Description
Terbutaline is a synthetic congener of adrenaline that acts at the
β2-receptor causing bronchodilation and tocolytic effects. It
was the first β2-selective adrenoreceptor agonist in general
clinical use. In 2011, the Food and Drug Administration (FDA)
placed a black-boxed warning on terbutaline stating that terbutaline
injections should not be given to pregnant women nor
should be used to prevent preterm labor or for long-term
(greater than 48–72 h) treatment of preterm labor. Oral terbutaline
should not be used at all due to its potential for
cardiac toxicity and death. Terbutaline is on the World Anti-
Doping Agency’s list of prohibited drugs for Olympic athletes
(except when a Therapeutic Use Exemption has been granted in
advance and when used by inhalation).
Originator
Bricanyl,Pharma-Stern,W. Germany,1971
Uses
Terbutaline is used as a bronchodilator and for the prevention
of premature labor. The FDA has added boxed warnings to
terbutaline for its use as a tocolytic for the prevention of
preterm labor. Unlabeled use includes treatment of hyperkalemia.
Terbutaline is being studied for its use in treatment of
certain neuromuscular disorders as well.
Uses
Terbutaline is used for preventing and relieving bronchospasms in bronchial asthma, chronic bronchitis, pulmonary emphysema, and other broncho-pulmonary diseases.
Definition
ChEBI: A member of the class of phenylethanolamines that is catechol substuted at position 5 by a 2-(tert-butylamino)-1-hydroxyethyl group.
Indications
Terbutaline (Brethine, Bricanyl) is a relatively specific
β2-adrenoceptor agonist.
Terbutaline can prevent premature labor, especially in
individuals who are more than 20 weeks into gestation
and have no indication of ruptured fetal membranes or
in whom labor is not far advanced. Its effectiveness in
premature labor after 33 weeks of gestation is much less
clear. Terbutaline can decrease the frequency, intensity,
and duration of uterine contractions through its ability
to directly stimulate β2-adrenoceptors. While it appears
to be especially selective for β2-receptor activation,
terbutaline does have some β1 activity as well.
Manufacturing Process
To a solution of 32 g of benzyl-t-butylamine in 300 ml of absolute ethanol at
reflux temperature was added 32 g of 3,5-dibenzyloxy-?-bromoacetophenone
in 10 ml of dry benzene. The mixture was refluxed for 20 hours and then
evaporated. When absolute ether was added to the residue, benzyl-tbutylamine
hydrobromide was precipitated. The precipitated compound was
filtered off and to the filtrate was added an excess of 2 N sulfuric acid. This
caused precipitation of the hydrogen sulfate of 3,5-dibenzyloxy-?-(benzyl-tbutylamino)-
acetophenone which was recrystallized from acetone/ether. If the product is crystallized from different organic solvents, the melting point will
vary with the type and amount of solvent of crystallization, but the product
can be used directly for hydrogenation.
15 g of 3,5-dibenzyloxy-?-(benzyl-t-butylamino)-acetophenone hydrogen
sulfate in 200 ml of glacial acetic acid were hydrogenated in a Parr pressure
reaction apparatus in the presence of 1.5 g of 10% palladium charcoal at
50°C and 5 atmospheres pressure. The reaction time was 5 hours. The
catalyst was filtered off, the filtrate was evaporated to dryness and the
hydrogen sulfate of 1-(3',5'-dihydroxyphenyl)-2-(t-butylamino)-ethanol was
received. This compound is hygroscopic, but it can be transformed into a
nonhygroscopic sulfate in the following manner.
The hydrogen sulfate was dissolved in water and the pH of the solution was
adjusted to 5.6 (pH-meter) with 0.1 N sodium hydroxide solution. The water
solution was evaporated to dryness and the residue dried with absolute
ethanol/benzene and once more evaporated to dryness. The remaining crystal
mixture was extracted in a Soxhlet extraction apparatus with absolute
methanol. From the methanol phase the sulfate of 1-(3',5'-dihydroxyphenyl)-
2-(t-butylamino)-ethanol crystallized. Melting point 246°C to 248°C.
Therapeutic Function
Bronchodilator
Mechanism of action
Terbutaline is a synthetic sympathomimetic amine. It is one of the most selective direct–acting
stimulants of β2-adrenoreceptors. It stimulates smooth muscle β2-adrenoreceptors in the
bronchi, relaxing them and relatively minutely acting on the β1—receptors of the heart.
