Br.J. Anaesth.

(1976), 48, 1175

THE INFLUENCE OF THREE ANTACIDS ON THE ABSORPTION AND

CLINICAL ACTION OF ORAL DIAZEPAM
S. G. NAIR, J. A. S. GAMBLE, J. W. DUNDEE AND P. J. HOWARD

SUMMARY

Diazepam 10 mg given orally alone or with one of the three antacids (aluminium hydroxide 40 ml,
magnesium trisilicate 30 ml, sodium citrate 30 ml) was given in a single dose at random to 200
women undergoing minor gynaecological procedures. The concomitant use of aluminium hydroxide
or sodium citrate hastened the onset of the soporific effect of diazepam marginally, while magnesium
trisilicate tended to delay it. The estimation of plasma diazepam concentrations over 90 min in a
similar series of 67 patients showed that the absorption of diazepam was increased significantly by
the use of aluminium hydroxide, but there were no striking differences in the four groups. The
clinical implications of these findings are discussed.

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The case for oral premedication has been reinforced
considerably since the introduction of the benzo-
diazepines. The low water- and high lipid-solubility
characteristics of the majority of these compounds
result in good absorption when given by mouth. Thus,
Gamble, Dundee and Assaf (1975) showed that oral
diazepam was absorbed better than diazepam ad-
ministered by i.m. injection. This finding was con-
firmed by studies of the plasma concentrations of
diazepam.
Further studies in this department have been con-
cerned with those factors which influence diazepam
uptake (Gamble et al., 1976), such as the use of
atropine and opiates which delay absorption and
aluminium hydroxide which enhances it (Gamble,
1975). This paper presents a study in which diazepam
was given either alone or with three antacids and
reports on the clinical effects and plasma concentra-
tions of diazepam which resulted. Such studies are
important in view of the fact that antacids influence
the gastrointestinal uptake of a number of drugs
(Harvey, 1975).
METHODS
Sedation study. This was carried out in four groups
each of 50 women of reproductive years, weighing
40-89 kg and scheduled for minor gynaecological
operations in the morning. The patients fasted over-
night and received diazepam 10 mg by mouth alone
or with one of the three antacids as premedication in
random fashion. Those known to be taking hypnotics
S. G. NAIR, M.B., M.S., F.F.A.R.C.S., D.A.; J. A. S. GAMBLE,
M.D., F.F.A.R.C.S.; J. W . DUNDEE, M.D., PH.D., F.F.A.R.C.S.,
M.R.C.P.; P. J. HOWARD, A.I.S.T.; Department of Anaes-
thetics, The Queen's University of Belfast, Northern Ireland.
or tranquillizers were excluded, except where medi-
cation had been discontinued for at least 4 weeks.
The premedication consisted of commercially
available diazepam 10 mg tablets (Valium, Roche)
given alone or with one of the following antacids in a
single dose: mist, magnesium trisilicate BPC 30 ml
(10 ml contains magnesium trisilicate 0.5 g, mag-
nesium carbonate 0.5 g and sodium carbonate 0.5 g);
aluminium hydroxide gel BP 40 ml (contains approxi-
mately 4% w/w aluminium oxide); sodium citrate
0.3 mol/litre solution 30 ml (made up in 10% syrup
and chloroform water, as described by Lahiri,
Thomas and Hodgson, 1973).
The doses employed were larger than those used
commonly, and the volumes of antacids were un-
equal. The larger volume of aluminium hydroxide
was given to compensate for its reported ineflicacy as
an antacid in vivo (Morrissey and Barreras, 1974;
Harvey, 1975). The patients were observed at 20, 40,
60 and 90 min after the drug administration or once
only between 60 and 90 min. On these occasions the
degree of drowsiness, apprehension, restlessness or
excitement and the incidence of dizziness, emetic
effects, tachycardia and arterial hypotension were
noted as described by Dundee, Moore and Nicholl
(1962a). On the basis of these observations, an
efficacy score ranging from 5 (excellent sedation) to 1
(patient very upset, with no sedation) was allocated
each time the patient was seen.
The patients were anaesthetized using a standard
technique of 2% methohexitone (initial dose 1.6 mg/
kg) with 75% nitrous oxide in oxygen (total flow
8 litre/min) with additional small increments of the
barbiturate as required. Induction complications were
noted and recorded as described by Dundee, Moore
and Nicholl (1962b).
1176 BRITISH JOURNAL OF ANAESTHESIA

