832 BRITISH MEDICAL JOURNAL VOLUME 286 12 MARCH 1983

Factors related to first dose hypotensive effect of captopril:

prediction and treatment
G P HODSMAN, C G ISLES, G D MURRAY, T P USHERWOOD, D J WEBB, J I S ROBERTSON

Abstract one in the past. Fifty six patients were receiving a beta-blocker, while
33 were also receiving a third, and 13 a fourth antihypertensive drug.
The blood pressure response to the first dose of captopril Eight were receiving bethanidine alone to facilitate certain investigative
(6 25 mg, 12 5 mg, or 25 mg) was measured in 65 treated, procedures.
severely hypertensive patients. Mean supine blood Antihypertensive treatment was stopped on the day of admission,
pressure was 187/108 mm Hg immediately before capto- when 21 patients underwent whole body neutron activation analysis
pril was given. Twenty one patients experienced a fall in for assessment of total body sodium.6 On the morning after admission
supine systolic pressure greater than 50 mm Hg, including an intravenous cannula was inserted so that corrective measures could
be started at once in the event of a dangerous fall in blood pressure;
five whose pressure fell more than 100 mm Hg and two the most severely hypotensive patients were given angiotensin II
whose pressure fell more than 150 mm Hg. Six patients (Hypertensin; Ciba) made up in 50 ,, dextrose to a concentration
developed symptoms of acute hypotension, including of 1 ,eg/l and administered by variable speed infusion pump.7
dizziness, stupor, dysphasia, and hemiparesis. Percentage Blood pressure was measured with a standard sphygmomanometer
reductions in blood pressure were greatest in those with after patients had lain supine for 45 minutes, and blood was drawn
secondary hypertension (p < 0-05), high pretreatment for measurement of serum sodium and creatinine concentrations (all
blood pressure (p < 0 05), and high concentrations of patients), plasma active renin concentration (normal range 10-50
plasma renin and angiotensin II (p < 0 01). No significant mU/1) (55 patients),8 and plasma angiotensin II concentration (normal
correlation was found between fall in blood pressure and range 5-35 pmol/l (5-35 pglml)) (34 patients).9 Captopril (Capoten;
serum sodium concentration, age, renal function, and Squibb) was then given by mouth in a dose of 6o25 mg (20 patients),
12 5 mg (21 patients), or 25 mg (24 patients) at the discretion of the
the dose of captopril given. investigator. All subjects remained supine for a further three hours,
A severe first dose effect cannot be consistently pre- during which blood pressure was measured at intervals of 10 minutes.
dicted in individual patients who have received other Statistical analyses of blood pressure were all based on the percent-
antihypertensive drugs for severe hypertension. Such age change in mean arterial pressure-that is, diastolic pressure plus
patients should have close medical supervision for at one third of the pulse pressure. All correlations quoted are Spearman's
least three hours after the first dose of captopril. rank correlations. The falls in blood pressure in the group with
essential hypertension and the group with secondary hypertension
were compared using Welch's modification of Student's t test, which
does not require the assumption of equal variances in the two groups.
Introduction As well as considering variables individually we used stepwise
regression analysis to assess the relations of several combinations of
When the angiotensin converting enzyme inhibitor captopril is variables to the percentage fall in blood pressure.
first given there is, within two hours, a fall in arterial pressure
that is proportional to the concurrent fall in the plasma concen-
tration of angiotensin II.' In some severely hypertensive
patients this initial fall in blood pressure is precipitous.2-5 The Results
incidence of this potentially dangerous event is unknown, and FIRST DOSE EFFECT
insufficient information is available to the clinician to aid in its
anticipation and, if necessary, treatment. Blood pressures immediately before the first dose of captopril
We report here a study of the hypotensive effect of the first ranged from 130,96 to 254/145 mm Hg (mean 187/108 mm Hg).
Mean plasma active renin concentration was significantly higher in
dose of captopril in 65 consecutive patients admitted for patients with secondary hypertension, but there were no significant
treatment of resistant hypertension. differences in the mean values before captopril of blood pressure or
serum sodium or creatinine concentration (table I).

