnternal Medicine,
Zuiderziekenhuis, Rotterdam , The Netherlands
diversit y is onl y partly explained in terms of varying bio-availability and pharmocokinetics.
Over the years the concept has been fostered that the assessment of the
phys iolog ical-biochemical profile of the hypertensive subject ma y be helpful to
particular patient. When parameters ofsympathetic nervous acti vity are dealt with in
that respect it must be taken into account that a partial overlap exists with such
variables as age, haemodynamics and renin status. In the final analysis the merits of
catecholamine profiling should be appraised over and above the potential predictive
values of the other parameters . Th is has proved to be an impossible task, due to a
lack of firm data. However, the exercise was favoured by the fact that most series
consisted of middle-of-the-road essential hypertensive patients, age and ren in being
Assessment of adrenergic (re)activity in essential hypertension;
questions about the validity of measurements of catecholamines
intensity of cardiac and vascular sympathetic nerve traffic, An y attempt to equate
these variables is interfered with by indi vidual and interindividual variations in
re-uptake, clearance and breakdown rate s of neurotransmitters. Moreover a
reciprocal relationship between receptor sensitivity and circulating catecholamine
levels has been established , and this relationship appears modulated by such factors
CATECHOLAMINE LEVELS AND ANTIHYPERTENSIVE THERAPY 257
Despite these and other reservations, the possibility exists that the susceptibility of
hypertensive subjects to anti-adrenergic drugs may be reflected by the urinary
excretion or the circulating levels ofcatecholamines.
Since renin profiling, up to a point, has been presented as a 'poor man's' substitute
for assessing adrenergic activity (Esler & Nestei, 1973; Bühler, Burkart, Lütold,
Küng, Marbet & Pfisterer, 1975), some progress may be made in the preselection of
suitable patients with respect to ß-adrenergic receptor blockade. It is considered to
be outside the scope ofthis paper to discuss the methodological aspects ofthe various
Urinary andplasmacatecholamines v, responsiveness of bloodpressureto antiadrenergic drugs
One of the earliest studies in which this concept was actually tested, has been
reported by Fournier, Hardin, Alexandre, Lombaert, Ronco, Bezoe, Desmet &
Quichaud (1976). In th is series of18 essential hypertensives, the hypotensive response
to the ßt-adrenoceptor blocking drug, acebutolol, was significantly related to the
response ofurinary catecholamine excretion to tilting in the control period (r = 0.65 ;
P < 0.01). The other investigations to be considered here are based on measurements
of plasma catecholamine (mainly noradrenaline) levels . Blood sam pIes have been
obtained after a variable period of supine rest, in the upright posture and/or during
exercise testing. The studies dealing with catecholamines during recumbency will be
Sampies for noradrenaline measurement were taken after supine rest. Patients were
treated with propranolol at daily dose levels of 40 , 80 and 320 mg respe ctively.
~ ~ 0 +-----'--+-'U-L"----'-_ .s;: on
Plasma propranolol concenlralion (ng mt- I)
Figure 1 Fall in systolic blood pressure (%) expressed in relation to pretreatment plasma
noradrenaline concentration. The fall in pressure was greater in patients with
elevated noradrenaline plasma concentration at plasma propranolol levels of 3 to 30 ng mr'',
(From Eslereral., 1977; with permission).
258 W. H. BIR KEN HÄGER & P. W. DE LEEUW
Pla sma levels of propranolol (1-3 h after the drug was taken) were roughly related to
dosage , but the curves between subjects varied widely. Sensitivity to propranolol on
the basis of plasma concentration appeared to be biph asic, in that a subgroup of
seven pat ient s with elevated plasm a norad renaline conc entration (above 210 ng
litre-') exh ibited already a hypotensive response at low plasma propranolol levels
(3-30 ng mi-I). The main group of patients (with plasma nor adrenaline levels below
210 ng litre-I) obviousl y lacked this enh anced hypotensive effect, since they needed
plasma propranolollevels of 30 ng mi- I or abo ve. The subgroup of sensitive patients
(Figure l) showed additional features of adrenergic overactivity, such as a relati vely
high heart rate and cardiac output and an increased left ventric ular ejection rate . The
find ing that they had also high ren in levels, must be detracted from the pragmatic
value ofthis interesting observation.
Twenty-five subjects with uncomplicated hypertension were stud ied under
metabol ic ward conditions , including a controlled sodium inta ke between 50 and
60 mmol 24 h-I (Birkenhäger, de Leeuw, Kho, Wester, Vandongen & Falke, 1977).
Blood sampies for noradrenaline measurements were taken at 10.00 h, after overnight
recumbency and fasting, with the use of an indwelling needle inserted one hour
before sampling. Pat ient s were then treated in hospital with an average daily dose of
320 mg of propranolol for aperiod of 14 days. Blood pressure readings were taken
and compared at 10.00 h. As shown in Figure 2, a trend toward s a higher degree of
responsiveness in the subjects with higher noradrenaline levels was observed but the
relation was by no means signi ficant,
... • • • • ~~ • ... -c CD • • -10 • • c:: ... c :> CD CI> • • • E • c::D. • •
0 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80
Control plasma noradrenaline concentrat lon (no ml-1j
Figure2 Absence of relationship between responsiveness to propranolol (measured by the
change in mean arterial pressure) and control plasma noradrenaline concentration during
recumbency and sodium restrietion. (From Birkenhäger etal., 1977).
Muiesan , Agab iti-Rosei, Alicandri & Fariello (1978) studied the acute effects of
the a-and p-adrenergic receptor blocking drug labet alol (100 mg i.v.) in 14
hypertensive patients, They found a significant correlation between the degree of
blood pressure redu ction and pretreatment plasma catecholamine concentration.
Th e reduction in total peripheral vascular resistan ce was also significantly related to
controI catechola mine levels (r = 0.89). Th e authors conclu ded that the level of
sympathetic act ivity can predict the haemodynamic effect of labetalol, and they
probably intended to accentuate the a -adrene rgic receptor blocking component of
CATECHOLAMINE LEVELS AND ANTIHYPERTENSIVE THERAPY 259
Bühler, Burkart, Lütold, Bertel & Pfisterer (1977) published a preliminary study
comparing plasma noradrenaline, adrenaline and dopamine levels, both at rest and
during dynamic exercise in four 'responders' and four 'non-responders' to treatment
with propranolol. Plasma levels of noradrenaline at rest and particularly during
exercise were higher in the responders, but the numbers were too small for a
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