Clinical Use
Terbutaline should be initially used only in an
appropriate hospital setting where any obstetric complications
can be readily addressed. After initial administration,
it can be used in the outpatient setting.
Concomitant use of β2-adrenergic agonists and corticosteroids
have additional diabetic effects and may
rarely lead to pulmonary edema.The combination of β2-
adrenergic agonists and magnesium sulfate can cause
cardiac disturbances, while coadministration of terbutaline
with other sympathomimetics can lead to the potentiation
of the actions of the latter drugs.
Side effects
Terbutaline is frequently used in the management of
premature labor, although it has not been marketed for
such use. Its effectiveness, side effects, precautions, and
contraindications are similar to those of all β2-adrenergic
agonists. Terbutaline can cause tachycardia, hypotension,
hyperglycemia, and hypokalemia. It can be
given orally in addition to subcutaneous or intravenous
administration.
Synthesis
Terbutaline, |á-[(tert-butylamino)methyl]-3,5-dihydroxybenzylic alcohol
(11.1.14), differs from the examined compounds mainly in the location of hydroxyl
groups in the benzene ring, and is synthesized by brominating 3,5-dibenzyloxy|ácetophenone into the appropriate 3,5-dibenzyloxybromoacetophenone (11.1.12), which is
reacted with N-benzyl-N-tert-butylamine, giving the aminoketone (11.1.13). Reduction
of this product by hydrogen over a palladium catalyst leads to terbutaline (11.1.14)
[16¨C18].
Environmental Fate
Terbutaline is administered as the sulfate. It is a white to graywhite,
crystalline powder; nearly odorless or with the faint odor
of acetic acid. Terbutaline has a slightly bitter taste. It has
a melting point of 247°C. Terbutaline sulfate is soluble at 1 g
per 1.5 ml water or 250 ml of ethanol. It is soluble in 0.1 N
hydrochloric acid, slightly soluble in methanol, and insoluble
in chloroform. While terbutaline is stable under normal
conditions as a solid, it is unstable in light. Terbutaline is
degraded through oxidative processes; this is enhanced in the
presence of trace levels of metals and in the presence of oxygen.
No information is currently available on breakdown in soil,
groundwater, or surface water.
Toxicity evaluation
The primary mechanism of terbutaline is the stimulation of
adenyl cyclase, which catalyzes cyclic adenosine monophosphate
(AMP) from adenosine triphosphate (ATP). In the
liver, buildup of cyclic AMP stimulates glycogenolysis and an
increase in serum glucose. In skeletal muscle, this process
results in increased lactate production. Direct stimulus of
sodium/potassium ATPase in skeletal muscle produces a shift
of potassium from the extracellular space to the intracellular
space. Relaxation of smooth muscle produces a dilation of the
vasculature supplying skeletal muscle, which results in a drop
in diastolic and mean arterial pressure (MAP). Terbutaline has
greater b2 selectivity, but overdose will have both β1 and β2
activity. Tachycardia occurs as a reflex to the drop in MAP or as
a result of β1 stimulus. β1-Adrenergic receptors in the locus
ceruleus also regulate norepinephrine-induced inhibitory
effects, resulting in agitation, restlessness, and tremor.
References
[1] C HOFFMANN. Comparative pharmacology of human beta-adrenergic receptor subtypes–characterization of stably transfected receptors in CHO cells.[J]. Naunyn-Schmiedeberg’s archives of pharmacology, 2004, 369 2: 151-159. DOI:
10.1007/s00210-003-0860-y[2] H Y LAU C K L P L Wong. Effects of beta 2-adrenergic agonists on isolated guinea pig lung mast cells.[J]. Agents and Actions, 1994, 42 3-4: 92-94. DOI:
10.1007/bf01983471[3] O A OLSSON L ? S. New lipophilic terbutaline ester prodrugs with long effect duration.[J]. Pharmaceutical Research, 1984, 1 1: 19-23. DOI:
10.1023/a:1016322524471[4] SALONEN R O. Actions of bronchodilator drugs, glucocorticoid, and their combinations on airways in rats and guinea pigs[J]. Basic & Clinical Pharmacology & Toxicology, 1985, 57 s3: 6-38. DOI:
10.1111/j.1600-0773.1985.tb03577.x