The patients were seen again 1 and 6 h after TABLE I. Details of patients in the four series receiving
operation and the occurrence of vomiting (including diazepam 10 mg by mouth, alone or with an antacid
retching) or nausea were noted. Where both nausea Average Average
and vomiting occurred this was classified as vomiting. Diazepam No. of age weight
Plasma concentration. This was measured con- 10 mg with patients (yr) (kg)
currently with the sedation studies on similar patients
50 29 57
who had consented to venous cannulation. Patients Aluminium hydroxide
in whom diazepam or its metabolite were present in gel (BP) 40 ml 50 33 60
the blood sample before the drug administration Mist, magnesium
were excluded. In all, 67 patients who were similar trisilicate (BPC) 30 ml 50 34 61
with respect to age and weight were studied. 0.3 mol/litre sodium
citrate 30 ml 50 29 58
The blood sampling technique was identical to that
described by Gamble and others (1975). A 10-ml
sample was obtained before drug administration Patient acceptability was satisfactory for all three
(control sample) and subsequently at 15, 30, 45, 60 antacids, although aluminium hydroxide gel appeared
and 90 min. These were transferred to heparinized to be the least palatable. A few patients thought that

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tubes and centrifuged, as soon as possible, at 3000
rev/min for 15 min, those samples awaiting centri-
fugation being stored in a refrigerator. The superna-
tant plasma was transferred into 5-ml polystyrene
containers and stored at 20 C until analysed. Parti-
cular care was exercised to avoid haemolysis and con-
tamination with heparinized saline during sampling.
After benzene extraction, plasma diazepam was
estimated by gas-liquid chromatography using an
electron capture detector with griseofulvin as the
internal standard, as described by Gamble and others
(1975). Duplicate analyses were carried out on each
sample. Plasma diazepam concentrations were ex-
pressed in ng/ml.
RESULTS
Table I shows that the patients in each of the four
sedation studies were broadly comparable with regard
to average age and weight.
the preparation of sodium citrate used in this study
was too sweet.
The incidence of drowsiness and apprehension in
the various series is displayed in table II. In general,
the concomitant use of either aluminium hydroxide
or sodium citrate enhanced the early soporific effect
of diazepam, but the difference (when "good" and
"fair" degrees of drowsiness are considered together)
was only significant with aluminium hydroxide at
20 min (x2 = 6.184; P<0.025) and with sodium
citrate at 90 min (x2 = 3.858; P<0.05). In contrast,
magnesium trisilicate tended to decrease the efficacy
of diazepam and at 60 min the incidence of notable
drowsiness with diazepam-magnesium trisilicate was
significantly less than with diazepam alone (x2 =
5.876; P< 0.025).
In general, the anxiolytic action of diazepam
paralleled its soporific effect in all series, particularly
when given with antacids.

TABLE I I . Percentage frequency of drowsiness and apprehension noted at fixed times following diazepam
10 mg given by mouth or with three antacids

Preanaesthetic medicationdiazepam 10 mg with:

Aluminium
hydroxide Mist, magnesium Sodium citrate
gel 40 ml trisilicate 30 ml 0.3 mol/litre 30 ml
Min: 20 40 60 90 20 40 60 90 20 40 60 90 20 40 60 90

Drowsiness
good 4 20 46 40 8 44 64 60 8 24 40 36 8 32 48 64
fair 8 26 24 30 32 20 16 28 20 8 4 20 12 16 24 24
slight 28 36 18 10 28 16 16 8 16 36 28 28 28 20 16 8

Apprehension
slight 36 22 4 10 36 16 8 12 24 16 8 0 44 32 32 4
moderate 18 6 6 6 4 4 0 0 0 0 0 0 8 4 0 0
ANTACIDS AND ORAL DIAZEPAM 1177
TABLE I I I . Significance of difference of the frequency of notable (good and fair) drowsiness in
patients receiving diazepam 10 mg by mouth with three antacids. In all cases the series with
the greater drowsiness appears first

Minutes after drug administration

Series compared 20 40 60 90

Aluminium hydroxide gel v. X2 9.014 12.267 11.161

mist, magnesium trisilicate P < 0.005 < 0.0005 < 0.001
Aluminium hydroxide gel v. X 2
3.8571
sodium citrate p <0.05
Sodium citrate v. X2 6.9376 11.1608
mist, magnesium trisilicate p <0.01 < 0.001

