Bambuterol Hydrochloride
A white or almost white crystalline powder. It exhibits poly-
morphism. Freely soluble in water; soluble in alcohol.
Adverse Effects, Precautions and Interactions as for Salbutamol Sulphate :
Adverse Effects
It is a beta-2 receptor stimulant.
Salbutamol may cause fine tremor of skeletal mus-
cle (particularly the hands), palpitations, and muscle
cramps. Tachycardia, tenseness, headaches, and
peripheral vasodilatation have been reported after
large doses, as has potentially serious hypokalae-
mia. Hypersensitivity reactions have occurred, in-
cluding paradoxical bronchospasm. angioedema.
urticaria. hypotension, and collapse.
The high doses of salbutamol used intravenously to
delay premature labour have been associated with
nausea and vomiting, and with severe adverse cardi-
ac and metabolic effects and pulmonary oedema.
Effects on electrolytes and metabolism. Salbutamol. in
common with other beta~-agonists. may have effects on the
electrolyte balance and on metabolism. In general the most
prominent effects that may be encountered are hypokalaemia
and hyperglycaemia. Not all studies have demonstrated such
metabolic effects and the degree of effect will often be de-
pendent upon the dose and route of salbutamol employed.
The effects are usually reversible but may, nevertheless, lead
to precautions in the use of salbutamol. Hypokalaemia may
be potentiated by concomitant therapy with corticosteroids,
diuretics, or xanthines: potassium concentrations should be
monitored in severe asthma, where such concomitant therapy
is required. Additionally, the induced hypokalaemia may pro-
voke arrhythmias, particularly in patients receiving digoxin.
Effects on the eyes. Salbutamol and to a greater extent rito-
drine have been implicated in retinopathy in the premature
infant when used for premature labour.
For reports of glaucoma precipitated by the combined admin-
istration of ipratropium bromide and salbutamol via a neb-
uliser. see Ipratropium Bromide.
Effects on the heart. Adverse cardiac effects with salbuta-
mol have mainly been tachycardia due to increased sympa-
thetic effects on the cardiovascular system. Such tachycardia
has sometimes occurred in persons using inhalers as well as
following parenteral therapy.2 It has been suggested that the
increased metabolic demand produced by tachycardia, espe-
cially following oral P2 agonists, might predispose to heart
failure or angina in some older patients.
Enhanced or additional cardiac arrhythmias have been report-
ed in patients receiving modified-release salbutamol or terbu-
taline. The decreased vagal (parasympathetic) stimulation.
and consequently increased sympathetic dominance of cardi-
ac function, together with a tendency to decreased baroreflex
sensitivity, that may occur with beta2z agonist inhalation are
similar to the risk factors which predispose to ventricular
tachyarrhythmias. However, no clinically significant
arrhythmias were seen in a study of patients given high-dose
inhaled salbutamol or fenoterol. As discussed under Effects
on Electrolytes and Metabolism above, hypokalaemia in-
duced by salbutamol may also lead to arrhythmias.
Effects on mental function. Visual hallucinations lasting
for an hour have been reported following administration of
nebulised salbutamol to an elderly patient. At the time of the
report the manufacturers were aware of 3 cases of hallucina-
tions in children given oral salbutamol but no such reaction
had been previously reported in adults given recommended
doses.
Effects on the muscles. A report on the nature and inci-
dence of side-effects of salbutamol in 50 patients with chronic
air-flow obstruction who had been taking 4 mg three times dai-
ly for a year. The incidence of side-effects was: finger tremor
42%, palpitation 20%. muscle cramp 46%. and other symp-
toms 6%.
Effects on the respiratory system. Paradoxical bron-
choconstriction has occasionally been reported following
bronchodilating therapy with nebulised solutions of salbuta-
mol and ipratropium bromide (see under Ipratropium Bro-
mide). It has been suggested that the preservatives
present in these nebuliser solutions could be responsible. In
addition, regular use of salbutamol (as opposed to use on an
as-needed basis) has been shown to increase airway hyperre-
sponsiveness to various stimuli. These effects may be due
specifically to the 5-enantiomer and it has been suggested
that accumulation of this enantiomer due to stereospecific
metabolism lies behind the phenomenon of tolerance (see be-
low).