Patients and methods TABLE i-Comparison of blood pressure and biochemical data before captopril in
Sixty five severely hypertensive patients, including 39 women, were patients with essential and secondary hypertension (values are means± SEM)
admitted to hospital for treatment with captopril. All had been
extensively investigated previously. No underlying cause for the Essential Secondary
hypertension was found in 36 patients. The remaining 29 had Supine blood pressure (mm Hg) 180/105 -5/2 195/112- 6,4
secondary hypertension: 20 had renal artery stenosis or occlusion and Serum sodium (mmol/1) 141 06 139 --09
Serum creatinine (gmol,ll) 183 30 206 -30
the remainder had other forms of renal disease. At the time of Plasma active renin (mU,1) 59 20 349 3 134*
admission 52 patients were receiving a diuretic, and all had received
p* 0-05.
Contversion: SI to traditional units-Sodium: 1 mmol/I 1 mEq/l. Creatinine:
1 ,mol/l 11-3 cug,1100 ml.

MRC Blood Pressure Unit, Western Infirmary, Glasgow Gll 6NT

G P HODSMAN, MB, MRCP, medical registrar The reduction in blood pressure in the whole group ranged from
C G ISLES, BSC, MRCP, senior medical registrar 12/0 to 174/82 mm Hg, the nadir occurring at a mean of 110 minutes
T P USHERWOOD, BSC, MRCP, medical registrar after the first dose of captopril (range 27-330 minutes). The average
D J WEBB, MB, MRCP, medical registrar fall in blood pressure was significantly greater in those with secondary
J I S ROBERTSON, FRCP, FRSE, consultant physician hypertension (52/29 mm Hg) than in those with essential hypertension
(33/18 mm Hg) (p < 0O05).
Department of Statistics, University of Glasgow Twenty one patients experienced a fall in supine systolic pressure
G D MURRAY, PHD, statistician greater than 50 mm Hg, including five whose pressure fell by more
Correspondence to: Dr G P Hodsman. than 100 mm Hg and two whose pressure fell by more than 150 mm Hg.
While supine six patients developed symptoms related to the acute
BRITISH MEDICAL JOURNAL VOLUME 286 12 MARCH 1983 833
TABLE II-Blood pressure and biochemical data in five patients who required urgent correction of hypotension by graded infusions of angiotensin II

Blood pressure (mm Hg) 0, Change in Plasma Serum Serum Dose of

Case Diagnosis mean arterial active renin sodium creatinine captopril
No Basal Nadir pressure (mU/1) (mmol/l) (,umol/l) (mg)
1 Renal artery occlusion 222/128 48/44 72 575 137 109 6 25
2 Renal artery stenosis 214/136 76/58 60 884 136 119 6-25
3 Essential hypertension 144/102 60/40 60 150 139 141 6-25
4 Renal artery stenosis 250/112 90/58 57 2756 122 87 25
5 Renal artery stenosis 186/120 110/50 51 2318 132 209 6-25

Conversion: SI to traditional units-Sodium: 1 mmol/l= 1 mEq/1. Creatinine: 1 ,umol/ 11-3 stg/100 ml.

hypotension, including dizziness, dysphasia, hemiparesis, drowsiness, 96 mm Hg. After 24 hours his neurological signs had resolved.
and stupor. One patient developed electrocardiographic changes of Cerebral dysfunction was possibly due to reduced perfusion pressure
acute myocardial ischaemia. Hypotension was corrected promptly by across stenosed carotid arteries, and treatment with captopril was
infusion of angiotensin II in five patients and more gradually by giving suspended pending further investigation.
0 9o/o saline in one (table II).