TABLE IV. Average ( + SEM) plasma diazepam concentrations (ng/ml) following diazepam 10 mg given by mouth alone or with
three antacids as shown

Average Min

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No. of wt
Diazepam 10 mg with patients (kg) 15 30 45 60 90

17 59.0 + 3.34 6522 12218 19924 19423

Aluminium hydroxide gel (BP) 40 ml 20 59.21.67 6924 177 + 24 19920 18814 17212
Sodium citrate 0.3 mol/litre 30 ml 15 59.9 2.01 45 16 107 27 154 25 181 22 172 15
Mist, magnesium trisilicate (BPC) 30 ml 15 57.0 1.94 66 20 101 25 122 14 153 19 156 17
no sample analysed.

AVERAGE PLASMA DIAZEPAM

AVERAGE EFFICACY SCORE DIAZEPAM 10 mg ORAL WITH: CONCENTRATION (ng ml)

A L U M I N I U M HYDROXIDE
* * MAGNESIUM mSIUCATE
Q OSOOIUM CITRATE

FIG. 1. Average efficacy scores and plasma concentrations before operation in two comparable groups
of patients over 90 min after the administration of diazepam 10 mg alone or with three antacids.
1178 BRITISH JOURNAL OF ANAESTHESIA
2.3 -i

22
i
7-

<. 2.1
r-
z

a
< 1.9

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Z

1.7 -

MEAN EFFICACY SCORE

FIG. 2. Correlation between log mean plasma diazepam concentrations and the mean efficacy
scores before operation (plotted on a log scale) in comparable groups of patients over 60 min after the
administration of diazepam 10 mg alone or with the three antacids as shown: diazepam 10 mg (X)
with: aluminium hydroxide ; magnesium trisilicate A; sodium citrate D.

Table III summarizes the comparable significance
values when diazepam was given with the various
antacids. This table is based on the incidence of
"good" and "fair" drowsiness and probability values
greater than the accepted 5% are not included. It
can be seen that sedation was best when aluminium
hydroxide was used.
Before operation there were no toxic effects attri-
butable to diazepam or its combination with antacids.
Figure 1 is a comparison of the time-course of the
sedative effect (as indicated by the mean efficacy
score) of diazepam 10 mg and the mean plasma con-
centrations in comparable groups of patients. It can
be seen that these follow a similar pattern for the first
hour, but sedation does not decrease with the decrease
in plasma concentrations.
DISCUSSION