The increased risk of pulmonary oedema associated with
salbutamol is mentioned under Pulmonary Oedema, below.
Increased mortality. Most of the recent attention on the
increased incidence of morbidity and mortality that has oc-
curred in asthmatic patients has concentrated on fenoterol, but
salbutamol has been implicated.
Overdosage. Reports of overdosage with salbutamol
have generally only described the features that may be ex-
pected such as tachycardia. CNS stimulation, tremor, hypoka-
laemia, and hyperglycaemia. Symptomatic treatment of the
adverse effects has proved successful. The plasma-potassium
concentration and pulse rate have been found to correlate with
the plasma concentration of salbutamol.
Pregnancy. Most adverse effects associated with salbutamol
in pregnancy relate to the cardiovascular and metabolic ef-
fects of the very high doses given by intravenous infusion in
attempts to delay premature labour (sec also under Pulmonary
Oedema, below). Thus myocardial ischaemia on stopping an
infusion and unifocal ventricular ectopics associated with
the hypokalaemic response lo intravenous salbutamol have
been reported. A further report concerned congestive heart
failure in a hypertensive woman. Metabolic acidosis follow-
ing salbutamol infusions in diabetic women has also been re-
ported.
Pulmonary oedema. Pulmonary oedema has occurred in
women given beta-2 agonists, including salbutamol for pre-
mature labour. The risk factors. the most important of which
is fluid overload, are discussed under Precautions, below.
Tolerance. Studies suggest that regular inhalation of a beta-2
agonist. although it continues to produce bronchodilatation.
increases airway hyperresponsiveness and may reduce the
protective effect against bronchoconstriction provoked by
stimuli such as bradykinin, methacholine Or allergen. Such
tolerance is considered another argument against regular use
of these agents. There is some evidence that for salbutamol
the effect may be due to the S(+)-enantiomer which unlike
the R(-)-enantiomer does not possess bronchodilating activi-
ty: stereo selective metabolism means that regular use of the
racemate could lead to accumulation of the r-enantiomer,
which provides a possible mechanism for the effect.
Precautions
Salbutamol and other beta, agonists should be given
with caution in hyperthyroidism, myocardial insuf-
ficiency, arrhythmias, susceptibility to QT-interval
prolongation, hypertension, and diabetes mellitus
(especially on intravenous administration where
blood glucose should be monitored since ketoacido-
sis has been reported).
In severe asthma particular caution is also required
to avoid inducing hypokalaemia as this effect may
be potentiated by hypoxia or by concomitant admin-
istration of other anti-asthma drugs (see under Inter-
actions. below); beta-2 agonists such as salbutamol
are not appropriate for use alone in the treatment of
severe asthma .
In women being treated for premature labour the
risk of pulmonary oedema means that the patient's
state of hydration and cardiac and respiratory func-
tion should be monitored very carefully; the volume
of infusion fluid should be kept to the minimum
(normally using glucose 5% as the diluent and
avoiding sodium chloride), and beta,-agonist thera-
py should be discontinued immediately and diuretic
therapy instituted if it occurs (bearing in mind the
risk of hypokalaemia with potassium-depleting diu-
retics). Other risk factors for pulmonary oedema in-
clude multiple pregnancy and cardiac disease,
which is a specific contra-indication; where cardiac
disease is suspected assessment by a physician ex-
perienced in cardiology is needed. Eclampsia and
severe pre-eclampsia are also contra-indications,
with special care needed in mild to moderate pre-
eclampsia. Other contra-indications include intra-
uterine infection, intra-uterine fetal death, antepar-
tum haemorrhage (which requires immediate deliv-
ery), placenta praevia. and cord compression: beta-2
agonists should not be used for threatened abortion.
For details of the precautions to be observed with
sympathomimetics in general, see adrenaline.
Abuse. Salbutamol inhalers have been subject to abuse, par-
ticularly by children and young adults. This has occurred in
both asthmatic and non-asthmatic individuals and has been
thought to be for the effect of sympathetic stimulation and for
the effect of the fluorocarbon propellants. The introduction of
fluorocarbon-free inhalers should reduce the latter motiva-
tion, although not the former.