FACTORS CORRELATED WITH FIRST DOSE EFFECT

CASE REPORTS
Positive correlations (table III) were observed between the percent-
Case 1-The figure shows serial measurements of blood pressure in age fall in blood pressure after the first dose of captopril and pre-
this 67 year old woman with renal artery occlusion. A combination of treatment values of both plasma active renin and angiotensin II
atenolol and frusemide had failed to control blood pressure adequately. concentrations (p < 0 01). Patients with a higher basal pressure were
Immediately before captopril was given plasma active renin concen- likely to have a greater percentage fall in pressure (p < 0 05), as were
tration was 575 mU/l, serum sodium concentration 137 mmol/l, and those with secondary hypertension (p <0 05). There was a positive
serum creatinine concentration 136 ,.emol/l (154 mg/100 ml). Her
blood pressure started to fall shortly after an oral dose of 6-25 mg
captopril and reached a nadir of 48/44 mm Hg after 27 minutes. She TABLE III-Spearman rank correlations comparing various factors with percent-
became profoundly drowsy until blood pressure was restored by an age change in mean arterial pressure after first dose of captopril
infusion of angiotensin II9 (2 ng/kg/min), which was continued for a
further two hours. An infusion of 1 5 litre 090o saline was given over Patients with:
the next 24 hours, when a further 6 25 mg captopril was given. Blood All n
Essential Secondary patients
pressure fell on this occasion from 230/126 to 156/80 mm Hg at one hypertension hypertension
hour, but she developed no symptoms of hypotension. Blood Plasma renin 0 315 0 592** 0 466** 55
pressure six months later was only moderately well controlled at Plasma angiotensin II 0.563* 0 454 0 519** 34
200/90 mm Hg with a combination of captopril 100 mg, frusemide Basal blood pressure 0-170 0-322 0.253* 65
Serum sodium 0 097 -0-242 -0 060 65
160 mg, and metoprolol 50 mg daily. Total body sodium - 0 301 -0 055 -0 212 22
Case 6-This 55 year old man with essential hypertension had Age -0-015 0.396* 0 197 65
Serum creatinine 0 218 -0-107 0 083 65
previously been receiving bendrofluazide, timolol, and hydralazine, Diuretic dose -0-269 0 534** 0 121 65
but blood pressure had remained inadequately controlled. He had
intermittent claudication and bilateral carotid artery bruits, though he *p< 005; **p<0 01.
had had no previous symptoms of cerebral ischaemia. All treatment
was stopped on the day before captopril was given. Immediately before
an oral dose of 25 mg captopril supine blood pressure was 206/132 correlation between the percentage fall in blood pressure and the dose
mm Hg, plasma active renin concentration was 71 mU/l, serum of diuretic in those with secondary hypertension (p < 0 01) but not in
sodium concentration was 140 mmol(mEq)/l, and serum creatinine those with essential hypertension. There were negative correlations
concentration was 100 ,4mol/l (1-13 mg/100 ml). On administration of between the percentage fall in blood pressure and both serum sodium
captopril blood pressure fell progressively and reached a nadir of concentration and total body sodium, but these were not significant.
130/88 mm Hg after 120 minutes. He then became dysphasic with Age and renal function did not appear to influence the fall in pressure,
loss of power in his left arm. An infusion of 1 litre 090° saline was which was also independent of the dose of captopril given.
given over 120 minutes when blood pressure had returned to 186/ Correlations between some physiologically related variables were
also examined. There was a significant negative correlation of serum
sodium concentration with plasma renin concentration (r = - 0447,
Captopril Angiotensrn II infusion p < 0 001) but not with plasma angiotensin II (r =-0 - 247), total body
625mg 0-5 1 2 ng/kg/min
sodium (r=0 184), serum creatinine concentration (r=0 081), or the
4" dose of diuretic given as previous treatment. Plasma renin concen-
240- tration correlated significantly with plasma angiotensin II concen-
tration (r = 0 79, p < 0 01) but not with total body sodium (r = 0 052)
or serum creatinine concentration (r = 0 248).
oi, 200-
I Testing different combinations of measurements against the
E percentage fall in blood pressure did not show any increase in the
E 160. ability of individual measurements to predict the fall.
a
u 120-
Discussion
8 801 When captopril is first given an acute and highly variable fall
in blood pressure occurs which may be very different from the
401 ultimate reduction in blood pressure achieved with long term
administration.' The magnitude of the acute fall is closely
related both to the initial plasma concentrations of renin and
6 io 40 60 80 100 120 40 160 180 angiotensin II and to the concomitant reduction of circulating
Time (minutes) angiotensin II concentrations.'0 -2 Patients with renovascular
Blood pressure in a 67 year old woman (case 1) after oral c:aptopril 6-25 mg. hypertension often sustain greater acute falls in blood pressure,
Profound hypotension was immediately corrected by gr aded infusion of associated with a greater increase in plasma renin concentration,
angiotensin II. than patients with essential hypertension." '4 Removal of the
834 BRITISH MEDICAL JOURNAL VOLUME 286 12 MARCH 1983