The four series were comparable as regards the
average duration of anaesthesia and the incidence of
excitatory phenomena, and respiratory upset during
induction was similar in each, as was the frequency
of emetic sequelae after operation.
Table IV shows the average plasma diazepam
concentrations following diazepam 10 mg alone or
with the three antacids. There were no striking
differences in the four series, except that the con-
comitant use of aluminium hydroxide resulted in a
significantly higher concentration at 30 min (t -
2.033; d.f. = 3 5 ; P<0.05), suggesting earlier
absorption.
It would have been helpful to attempt to correlate the
degree of sedation with the plasma concentrations in
individual patients. However, this was not possible
since blood sampling interferes with the clinical
assessment of sedation. A plot of mean efficacy scores
against mean plasma concentrations in similar groups
of patients gives a sigmoid curve, since there is a
minimum plasma diazepam concentration below
which there would be no drug-induced soporific
effect and once diazepam has induced sleep there is
no increase in the efficacy score with increasing
plasma concentrations. This is overcome in figure 2
by the use of logarithms. The plasma concentration-
ANTACIDS AND ORAL DIAZEPAM
response relationship of all series is parallel except for
the 60-min reading with aluminium hydroxide, and
this is explained by the earlier onset of action and the
more rapid increase in plasma concentration when
this antacid is used.
The main site of absorption of most drugs is
thought to be the upper small intestine (Smith and
Rawlins, 1973). However, the stomach is a potentially
important absorption site when the pH is favourable
(Travell, 1940; Hogben et al., 1957). Thus several
factors could account for the altered absorption of
diazepam when combined with antacids, including
changes in the rate of gastric emptying and changes
in gastric pH.
One would have expected that any antacid which
increases the gastric pH to near that of the pKa of
diazepam (3.3) would enhance absorption of the drug
from the stomach. It is possible that this was achieved
to a greater extent by aluminium hydroxide than any
of the other antacids used in this study.
The use of antacids before operation has increased
greatly in recent years, particularly in obstetrics
(Crawford, 1971; Peskett, 1973). The sequelae of
aspiration of gastric contents are lessened by reducing
gastric acidity. Magnesium trisilicate is probably the
most popular antacid for this purpose, being recom-
mended by Taylor and Pryse-Davies (1966) and
Crawford (1970). However, apart from being pala-
table there seems little else to recommend it (Harvey,
1975). It is not a very effective antacid (Kirsner,
1941; Armstrong and Martin, 1953; Lahiri, Thomas
and Hodgson, 1973; Morrissey and Barreras, 1974)
and has a potential toxicity (Joekes, Rose and Sutor,
1973) which appears to have been forgotten. Our
studies would not support its superiority over alu-
minium hydroxide or sodium citrate but the present
findings apply only to a single dose; the situation may
be different with repeated administrations.
The clinical significance of the findings of this
study may lie as much in increasing the safety of an
oral premedicant as in enhancing its action. Irres-
pective of whether or not an antacid increases the
uptake of an oral premedicant, its use before operation
can be recommended. If it does both, as in the case of
aluminium hydroxide and diazepam, its use should
be encouraged.
ACKNOWLEDGEMENTS
We thank the gynaecological staff at Musgrave Park and
Belfast City Hospitals for their co-operation and Mrs
Margaret Kennedy and Dr J. K. Lilburn for assistance.
Technical help was made available through grants from the
1179
Northern Ireland Eastern Health and Social Services Board
and Roche Products Ltd.
REFERENCES
Armstrong, J., and Martin, M. (1953). An in vitro evalua-
tion of commonly used antacids with special reference to
aluminium hydroxide gel and dried aluminium hydroxide
gel. J. Pharm. Pharmacol., 5, 672.
Crawford, J. S. (1970). The anaesthetist's contribution to
maternal mortality. Br. J. Anaesth., 42, 70.
(1971). Anaesthesia for obstetric emergencies. Br. J.
Anaesth., 43, 864.
Dundee, J. W., Moore, J., and Nicholl, R. M. (1962a).
Studies of drugs given before anaesthesia. I: A method
of preoperative assessment. Br. J. Anaesth., 34, 458.
Dundee, J. W., Moore, J., and Nicholl, R. M. (1962b).
Studies of drugs given before anaesthesia. II: A method
for assessing their influence on the course of anaesthesia.
Downloaded from http://bja.oxfordjournals.org/ by guest on November 4, 2016
Br. J. Anaesth., 34, 523.
Gamble, J. A. S. (1975). Some factors influencing the
absorption of diazepam. Proc. R. Soc. Med., 68, 22.
Assaf, R. A. E., Mackay, J. S., Kennedy, M. S., and
