Indication:
Premature uterine contraction
Summary-
Hexaprenaline appears to be a safe and effective agent for the treatment of premature
uterine contrations. Limited available data suggest that at doses that produce effective
tocolysis, side effects , particularly maternal tachycardia, are less frequent or severe
than those seen with current used Beta2- agonist tocolytics.
Additional data are required to determine the relative place in therapy. An NDA has
been filed by Altana and is currently pending. On February 2, 1990 the FDAs Fertility
and Maternal Health Drugs Advisory Committee recommended approval for
hexoprenaline for suppression of uterine contractions during premature labor.
Hexoprenaline which will be available as Delaprem is currently available in several
other countries
Adverse Reaction:
Side effects-
Hexoprenaline shares the side effect profile of the Beta2- agonists such as tremor,
tachycardia,(maternal and fetal) arrhythmias(supraventricular and ventricular,)
myocardial ischemia, hypotension, hyperglycemia. However, available data
suggest that frequency and and severity of these adverse effects is less seen with
Beta2-agonist tocolytes currently available in clinical use( eg. ritodrine, terbutaline
(Brethine, Bricardyl) and are usually seen in the higher dose ranges.
A recent report also describes non-cardiac pulmonary edema, a recognized
complication of this form of therapy but not previously reported with hexoprenaline.
As with other Beta2- agonist tocolytics , preexisting myocardial dysfunction , iatrogenic
fluid overload and the concomittant administration of glucocorticosteroids appear to
increase the risk of this complication.
Pharmacology/ Pharmacokinetics:
Pharmacology-
Hexoprenalin sulfate is a Beta2- selective adrenergic agonist. Structurally it
two norepinephrine molecules joined through their amino groups by a hexamethylene
bridge. This compound while retaining the catachol moiety , has a longer duration of
action than the classic catacholamines ( eg.isoproternol eg Isupril) and is orally active.
Stimulation of uterine Beta2 receptors results in a decrease in frequency and intensity
of uterine smooth muscle contration, believed to be due to a decrease in myometrial
cellular calcium.
Pharmacokinetics-
A lack of published data in humans precludes an accurate description of the
pharmacokinetic profile of hexoprenaline. however certain characterstics
may be inferred from available clinical trials.
Following administration of an IV bolus of 7.5mcg , the mean time to onset of stable
uterine activity was 12.9 +/- 6.9 minutes, with return to baseline activity
at 33.7+/- 17.8 minutes. Similar values (34.9+/- 12.7 minutes were reported for the
time required for the heart rate to return to baseline
Return to uterine activity and heart rate baselines was similar following discontinuatiion
of a continous infusion of 0.38mcg/min for 20 minutes( 37.3 +/- 13 minutes, respy.).
In rats two methylated metabolites have been identified , one of which is very active.
Clinical trials-
In available published clinical trials, hexoprenaline is an effective tocolytic. When
compared to ritodrine,equivalent tocolytic doses produced less maternal tachycardia
and elevation of systolic pressure. It has been used as an IV bolus or bolus plus
infusion to control contraction related fetal heart rate abnormalites, a marker of
fetal distress.
In this later setting, the desired increase in fetal heart rate was attributed to control
of uterine contractions and possibly an increase in placental blood flow, since
< 1% of hexoprenaline was shown to cross the placenta in rabbits and in an invtro
model
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