direct vasoconstrictor effect of angiotensin II is probably a tive days to prevent excessive reduction in blood pressure after
major, if not necessarily the sole,' 15 factor in the reduction of each daily dose of captopril.
blood pressure in the first few hours after inhibition of con- In this study the use of lower doses of captopril (6-25 mg)
verting enzyme. conferred no protective effect. Smaller incremental dosage
A significant negative correlation between serum sodium and increases in the range 1-5 mg should, however, be explored in
plasma renin concentrations has previously been shown in more detail as an approach to avoiding sudden, virtually complete
treated and untreated hypertensive patients and in cardiac suppression of generation of angiotensin II with its attendant
failure.'6 -18 Our results thus confirm the generally agreed fall in blood pressure. A severe first dose effect cannot be
relations between sodium, renin, and angiotensin II, although consistently predicted in individual patients who have received
these may be modified by the effects of previous hypotensive other antihypertensive drugs for severe hypertension. Such
treatment. Interestingly, however, in this series serum sodium patients should have close medical supervision for at least
concentration was not significantly correlated with the fall in three hours after the first dose of captopril.
blood pressure after captopril. The preceding dose of diuretic
was significantly related to the fall in blood pressure in patients
with secondary hypertension but not in those with essential References
hypertension. Greater falls in blood pressure occurred in those
patients with secondary hypertension and, as is the case with Atkinson AB, Brown JJ, Cumming AMM, et al. Captopril in renovascular
most hypotensive drugs, in those in whom initial pressures were hypertension: long-term use in predicting surgical outcome. Br Med J
1982 ;284 :689-93.
highest. Renal function was not correlated with the fall in blood 2 Case DB, Atlas SA, Laragh JH, Sealey JE, Sullivan PA, McKinstry DN.
pressure. Clinical experience with blockade of the renin-angiotensin-aldosterone
We consider that the effect of the first dose carries a consider- system by an oral converting enzyme inhibitor (SQ 14225, captopril) in
able risk in severely hypertensive patients, who are particularly hypertensive patients. Prog Cardiovasc Dis 1978;21:195-206.
3 McGrath BP, Matthews PG, Johnston CI. Acute changes in blood
vulnerable to sudden reductions in cerebral perfusion pressure, pressure and vasoactive hormones after captopril in hypertensive
with the dangers of boundary zone cerebral infarction.19 20 In patients. Clin Exp Pharmacol Physiol 1980;7:487-91.
this study 8% of patients sustained an acute reduction of mean 4 Atkinson AB, Robertson JIS. Benefits versus risks of captopril therapy.
arterial pressure in excess of 500o within two hours of receiving In: Brunner HR, Gross F, eds. Recent advances in hypertension therapy:
captopril. Amsterdam, Oxford, Princeton: Excerpta Medica, 1981:
captopril. Sudden suppression of the formation of angiotensin II 50-63.
is probably the most important factor, though other processes 5 Raine AEG, Ledingham JGG. Clinical experience with captopril in the
may also play a part. Possibly, in addition to arterial dilatation, treatment of severe drug-resistant hypertension. Am J Cardiol 1982;
venodilation and a fall in right atrial pressure may contribute to 49:1475-9.
6 Williams ED, Boddy K, Harvey I, Haywood JK. Calibration and evaluation
sudden circulatory collapse in patients with pre-existing volume of a system for total body in vivo activation analysis using 14 MeV
depletion and poor cardiac reserve. neutrons. Phys Med Biol 1978;23:405-15.
Unfortunately, our analysis shows that a severe first dose 7 Atkinson AB, Brown JJ, Fraser R, et al. Antagonists and inhibitors of the
effect cannot be predicted consistently in individual patients. renin-angiotensin-aldosterone system in the treatment of hypertension.
In: Robertson JIS, Pickering GW, eds. The therapeutics of hypertension.
Nevertheless, the present findings suggest that caution should be London: Royal Society of Medicine, 1980:29-61. (International
observed particularly in patients with secondary hypertension, Congress and Symposium Series No 26.)
especially if they are already taking diuretics; patients with very 8 Millar JA, Leckie BJ, Morton JJ, Jordan J, Tree M. A microassay for
high blood pressure; and patients with low or low normal serum active and total renin concentration in human plasma based on antibody