Howard, P. J. (1975). Estimation of plasma diazepam:
critique of a method using gas-liquid chromatography
and benzene extraction. Anaesthesia, 30, 159.
Dundee, J. W., and Assaf, R. A. E. (1975). Plasma
diazepam levels after single dose oral and intramuscular
administration. Anaesthesia, 30, 164.
Gaston, J. H., Nair, S. G., and Dundee, J. W. (1976).
Some pharmacological factors influencing the absorption
of diazepam following oral administration. Br.J. Anaesth.,
48, 1181.
Harvey, S. C. (1975). Gastric antacids and digestants; in
The Pharmacological Basis of Therapeutics (eds L. S.
Goodman and A. Gilman), 5th edn, Ch. 3, p. 960. New
York: Macmillan.
Hogben, A., Schanker, L. S., Tocco, D. J., and Brodie,
B. B. (1957). Absorption of drugs from the stomach.
II: The human. J. Pharmacol. Exp. Ther., 120, 540.
Joekes, A. M., Rose, G. A., and Sutor, J. (1973). Multiple
renal silica calculi. Br. Med. J., 1, 146.
Kirsner, J. B. (1941). A further study of the effect of various
antacids on the hydrogen ion concentration of the gastric
contents. Am. J. Dig. Dis., 8, 53.
Lahiri, S. K., Thomas, T. A., and Hodgson, R. M. H.
(1973). Single-dose antacid therapy for the prevention of
Mendelson's syndrome. Br. J. Anaesth., 45, 1143.
Morrissey, J. F., and Barreras, R. F. (1974). Drug therapy:
antacid therapy. N. Engl.J. Med., 290, 550.
Peskett, W. G. H. (1973). Antacids before obstetric anaes-
thesia. A clinical evaluation of the effectiveness of mist,
magnesium trisilicate BPC. Anaesthesia, 28, 509.
Smith, S. E., and Rawlins, M. D. (1973). Variability in
Human Drug Response, p. 25. London: Butterworth.
Taylor, G., and Pryse-Davies, J. (1966). The prophylactic
use of antacids in the prevention of the acid-pulmonary
aspiration syndrome (Mendelson's syndrome). Lancet, 1,
288.
Travell, J. (1940). The influence of the hydrogen ion
concentration on the absorption of alkaloids from the
stomach. J. Pharmacol. Exp. Ther., 69, 21.
1180
INFLUENCE DE TROIS ANTI-ACIDES SUR
L'ABSORPTION ET L'ACTION CLINIQUE DU
DIAZEPAM ADMINISTRE PAR VOIE ORALE
RESUME
Dix mg de diazepam administres par voie orale seul ou
avec l'un des trois anti-acides: hydrate d'aluminium 40 ml,
trisilicate de magnesie 30 ml, citrate de soude 30 ml, ont
ete donnes au hasard, en une seule dose a 200 femmes
subissant des interventions gynecologiques mineures.
L'usage concomitant de Phydrate d'aluminium ou du
citrate de soude a active marginalement le commencement
de Peffet soporifique du diazepam, alors que le trisilicate de
magnesie a plutdt eu tendence a le retarder. L'estimation
des concentrations de diazepam dans le plasma sur 90 min
dans une serie similaire de 67 patientes montre que Pabsorp-
tion de diazepam a ete augmentee d'une maniere significa-
tive par l'emploi d'hydrate d'aluminium, mais il n'y a eu
aucune difference frappante dans les quatre groupes. On
expose dans cette communication les implications cliniques
de ces constatations.
DER EINFLUSS VON DREI ANTACIDAE AUF
ABSORPTION UND KLINISCHE WIRKUNG VON
ORAL VERABREICHTEM DIAZEPAM
ZUSAMMENFASSUNG
Oral verabreichtes Diazepam (10 mg)allein oder mit
einem der drei Antacidae (40 ml Aluminiumhydroxyd,
30 ml Magnesiumtrisilikat, Natriumzitrat 30 ml)wurde
als Einzeldosis wahllos an 200 Frauen gegeben, die kleineren
gynakologischen Operationen unterzogen wurden. Die
BRITISH JOURNAL OF ANAESTHESIA
gleichzeitige Verwendung von Aluminiumhydroxyd oder
Natriumzitrat beschleunigte das Eintreten der lindernden
Wirkung von Diazepam ein wenig, wahrend es durch
Magnesiumtrisilikat eher verzogert wurde. Schatzungen
der Plasma-Diazepamkonzentrationen innerhalb von 90
Minuten bei einer ahnlichen Serie mit 67 Patientinnen
zeigte, dass die Diazepam-Absorption durch die Verwen-
dung von Aluminiumhydroxyd wesentlich erh6ht wurde,
doch gab es in den vier Gruppen keine auffallenden
Unterschiede. Die klinische Bedeutung dieser Ergebnisse
wird diskutiert.
LA INFLUENCIA DE TRES ANTACIDOS SOBRE
LA ABSORCION Y ACCION CLINICA DE
DIAZEPAM POR VIA ORAL
SUMARIO
Diazepam 10 mg en administration oral, solo o con uno
de los tres antacidos (hidr6xido de aluminio 40 ml,
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trisilicato magnesico 30 ml, citrato sodico 30 ml), fue dado
en dosis unica aleatoria a 200 mujeres sometidas a inter-
venciones menores ginecoldgicas. El empleo concomitante
de hidr6xido de aluminio o de citrato sodico acelero
marginalmente el comienzo del efecto soporifico del
diazepam, mientras que el trisilicato magnesico tendio a
demorarlo. El calculo de concentraciones plasmaticas de
diazepam en 90 min durante una serie similar de 67
pacientes mostr6 que la absorcion de diazepam fue
aumentada significativamente por el empleo de hidroxido
de aluminio, pero no habia diferencias notables en los
cuatro grupos. Se comentan las implicaciones clinicas de
estos hallazgos.