Pregnancy. Inhalation has particular advantages as a means
of administration of beta-2 agonists during pregnancy because
the therapeutic action can be achieved without the need for
plasma concentrations liable to have a pharmacological effect
children : It is twice more effective than terbutaline and is safe above 2 yrs. Of age only.
Interactions
As mentioned under Effects on Electrolytes, above,
concomitant administration of salbutamol and other
beta; agonists with corticosteroids, diuretics, or
xanthines increases the risk of hypokalaemia, and
monitoring of potassium concentrations is recom-
mended in severe asthma, where such combination
therapy is the rule. For an outline of interactions as-
sociated with sympathomimetics in general, see
adrenaline.
Antidepressants. For an apparent interaction between terb-
utaline and toloxatone, a reversible inhibitor of monoamine
oxidase type A (RIMA) see Sympathomimetics like adrenaline.
Cardiac glycosides. Hypokalaemia produced by beta; ago-
nists may also result in an increased susceptibility to
digitalis induced arrhythmias although salbutamol
intravenously and by mouth can also decrease serum
concentrations of diqoxin (see Sympathomimetics. adrenaline).
Corticosteroids. Corticosteroids and beta; agonists may
both produce falls in plasma potassium concentrations; there
is evidence that such falls can be exacerbated by concomitant
administration. The possibility of enhanced hyperglycaemic
effects from such a combination should also be borne in mind.
Diuretics. Hypokalaemia is known to be a possible side-ef-
fect during treatment with beta-2 agonists such as
salbutamol or terbutaline. and this may be enhanced during
concomitant diuretic therapy:' in addition the arrhythmogenic
potential of this interaction may be clinically important in
patients with ischaemic heart disease.
Muscle relaxants. Salbutamol given intravenously has been
reported to enhance the neuromuscular blockade produced by
pancuronium and by vecumnium, see p. 1307.
Sympathomimetics. Patients receiving salmeterol may re-
quire salbutamol to control an acute attack of bronchospasm.
One study indicated that the effects might be additive.' but
another demonstrated that patients receiving salmeterol had
reduced sensitivity to salbutamol and might need higher doses
of the latter for acute relief.'
Xanthines. An enhanced hypokalaemic effect may occur
during coadministration of salbutamol with theophylline.
See also under terbutaline and Sympathomimetics,
under Interactions for theophylline for the potentia-
tion of other effects.
Bambuterol is not recommended for patients with severely
impaired liver function as its metabolism would be unpredict-
able. It is unsuitable for the relief of acute bronchospasm or
in patients with unstable respiratory disease.
Bambuterol inhibits plasma cholinesterases and can prolong the action of drugs such
as suxamethonium that are inactivated by these enzymes.
Pharmacokinetics
Nearly 20% of a dose of bambuterol is absorbed from the gas-
tro-intestinal tract following oral administration. It is slowly
metabolised in the body to its active metabolite, terbutaline,
peak terbutaline concentrations are reported to occur about 4
to 7 hours after a dose of bambuterol as tablets. The slow rate
at which metabolism occurs determines the prolonged dura-
tion of action of bambuterol of at least 24 hours. Hydrolysis
of bambuterol to terbutaline and carbamic acid leads to inhi-
bition of plasma-cholinesterase activity that can be correlated
with plasma concentrations of terbutaline. For the metabo-
lism and excretion of terbutaline.
Uses and Administration
Bambuterol is an inactive prodrug of terbutaline ,
a direct-acting sympathomimetic with predominantly beta-
adrenergic activity and a selective action on beta; receptors
(beta; agonist). It has similar actions and uses to those of
salbutamol, except that it has a more prolonged duration of
action (at least 24 hours). Bambuterol hydrochloride is used
as a long-acting bronchodilator for persistent reversible air-
ways obstruction in conditions such as asthma. The
usual dose is 10 to 20 mg by mouth once daily at bedtime:
starting doses should be halved in patients with moderately or
severely impaired renal function.