sodium concentratioDns. If the pretreatment plasma renin or trapping. Clin Chim Acta 1980;101:5-15.
9 Dusterdieck G, McElwee G. Estimation of angiotensin II concentration
angi Atensin II concentration is known greater precision of in human plasma: some applications to physiological and clinical states.
prediction is possible, with a high concentration indicating high EurJ Clin Invest 1971;2:32-5.
10 Laragh JH, Case DB, Atlas
risk. SA, Sealey JE. Captopril compared with other
antirenin system agents in hypertensive patients: its triphasic effects on
As no single test or combination of tests in this study identified blood pressure and its use to identify and treat the renin factor.
all patients at risk our policy is for every patient to receive close Hypertension 1980;2:586-93.
medical supervision for at least three hours after the first dose of " Morton JJ, Tree M, Casals-Stenzel J. The effect of captopril on blood
captopril; during this time the patient remains supine and blood pressure and angiotensins I, II and III in sodium depleted dogs:
problems associated with the measurement of angiotensin II after
pressure is checked at 10 minute intervals. inhihition of converting enzyme. Clin Sci 1980;58:445-50.
In the event of a profound fall in blood pressure we consider 12 Atkinson AB, Morton JJ, Brown JJ, et al. Captopril in clinical hyper-
that the most appropriate and effective treatment is to restore tension: changes in components of the renin-angiotensin system and in
immediately the substance whose loss led to the reduction in body composition in relation to fall in blood pressure with a note on
measurement of angiotensin II during converting enzyme inhibition.
pressure. Thus we have found that graded infusion of angiotensin Br Hearty 1980;44:290-6.
II (starting dose 0 5 ng/kg/min, range 0 5-8 ng/kg/min) is fully 13 Imai Y, Abe K, Otsuka Y, et al. Exaggerated response of renin secretion to
effective in immediately restoring and maintaining blood captopril (SQ 14225) in renovascular hypertension. J3pn Heart J 1980;
pressure. Care must be taken not to give an excessive dose and 6:793-802.
14 McGrath BP, Matthews PG, Johnston CI. Use of captopril in the diagnosis
so raise blood pressure too far. By comparison, rapid infusion of of renal hypertension. Aust NZJ Med 1981 ;11 :359-63.
0 9%, saline is a less effective and less prompt method of restoring 15 Tree M, Morton JJ. Evidence that the acute hypotensive effect of captopril
blood pressure; moreover, it might prove dangerous in some in dogs is not wholly explained by a reduction of plasma angiotensin II
patients with impaired cardiac function. and its direct vasoconstrictor effect. Clin Sci 1980;59:451-6.
16 Brown JJ, Davies DL, Lever AF, Robertson JIS. Plasma renin concen-
Controlled volume repletion with saline before administration tration in human hypertension. Relationship between renin, sodium and
of captopril should in theory reduce the risk of profound potassium. Br Med J 1965;ii:144-8.
hypotension, as it will also reduce plasma renin and angiotensin 17 Brown JJ, Davies DL, Johnson NW, Lever AF, Robertson JIS. Renin
II concentrations. It is, however, impractical to give an infusion relationships in congestive heart failure, treated and untreated. Am
to all patients to whom captopril is to be given, and patients at Hearty 1970;80:329-42.
18 Levine TB, Franciosa JA, Urobel T, Cohn JN. Hyponatraemia as a marker
special risk cannot be consistently identified. Stopping diuretic for high renin heart failure. Br Heart3 1982;47:161-6.
treatment before captopril is given may also reduce the risk of 19 Graham DI, Jones JV. Hypertension and the cerebral circulation with
hypotension, but care should be observed in some patients with special reference to the pathophysiology of central nervous system
very high blood pressure or borderline cardiac function. complications of treatment. In: Robertson JIS, Pickering GW, eds.
The therapeutics of hypertension. London: Royal Society of Medicine,
After a profound fall in blood pressure has been corrected 1980:105-13. (International Congress and Symposium Series No 26.)
with an infusion of angiotensin II our usual policy is to give at 20 Hodsman GP, Robertson JIS, Semple PF, Mackay A. Malignant hyper-
least 1 litre 0 9% saline over 24 hours before repeating the test tension and oral contraceptives: four cases, with two due to the 30 ,ug
dose of captopril. By infusing saline slowly we have not provoked oestrogen pill. Eur HeartJ 1982;3:255-9.
cardiac failure. One patient required 4 1 saline over four consecu- (Accepted 30 December 1982)